New benzazepine derivatives, medicaments containing the same and their use to prepare medicaments

The invention likewise encompasses the use of the novel compounds for the treatment of Alzheimer's disease and related states of dementia, and for the treatment of Langdon-Down syndrome (Mongolia, chromosome 21 trisomy).

Galanthamine acid addition salts which has a structural chemical formula

<img file="PL190032B1_D0001.tif" />

and some analogs thereof are known as pharmaceutical active substances which inhibit the synaptic enzyme acetylcholinesterase. Therefore, galantamine is used pharmacologically in the symptoms of paralysis following spinal cord gray matter and in various diseases of the nervous system.

Galantamine and some of its derivatives are also used in the symptomatic treatment of Alzheimer's disease and related states of dementia (EP 236 684 B1).

Galantamine is chemically an alkaloid of the morphine group that can be obtained from snowdrops (Galanthus woronowii, G. nivalis etc.) and other Amaryllidacees.

In addition to obtaining galanthamine from vegetable sources, chemical methods for the synthesis of galanthamine and its analogs, including its acid addition salts, are also known (WO 95/27715).

Down syndrome comes down to the tripling of chromosome 21, i.e. patients have a complete set of 47 instead of 46 chromosomes, which can be easily detected cytologically. Trisomy 21 is associated with moderate to severe mental disability and a range of signs of bodily distortion. Until now, causal treatment is not possible. Existing handicaps can be influenced by targeted therapeutic measures, but there is usually a need for help.

190 032

The novel compounds according to the invention are the benzoazepine derivatives of the general formula (II)

<img file="PL190032B1_D0002.tif" />

wherein Ri, R2 are either the same or different and are hydrogen, F, Cl, Br, J, CN, NC, OH, SH, NO2, SO3H, NH2, CF3 or lower (C1-C6), optionally branched, optionally substituted an (Ar) alkyl or (Ar) alkoxy group or an amino group which is substituted by one or two, identical or different, lower (C1-C6), optionally branched, optionally substituted (Ar) alkyl or (Ar) alkylcarbonyl or (Ar) ) alkyloxycarbonyl, or represent a COOH group, COO (Ar) alkyl, CONh, CON (Ar) alkyl, or - (CH2) n-Cl, - (CH₂) n-Br, - (CH2) n-OH, - (CH2) n-COOH, - (CHjn-CN, - (CH2) n-NC, and R1-R2 may also be collectively defined as -CH = CH -CH = CH-, -O- (CH2) nO- n = 1-3,

R3 = Ri, especially OH and OCH3, hereinafter

R2-R3 together may form -O- (CH2) nO-, with n = 1-3,

R4, R5 or both are hydrogen or are alternately each hydrogen or (Ar) alkyl, (Ar) alkenyl, (Ar) alkynyl with an S-Rs group, where Rs is hydrogen or lower (C1-C10), optionally branched , optionally substituted with (Ar) alkyl, with SO-Rs group, SO2R8 with OH group, O-protecting radical (such as TMS, TBDMS), with O-CS-N-Rs group (thiourethanes) with O-CO group -N-R9, with R9 having the following meanings:

<img file="PL190032B1_D0003.tif" />

with an O-CO-Rs group (ester, Rs see above), especially also esters with an amino acid substitution pattern, such as

<img file="PL190032B1_D0004.tif" />

COOBn

NH-t-BOC

<img file="PL190032B1_D0005.tif" />

hereinafter R4, R5 = together are hydrazones (= N-NH-Rio, = NN (R10, R11), oximes (= NO-R11), where R10 is hydrogen, lower (Ci-C₆), an optionally branched, optionally substituted (Ar) alkyl or (Ar) alkylcarbonyl group. or (Ar) alkylcarbonyloxy and

190 032 with a sulfonyl group such as a tosyl (p-toluenesulfonyl) and mesyl (methanesulfonyl) group, and R11 is hydrogen, lower (Cj-C6), optionally branched, optionally substituted with (Ar) alkyl or (Ar) alkylcarbonyl, and a sulfonyl group, such as tosyl and mesyl groups, and with substituents of the type:

<img file="PL190032B1_D0006.tif" />

'jjCOORe where Yj, Y2 = O, S, NH or NR 10 (the supernumerary values ​​are in each case -H), where in the case of R4 * H the symbol R5 is also an OH group or in the case of R5 * H the symbol R4 may also be a group . OH, Gj, G2 have the same or different meanings: -C (Rj3, R14) - where R13, R14 may be hydrogen, OH, lower, optionally branched, optionally substituted (Ar) alkyl, aryl, (Ar) alkoxy or aryloxy, or together they can be an alkylspirane group (a C3-C7-spiran ring), hereinafter Gj and G2 together constitute a group

CH

CH \

m = 1-7,

G3 is the group -CH2- or = CO,

Ró is a group - (G4) p- (G5)_q-G₆ zp, q = 0-1, where G4 meets the following definitions: - (CH2) r, -C (Ri5, Ri6) - (CH2) r-. zr = 1-6 and R15, Rj = hydrogen, lower, optionally branched, optionally substituted (Ar) alkyl, cycloalkyl, aryl, and is -O- or -NR15-,

ABOUT₂) s CH CH

CH₂) tzs = 1-4, t = 0-4,

<img file="PL190032B1_D0007.tif" />

that is, an ortho-, meta- or para-disubstituted aromatic radical,

190 032

<img file="PL190032B1_D0008.tif" />

wherein G7 is NR15, O or S,

G5 can be the same or different from the symbol G4 and if p is 1, it is additionally S,

Gó meets the following definitions:

<img file="PL190032B1_D0009.tif" />

with R17, Rj8, R19 and R20 singly or together being identical or differently hydrogen, lower, optionally branched, optionally substituted (Ar) alkyl, cycloalkyl or aryl groups, whereby R17 and R18 or R19 and R20 together may form a cycloalkyl group (o 3-8 ring members),

G8 = O, S, NH, NR₂1, - (CH2) "-,

R21 = CHO, COOR17, either unsubstituted or by one or more F, Cl, Br, J, NO2, NH2, OH, alkyl, alkyloxy, CN, NC, CF3, CHO, COOH, COOalkyl, SO3H, SH, S groups -alkyl, an equally or differently substituted (hetero) aryl radical (with heteroaryl being, especially 2-pyridyl, 4-pyridyl, 2-pyrimidinyl) or a methyl group which is substituted with 1-3 unsubstituted or with one or more F groups, Cl, Br, J, NO2, NH2, alkyl, alkyloxy, CN, NC or CF3 with identical or differently substituted phenyl radicals,

Gó can also mean:

<img file="PL190032B1_D0010.tif" />

^18

190 032

<img file="PL190032B1_D0011.tif" />

<img file="PL190032B1_D0012.tif" />

<img file="PL190032B1_D0013.tif" />

-CHO, COOR17, -CONR17, lower, optionally branched, optionally substituted (Ar) alkyl, (Ar) alkenyl, (Ar) alkynyl, cycloalkyl or aryl, -O-Rj7, -NR17R18, phthalimide, -CN or - NC, a

[X] exists only if and is the ion of a pharmacologically acceptable inorganic and organic acid, when the substituents R5 and R6 are present and thus the nitrogen has a positive charge, Z = N +.

The medicaments can be used successfully to treat Alzheimer's disease and related states of dementia, and to treat Langdon-Down syndrome.

The invention also relates to the use of the previously discussed compounds for the preparation of a medicament for the treatment of Alzheimer's disease and related dementias, and for the treatment of Lang don-Down syndrome.

Particularly preferred according to the invention are the compounds set out in the list below. This compilation also lists the ACHE inhibitory values ​​(IC50 value, which is the 50% inhibition concentration) of the compounds of the invention which are relevant for the effectiveness.

The inhibition of acetylcholinesterase was determined according to the modified Ellmann method (Lit. 44), using human serum from a pool of 10 test subjects as the serum.

Method: 520 μΐ test substance solution (concentrations from 10 to⁴ up to 10'7, in exceptional cases up to 10 '⁹ mol / l) in 0.02 M tri (hydroxymethyl) aminomethane, buffered with HCl to pH = 7.8, and 400 μΐ of mnitrophenol solution (Sigma Diagnostics, Art. 420-2) were incubated in a semi-microcuvette in at 37 ° C with 40 μΐ of cholinesterase (Sigma Diagnostics, Art. 420-Mc, 1:15 diluted with water) and 160 μΐ of serum, and within 5 minutes the changes in absorption were measured against the reference sample on a Beckmann spectrophotometer, type DU-50, using Kinetics. The values ​​are given in% of the reference sample and the 50% inhibition concentration (IC50) was calculated from the course of the curve.

List of new compounds of the type with the general formula:

<img file="PL190032B1_D0014.tif" />

[X]

190 032

<td>² Ή ο 0 σ 1 in</td><td></td><td>Ο »—ł</td><td></td><td>Χϊ *</td><td>Ul</td><td>m</td><td>1&gt; 150 I.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>ABOUT σι</td><td>ABOUT r *</td><td>m o. o</td><td>tn r *</td>

<td>&lt;1 Ο</td><td>δ</td><td>2 AT</td><td>δ</td><td>tsj δ</td><td>2 AT</td><td>δ δ</td><td>δ</td><td>δ</td><td>2 * Ο</td><td>δ</td><td>δ</td><td>2 * AT</td><td>δ</td><td>δ</td><td>δ ~</td><td>2 &lt;J</td><td>(M. δ</td><td>CM δ</td><td>2 ' AT</td><td>δ</td>

<td>X</td><td>AND Μ WHAT</td><td> 1</td><td> 1</td><td> 1</td><td>AND</td><td>and</td><td> 1</td><td>Ł</td><td>AND</td><td>ι</td><td> ,</td><td> 1</td><td>AND</td><td>AND</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td>

<td>Ι&gt; 3</td><td> *2</td><td> 2</td><td> 2</td><td>Ζ</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td>with</td><td>with</td><td> 2</td><td> 2</td>

<td> £</td><td> 2</td><td>and</td><td>ι</td><td> 1</td><td> 1</td><td> ,</td><td>AND</td><td>AND</td><td>AND</td><td>Ł</td><td> ,</td><td>Ł</td><td> 1</td><td>AND</td><td> 1</td><td>ί</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td>

<td></td><td>ο s</td><td>2 υ</td><td>δ</td><td>2 AT</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 0</td><td>2 Ο</td><td> §</td><td>rt δ</td><td>δ</td><td></td><td>2 2 1 δ</td><td> 2</td><td>rt 2 AT</td><td>rt δ</td><td>S? AT</td><td>2 AT</td>

<td> £</td><td> 2</td><td> 2</td><td>2 Ο</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td>2 Ο</td><td rowspan="2">ά 1 § ? δ ά</td><td rowspan="2">AND Ο ι rt 2 AT δ AND g ά</td><td rowspan="2">1 Ο AND δ AND δ ?</td><td rowspan="2">ά and CM 2 AT έ s</td><td> 2</td><td rowspan="2">ά 1 δ 1 CM 1</td><td rowspan="2">1 AND CM 2 u 1 CM !</td><td rowspan="2"> ?</td><td rowspan="2"> ?</td><td> 2</td><td> 2</td><td> 2</td>

<td> 2</td><td>2 Ο</td><td>δ</td><td> 2</td><td> §</td><td>δ</td><td>δ</td><td>δ</td><td> 2</td><td>δ έ 1 δ *</td><td>Q - \ -s 12 Γ</td><td>ABOUT _£&gt; -eo MA Γ</td><td>MA F ° 1</td>

<td> £</td><td>δ</td><td>δ</td><td>2 Ο</td><td>δ</td><td>2 Ο</td><td>«Η 2 υ</td><td>δ</td><td>δ</td><td>δ</td><td>δ</td><td>δ</td><td>δ</td><td>Ρ&gt; δ</td><td>2 υ</td><td>rt δ</td><td>rt δ</td><td>rt δ</td><td>δ</td><td>δ</td><td></td>

<td> £</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td> 2</td><td></td>

<td> £</td><td> 2</td><td>Μ 2</td><td>Μ 2</td><td>Μ 2</td><td>in 2</td><td> 2</td><td>AT 2</td><td>ui 2</td><td>AT 2</td><td> 2</td><td>AT 2</td><td>Μ 2</td><td>ki 2</td><td>Ui 2</td><td>Ul 2</td><td>AT 2</td><td>Ul 2</td><td> 2</td><td> 2</td><td></td>

<td>ι ι · υ Ή ΜΛ 2 ffl 0 U Μ C</td><td>AND</td><td> 1 +</td><td> 1 +</td><td>Τ</td><td>and +</td><td> -</td><td> +</td><td> 1 +</td><td>ι +</td><td> ? +</td><td>AND V. +.</td><td> 1 +</td><td>AND +</td><td>AND and</td><td>1 and</td><td>1 - * p. and</td><td>1 'χ. +</td><td>T.</td><td> 7</td><td> 7</td>

<td>Subs- dance no .:</td><td>Μ 2 3?</td><td>γ-4</td><td>CM</td><td>m</td><td></td><td> 2</td><td> 2</td><td>Γ *</td><td> 00</td><td>&lt;Τι</td><td>ο r-w</td><td>»Η f "4</td><td>r \ j rrt</td><td>cn</td><td>X »· in</td><td>ui r * 4</td><td> \0 -4</td><td>Γ * - in</td><td>2 cH</td><td>&lt;Background and - ł</td>

190 032

<td>Ο CM</td><td>m ιΠ</td><td>m C0</td><td>m CM</td><td>m OO</td><td>m -about*</td><td></td><td></td><td></td>

<td>X at</td><td>Μ X υ</td><td>X υ</td><td>X AT</td><td>in X at</td><td>X at</td><td>δ</td><td>X υ</td><td>δ</td>

<td>AND</td><td> 1</td><td> 1</td><td>Ł</td><td> »</td><td>l</td><td> 1</td><td> 1</td><td> 1</td>

<td>ζ</td><td>ζ</td><td>ζ</td><td>WITH</td><td>with</td><td>with</td><td>with</td><td>with</td><td>WITH</td>

<td> 1</td><td> 1</td><td> 1</td><td>Ł</td><td> 1</td><td></td><td> 1</td><td>Ł</td><td> 1</td>

<td>»-Ι δ</td><td>X υ</td><td>ο δ</td><td>δ</td><td>Π δ</td><td>δ</td><td>X at</td><td>&lt;n X at</td><td>X AT</td>

<td>X</td><td></td><td></td><td></td><td></td><td>about about m 1 Ύ MA s</td><td>c m ABOUT O JJ about «</td><td> __οΧ ^ χ € ΟΟΒη NH-t-BOC</td><td>c m ABOUT 8 θ 9 sts ο4'ϊ about</td>

<td>ο " λ · ι | 0 ΙΖ r °</td><td>Ρ ΙΖ &lt;Γ "</td><td>Ρ ΙΖ r</td><td>and MA «Γ</td><td>and MA &lt;T.</td><td>X</td><td>X</td><td></td><td></td>

<td></td><td>Λ X υ</td><td>η δ</td><td>X at</td><td>rt δ</td><td>&lt;n IN υ</td><td>&lt;* » δ</td><td></td><td></td>

<td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td></td><td></td>

<td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>K.</td><td></td><td></td>

<td>Τ</td><td>ι</td><td>and</td><td>Ł</td><td> +*</td><td> 1</td><td>Ł</td><td>-b</td><td>T.</td>

<td>ο CM</td><td>ι — Ι CM</td><td>CM CM</td><td>m CM</td><td>•and* CM</td><td>m CM</td><td>M? CM</td><td>r * CM</td><td>00 CM</td>

190 032

H.

<img file="PL190032B1_D0015.tif" />

190 032

<td></td><td></td><td>Ν υ Ν 10 3 and Ν 0 AT ν and</td><td>Ν AT Ν IN 3 &amp; ο at φ - »4 £ 3</td><td>Ο (Ν</td><td>Ν υ Ν this 3 α ν ' Ο £ 4 Φ &lt;4 C.</td><td></td><td>cn</td><td></td><td></td><td></td><td>CT d</td><td></td><td></td><td>N ϋ N 10 3 and N 8 Φ •and</td><td>N AT N &lt;0 and N 0 14 Φ and</td><td></td><td></td><td></td><td> ! &gt;150 1</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>CM X at</td><td>CM X ο</td><td>δ '</td><td>CM X υ</td><td>δ</td><td>X υ</td><td>CM X υ</td><td>X at</td><td>CM X about</td><td>CM X AT</td><td>X AT</td><td>X AT</td><td>X t&gt;</td><td>s</td><td>CM X at</td><td>and? at</td><td>CM X at</td><td>&lt;M δ</td><td> £</td><td>X about</td><td>Cm X at</td><td>χ⁴at</td><td>X AT</td><td>X AT</td><td>CM X at</td><td>CM X (J.</td><td>CM X at</td>

<td>AND</td><td> 1</td><td> 1</td><td>AND</td><td> 1</td><td> 1</td><td>Ł</td><td>AND</td><td>and</td><td> 1</td><td> 1</td><td> 1</td><td>vol</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td>J.</td><td>Ł</td><td> 1</td><td> 1</td><td>Ł</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td>

<td>WITH</td><td>Ζ</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>with</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>with</td><td>X</td><td>with</td><td>with</td><td>WITH</td><td>WITH</td><td>with</td><td>with</td><td>with</td><td>WITH</td><td>with</td>

<td>ι</td><td> 1</td><td> 1</td><td> 1</td><td> ,</td><td> 1</td><td> 1</td><td>Ł</td><td>AND</td><td> 1</td><td> 1</td><td></td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td>and</td><td> 1</td><td> 1</td><td>Ł</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td>

<td>χ Oh 1 CM X at</td><td>Γ&gt; 8</td><td>^ 4 &gt; σι Λί Φ χ C.</td><td>r — 1 Η σι 14 «Ί 8 * CL</td><td>4-&gt; ω § X at</td><td> 5 5</td><td>C \ J at</td><td> 0</td><td>Ao</td><td>Λ X £? oz</td><td>ABOUT with</td><td>Q</td><td>those X at s</td><td>at s</td><td>ΓΊ X X at Ϊ at</td><td>rt 0</td><td>and</td><td>n AT 1 ABOUT at</td><td>H. &gt; 1 AJ Φ</td><td>0 1 CM CM 5 1 ABOUT &lt;J</td><td>§ AND AT</td><td>§ 1 CM X at 1 CM s</td><td>X about 1 s 1 x⁴at</td><td>CM 1 CM X at 1 CM X at</td><td>X 1 X at</td><td>£ at 1 8</td><td>s X about</td>

<td rowspan="2"> ?</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td>

<td>X § ό</td><td>X ο</td><td>X ο</td><td>X ο</td><td>X ο</td><td>X ο</td><td> §</td><td>X about</td><td> §</td><td>X about</td><td> §</td><td>X about</td><td>X about</td><td>X about</td><td>X about</td><td>X about</td><td> §</td><td>X about</td><td>X about</td><td> §</td><td> §</td><td>X about</td><td>X about</td><td>X about</td><td>X about</td><td>X about</td>

<td>δ</td><td>&lt;• 7 δ</td><td>π X υ</td><td>«Η δ</td><td>X υ</td><td>Γ7 δ</td><td>X at</td><td>&lt;-&gt; X at</td><td>δ</td><td>n δ</td><td>δ</td><td>&lt;ł X at</td><td>Λ X about</td><td>&lt;n X at</td><td>δ</td><td>rt X at</td><td>δ</td><td>about X at</td><td>X at</td><td>s</td><td>X at</td><td>c&gt; X at</td><td>&lt;1 X at</td><td>Λ δ</td><td>δ</td><td>X CJ</td><td>n δ</td>

<td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td>

<td>X</td><td>Ul X</td><td>14 X</td><td>14 X</td><td>Μ X</td><td>at X</td><td>Ul X</td><td>Ul X</td><td>Ul X</td><td>Ul X</td><td>Ul X</td><td>&gt; 4 X</td><td>Ui X</td><td>Ul X</td><td>at X</td><td>U | X</td><td>Ul X</td><td>Of the Jagiellonian University X</td><td>Ul X</td><td>Ui X</td><td>14 X</td><td>Ul X</td><td>X</td><td>14 X</td><td>Ul X</td><td>X</td><td>X</td>

<td>L. +</td><td> 1 \ 4-</td><td>'Χ. and</td><td>τ 4 ^</td><td> 4</td><td> 1 \ 4·</td><td>vol '' ν 4</td><td> 1 +</td><td> 7 4-</td><td> 1 +</td><td> 1 \ 4^</td><td> 7 4-</td><td>AND \ 4</td><td>l 4-</td><td> 7 +</td><td> 1</td><td>7 '-χ. -4</td><td> 4,</td><td>7 • V. 4</td><td>7 and</td><td> 4-</td><td> 1 4,</td><td> 7 4-</td><td> +</td><td>and</td><td> 4-</td><td> 7 4-</td>

<td>Γ- Τ '</td><td>00 Τ</td><td>&lt;71 Τ '</td><td>ο LT)</td><td>»Η ιη</td><td>CM ιΛ</td><td>m &lt;n</td><td>τ ' ιΛ</td><td>m lD</td><td>kO ιΩ</td><td>r- uo</td><td>What m</td><td>σι ιΛ</td><td>ABOUT φ</td><td>r4 Φ</td><td>CM Φ</td><td>Γ0 Φ</td><td>T * kD</td><td>in kD</td><td>φ kD</td><td>r * kD</td><td>03 Φ</td><td>σ » kD</td><td>ABOUT Γ-</td><td>r- &lt; Γ-</td><td>CM r-</td><td>m c- *</td>

190 032

<td></td><td></td><td>N at N «1 α 8 0 M. Φ d C.</td><td>N υ N in 1 0 d (V H. C.</td><td>M. AT N IN 3 and N 0 M. V £</td><td>about ul cont Λ</td><td></td><td>about this td Λ</td><td>N AT N 3 8 ABOUT M. Φ d c</td><td>ABOUT tn cont Λ</td><td>about Ub rd Λ</td><td>I&gt; 150 I.</td><td></td><td>8 N 3 &amp; 0 at Φ d c:</td><td> [ &gt;150</td><td>about iSi rd Λ</td><td>about n</td><td>X</td><td>CN</td><td>Ub</td><td></td>

<td>&lt;μ X AT</td><td>CM X at</td><td>CM s</td><td>«Μ δ</td><td>δ</td><td>δ¹</td><td>&lt;M 6</td><td>«Μ X at</td><td>X at</td><td>δ *</td><td>s</td><td>X at</td><td>δ *</td><td>g</td><td>δ</td><td>j £ * at</td><td>X * CJ</td><td>f'4 X at</td><td>X ABOUT</td><td>SC at</td><td>and? at</td>

<td> 1</td><td>AND</td><td> ,</td><td> 1</td><td> 1</td><td> ,</td><td> 1</td><td>AND</td><td> 1</td><td> ,</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td>7 X</td><td>cont AT</td><td>cont AT</td><td>'d X</td>

<td>with</td><td>with</td><td>with</td><td>WITH</td><td>WITH</td><td>WITH</td><td>WITH</td><td>with</td><td>with</td><td>WITH</td><td>with</td><td>WITH</td><td>WITH</td><td>WITH</td><td>with</td><td>with</td><td>WITH</td><td>with</td><td>with</td><td>k WITH</td><td>WITH</td>

<td> 1</td><td>l</td><td> 1</td><td>l</td><td> 1</td><td>AND</td><td> 1</td><td> 1</td><td> 1</td><td>AND</td><td> 1</td><td> 1</td><td>vol</td><td> 1</td><td>vol</td><td> 1</td><td> 1</td><td>δ</td><td>X at</td><td>X at</td><td>X at</td>

<td> 0</td><td>r » X at</td><td>X at</td><td>Cl X at</td><td>X at</td><td>δ "</td><td>δ</td><td>g</td><td>Cl X at</td><td>δ</td><td>Cl X at</td><td>X at</td><td>x ' at</td><td>Cl X about</td><td> 5</td><td>n δ</td><td>δ</td><td>tn X £? 0-2</td><td>about with</td><td> 0</td><td>Q &lt;</td>

<td>X</td><td>1Λ δ</td><td>X about</td><td>X about</td><td>g</td><td>g</td><td rowspan="2">X ir</td><td>δ 1</td><td>&lt;M Cl X at</td><td>X about in «Μ δ</td><td rowspan="2">about X υ 1 X with 1 ir</td><td>4J 1</td><td rowspan="2">VI Ε- » CX X with 1 fi</td><td rowspan="2">CM 1 2 o = / ZI with</td><td rowspan="2">CN with \\</td><td rowspan="2">X about about about o = Z ?and with</td><td>£ with</td><td>X</td><td>X</td><td>X</td><td>X</td>

<td> §</td><td>1 ΪΓ</td><td></td><td>F.</td><td></td><td>and</td><td>WITH 1</td><td>with 1 and</td><td>1 g 1 WITH II</td><td>X with 1 1?</td><td>1 with</td><td>X about</td><td> §</td><td> §</td><td>X about</td>

<td>&lt;n X at</td><td>Those X &lt;J</td><td>CJ X υ</td><td>cl δ</td><td>Cl δ</td><td>n X at</td><td>those δ</td><td>m δ</td><td>those X at</td><td>&lt;1 X at</td><td>δ</td><td>X at</td><td>those X at</td><td>Cl X at</td><td>X at</td><td>X at</td><td>Cl X α</td><td>n δ</td><td>X at</td><td>X about</td><td>X CJ</td>

<td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td>

<td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td> $</td><td>X</td><td>X X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td>

<td>T. -s</td><td>1 • V » +</td><td> 1 +</td><td> 7 +</td><td> 7 +</td><td> 7 +</td><td>Ł +</td><td>Λ +</td><td> 7 +</td><td> 1 +</td><td> 7 +</td><td> 7 +</td><td> 1 +_</td><td> 1 +</td><td> 7 +</td><td> 1 +</td><td> 1</td><td> 1</td><td> 7</td><td> 1</td><td> 1</td>

<td>r-</td><td>m r *</td><td>this r · »</td><td>Π » r</td><td>X Γ **</td><td>cn r *</td><td>about o. o</td><td>rd X</td><td>CN X</td><td>X X</td><td>* s * X</td><td>in X</td><td>kO X</td><td>r * X</td><td>X X</td><td>cn WHAT</td><td>about cn</td><td>r4 cn</td><td>CN cn</td><td>cn cn</td><td>* 3 cn</td>

190 032

<td></td><td></td><td></td><td>N AT N &lt;n 3 0 * N ABOUT • fł C.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>ABOUT m and-( AND</td><td>r-</td><td></td><td></td>

<td>^εΗΟ</td><td>£ AT</td><td>£ AT</td><td>(No. £ AT</td><td>£ ABOUT</td><td>at</td><td>υ</td><td>l</td><td>£ AT</td><td>X AT</td><td>£ AT</td><td>and* s</td><td>«Μ £ ABOUT</td><td>X AT</td><td>£ AT</td><td>£ ABOUT</td><td>£ AT</td><td>-f¹AT</td><td>N δ</td><td>£ CJ</td>

<td>'r — 1 AT</td><td>«—1 υ</td><td>«—M υ</td><td></td><td>'m £</td><td>Ή &lt;β £</td><td> 1</td><td> 1</td><td> 1</td><td>Ł</td><td> 1</td><td> 1</td><td>AND</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td>AND</td><td>l</td>

<td>t- WITH</td><td>with</td><td>WITH</td><td>F. WITH</td><td>f WITH</td><td>WITH</td><td>WITH</td><td>with</td><td>WITH</td><td>WITH</td><td>WITH</td><td>with</td><td>WITH</td><td>WITH</td><td>WITH</td><td>WITH</td><td>WITH</td><td>with</td><td>with</td><td>WITH</td>

<td>n £ AT</td><td> £</td><td>r *&gt; £ AT</td><td>£ at</td><td>n £ υ</td><td>£ about</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td>and</td><td> 1</td><td>AND</td><td>Ł</td><td> 1</td><td>and</td><td> !</td><td>Ł</td><td>AND</td><td>AND</td>

<td>Q</td><td> 0 &lt;</td><td>Q</td><td>'about Ł</td><td>ι — 1 -H b&gt; t | ftj and about t | and</td><td>1 £ AT</td><td>X AT</td><td>s</td><td>£ AT</td><td>s</td><td>Q © /</td><td>Q</td><td>LL. b &gt; ς</td><td>P. © o = ^</td><td>P. ° = \</td><td>£ AT</td><td>£ ABOUT</td><td> £</td><td>£ (J.</td><td>'AND £ AT</td>

<td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td rowspan="2"> ?</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td rowspan="2">1 ABOUT 1 £ ABOUT fM £ AT 1 ABOUT 1</td><td> £</td><td> £</td><td> £</td><td> £</td>

<td>OH</td><td>£ ABOUT</td><td>£ ABOUT</td><td>£ ABOUT</td><td>£ about</td><td>£ ABOUT</td><td>£ ABOUT</td><td>£ £ - · 1 ABOUT</td><td>£ ABOUT</td><td> §</td><td> §</td><td>£ ABOUT</td><td>£ ABOUT</td><td>£ ABOUT</td><td>£ ABOUT</td><td>£ ABOUT</td><td> §</td><td>X ABOUT</td>

<td>n £ AT</td><td>£ AT</td><td>n £ AT</td><td>£ AT</td><td>&lt;&gt; £ AT</td><td>ri £ AT</td><td>£ AT</td><td>X at</td><td>π £ AT</td><td>l * l £ AT</td><td>s</td><td>n £ AT</td><td>r · » £ AT</td><td>X AT</td><td>ΓΊ £ AT</td><td>£ AT</td><td>1- ^ £ AT</td><td>&lt;-&gt; £ AT</td><td>£ AT</td><td>Λ £ AT</td>

<td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td>X</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td>

<td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td>tl £</td><td>tl £</td><td>t | £</td><td> £</td><td>mp £</td><td> £</td><td>t | £</td><td>t | £</td><td>t | £</td><td>t | £</td><td>t | £</td><td> £</td><td>ABOUT WITH</td><td>£ WITH</td>

<td> 1 (-)</td><td> £</td><td> +</td><td>vol</td><td>T.</td><td> 1</td><td>T. +</td><td> 7 £</td><td> 1 +</td><td> 7</td><td> 7 +</td><td> 7 +</td><td>Ł +</td><td>1 X. +</td><td> 7 +</td><td> 7 +</td><td> 7</td><td> 1 +</td><td></td><td> 1</td>

<td>m ΟΊ</td><td>&lt;0 cn</td><td>r * o&gt;</td><td>00 σ&gt;</td><td>ΟΊ ΟΊ</td><td>about about fł</td><td>in O «-1</td><td>CN ABOUT r — 1</td><td>about r-w</td><td>«R about t-w</td><td>m about r-1</td><td>kO ABOUT i-1</td><td>r * about r-1</td><td>CD ABOUT rH</td><td>cn about</td><td>O r-1 i-l</td><td>rH rH loam</td><td>CM iH 1-H</td><td>r rH rH</td><td>CD r-1 i-1</td>

190 032

A special case of general formula (I) is general formula (II):

<img file="PL190032B1_D0016.tif" />

formula (II)

<td>Pat II no .:</td><td>Chiral</td><td>Rr</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>G3</td><td>DB *</td><td>IC_M.</td>

<td> 113</td><td> (+/-)</td><td>Br</td><td>H.</td><td>CH3</td><td> =0</td><td></td><td>CH2</td><td>Yes</td><td> 5</td>

<td> 114</td><td> (+/-)</td><td>Br</td><td>H.</td><td>CH3</td><td>OH</td><td>H.</td><td>CH2</td><td>Yes</td><td></td>

<td> 115</td><td> (+/-)</td><td>H.</td><td>H.</td><td>CH3</td><td>OH</td><td>H.</td><td>CH2</td><td>Yes</td><td> &gt;150</td>

<td> 116</td><td> (+/-)</td><td>Br</td><td>H.</td><td>CH3</td><td>OH</td><td>H.</td><td>CH₂</td><td>no</td><td> 50</td>

* DB = double bond

Throughout the table, the abbreviation "Chiral" indicates the chirality of that specific excipient (educa). The rotation values ​​of these products are included in the experimental section.

Compounds according to the invention as contained in medicaments may be administered in any suitable chemical form, such as, e.g., acid addition salt, or in physical form. For example, they can be applied as hydrobromide, hydrochloride, methyl sulfate or methiodide.

The medicaments can be administered to patients orally or by subcutaneous or intravenous injection, or intracerebroventricularly using an implanted container.

It may be necessary to start with doses lower than ultimately effective.

The usual dosage amounts for the administration of medicaments containing the active substances of the present invention depend on the nature of the compound used and the condition of the patient. Thus, typical dosage amounts are in the range of 0.01-1.0 mg per day and 1 kg of body weight depending on age, physical condition and other medical prescription.

The medicaments according to the invention may be present in the following specific formulations:

tablets or capsules, containing 0.55-50 mg enteric solution, containing 0.1-30 mg / ml liquid preparation for oral administration at a concentration of 0.1-15 mg / ml.

The compounds according to the invention may also form a transdermal system which releases 0.1-10 mg / day.

The transdermal dosage system consists of a reservoir layer that contains 0.1-30 mg of the active ingredient in free base or salt form optionally together with a penetration enhancer, e.g. dimethyl sulfoxide or a carboxylic acid such as caprylic acid, and a skin-neutral polyacrylate. e.g. a hexyl acrylate / vynyl acetate / acrylic acid copolymer, together with a plasticizer e.g. isopropyl myristate. An outer layer, impermeable to the active ingredient, for example a metal-coated siliconized polyethylene patch with a thickness of, for example, 0.35 mm, serves as a casing. For example, a dimethylaminomethyl acrylate / methyl acrylate copolymer in an organic solvent is used to form an adhesive layer.

The following are examples of methods by which the compounds of the invention can be prepared:

190 032

Experimental part General tips:

• thin-layer chromatography with silica gel called Kieselgel 60 F254 (Merck company, article no. 5554) • Abbreviations used:

NH4OH concentrated aqueous ammonia solution PE petroleum ether (40-60 ° C) • p-Ts = p-Tos = p-toluenesulfonyl • CE = capillary electrophoresis • rotation values ​​were generally measured for concentration c = 0.1 • melting point was determined by heated tabletop microscope according to Kofler, values ​​are uncorrected • glass autoclave from Btichi (TinyClave, MiniClave) • water content of the solvent, if given, determined according to Karl Fischer • Elemental microanalyses were performed in the microanalytical laboratory of the Institute of Physical Chemistry of the University of Vienna under the supervision of Mr. Mag. J. Theiner • NMR spectra were obtained with a Bruker 200 FS FT-NMR spectrophotometer; CDCl 2 or DMSO-d $ and H-NMR was used as solvent: measurement frequency 200.13 MHz, internal state 1 inr:

CDCl3 (δ = 7.26 ppm) or DMSO-d6 (δ = 2.50 ppm)

13C-NMR: measurement frequency 50.02 MHz, internal standard:

CDCl3 (δ - 77.0 ppm) or DMSO-d6 (δ = 39.5 ppm)

Partitions in spectroscopy-NMR are determined as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet.

The multiplicity of the spectra- ^ C was determined, where necessary, by means of the-DEPT experiments, and the assignment of the spectra-¹H by way of experiments - COZY.

Uncertain assignments are marked with *.

• Experimental part:

(+/-) 8-bromogalanthamine (1), (+/-) 8-bromoepigalanthamine (2)

24 ml (36 mmol) of a 1M-DIBAL-H solution in toluene are added dropwise at 0 ° C to a suspension of 4.0 g (10.5 mmol) of bromo-N-formylnarredine in 60 ml of toluene. The reaction mixture is stirred for 1 hour at room temperature, the remaining reducing agent is decomposed with water and then 20 ml of concentrated NH 4 OH are added. After stirring for 20 minutes at room temperature, the precipitated material is filtered off, the organic layer is separated, and the aqueous layer is washed with 50 ml of toluene. The residue is separated by column chromatography. Yield: 0.9 g (23.3%) of compound 1 and 0.8 g (20.7%) of compound 2.

Data for bromogalanthamine (1):

• molecular weight: Ci7Hi9BrNO3: 365.23 • HRKBr): 689.03m; 778.57m; 839.37m; 989.86m; 1050.66s; 1212.43s; 1279-1434.08s; 14.72s; 1613.99s; 2667.39m; 3370-3778br.

• 1i-NMR (CDClb): 6.09 (s, 1H); 6.06 (m, 2H); 4.60 (d, 1H); 4.15 (t, 1H); 3.92 (d. 1H);

3.82 (s, 3H); 3.24 (m, 1H); 2.98 (dt, 1H); 2.68 (dd. 1H); 2.42 (s, 3H); 2.05 (m, 2H); 1.60 (dt, 1H).

• ^,3C-NMR (CDClb): 145.32 s; 144.00 s; 133.96 s; 127.95 d; 127.68 s; 126.51 d; 115.61 d;

114.22 s; 88.56 d; 61.58 d; 58.561; 55.95 q; 5 ^, ^^ 1; 48.56 s; 42.06 q; 33,471; 29.69t. Data for brornogalanthamine (2):

• molecular weight: Cj7Hj &lt;&gt; BrNO3: 365.23 • IR (KBr): 667.95w; 752m; 836.68m; 1040.31s; 1208.39s; 12.82m; 1435.25m; 1485.72m; 1512.94w; 1558.27w; 1615.19m; 1667.14w; 2943.24w; 3360-3575br.

• 11-NMR (CDCl 2): ​​6.85 (s, 1H); 5.96 (AB, 22); 4.69 (m, 2H); 4.28 (d. 1H); 3.90 (d, 1H);

3.83 (s. 1H); 3.25 (m, 1H); 2.95 (m, 1H); 2.85 (dt, 1H); 2.36 (s. 3H); 2.15 (td, 1H), 1.69 (m, 2H).

190 032 • ⁿC-NMR (CDCl3 + DMSO-d6): i45.84s; i43.49 s; i33.89 s; i33, i4 d; i26, i2 s; and 24.35 d; ii 5.04 s; ii 3.0i s; 88.26 d; 6i, i0 d; 57.41; 55.58 q; 52.84 t; 47.86 s; 4i, 20q; 33.35 t; 3i, 43 t.

(+/-) brovogalanΐavina (i)

Method-1:

To a solution of 2.0 g (5.6 mmol) of compound (4) in 20 ml of water, 5 ml of 89% HCOOH, 5 ml of 37% CH2O are added and the mixture is refluxed. After refluxing for 5 minutes, the reaction mixture is diluted with water, adjusted to pH = 9 with 25% NH4OH and extracted 3 times with 20 ml of CH2Cl2 each time. The combined organic layers are dried over Na2SO4, filtered and evaporated in vacuo. Chromatographic purification of the residue (50 g silica gel, CHCl₃: MeOH = 97: - 95: 5) a colorless foam is obtained. Yield: 2.0 g (96.4%).

Method 2:

100 ml (100 vol.) ΜM L-Selectrid reagent solution at 0 ° C is added dropwise to a suspension of 10 g (26.4 mmol) of bromo-N-formylnarredine in 200 ml of THF over 30 minutes. After stirring for 60 minutes at 0 ° C, the reagent is decomposed with water and the reaction mixture is mixed with 100 ml of a 25% NH4OH solution. After stirring for 30 minutes at room temperature, the solvent is concentrated to half its volume in vacuo, transferred to a separatory funnel, mixed with 100 ml of 25% NH4OH and extracted three times with 200 ml of CITCA. The combined organic layers are dried over Na2SO4, filtered and the solvent is evaporated off in vacuo. 50 ml of H 2 O, 30 ml of 98% HCOOH, 30 ml of 37% CH 2 O solution are added to the residue and the reaction mixture is refluxed. After refluxing for 15 minutes, the reaction mixture is neutralized with NH4OH and extracted three times with 200 ml of CH2G2 each time. The combined organic layers are dried over Na2SO4, filtered and the solvent is evaporated off in vacuo. After chromatographic purification (600 g silica gel, CHCl₃: MeOH = 9: and? 8: 2) the residue gives a colorless foam. Yield: 6.4 g (66.2%).

Method for producing the racemate, (-) or (+) bromogalantine (i, 3, iii):

Method A '

To a solution of 4.00 g (0.8 mmol) of nivalin in 40 ml of 30% formic acid, 40 ml of 30% hydrogen peroxide solution are added and the reaction mixture is quickly heated to 100 ° C. After 20 minutes, the reaction mixture is quickly cooled to room temperature, made basic with concentrated aqueous ammonia solution and extracted three times with 50 ml of ethyl acetate each time. The organic layer was washed once with a saturated aqueous solution of sodium chloride, dried (Na2SO4), filtered and evaporated to give 2.55 g (64% of theory) of colorless crystals, mp 76-77 ° C, rotation [ajjCHCl ] = -93 ° for compound 3.

DC: CHCl₃: MeOH = 9: i.

Method B

A solution of 0 g (2.84 mmol) of racemic N-desmethylbromogalanthamine (4) in ml of 37% formalin, 2 ml of formic acid and 5 ml of water is stirred for 3 hours at 70 ° C. After cooling, the mixture is made basic with concentrated aqueous ammonia solution and left to crystallize for 20 hours at 4 ° C. The precipitate was filtered off with suction and dried at 50 ° C / 20 vv, thereby obtaining 0.85 g (82% of theory) of colorless crystals, mp 76-77 ° C for compound i.

DC: CHCl3: MeOH = 9: i.

Method C:

See the general procedure for reduction with L-Selectride.

NMR data for compounds (i, 3, lii)

190 032 'H-NMR (CDClb; δ (ppm)): 1.60 (ddd, 1H, H-9, J (9') = 14.2 Hz); 1.90-2.15 (m, 2H, H-975, J (5.5 ') = 15.1 Hz); 2.20 (b, 1H changes to D2O, OH); 2.45 (s, 3H, NCH3): 2.65 (ddd, 1H, H-5 ', J &amp; lt; 1 &amp; gt; = 15.1 Hz): 2.95 (ddd, 1H, H-10, J_G.0 10 ') = 15.6 Hz); 3.25 (ddd, 1H, H-10 ', J (10') = 15.6 Hz); 3.80 (s, 3H, OCH3): 3.95 (d, 1H, H-12, J₀₂ 12) = 16.0 Hz); 4.15 (dd, 1H, H-6); 4.30 (d, 1H, H-12 ', J (_I2, i2 ') = 16.0 Hz); 4.60 (b, 1H, H-4a); 5.95-6.10 (m, 2H, H-7/8); 6.90 (s. 1H. H-2).

¹³C-NMR (CDCl3; δ (ppm)): 29.7 (t, C-5); 33.5 (t, C-9); 42.1 (q, NCH3); 48.6 (s, C-8a);

53.3 (t, C-10); 55.9 (q, OCH3); 58.7 (t, C-12); 61.6 (d. C-6); 88.6 (d. C-4a); 114.2 (s, C-1); 115.6 (d, C-8); 126.5 (t, C-2); 127.6 (s, C-123); 127.9 (t, C-7); 134.0 (s, C-12b); 144.0 (5, C-3a);

145.3 (s, C-3).

N-desmethylbromogalanthamine (4):

Method A:

50.0 g (132 mm 2k) of N-formylbromonarravine is suspended in 250 ml of absolute tetrahydrofuran and at a temperature from -25 ° C to -20 ° C with 430 ml (430 mmol) of the reagent solution Ε ^^ οΜΡ in tetrahydrofuran After 3 hours, hydrolysis is carried out with phtidol / tftryhyprofurin (1: 1), the reaction mixture is concentrated to a volume of about 200 ml, mixed with 400 ml of ethanol and concentrated again to a volume of 200 ml to separate the boric acid. The residue is taken up in 500 ml of ethanol, mixed with 62% aqueous hydrobromic acid until pH = 1 is reached, and stirred for 24 hours at room temperature. The resulting precipitate is filtered off with suction and washed with a little ethanol. After the precipitate has dried, it is dissolved in 500 ml of water. The aqueous layer is slowly made alkaline with concentrated aqueous ammonia solution while cooling under vigorous suspension so that the product precipitates. The precipitate is left to crystallize in a refrigerator and then filtered off. Extraction of the filtrate with ethyl acetate yields a second product fraction, resulting in a total of 33.5 g (72% of theory) of colorless crystals of compound 4.

DC: CHCl3: MeOH - 95: 5.

Method B:

See the general procedure for reduction with L-Selectride.

¹H-NMR (CDCl3; δ (ppm)): 165-1.85 (m, 2H, H-9/9 '); 1.98 (ddd, 1H, H-5); 2.25 (b, 2H replacement for D₂O, NH / OH); 2.62 (ddd, 1H, H-5 '); 3.05-3.35 (m, 2H, H -10 / 10 '); 3.80 (s, 3H, OCH3); 3.85 (d, 1H, H12, J₀₂ j2) = 14.7 Hz); 4.10 (dd, 1H, H-6); 4.48 (d, 1H, H-12 ', R 12, 129 = 14.7 Hz); 4.56 (b, 1H, H-4a); 5.90-6.05 (m, 2H, H-7/8); 6.85 (s, 1H, H -2)^bC-NMR (CDClb; δ (ppm)): 29.7 (t, C-5); 39.8 (t, C-9); 46.6 (t, C-10); 49.3 (s. C-8a); 52.7 (t, C-12), 56.0 (q, OCH3); 61.7 (d. C-6); 88.4 (d. C-4a); 113.0 (s, C-1); 115.5 (d, C-8); 126.8 (d, C-2); 127.9 (d, C-7); 131.6 (s, C-12a): 134.1 (s, C-12b); 144.0 (s, C-3a); 145.8 (s, C-3).

(+/-) N-demethyl-bromogalanthimida (4), (+/-) N-pemphtyl-epibromogalanthavine (7)

3.0 g (11.8 mmol) of LiAlH (BuO) 3 in 15 ml of THF are added dropwise to a suspension of 1.0 g (2.6 mmol) of bromo-N-formyl narvedd in 5 ml of THF at 0 ° C for 30 minutes. After 30 minutes of stirring at 0 ° C, the mixture is refluxed. After refluxing for 22 hours, the complex formed with the reagent is decomposed with water, and the reaction mixture is mixed with 10 ml of a 25% -NH4OH solution. After stirring for 30 minutes at room temperature, the solvent is concentrated to half its volume in vacuo, transferred to a separatory funnel, mixed with 10 ml of a 25% -NH4OH solution and extracted with three 20 ml portions of CH2CB. The combined organic layers are dried over Na2SO4, filtered and the solvent is evaporated off in vacuo. Chromatographic purification (60 g of silica gel; CHCl2: MeOH = 95: 5 → 9: 1 → 8: 2) of the residue gave two products: 300.0 mg (32.2%) N-dimethylbrovogalanthamine ( 4) in the form of a colorless foam and 270 mg (29.0%) of N-diphmatyl-edibrovogalyntamine (7) in the form of a colorless dyad.

190 032

Data for N-desmethyl-epibromogalanthamine (7):

• molecular weight: Ci6H]₈BrNO3: 352.2i. IR (KBr): 78i, 60w; 834.28w; 976.63w; i050.28m; II79.73m; i2ii, 87m; 1280.07v; 1435.24v; i486, i0m; i6-16.37m; 2923.54w; 3700-2900mbr.

• H-NMR (CDCl 2): ​​6.86 (s, 1H); 5.92 (AB, 2H); 4.56 (m, 2H); 4.50 and 3.82 (AB, 2H);

3.80 (s, 3H); 3.28 (m, 2H); 2.52 (m, 1H); 2.20-1.70 (m, 3H).

• C-NMR (CDCl 3): 146.73s; 143.91s; 134.10s; 132.17s; 132.17d; 131.48d; 126.34d; 115.34d; 112.44s; 88.5 Id; 62.8ld; 56.10q; 52.34t; 49.25s; 46.82t; 40.52t; 32.07t.

(-) - N-desmethylbromogalanthamine (5) and ('UN-demethylbiOmogalanthamine (6) (- ^ N-desmethylbromogalanthamine (5)

A solution of 4.4 g (11.4 vol) of (-) - O, O-di-p-toluoyltartaric acid is added dropwise to a solution of 10.0 g (28.4 mmol) of N-desmethylbromogalanthamine (4) racemate in 30 ml of methanol. in 5 ml of methanol and then washed with 1 ml of methanol. The solution is treated with a seed crystal (without a seed crystal it may take several weeks to form crystals) and left for 2 days at 4 ° C. Then it is rubbed thoroughly with a glass stick and then left to stand for 2-5 days at 4 ° C, while still thoroughly agitating with a glass stick. The precipitated salt is then filtered off with suction, washed three times with ice-cold methanol and taken up in 100 ml of water. The aqueous layer was made basic with concentrated aqueous ammonia solution and extracted three times with 60 ml of ethyl acetate each time. The combined organic layers were washed once with a saturated aqueous solution of sodium chloride, dried (N2SO4, activated carbon), filtered and evaporated to give 1.90 s (38% of theory) of colorless crystals of compound 5 with a twist value of [α, CHCl] = -104 ° (excluding errors according to CE&gt; 99.9%). The methanolic mother liquor is evaporated, the residue is taken up in 100 ml of water and worked up as above for pure salt, whereby 7.13 g (88% of theory) of the crude product which is used for the preparation of compound 6 can be recovered.

(+) - N-devetylobromogalantavina (6)

A solution of 3.12 g (8.1 mmol) is added dropwise to a solution of 7.13 g (20.2 vol) recovered from the preparation of N-demethylbromogalanthamine (this slightly enriched compound forms crystals faster than racemic compound 4) in 10 ml of methanol. (+) - 0.0-di-p-toluoyltartaric acid in 4 ml of methanol, washing with 1 ml of methanol. This solution is treated with a seed crystal (without a protecting crystal, it may take several weeks for crystal formation) and processed as for 5 to give 2.02 g (57% of theory) of colorless crystals of 6 with a value of torsion [a] o [CHCl3] = + 102 ° (excluding errors according to CE&gt; 99.9%).

C16Hi8BrNO3 * 1.05 C20H115O8 * 1.01 H2O (JOS 1500) 776.11 g / mol Calculated: C 57.26 H 5.05 N 1.80 Found: C 57.28 H5.12 N 1.82.

Propylene glycol ketal with (1) bromo-N-formylcaredine

100 g of bromo-N-formylnarredine, 100 g of propylene glycol and 0.5 g of H2SO4 are boiled under reflux in 800 ml of toluene (at room temperature, 2-phase) under vigorous mechanical stirring (from approx. 90 ° C homogeneously ) and heated to the boil for 14 hours, against the separation of water. After cooling, the layers are separated (the upper layer is toluene), the propylene glycol layer is extracted twice with 100 ml of toluene, the combined toluene layers are shaken with 2 portions of 200 ml of saturated maHCO3, dried over Na2SO4 and evaporated. . Yield: 115.3 g of the yellowish foam of compound 8 (100% of theory) which crystallized overnight.

Column chromatography (60 g of silica gel Kieselgel 60, CHCl3 / 1-2% MeOH) of 1.0 g of product yielded 0.80 g of a colorless foam which was crystallized from EtOAc. Melting point: 170-171 ° C.

Molecular weight of C20H22BrNO3: 436.28

190 032 ^]H-NMR (CDCl 2: 8.12 (d, H); 6.88 (s, H); 5.96-6.17 (m, H); 5.75 (dd, H); 5.68 ( d, H / 2); 5.10 (d, H / 2); 4.53 (b, H); 4.48 (d, H / 2); 4.31 (d, H / 2); 3 , 12-4.38 (m, 5H); 3.82 (s, 3H); 2.562.80 (m, H); 2.05-2.35 (dd, H); 1.83-2.05 (m, 2H): 1.22-1.47 (m, 3H).

¹³C-NMR (CDCl₃): 162,48; 161,72; 147,17; 144,89; 144,64; 132,16; 129,04; 128,51 ; 128,57; 127,82; 127,70; 127,61; 115,70; 115,48; 127,09; 126,77; 126,5; 113,20; 111,66 ; 102,38; 102,22; 87,25; 87,07; 73,38; 72,46; 71,67; 71,41; 71,23; 70,55; 70,28; 55,92; 51,52 ; 46,18; 48,43; 40,77; 39,29; 36,07; 35,97; 34,58; 33,68; 33,44; 33,13; 18,68; 17,59; 17,45.

Note NMR, diastereoisomers: due to the addition of the (+/-) - propylene chiral center, the formation of diastereoisomers takes place, causing the signal to split into a signal caused by the formyl group.

Propylene glycol ketal with (+/-) narwedine (9)

37.5 g of LiAIHa a atmosaeme frgznu are placed in a pre-dried 4-liter infusion kc ^ lbJe and 800 ml of THF are fed from the separator, while under strong pSznSeuSa the temperature rises to about 45 ° C (depending on the water content in THF and reaction flask). Thereafter, 114 g of compound 8 (crude) in 400 ml of THF was added dropwise over 15 minutes, with the temperature rising to reflux (approx. 65-68 ° C). The mixture is heated under reflux for 10 hours with mechanical stirring, cooled, and 100 ml of water in 100 ml of THF are added while cooling.

After taking 10 ml, analysis with NH4OH and extraction with EtOAc (3 portions of 20 ml), an oily product (9) is obtained after evaporation. Column chromatography (5 g of silica gel type 60, CHCl2 / 3-5% MeOH) 0.17 g of the product gives: 0.1 g of a colorless foam. Treatment of the residue: analogous, but without column chromatography. Yield: 87.5% of theory. Molecular Weight: (C 20 H 25 NO 4): 343.42 'H-NMR, (CDCl 2): ​​6.60 (dd, 2H); 6.16 (dt, H); 5.68 (dd, H); 4.55 (m, H); 4.38-4.00 (m, 3H),

3.80 (s, 3H); 3.68-2.95 (m, 4H); 2.78-2.60 (m, H); 2.35 (s. 3H); 2.24-2. 02 (m, 2H); 1.62 (bd, H); 1.28 (t, 3H).

¹³C-NMR (CDClb): 146.59; 143.92; 132.04; 131.90; 129.57; 129.16; 128.86; 128.76; 128.39; 127.44; 126.92; 126.12; 126.02; 121.16; 111.05; 110.90; 110.77; 102.87; 102.73; 87.23; 73.15; 72.24; 71.43; 71.12; 70.44; 70.17; 60.28; 55.59; 55.53; 55.45; 53.83; 47.87; 47.80; 47.75; 41.80; 41.70; 34.84; 33.95; 33.66; 33.37; 18.66; 17.62; 17.43.

NMR footnote, diasterzoisomzra: due to the addition of a chiral center with the use of the (T ^ -propylene) group, diastresomers are formed, which cause the signal to split into a signal caused by the formyl group.

Ethylene glycol ketal with N-phermylebromenarvedine (10): 10.0 g (26.5 mmol) of Nformylebremenarvedyuy is refluxed in 20 g of ethylene glycol and 200 ml of toluene with 0.1 ml of concentrated sulfuric acid in the presence of a water separator . After 24 hours, the toluene layer is decanted and the ethylene glycol layer is boiled once with toluene. The combined toluene layers were washed twice with saturated aqueous sodium bicarbonate solution and evaporated to give quantitatively colorless crystals of 10, mp 192-193 ° C.

DC: EtOAc: MeOH = 99: 1 ¹H-NMR (CDCl2; δ (ppm)): 1.75-2.10 (m, 2H, H-9/9 '); 2.15 (dd, 1H, H-5 ', J₍₅, 5-) = 16.5 Hz); 2.65 (dd, 1H, H-5 ', J₍s,₅') = 16.5 Hz); 3.60 (ddd, 1H, H-10); 3.80 (s, 3H, OCH3); 3.90-4.10 (m, 5H, H-10 ', O-CH2-CH2-O); 4.30 (d, 1H, 12, 32?, J (12.12-) = 17.8 Hz); 4.50 (d, 1H, H-12 'KenformerB); 4.55 (d, 1H, H-4a); 5.10 (d, 1H, ^ -12 ^^^, J &lt;and 2.12 ') = 17.8 Hz); 5.65 (d, 1H, H12 'b); 5.70 (d, 1H, H-8); 6.10 (t, 1H, H-7): 6.85 (s, 1H, H-2); 8.10; 8.15 (2 * s, 1H, CHOsunfoΓzlrr A / b)

13 C-NMR (CDClb: δ (ppm)): 32.9 (t, C-5) 36.0 (t, C-9); 39.3; 40.7 (2 * t, C10ι ")" {(ηζζa / b) and 48.4 (s, C-8a): 46.1; 51.4 (2 * t, C-12e "nforzrrA'B); 55.9 (q, OCH3), 64.2,

65.1 (2 * t, O-CH2-CH2-O); 86.9; 87.1 (2 * s, ab); 102.0 (s, C-6); 111.6 (d, C-2);

115.4; 115.7 (2 * d, a / b); 126.4 (s, C-12a); 126.7 (s. C-1); 127.5; 127.7 (2 * t,

190 032

C-7conformer A / Β), 132.0, 132.1 (2 * s, C-12bkonfonner A / b),

147.1 (^ i, t C-3), 161.6) 1624 (2 * _S.) CHO, onom «rAB)

Ethylene glycol ketal with narwedine (11):

M.^4,6; H.^{4,8 (2}* S.^, C-Sakofom (A / B);

Method A:

To a suspension of 2.0 g (4.74 mmol) of compound 10 in 50 ml of absolute tetrahydrofuran was added dropwise at 0 ° C 20 ml of a 0.9 molar solution of lithium aluminum hydride in diethyl ether. The mixture is then allowed to warm to room temperature and finally refluxed (bp 52 ° C). After 50 hours and after cooling, it is hydrolyzed with 3 ml of a 2: 1 mixture of tetrahydrofuran and water. Then 50 ml of water and 50 ml of concentrated aqueous ammonia solution are added and the aqueous layer is extracted three times with 50 ml of ethyl acetate each time. The combined organic layers are washed once with saturated sodium chloride solution, dried (Na2SO4) and evaporated. Purification by MPLC with EtOAc: MeOH = 8: 2 gave 820 mg (52.5% of theory) of colorless crystals of compound 11, mp 109-110 ° C.

DC: CHCl 3: MeOH - = 9): 1

Method B:

1.0 g (3.5 mmol) of (-) - narwedine is refluxed in 2.0 g ethylene glycol and 20 ml toluene with 0.05 ml concentrated sulfuric acid in the presence of a water separator. After 24 hours, the toluene layer is decanted and the ethylene glycol layer is boiled once with toluene. The combined toluene layers were washed twice with a saturated aqueous sodium bicarbonate solution and evaporated, thereby obtaining quantitatively colorless crystals of compound 11.

DC: CHCl3: MeOH = 9: 1 (CDCl3; δ (ppm)): 1.65 (ddd, 1H, H-9, J (99y = 13.4 Hz); 2.10 (ddd, 1H, H- 9 ', J99 = 13.4Hz); 2.15 (dd, 1H, H-5, J₍₅ s-) = 14.2 Hz); 2.40 (s, 3H, NCH₃3; 2.55 (dd, IH, H-5 ', J₍(₅') = 14.2 Hz); 3.05 (ddd, 1H, H-10); 3.20 (ddd, 1H, H-10 '); 3.60 (d, 1H, H-12, J (K / i2-) = 16.0 Hz); 3.80 (s, 3H, OCH3); 3.90-4.05 (m, 4H, O-CH2-CH2-O); 4.10 (d, 1H, H-12 ', J (_AT 16.0 Hz); 4.55 (dd, 1H, H-4a); 5.65 (d, 1H, H-8, J_P.9) = 9.8 Hz); 6.15 (d, 1H, H-7, Jp8) = 9.8Hz); 6.55; 6.60 (AB, 2H, H-1/2) '

13 C-NMR (CDCl 3; δ (ppm)): 33.2 (t, C-5); 33.8 (t, C-9); 41.7 (q, N-CH3); 47.8 (t, C-10);

53.8 (s. C-8a); 55.5 (q, OCH3); 60.2 (t, C-12); 64.0; 65.0 (2 * t, O-CH2-CH2-O); 87.1 (d. C-4a);

102.5 (s, C-6); 110.9 (d, C-8); 121.1 (d, C-2); 125.9 (d, C-7); 128.7 (s. C-12a); 128.9 (s, C-12b);

131.8 (d, C-1); 143.8 (s, C-3a); 146.5 (s, C-3).

(+/-) - 2-h-hydroxyethyl ether galanthamine (12)

1.0 g of educ (10) is dissolved in 25 ml of ThF, cooled to 0 ° C, added dropwise with ml of JJAIH4 / TIIF (1M) over 5 minutes and stirred for 30 minutes at 0 ° C. The mixture is then heated to reflux for 48 hours, 25 ml of NH 4 OH (25%) are added dropwise and the mixture is extracted 4 times with 20 ml of EtOAc. The organic layers are dried over Na2SO4 and evaporated. Yield: 0.76 g of a yellowish oil (compound 12) (92.9% of theory). Column chromatography (40 g of silica gel type 60, CHCl2 / 2-7% MeOH) gives: 0.62 g of a colorless foam.

Molecular Weight: (C9H24NO4): 330.40.

Ethylene glycol ketal with N-demetslobromonawed) solid (13)

9.0 g (21.3 mmoles) of ethylene glycol ketal from N-formylb1. ^ (^ N ^ &lt;^ d ^ y ^ O) are suspended in 100 mL of absolute tetrahydrofuran. 28.4 ml (25.6 mmol) of 0.9 N lithium aluminum hydride solution are added at -15 ° C to at most -10 ° C and stirred at this temperature. After 20 minutes, a further portion of ml is added dropwise. 0.9 N lithium aluminum hydride solution in diethyl ether and stirring continued for 20 minutes at -15 ° C to -10 ° C. Then it is hydrolyzed with 15 ml of tetrahydrofhram water 2: 1, this solution is concentrated on a rotary evaporator and the residue is taken up in 200 ml of water and extracted three times with 100 ml of ethyl acetate three times. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried (Na2SO4) and evaporated to give 6.53 g (78% of theory) of colorless crystals of Compound 13.

DC: CHCl3 MeOH = 95: 5 EtOAc: MeOH = 9: 1.

1 H-NMR (CDCl 3; δ (ppm)): 1.70-1.85 (b, 1H replaces D 2 O, NH); 1.80 (dd, 1H, H-9); 1.90 (dd, 1H, H, 9 '); 2.15 (dd, 1H, H-5, J₍₅, 5-) = 1 ° C, 0 Hz); 2.65 (dd, 1, H-5 ', J₍₅ 59 = 16.0 Hz); 3.20 (ddd, 1H, H-10); 3.80 (s, 3H, OCH3); 3.85-4.10 (m, 6H, H-10 '/ 12, HO-CH2-CH2-O); 4.50 (d, 11H H-12 ', J ((2, ii ·) = 14.2 Hz); 4.60 (dd, 1H, H-4a); 5.65 (dd, 1H, H -8, J ™ = 9.8 1Hz); 6.15 (dd, 1H, H-7, J57_;8; = 9.8 Hz); 6.85 (s, 1H, H -2). '

Ethylene glycol ketal from N-benzyl-bromonarvedine (14):

250 mg (0.63 vol.) of ethylene glycol ketal with N-desmethylbromonarvedin (13) and 63 mg (0.63 mmol) of triethylamine are placed in 15 ml of absolute tetrahydrofuran, 108 ml (0.63 vol.) of bromide are added at room temperature benzyl and then stirred for 24 hours. The reaction mixture is mixed with 50 ml of water and the aqueous phase is extracted three times with 20 ml of ethyl acetate. The combined organic layers were washed once with a saturated aqueous sodium chloride solution, dried (Na2SO4) and evaporated to give 260 mg (85% of theory) of colorless crystals of Compound 4, mp 118-119 ° C.

DC: EtOAc: MeOH = 9: 1 'H-NMR (CDCl2; δ (ppm)): 1.65 (ddd, 1H, H-9, J2' = 14.2 Hz); 2.05-2.30 (v, 2H, H-5, H-9 '); 2.65 (dd, 1H, H-5 ', J55 5'; = 13.4Hz); 3.00-3.30 (v, 2H, H -10 / 10 '); 3.70 (s, 2H, CH2Ph); 3.80 (s, 3H, OCH3); 3.90-4.20 (m, 5H, H12, O-CH2-CH2-O); 4.35 (dd, 1H, H-12 ', J (2.12') = 15.1 Hz); 4.60 (ddd, 1H, H-4a); 5.70 (d, 1H, H-8, J (78) = 9.8Hz); 6.25 (d, 1H, H-7, J57, O; = 9.8 Hz); 6.85 (s, 1H, H -2); 7.25-7.30 (m, 5H, Ph) '

13 C-NMR (CDClb; δ (ppm)): 33.1 (t, C-5), 33.4 (t, C-9); 48.5 (s. C-8a); 50.7 (t, C-10):

55.8 (q, OCH₃); 56.4 ((, C-12); 56.9 (t, CIL-Ph); 64.2; 65.1 (2 * t, O-CH₂-CH₂-ABOUT); 8 '^^, ł (d, C-4a);

102.3 (s, C63); 113.6 (Si Cl); 115.6 dd, C-8); 126.6 (s, Ph-1); 127.1 dd C-7) and 128.2; 128.9 66 * d, Ph-2 - 6, C-2); 133.1 (s. C-12a); 137.9 (s, C-12b); 144.2 (s. C-3a); 146.3 (s, C-2).

N-desmethylbromonarvedine (15):

Method A:

see general practice for cleavage of the ethylene glycol protecting group

Method B:

9.0 g (21.3 (η, οla) of the N-formyloromoricovenyriy 00 ketal) were suspended in 100 ml of absolute tetrahydrofuran, at a temperature of -25 ° C to at most -20 ° C are added with 28, 4 ml (25.6 vol.) Of 0.9 N lithium aluminum hydride solution in diethyl ether and stirred at this temperature. After 20 minutes, a further 10 ml (9.0 vol.) Of a 0.9 N lithium aluminum hydride solution in diethyl ether was added dropwise and stirring continued for 20 minutes at -25 ° C to -20 ° C. Then it is hydrolyzed with 15 ml of tetrαhydrofurin: water 2: 1, this solution is concentrated in a rotary evaporator, and the residue is taken up in 200 ml of 2N hydrochloric acid and stirred for 15 minutes. The aqueous layer was mixed with 5.71 g (38.1 vol) of L - (+) - tartaric acid, alkaliZed with a concentrated aqueous yvonic acid solution and extracted three times with 100 ml of ethyl acetate each time. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried (Na2SO4) and evaporated to give 6.53 g (78% of theory) of colorless crystals of 15.

DC: CHCl2: MeOH = 95: 5 EtOAc: MeOH = 9: 1.

1 H-NMR (CDCl 2; δ (ppm)): 1.90-2.15 (v, 2H, H-9/9 '); 2.75; 2.95 (AB, 2H, H-5/5 ',

J (5.5 ') = 16.0 Hz); 3.10-3.35 (v, 2H, H -10/10) 1; 3.75 (s, 3H, O-CH3); 3.90 (d, 1H, H-12,

J (12 ') = 16.4 Hz); 4.40 (d, 1H, H-12, J (, 2, 129 = 16.4Hz); 4.55 (dd, 1H, H-4a); 5.90 (d, 1H, H-8,

J (78) = 10.7 Hz); 6.90 (s, 1H, H -2); 7.05 (d, 1H, H-7, ^ 7/8 = 10.7Hz)

190 032

13 C-NMR (CDCl · ,; δ (ppm)): 3.63 (t, C-5); 37.0 (t, C-9); 45.6 (s, C-8a); 49.5 (t, C-10); 51.3 (t, C-12); 55.9 (q, OCH3; 87.9 (d, C-4a); 112.5 (s, Cl); 116.0 (d, C-8); 126.6 (d, C-7); 129.6 (s, C-12a); 132.0 (s, C-12b); 143.7 (s, C-3a); 144.8 (d, C-2); 146.6 (s, C-3).

Bromonarvedine (16):

Method A · see general procedure for cleavage of the protective group of ethylene glycol

Method B

9.0 g (21.3 mmol) of N-formylbromonamvedine ketal (10) are suspended in 100 ml of absolute tetrahydrofuran, at a temperature of -5 ° C to at most 0 ° C, 10.0 ml ( 26.0 mmon) of a 2.6 N lithium carbon hydride solution in tetrahydrofuran and stirred at this temperature. After 20 minutes, a further 5 ml (13.0 mmon) of a 2.6 N lithium hydroxide solution in diethyl ether was added dropwise and stirring continued for 20 minutes at -5 ° C to 0 ° C. Then it is hydrolyzed with 15 ml of tetrahydrofuran: defect 2: 1, this solution is concentrated on a rotary evaporator, and the residue is taken up in 200 ml of 2N hydrochloric acid and stirred for 15 minutes. The aqueous layer was mixed with 6.4 g (42.9 mmol) of L - (+) - tartaric acid, made basic with concentrated aqueous ammonia solution and extracted three times with 100 ml of ethyl acetate each time. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried (Na2SO4) and evaporated to give 6.21 g (80% of theory) of colorless crystals of Compound 16.

DC: CHCl3: MeOH = 95: 5 EtOAc: MeOH = 9: 1.

1 H-NMR (CDCl 3; δ (ppm)); 1.90 (ddd, 1H, H-9, J₍₉9 = 12.5 Hz); 2.25 (ddd, 1H, H-9 ', J (9') - 12.5Hz); 2.45 (s, 3H, NCH3); 2.75 (dd, 1H, H -5, J 5.59 = 17.8 Hz); 2.95-3.25 (m, 3H, H-5710/10 '); 3.85 (s, 3H, OCH3); 3.95 (d, 1H, H-12, J_G.2 12 ') = 16.9 Hz); 4.25 (d, 1H, H-12 ', J (2.12') = 16.9Hz); 4.70 (dd, 1H, H-4a); 6.05 (d, 1H, H-8, J (7.8) = 9.8Hz); 6.95 (s, 1H, H -2); 7.00 (d, 1Η, H-7, J_{(7 8}) = 9/8 Hz)

13 C-NMR (CDCl 3; δ (ppm)): 33.0 (t, C-5); 36.9 (t, C-9); 42.9 (q, NCH3); 49.2 (s. C-8a);

53.5 (t, C-10); 56.1 (q, OCH₃3; 58.9 (t, C-12); 88.0 (C-4a); 114.0 (s, Cl); 116.3 (d. C-2);

127.2 (d, C-8); 127.9 (s, C-12a); 131.6 (s, C-12b); 143.9 (s, C-3a); 144.4 (d, C-7), 146.5 (s, C-3); 193.9 (s, C-6).

Cleavage of the protecting group of the ethylene glycol ketal (15,16-narwedine):

<td>Substance No.</td><td>Edidrtnr</td><td>R</td><td>R6</td><td>SF, MG</td>

<td> 15</td><td> 13</td><td>Br</td><td>H.</td><td></td>

<td>narwedine</td><td> 11</td><td>H.</td><td>CH3</td><td>CnHDNOj ^^]</td>

<td> 16</td><td> 110</td><td>Br</td><td>CH3</td><td>C.₁₇H.₁1BrNO3 [064.25]</td>

5.0 g of educg are dissolved: in 100 ml of 0N m / s swani acid logrzerog for 30 minutes to the temperature of 100 ° C. After cooling, it is made alkaline with concentrated aqueous ammonia solution and the product is filtered off with suction and dried at 50 ° C / 20 mm Hg or extracted with ethyl acetate, dried (NaSO 4 and evaporated.

DC: CHCl3: MeOH = 9: 1

<td>Substance No.</td><td>Name</td><td>Performance</td><td>Tt .:</td>

<td> 15</td><td></td><td>91% colorless crystals</td><td>173-174 ° C</td>

<td>narwedine</td><td>narwedine</td><td>quantitatively colorless crystals</td><td></td>

<td> 16</td><td>bromoo-rwedyoa</td><td>quantitatively colorless crystals</td><td>75-77 ° C</td>

190 032

Narvedine:

1 H-NMR (CDCl 3; δ (ppm)): 1.85 (ddd, 1H, H-9, J₍₉9) = 14.2 Hz); 2.25 (ddd, 1H, H-9 ', J (9.9') = 14.2 Hz); 2.75 (ddd, 1H, H-5, J (5.5 ') = 17.8 Hz); 3.05-3.30 (m, 3H, H -5 '/ 10 / 10t'); 3.70 (d, 1H, H-12, J (12.12 ') = 12.5 Hz); 3.80 (s, 3H, OCH3); 4.10 (d, 1H, H-12 ', J₀₂ 12) = 12.5 Hz); 4.70 (b, 1H, H-4a); 6.00 (d, 1H, H-8, J (7_;8) = 9/8 Hz); 6.60-6.70 (m, 2H, H1 / 2); 6.95 (d, 1H, H-7, J (7.8) = 9/8 Hz) &amp; lt; 1 &amp; gt; C-NMR (CDCl3; δ &amp; lt; 5 &amp; gt;)): 33.3 (t, C-5); 37.3 (t, C-9); 42.5 (q, NCH3); 49.0 (s, C-8a); 54.1 (t, C-10); 56.0 (g, OCH3); 60.7 (t, C-12); 88.0 (d, C-4a); 111.9 (d, C-2); 122.0 (d, C-8); 127.1 (d, Cl); 129.4 (s, C-12a); 130.6 (s, C-12b); 144.0 (d, C-7); 144.4 (s. C-3a); 147.0 (s, C-2); 194.4 (s, C-6).

General rules of procedure for reduction with L-Selectride:

<td>Substance no</td><td>Edukt no</td><td>Ri</td><td>R6</td><td>Summary formula MG</td>

<td> 4</td><td>bromoformyl- narwedine</td><td>Br</td><td></td><td>C.₁₆H.₁₈BrNO₃ [352,24]</td>

<td> 3</td><td>b romonarvedine</td><td>Br</td><td>ch₃</td><td>C17H₂oBrNO₃ [366,26]</td>

<td> 42</td><td> 41</td><td>Br</td><td></td><td>Ci9H₂2BrNO₃ [392,30]</td>

<td> 45</td><td> 44</td><td>Br</td><td>-jO</td><td>C.₂₃H.₂₄BrNO₃ [442,36]</td>

<td> 46</td><td> 47</td><td>H.</td><td>© O</td><td>C.₂₃H.₂₅WELL₃ [363,46]</td>

100 mg of educt is suspended in 5 ml of absolute tetrahydrofuran and at a temperature of -5 ° C to 0 ° C is added with 1.2 equivalents of a 1N solution of L-Selectride in tetrahydrofuran. After 30 minutes, hydrolysis is carried out with tetrahydrofuran: water 1: 1, the reaction mixture is concentrated on a rotary evaporator, the residue is taken up in 50 ml of 2N hydrochloric acid and stirred overnight at room temperature. The aqueous layer is washed with 20 ml of diethyl ether and, under cooling and vigorous stirring, slowly alkalinize with a concentrated aqueous ammonia solution such that the product precipitates. The precipitate was left to crystallize out in the refrigerator for a few days and then filtered off under reduced pressure. Two product fractions are obtained by extraction of the filtrate with ethyl acetate. The crude product is purified by column chromatography (15 g silica gel, recycle:

CHCl · ,: MeOH = 9: 1).

DC: CHCl3: MeOH = 9: 1

190 032

<td>Substance no</td><td>Name</td><td>Performance</td><td>Tt .:</td>

<td> 4</td><td>(6R) -4a, 5,9,10,11,12-hexahydro-1-bromo-3-methoxy-6H-benzofuro [3a, 3,2-ef] [2] benzazepinol-6</td><td>90% colorless crystals</td><td></td>

<td> 3</td><td>(6R) -4a, 5,9,10,1,1,12-hexahydro-1-bromo-3-methoxy-1,1-methyl-6H-benzofuro [3a, 3,2-ef] - [2] benzazepinol- 6</td><td>quantitatively colorless crystals</td><td>76-77 ° C</td>

<td> 42</td><td>(6R) 4a, 5,9,10,1,1,12-hexahydro-1-bromo-3-methoxy-11- (2-propenyl) -6H-benzofiro- [3a, 3,2-ef] [2 ] benzazepinol-6</td><td> 30%</td><td></td>

<td> 45</td><td>(6R) -4a, 5,9,10,1,1,12-hexahydro-1-bromo-3-methoxy-11- (phenylmethyl) -6H-benzofuro- [3a, 3,2-ef] [2] benzazepmol -6</td><td> 50%</td><td></td>

<td> 46</td><td>(6R) -4a, 5,9,10,11, 12-hexahydro-3-methoxy-1-1- (phenylmethyl) -6H-benzofuro [3a, 3,2-ef] - [2] benzazepinol-6</td><td> 80%</td><td></td>

Carbamates and thiocarbamates (-) - galantamines

<td>Product</td><td>Summary formula</td><td>R</td><td>Method</td><td>R</td>

<td></td><td>C2₄H2iNiO4 [406.48]</td><td>(-) - Galantaminophenyl carbamate</td><td>AND</td><td>Ao H.</td>

<td> 17</td><td>C26H29N2O4 [433,531</td><td>(-) - galantaraine-Ra-roethiobenzyl carbamate</td><td>AND</td><td></td>

<td> 19</td><td>C26H29N2O4 [433.53]</td><td>(-) - Galantamine-Sa-methylbenzyl carbamate</td><td>AND</td><td>0 ch₃Λχι</td>

<td></td><td>C23H2BN2O4 [456.54]</td><td>(-) - Galantamine-α-naphthyl carbamate</td><td>B</td><td>J J0L Ίτιΐ H.</td>

<td></td><td>C22H30N2O4 [386.49]</td><td>(-) - Galantamine n-butyl carbamate</td><td>AND</td><td>ABOUT H.</td>

<td> 21</td><td>CziHzsNiOjS [422.55]</td><td>{-) -galantaminophenyl thiocarbamate</td><td>B</td><td>Ao H.</td>

<td> 23</td><td> [402,56]</td><td>(-) - Galantamine n-butyl thiocarbamate</td><td>B</td><td>H.</td>

Method A:

1.2 equivalents of isocyanate or thioisocyanate under argon are added to a solution of 500 mg (1.74 mmol) of (-) - galanthamine in 50 ml of absolute tetrahydrofuran and stirred under reflux for 24 hours. The reaction mixture was evaporated and the residue was purified by column chromatography (acetone: methanol = 9: 1) to obtain colorless crystals.

DC: toluene: MeOH = 4: 1

190 032

Method B:

mg (2.62 mmol) of sodium hydride (95%) in an atmosphere at room temperature. 1.2 equivalents of an isocyanate or a thioisocyanate are then added dropwise thereto, and stirring is continued for 3 hours. The reaction mixture is poured into 150 ml of water and extracted twice with 150 ml of ethyl acetate each time. The organic layers are washed once with 150 ml of water, dried over sodium sulfate and evaporated. The residue is purified by column chromatography (acetommethanol = 9: 1) to obtain colorless crystals.

DC: toluene: MeOH = 4: 1.

<td>Product</td><td>Efficiency [% of theory]</td><td>* Oo (25'C, c = l)</td><td>Melting point [° C]</td>

<td></td><td>94 (Lit. [15]: 80%)</td><td> -43,6’</td><td>85-86 (Lit. [15]: 85-87)</td>

<td></td><td>58 (Lit. [15]: 60%)</td><td> -56,0’</td><td>199-203 (Lit. [15]: 203-204)</td>

<td></td><td>93 (Lit. [15]: 100%)</td><td> -57,0’</td><td>48-51 (Lit. [15]: 47-49)</td>

<td> 17</td><td> 96</td><td> -45,5’</td><td> 74-77</td>

<td> 19</td><td> 99</td><td> -48,0’</td><td> 135-136</td>

<td> 21</td><td> 97</td><td> -22,5</td><td> 175-176</td>

<td> 23</td><td> 71</td><td> -48,5</td><td> 165-167</td>

1 H-NMR [CDCl₃; δ (ppm)]:

<td>Proton</td><td></td><td></td><td></td><td> 17</td>

<td>H._and-5</td><td>1.60; m</td><td>1.60; m</td><td>1.58; m</td><td>1.60; m</td>

<td>H.-1</td><td>2.10; m</td><td>2.10; m</td><td>2.10; m</td><td>1.90; m</td>

<td>Ht-5</td><td>2.20; m</td><td>2.18; m</td><td>2.15; no</td><td>2.10; m</td>

<td>ch₃-n</td><td>2.40; s</td><td>2.4; s</td><td>2.40; s</td><td>2.38; s</td>

<td>Hb-1</td><td>2.75; this year</td><td>2.80; this year</td><td>2.65; this year</td><td>2.68; this year</td>

<td>Ht, -6</td><td>3.10; m</td><td>3.08; m</td><td>3.05; m</td><td>3.05; m</td>

<td>Ha-6</td><td>3.30; m</td><td>3.30; m</td><td>3.15; m</td><td>3.25; m</td>

<td>Hb-8</td><td>3.70; this year</td><td>3.68; this year</td><td>3.65; this year</td><td>3.65; this year</td>

<td>CH; —O—</td><td>3.85; s</td><td>3.85; s</td><td>3.85; s</td><td>3.80; s</td>

<td>H._and-8</td><td>4.15; this year</td><td>4.15; this year</td><td>4.10; this year</td><td>4.10; this year</td>

<td>H-12a</td><td>4.55; vol</td><td>4.59; m</td><td>4.50; vol</td><td>4.55; vol</td>

<td>H-2</td><td>5.40; vol</td><td>5.45; vol</td><td>5.23; vol</td><td>5.25; vol</td>

<td>H-3</td><td>5.95; dd</td><td>6.00; dd</td><td>5.90; dd</td><td>5.85; dd</td>

<td>H-4</td><td>6.30; d</td><td>6.35; d</td><td>6.20; d</td><td>6.25; d</td>

<td>H-9</td><td>6.60; d</td><td>6.60; d</td><td>6.55; d</td><td>6.55; d</td>

<td>H-10</td><td>6.65; d</td><td>6.70; d</td><td>6.60; d</td><td>6.65; d</td>

<td rowspan="5">various H.</td><td>6.95 (3.1H, -NH-)</td><td>7.35 (3.1H, -NH-)</td><td>0.9 (t, 3H, CH₃-)</td><td>1.45 (m, 3H, CHj-)</td>

<td>7.0-7.3 (m, 5H, Ph)</td><td>7.5-7.9 (m, 7H, Naf)</td><td>1.3Q (m, 2H, CH3-CH2-)</td><td>4.48 (m, 1H, -CH-)</td>

<td></td><td></td><td>1.42 (m, 2H, (-CH2-CH2-)</td><td>5.20 (3.1H, -NH-)</td>

<td></td><td></td><td>3.15 (m, 2H, (-NH-CH2-)</td><td>7.28 (m, 5H, Ar-H)</td>

<td></td><td></td><td>4.85 (3.1H, -NH-)</td><td></td>

190 032

<td>Proton</td><td> 19</td><td> 21</td><td> 23</td>

<td>H._and-5</td><td>1.55; n</td><td>1.60; n</td><td>1.65; n</td>

<td>H._and-1</td><td>2.10; dd</td><td>2.00; n</td><td>2.00; n</td>

<td>Hj-5</td><td>1.90; n</td><td>2.15; n</td><td>2.10; n</td>

<td>CH3-H-</td><td>2.40; s</td><td>2.35; s</td><td>2.38; and</td>

<td>Hb-1</td><td>2.70; this year</td><td>2.60; no</td><td>2.75; n</td>

<td>Hb-6</td><td>3.02; n</td><td>3.00; n</td><td>3.05; n</td>

<td>H, -6</td><td>3.25; n</td><td>3.25; n</td><td>3.50; n</td>

<td>Hb-8</td><td>3.65; this year</td><td>3.60; this year</td><td>3.70; this year</td>

<td>CH3-O-</td><td>3.80; s</td><td>3.70; s</td><td>3.80; s</td>

<td>Ha-8</td><td>4.10; this year</td><td>4.05; this year</td><td>4.10; this year</td>

<td>H-12a</td><td>4.55; vol</td><td>4.50; vol</td><td>4.55; vol</td>

<td>H-2</td><td>5.28; vol</td><td>5.90; n</td><td>6.30; vol</td>

<td>H-3</td><td>5.90; dd</td><td>6.00; dd</td><td>5.95; dd</td>

<td>H-4</td><td>6.20; d</td><td>6.25; d</td><td>6.05; d</td>

<td>H-9</td><td>6.55; d</td><td>6.50; d</td><td>6.55; d</td>

<td>H-10</td><td>6.65; d</td><td>6.10; d</td><td>6.65; d</td>

<td rowspan="5">various H.</td><td>1.50 (d, 3H, CH3-)</td><td>6.9-7.25 (d, 5H, Ph-H)</td><td>0.90 (t, 3H, CH3-)</td>

<td>4.80 (n, 1H, -HH-CH-CHj)</td><td>8.40 (3.1H, -HH-)</td><td>1.30 (n, 2H, CH₃-CH₂-)</td>

<td>5.20 (s, 1H, -HH-)</td><td></td><td>1.60 (n, 2H, -CH2-CH2-CH2-)</td>

<td></td><td></td><td>3.25 (n, 2H, -HH-CH₂-)</td>

<td></td><td></td><td></td>

i3C-NMR [CDCl3; δ (ppm)]:

<td>| C-atcrn</td><td></td><td></td><td></td><td> 17</td>

<td>C-1</td><td>27.8; vol</td><td>27.9; vol</td><td>29.1; vol</td><td>27.9; vol</td>

<td>C-5</td><td>34.1; vol</td><td>34.3; vol</td><td>34.2; vol</td><td>34.2: m</td>

<td>CH3-H-</td><td>41.7; q</td><td>41.9; q</td><td>40.5; q</td><td>41.7; q</td>

<td>C-4a</td><td>47.8; d</td><td>47.9; s</td><td>47.7; s</td><td>47.8; s</td>

<td>C-6</td><td>53.6; vol</td><td>53.7; vol</td><td>53.8; vol</td><td>53.6; vol</td>

<td>CH₃-ABOUT</td><td>55.6; q</td><td>55.7; q</td><td>55.5; s</td><td>55.6; s</td>

<td>C-8</td><td>60.3; vol</td><td>60.4; vol</td><td>60.3; vol</td><td>60.3; vol</td>

<td>C-2</td><td>63.6; d</td><td>64.0; d</td><td>62.9; d</td><td>63.2: d</td>

<td>C-12a</td><td>86.3; d</td><td>86.3; d</td><td>86.3; d</td><td>86.3; d</td>

<td>C-3</td><td>110.9; d</td><td>111.0; d</td><td>110.9; d</td><td>111.0; d</td>

<td>C-4</td><td>118.6; d</td><td>119.0; d</td><td>121.2; d</td><td>121.2, d</td>

<td>C-9</td><td>121.4; d</td><td>120.7; d</td><td>123.4; d</td><td>123.3; d</td>

<td>C-10</td><td>130.4; d</td><td>128.5; d</td><td>129.8; d</td><td>128.3; d</td>

<td>C-8a</td><td>132.0; s</td><td>129.2; s</td><td>129.1; s</td><td>129.2; s</td>

<td>C-11b</td><td>138.0; s</td><td>132.1; s</td><td>132.1; s</td><td>132.1; s</td>

<td>C-11a</td><td>143.7; s</td><td>143.8; s</td><td>143.7; s</td><td>143.6; s</td>

<td>C-11</td><td>146.3; s</td><td>146.4; s</td><td>146.3; s</td><td>146.3; s</td>

<td rowspan="5">various C.</td><td>122.8 (d, Ar-C)</td><td rowspan="2">120.7; 121.4; 123.0; 125.7 125.9, -130.6 (0.6 petroleum C)</td><td>13.5 (q, CH3-CHi-)</td><td>22.4 (q, CHj-)</td>

<td>123.0 (d, Ar-C)</td><td>19.7 (tdHi- ^ CH »-)</td><td>50.6 (d.-NH-CH-)</td>

<td>128.7 (d, 3Ar-C)</td><td>126.7 (s, petrol. C-8a)</td><td>27.9 (t, -CH-CH2-)</td><td rowspan="2">125.8, '127; 129.9; (d, SAr-C)</td>

<td>19Q (Λ Łr-G</td><td>132.1 (5, petroleum C-4a)</td><td>40.5 (t, -HH-CH2-)</td>

<td></td><td>134.0 (s, petrol. C-1)</td><td>156.1 (3, - &lt;C-NH-)</td><td>143.7 (s, Ar-C)</td>

190 032

<td>C-atom</td><td> 19</td><td> 21</td><td> 23</td>

<td>C-1</td><td>27.9; vol</td><td>27.5; vol</td><td>30.9; vol</td>

<td>C-5</td><td>34.3; vol</td><td>34.1; vol</td><td>34.1; vol</td>

<td>CH₃-N-</td><td>41.8; q</td><td>41.8; q</td><td>41.8; q</td>

<td>C-4a</td><td>47.8; s</td><td>47.9; s</td><td>48.0; vol</td>

<td>C-6</td><td>53.6; vol</td><td>53.6; vol</td><td>53.6; vol</td>

<td>CH-O</td><td>55.5; q</td><td>55.0; q</td><td>55.5; q</td>

<td>C-8</td><td>60.3; vol</td><td>60.3; vol</td><td>60.3; vol</td>

<td>C-2</td><td>63.1; d</td><td>71.2; d</td><td>69.7; d</td>

<td>C-12a</td><td>86.3; d</td><td>86.1; d</td><td>86.3; d</td>

<td>C-3</td><td>110.9; d</td><td>110.9; d</td><td>110.8; d</td>

<td>C-4</td><td>121.2; d</td><td>120.8; d</td><td>121.3; d</td>

<td>C-9</td><td>123.3; d</td><td>121.5; d</td><td>122.7; d</td>

<td>C-10</td><td>128.3; d</td><td>128.7; d</td><td>129.2; d</td>

<td>C-8a</td><td>132.1; s</td><td>130.0; s</td><td>131.0; s</td>

<td>C-11b</td><td>143.7; s</td><td>131.3; s</td><td>132.0; s</td>

<td>C-11a</td><td>143.9; s</td><td>137.7; s</td><td>143.7; s</td>

<td>C-11</td><td>146.3; s</td><td>143.7; s</td><td>146.3; s</td>

<td rowspan="5">various C.</td><td>22.4 (q, -CH₃)</td><td rowspan="2">100.8-128.7 (d, 5Ar-C) 129.1 (s, Ar-C)</td><td>13.6 (t, -CH3)</td>

<td>50.6 (d, -NH-CH-CHj)</td><td>19.9 (t, CHH₂-CH3)</td>

<td>155.3 (3, -COC-NH-)</td><td>146, 3 (a, OSC-NH-)</td><td>27.8 (t, -CH2-CH2-CH2-)</td>

<td></td><td></td><td>4 4,9 (t, -NH-CH2-CH2-)</td>

<td></td><td></td><td>189.1 (s, -OSC-NH-)</td>

Carbamates and thiocarbamates (+) - galantamines

<td>Product</td><td>Surar pattern</td><td>Name</td><td>R</td>

<td></td><td>C.₂4^H.26N₂^ABOUT4 [406,48]</td><td>(+) - galanthannophenyl carbamate</td><td>λο H.</td>

<td> 18</td><td>C2SH29N2O4 [433.53]</td><td>k ^ and ^ 1 ^ Jamman (+) -galanthane.no-Ra-methylbenzyl</td><td>About ch₃</td>

<td> 20</td><td> 026^29(204 [433,53]</td><td>(+) -galanthamine Sa-methylben-2yl carbamate</td><td>0 ch₃Λ^νΧό</td>

<td> 22</td><td>CciHjsNjĄS [422.55]</td><td>(+) - galantamnophenyl thiocarbamate</td><td>Λ-0 H.</td>

<td> 24</td><td>C.₂₂H3 "N₂ABOUT₃S. [402.56]</td><td>(+) - galanthamine-n-butyl thi.carbaniate</td><td>H.</td>

General rule of procedure:

mg (2.62 mmol) of sodium hydride (95%) under argon is added to a solution of 500 mg (1.74 mmol) of (+) - galanthamine in 15 ml of absolute dimethylformamide and stirred for 30 minutes at room temperature. 1.2 equivalents of an isocyanate or a thioisocyanate are then added dropwise thereto, and stirring is continued for 3 hours. The reaction mixture is poured into 150 ml of water and extracted twice with 150 ml of ethyl acetate each time. The organic layers are washed once with 150 ml of water, dried over

190 032 with sodium sulfate and evaporated. The residue was purified by column chromatography (acetone: methanol = 9: 1) to obtain colorless crystals.

DC: toluene: MeOH = 4: 1.

<td>Product</td><td>Usage [% ^ d.theoret.J</td><td>* a "(25^eC, c = 1)</td><td>Melting temperature ['C]</td>

<td></td><td> 84</td><td> +51,9’</td><td> 77-80</td>

<td> 18</td><td> 42</td><td> +55,6’</td><td> 58-60</td>

<td> 20</td><td> 47</td><td> +56,5’</td><td> 55-57</td>

<td></td><td> 56</td><td> +43,5’</td><td> 195-198</td>

<td></td><td> 91</td><td> +42,0’</td><td> 52-55</td>

<td> 22</td><td> 61</td><td> +1(0,4’</td><td> 75-78</td>

<td> 24</td><td> 73</td><td> +31,2’</td><td> 122-125</td>

(-) - epigalaotamine esters with N-other-Boc-amino acid

<td>Product</td><td>Summary formula</td><td>Name</td><td>R</td>

<td> 25</td><td>^C.2e^H.32^N2°6 [444,55]</td><td>(-) - epigalantimine ester with Nt-Boc-glycine</td><td>Λ-BOC H.</td>

<td> 26</td><td> [592,74]</td><td>(-) - epigalanthemine ester with Nt-Boc-L-aspartic acid β-benzyl ester</td><td>hn ^ -^boc^ x / COOBn</td>

<td> 28</td><td>CjatholEOi [592.74]</td><td>(-) - epigallantemin ester with Nt-Boc-D-aspartic acid β-benzyl ester</td><td>✓Ae ^ / COOBn</td>

<td> 29</td><td>C.₂₇H._3BN; Ot, S [518.65]</td><td>ester (-) - epigalline of ttmin with Nt-Boc-L-mthionine</td><td>hn ^^bocJ ^_s.ch₃</td>

<td> 31</td><td>C ^ -HjN-OgS [518.65]</td><td>(-) - epigallanthyl ester with Nt-Boc-D-methionine</td><td>^ t-BOC HN. &gt; ^ ~_s^ ch₃</td>

<td> 32</td><td>C3₁H._3BWELL₆ [534,65]</td><td>(-) - epigallanthin ester with Nt-Boc-L-phenylalanine</td><td> '•^bocIN</td>

General rule of procedure:

800 mg (2.78 moles) of (-) - galanthamm, 1.2 equivalents of t-Boc-amino acid and 876.0 mg (3.34 mmol) of triphenylphosphine are placed in 50 ml of absolute tetrahydrofurin. After adding 581.7 mg (3.34 mmol) of diethyl azodicarboxylate (DEAD), the reaction mixture is stirred for 3 hours at room temperature. After the reaction, the solution was evaporated and the oily residue was purified by column chromatography, first in ethyl acetate to separate a large number of highly flowing by-products, and then in acetone. The oily product expands to a foam on drying under vacuum, which then solidifies in air.

DC: acetone: MeOH = 9: 1.

<td>Product</td><td>Performance [% w / d.theoret ·]</td><td>ao (25'C, c = 1)</td><td>Melting point ['C]</td>

<td> 25</td><td> 93</td><td> -187,3’</td><td> 65-66</td>

<td> 26</td><td> 50</td><td> -146,6’</td><td> 53-56</td>

<td> 26</td><td> 53</td><td> -140,0’</td><td> 63-67</td>

<td> 29</td><td> 78</td><td> -181,7’</td><td> 117-119</td>

<td> 31</td><td> 62</td><td> -140,6’</td><td> 126-130</td>

<td> 32</td><td> 44</td><td> -159,1’</td><td> 67-69</td>

190 032 &amp; apos; H-NMR? CDCl?; δ (ppm)]:

<td>Proton</td><td> 25</td><td> 26</td><td> 28</td>

<td>H.-5</td><td>1.65; m</td><td>1.65; m</td><td>1.60; m</td>

<td>H.-1</td><td>1.85; m</td><td>1.80; m</td><td>1.70; m</td>

<td>Hb-5</td><td>2.18; m</td><td>2.20; m</td><td>2.15; ra</td>

<td>CH3-N-</td><td>2.40; s</td><td>2.35; s</td><td>2.40; s</td>

<td>Hb-1</td><td>2.80; m</td><td>2.80; m</td><td>2.70; m</td>

<td>He-6</td><td>3.05; m</td><td>3.10; m</td><td>3.10; m</td>

<td>H, -6</td><td>3.25 m</td><td>3.25; m</td><td>3.25; m</td>

<td>Hb-8</td><td>3.65; this year</td><td>3.65; this year</td><td>3.60; this year</td>

<td>CHj-O-</td><td>3.80; s</td><td>3.85; s</td><td>3.85; s</td>

<td>Η »-8</td><td>4.05; this year</td><td>4.05; this year</td><td>4.05; this year</td>

<td>H-12a</td><td>4.55; vol</td><td>4.60; vol</td><td>4.55; vol</td>

<td>H-2</td><td>3.90; d</td><td>4.55; d</td><td>4.50; d</td>

<td>H-3</td><td>5.70; d</td><td>5.60; d</td><td>5.70; d</td>

<td>H-4</td><td>6.15; d</td><td>6.05; d</td><td>6.10; d</td>

cd table

<td>H-9</td><td>6.55; d</td><td>6.55; d</td><td>6.55; d</td>

<td>H-10</td><td>6.65; d</td><td>6.65; d</td><td>6.65; d</td>

<td rowspan="6">various H.</td><td>1.45 (s, 9H, 3xCHj-)</td><td>1.45 (s, 9H, 3xCHi-)</td><td>1.45 (s, 9H, 3xCHj-)</td>

<td>1.80 &lt;t, 2H, -OOC-CHj-)</td><td>2.90 (ra, 1H.-OOC-CH-)</td><td>2.90 (m, IH, -OCC-CH-!</td>

<td>5.60 (3, IH, -NH-COO-)</td><td>3.0 (d, 2H, -CHa-COOBn)</td><td>3.0 (d, 2H, -CH2-COOBr.)</td>

<td></td><td>5.10 (3.2H, -OOC-CHj-Ph)</td><td>5.15 (3.2H, -OOC-CH-Ph;</td>

<td></td><td>5.60 (a, IH, -NH-COO-)</td><td>S, 60 &amp; lt; 3.1H, -NH-COO-!</td>

<td></td><td>7.30 (m, 5H, Ph-H)</td><td>7.35 (m, SH,? HK)</td>

<td>Proton</td><td> 29</td><td> 31</td><td> 32</td>

<td>H._and-5</td><td>1.65; m</td><td>1.65; m</td><td>1.65; m</td>

<td>Ha-1</td><td>1.80; m</td><td>1.80; m</td><td>1.80; m</td>

<td>Hb-5</td><td>1.95; m</td><td>1.95; m</td><td>2.20; m</td>

<td>ch₃-n-</td><td>2.10; s</td><td>2.40; s</td><td>2.40; s</td>

<td>Hb-1</td><td>2.85; m</td><td>2.75; m</td><td>2.80; ra</td>

<td>Hb-6</td><td>3.05; m</td><td>3.05; m</td><td>3.00; m</td>

<td>H._and-6</td><td> 3_r25; m</td><td>3.25; m</td><td>3.25; ra</td>

<td>Hb-8</td><td>3.65; this year</td><td>3.60; this year</td><td>3.60; this year</td>

<td>CH₃-ABOUT-</td><td>3.85; s</td><td>3.85; s</td><td>3.85; s</td>

<td>Hj-8</td><td>4.05; this year</td><td>4.05; this year</td><td>4.05; this year</td>

<td>H-12a</td><td>4.60; vol</td><td>4.60; vol</td><td>4.55; vol</td>

<td>H-2</td><td>4.40; m</td><td>4.40; m</td><td>4.50; m</td>

<td>H-3</td><td>5.70; d</td><td> 5,70; 7</td><td>5.50; vol</td>

<td>H-4</td><td>6.15; d</td><td>6.15; d</td><td>6.10; d</td>

<td>H-9</td><td>6.55: d</td><td>6.55: d</td><td>6.55: d</td>

<td>H-10</td><td>6.65; d</td><td>6.65; d</td><td>6.65; d</td>

<td rowspan="6">various H.</td><td>1.45 (3.9H, 3xCHi-)</td><td>1.40 (s, 9H, 3xCEj-)</td><td>1.40 (3.9H, 3xCH₃-)</td>

<td>2.10 (s, 3H, CHi-S-)</td><td>2.10 (s, 3H, CHi-S-)</td><td>3.10 (m, IH, -OOC-CH-)</td>

<td>9 9Π i ™ 9W </td><td>2.15 (m, 2H, -CHz-CHz-S-}</td><td>S.fiOim, 2H-CH_;-Ph)</td>

<td>2.55 (No., 2H, -CH2-CH₂-S-)</td><td>2.50 (m, 2H, -CH2-CH2-S-)</td><td>5.10 (s, 1H, -NH-COO-)</td>

<td>2.60 (m, IH, -OOC-CH-CHi-)</td><td>2.60 (m, IH, -OOC-CH-CH :-)</td><td>6.10-6.30 (m, 5H, Ph-H)</td>

<td>5, 15 (3, IH, -NH-COO-)</td><td>5.15 (3, IH, -NH-COO-)</td><td></td>

190 032 ¹³C-NMR [CDCl₃; ó (ppm)]

<td>C-atom</td><td> 25</td><td> 26</td><td> 28</td>

<td>C-1</td><td>28.1; vol</td><td>29.1; vol</td><td>28.9; vol</td>

<td>C-5</td><td>33.9; vol</td><td>33.9; with</td><td>34.1; vol</td>

<td>CH, -N-</td><td>41.9; q</td><td>41.8; q</td><td>42.0; q</td>

<td>C-4a</td><td>47.9; s</td><td>47.9; s</td><td>48.0; s</td>

<td>C-6</td><td>53.8; vol</td><td>53.8; vol</td><td>53.9; vol</td>

<td>CH₃-ABOUT-</td><td>55.8; q</td><td>55.8; q</td><td>55.9; q</td>

<td>C-8</td><td>60.2; vol</td><td>60.2; vol</td><td>60.3; vol</td>

<td>C-2</td><td>67.4; d</td><td>68.0; d</td><td>68.0; d</td>

<td>C-12a</td><td>87.4; d</td><td>87.4; d</td><td>87.5; d</td>

<td>C-3</td><td>111.1; d</td><td>111.1; d</td><td>111.2; d</td>

<td>C-4</td><td>121.5; d</td><td>121.4; d</td><td>121.5; d</td>

cd table

<td>C-9</td><td>126.6; d</td><td>126.5; d</td><td>126.6; d</td>

<td>C-10</td><td>127.4; d</td><td>128.1; d</td><td>128.3; d</td>

<td>C-8a</td><td>128.9; s</td><td>129.0; s</td><td>129.1; and</td>

<td>C-11b</td><td>132.3; s</td><td>132.3; s</td><td>132.4; s</td>

<td>C-1 la</td><td> 143,7; 3</td><td>143.8; s</td><td>143.8; s</td>

<td>C-II</td><td>146.5; s</td><td>146.5; s</td><td>146.6? s</td>

<td rowspan="11">various C.</td><td>28. L (q, 3xCH ;-)</td><td>28.1 (q, 3xCHj-)</td><td>28.2 (q, 3xCHj-)</td>

<td>42.4 (t, -OOC-CHj-NH '</td><td>36.8 (t, -CHj-)</td><td>36.9 (t, -CHj-)</td>

<td>79.7 (s, -OC (CH₃) j)</td><td>50.0 (d, -CH-)</td><td>50.1 (d, -CH-)</td>

<td>155.6 (3, -OOC-CHj-NH-)</td><td>66.6 (t, -O-CHj-Ph)</td><td>66.7 (t, -O-CH.-Ph)</td>

<td>169.6; (3, -NH-COO-)</td><td> 79,7&lt;₃, -OC (CKj)₃)</td><td>80.0 (3, -OC (CH₃) j)</td>

<td></td><td>128.2-128.4 (d, 4Ar-C)</td><td>128.3-128.5 (d, 4Ar-C)</td>

<td></td><td>131.8 (d, Ar-C)</td><td>135.4 (d, Ax-C)</td>

<td></td><td>135.3 (s, Ar-C)</td><td>155.2 (s, -OOC-CH-)</td>

<td></td><td>155.1 (s, -OOC-CH-)</td><td>170.2; (3, -NH-COO-)</td>

<td></td><td>170.2; (3, -NH-COO-)</td><td>170.5 (3, -COOBn)</td>

<td></td><td>170.4 (3, -COOBn)</td><td></td>

<td>C-atom</td><td> 29</td><td> 31</td><td> 32</td>

<td>C-1</td><td>28.1; vol</td><td>28.1; vol</td><td>2B, 1; vol</td>

<td>C-5</td><td>33.9; vol</td><td>34.0; vol</td><td>33.9; vol</td>

<td>CHj-N-</td><td>41.8; q</td><td>41.9; q</td><td>41.9; q</td>

<td>C-4a</td><td> 48,0; 3</td><td>48.0; s</td><td> 47,9; 5</td>

<td>C-6</td><td>53.8; vol</td><td>53.8; vol</td><td>53.8; vol</td>

<td>CHj-O-</td><td>55.8; q</td><td>55.8; q</td><td>55.8; q</td>

<td>C-8</td><td>60.2; vol</td><td>60.2; c</td><td>60.2; vol</td>

<td>C-2</td><td>67.4; d</td><td>67.7; d</td><td>67.5; d</td>

<td>C-12a</td><td>87.4; d</td><td>87.3; d</td><td>87.4; d</td>

<td>C-3</td><td>111.1; d</td><td>111.1; d</td><td>111.1; d</td>

<td>C-4</td><td>121.5; d</td><td>121.5; d</td><td>121.4; d</td>

<td>C-9</td><td>126.4; d</td><td>126.6; d</td><td>126.4; d</td>

<td>C-10</td><td>128.4; d</td><td>128.3; d</td><td>128.2; d</td>

<td>C-8a</td><td>129.0; s</td><td>129.0; s</td><td> 131,7, 3</td>

<td>C-11b</td><td>132.3, - p</td><td>132.3; s</td><td>132.7; s</td>

<td>C-1 la</td><td>143.8; and</td><td>143.7; s</td><td>143.8; s</td>

<td>C-II</td><td>146.5; s</td><td>146.5; s</td><td>146.5; s</td>

<td rowspan="8">rćins C</td><td>1ς δ tn -a-ru.i</td><td>15 4 In -ς-ęwu</td><td>28 l (q.3xCH, -&gt;</td>

<td>28.1 (q, 3xCHj-)</td><td>28. L (q, 3xCH ;-)</td><td>38.4 (t, -CH; -Ph)</td>

<td>29.6 (t, -CH.-CHj-S-)</td><td>29.8 (t.-CIfc-CłŁ-S-)</td><td>54.5 (d, -CH-)</td>

<td>32.1 [t, -CH; -CH₃-Sl</td><td>32.1 (t, -CH; -CH₂-S-)</td><td>79.7 (s, -OC (CH₃) i)</td>

<td>52.8 (d, -CH-)</td><td>52.8 (d, -CH-)</td><td>126.8-131.8 (d, SAr-C)</td>

<td>79.9 (a, -OC (CHj) j)</td><td>79.8 (3, -OC (CHj) j)</td><td>136.9 (s, Ar-C)</td>

<td>155.2 (s, -OOC-CH-)</td><td>155.1 (s, -OOC-CH-)</td><td>154.9 (s, -OOC-CH-)</td>

<td>171.5 (3, -OOC-NH-)</td><td>171.5 (s, -OOC-NH-)</td><td>171.7 (3, -OOC-NH-)</td>

190 032

(+) - epigalanthamine esters with Ν-ΙΠ-n-Boc-amino acid

<td>Product</td><td>Summary formula</td><td>Name</td><td>R</td>

<td> 27</td><td>C.₃₃H4oN₂0₄ [592,74]</td><td>(+) - epigalanthamine ester with β-benzyl ester of Nt-Boc-L-aspartic acid</td><td>_HN.tB ° C / ^ x / COOBn</td>

<td> 30</td><td>CjiHjgNjOgS</td><td>(+) - epigalanthamine ester with Nt-Boc-methionine</td><td>ην '¹-^βο°</td>

General rule of procedure:

800 mg (2.78 mmol) of (+) - galanthamine, 1.2 equivalents of t-Boc-amino acid and 876.0 mg (3.34 mmol) of triphenylphosphine are placed in 50 ml of absolute tetrahydrofuran. After adding 581.7 mg (3.34 mmol) of diethyl azodicarboxylate (DEAD), the reaction mixture is stirred for 3 hours at room temperature. After the reaction, the solution was evaporated and the oily residue was purified by column chromatography, first in ethyl acetate to separate a large number of highly flowing by-products, and then in acetone. The oily product expands to a foam on drying under vacuum, which then solidifies in air.

<td>Product</td><td>Efficiency [% of theory]</td><td>and_D(25'C, c = l)</td><td>Melting point [° C]</td>

<td> 27</td><td> 75</td><td> +121’</td><td> 130-134</td>

<td>3o</td><td> 41</td><td> +117’</td><td> 112-115</td>

(±) -bromogalanthamine phenyl carbamate (33)

400 mg (1.09 mmol) of crude bromogalanthamine are dissolved in 15 ml of absolute THF, added with 390 mg (3.28 mmol) of phenyl isocyanate under argon and heated to reflux for 24 hours. The reaction mixture is evaporated and the residue is purified by column chromatography (EE: MeOH = 3: 2): 450 mg (85% of theory) of colorless crystals

DC: EE: MeOH = 3: 2 &amp; apos; H-NMR tCDCf3; δ (ppm)]:

1.60 (m, 1H, H._and-5); 2.10 (m, 1H, H._b-5); 2.35 (m, 1H, H._and-1); 2.40 (s, 3H, N-CH₃); 2.70 (br. D, 1H, Hb-1); 3.0 (m, 1H, H._b-6); 3.20 (m, 1H, H._and-6); 3.80 (s, 3H, CH₃ABOUT-); 3.95 (dd, 1H, H-3); 4.30 (br. D, 1H, H._and.8); 4.55 (t, 1H, H-12a); 5.35 (t, 1H, H -2); 5.95 (dd, 1H, H-3); 6.30 (d, 1, H-4); 6.90 (s, 1H, H-10); 7.0 (s, 1H, -OOC-NH-); 7.0-7.30 (m, 5H, Ar-H).

*³C-NMR [CDCl₃; δ (ppm)]:

27.7 (t, Cl); 34.2 (t, C-5); 42.0 (s, N-CH₃); 48.5 (s. C-4a); 53.4 (t, C-6); 56.0 (q, CH₃ABOUT-); 58.6 (t, C-8); 63.6 (d. C-2); 86.6 (d, C-12a); 113.9 (3, C-9); 115.7 (d, C-3); 118.7 (d, C-4); 123.2; 123.5 (d, 2 Ar-C); 127.9 (s, C-8a); 128.9 (d, C-10); 130.3 (s, 3 Ar-C); 133.3 (s, Cl Ib); 138.0 (s, Ar-C); 144.0 (s, Cl Ia); 146.1 (s, C-II); 153.3 (s, -OOC-NH-).

(±) -bromogalanthamine-Ra-methylbenzyl carbamate (34)

510 mg (1.39 mmol) of crude bromogalanthamine are dissolved in 20 ml of absolute THF, 615 mg (4.18 mmol) of R - (+) - α-methylbenzyl isocyanate are added under nitrogen atmosphere and the mixture is stirred for 2 days as it is. boiling against reflux. The reaction mixture was evaporated and the residue was purified by column chromatography (EE: MeOH = 4: 1): 600 mg (84% of theory) of colorless crystals.

DC: EE: MeOH = 4: 1 1 H-NMR [(CDCl₃); δ (ppm)]:

1.40 (s, 3H, CH₃-); 1.55 (m, 1H, H._and-5); 2.0 (m, 1H, H._and-1); 2.05 (m, 1H, H._b-5); 2.35 (s,

3H, N-CH₃); 2.65 (m, 1H, H._b-1); 2.95 (m, 1H, H._b-6); 3.25 (m, 1H, H._and-6); 3.75 (s, 3H, CH₃ABOUT-);

3.95 (d, 1H, H._b-8); 4.25 (d, 1H, H._and-8); 4.50 (t, 1H, H-12a); 4.80 (m, -NH-CH-); 5.20 (s, 1H,

190 032

-NH-CH-): 5.22 (t, 1H, H -2); 5.88 (dd, 1H, H-3); 6.20 (d, 1H, H-4); 6.90 (s, 1H, H-10); 7.30 (v, 5H, Ar-H).

^BC-NMR [(CDCb); δ (ppm)]

22.1 (q, -CH-CH3); 22.1 (s, -CH-CH3); 27.5 (t, C-1); 30.7 (t, C-5); 41.4 (q, N-CH 3); 48.1 (5, C-4a); 52.8 (t, C-6); 55.6 (q, CH3O-); 58.0 (t, C-8); 62.7 (d. C-2); 86.2 (d, C-12a); 113.4 (s, C-9); 115.3 (d. C-4); 123.6; 125.6; 126.8 (d, 3Ar-C); 127.3 (s, Ar, C); 128.1; 129.3 (d, 2 Ar-C); 132.9 (s, C-8a); 143.0 (s, C-11b); 143.7 (s. C-11a); 145.7 (s, C-11); 155.0 (s, -OOC-NH-).

(±) -N-penty ^^ - d ^^ e ^ lob ^^^ ogalantamine (35)

430 mg (2.84 vol) of n-pentyl bromide are added dropwise to a solution of 100 mg (2.84 vol) of crude davetylbromogalantavine under argon at room temperature. The reaction mixture was then stirred under reflux for 2 days. The mixture is evaporated, the oily residue is taken up in 10 ml of water and adjusted to a pH of 10 with concentrated sodium hydroxide, whereby a yellowish precipitate is formed. The precipitate is filtered off with suction, washed with a little water and after drying (becomes sticky in air) it is purified by chromatography (chloroforv: ycetene = 85:15): 510 mg (43% of theory) of a brown-colored oil.

DC: CHCl3: acetone = 85:15 'H-NMR [CDCl3; δ (ppm)]:

0.90 (t, 3H, -CH3); 1.30 (m, 4H, -CH2-CH2-CH3); 1.50 (t, 2H, -N-CH2-); 1.55 (m, 1H, Ha-5); 1.98 (v, 1H, H - 1); 2.15 (v, Hb-5); 2.30 (s, OH); 2.50 (sext, 2H, -CH2-CH2-CH3); 2.65 (dd, 1H, Hb-1); 3.05 (m, 1H, Hb-6); 3.28 (m, 1H, Ha-); 3.80 (s, 3H, CH3O-); 3.95 (br. D, 1H, Hb-8); 4.10 (t, 1H, H -2); 4.35φ, 1H, Ha-8); 4.55 (t, 1H, H-12a); 6.0 (dd, 1H, H-3); 6.10 (d, 1H, H-4); 6.85 (s, 1H, H-10).

ⁿC-NMR [CDCb; δ (ppm)]:

13.9 (q, -CH3); 22.4 (t, -CH2-CH2-CH3); 27.1 (t, -CH2-CH2-CH3); 29.4 (t, N-CH2-CH2-);

29.7 o, C - 1) 3 ^, 1 o, N-CH2-CH22) 48.8 ((, C ^ -) 52.5 φ C-55) 52.3 φ C-6)) 56 .0 (q, CH₃O--) 56.0 (t, C-8); 61.7 (d, C-2); 8: 8.07 (d, C-12a); (s, C-9); (d, C-3); (d, C-4);

127.8 (d, C-10); 1281 (s. C-8a); 1341 (s. C-11b); 144.0 (s, C-11), 145.3 (s, C-11).

O-TBdMs -N-damatylobrovogalantimine (36):

A solution of 200 mg (0.57 goiter) compound 4, 63 mg (0.63 goiter) triethylamine, 38 mg (0.57 goiter) imidizole, 157 mg (1.14 goiter) potassium carbonate and 171 mg (1.14 goiter) ) t-butyldimatylchlorosiline in 15 ml of absolute tatryhydrofurin is heated under reflux for 12 hours. Then it was stripped on a rotary evaporator and the residue was purified by column chromatography (15 g silica gel, circulating medium: CHCl3: MaOH = 95: 5), yielding 30 mg (12% of theory) of oily compound 36.

DC: CHCUMeOH = 9: 1.

1 H-NMR (CDCl 2; δ (ppm)): 0.09 (s, 9H, C (CH3) 3); 0.85 (s, 6H, Si (CH3) 2); 1.82 (dd, 1H, H-9); 1.96-2.14 (m, 2H, H-975); 2.34 (ddd, 1H, H-5 '); 3.31 (ddd, 1H, H-10); 3.51 (ddd, 1H, HW)); 3.80 (s, 3H, OCH3); 3.86 (d, 1H, H-12): 4.46 (b, 1H, H-6); 4.60 (b, 1H, H-4a); 4.22 (d, 1H, H-12 '); 5.98 (dd, 1H, H-8); 6.01 (d, 1H, H-7); 6.88 (s, 1H, H -2).

O-TMS-brovogylantimmy (37):

A solution of 800 mg (2.19 vol.) Of rαcavichal bromogαlantyvin (1), 260 mg (2.40 mmol) of trivatylsilyl chloride and 243 mg (2.40 vol.) Of triethyloyvin in 30 ml of absolute tetrahydrofuran is heated to reflux. After 2 hours, a further 130 mg (1.2 vol) of trivatylsilyl chloride was added dropwise and heated to reflux for 1 hour. The reaction mixture was then evaporated, taken up in a little dichloromethane and purified on a suction column, quantitatively giving light yellow colored crystals of compound 37, having a mp of 228-230 ° C.

DC: CHCUMeOH = 9: 1

ZH-NMR (CDCl3; δ (ppm)): 0.10 (s, 9H, Si (CH3) 3); 1.75 (broad) d, 1H, H-9); 2.00-2.20 (v, 2H, H975); 2.35-2.50 (broad d, 1H, H-5 '); 2.50 (s, 3H, NCH3); 3.0-3.15 (v, 1H, H, 10); 3.50

190 032 (ddd, 1H, H-10 '); 3.85 (s, 3H, OCH3); 4.20 (d, 1H, H-12, J₀₂ 12 ') = 16/0 Hz); 4.25 (b, 1H, H-6); 4.50 (d, 1H, H-12 ', J (12.12 &amp; lt;) = 16.0 Hz); 4.60 (dd, 1H, H-4a); 5.90 (dd, 1H, H-8, s) = 9/8 Hz); 6.00 (dd, 1H, H-7, J (₂, 8 = 9.8 Hz); 6.90 (s, 1H, H -2). '(mO-TBDMS-bromogalanthamine (38):

A solution of 2.0 g (5.46 mmol) (-) - bromogaladtavides (3), 1.23 g (8.20 mmol) tert-butyl pvumatylchlorosilane and 0.61 g (6.00 mmol) triethylamine in 50 ml of tetrahydrofuran is heated for 4 hours at 50 ° C. The tetrahydrofuran is then stripped off in a rotary evaporator, the residue is taken up in a small amount of dihaloetadium and purified over a 1 cm high silica gel column, yielding 1.8 g (69% of theory) of amorphous, ductile compound 38 with a twist value an²⁰[CHCl3] = -66 °.

'. H-NMR (CDCl₃; δ (ppm)): 0.05 (s, 6H, Si (CH3) 2); 0.90 (s, 9H, SiC (CH3) 3); 1.75-1.90 (in,

1H, H-9); 1.95-2.10 (m, 2H, H-5/9 ', J (5.5') = 16.9 Hz); 2.55 (s, 3H, NCH3); 2.65 (dd, 1H, H-5 ', t J (5 5') = 16.9 Hz; 3.00-3.15 (m, 1H, H-10, J (10 10 ') = 12 , 5 Hz); 3.45 (ddd, 1H, H-10 ', J (_IN 10 - = 12.5 Hz); 3.85 (s, 3H, OCH3); 4.15 (dd, 1H, H-6); 4.20 (d, 1H, H-12, J₀2, 129 = 16.0 Hz); 4.45 (d, 1H, H-12 ', J₀2.12 ') = 16.0 Hz); 4.60 (b, 1H, H-4a); 5.59; 6.05 (AB, 2H, H-7/8, J (7.8) = 10.7 Hz); 6.95 (s, 1H, H -2).

O-TBDMS-Galantavine (39):

A solution of 500 mg (1.36 mmol) of galanthine hydrobromide, 137 mg (1.36 mmol) of triethylamine, 224 mg (1.36 mmol) of potassium carbonate and 244 mg (1.63 mmol) of t-butyl-dimethylchlorosilane in 20 ml of absolute tetryhydrofuride and 5 ml of absolute N, N-dimatylformamide are stirred for 4 hours at 60 ° C. The reaction mixture was then evaporated and purified on a 1 cm high silica gel column, yielding 320 mg (59% of theory) of yellow-colored oily compound 39.

DC: CHC1₃: MeOH = 9: 1.

1.H-NMR (CDC (₃; δ φριη)): 0.0); 0.00 (2 * s, 2H, Si (CH₃)₂); 0.12); 0.90 (2 * s, 9H, SiC (CH3) 3); 1.55 (ddd, 1H, H-9, RH 9.99 = 14.2 Hz); 2.00-2.20 (m, 2H, H-5/9 ', J (9.9') = 14.2 Hz); 2.25-2.45 (w, 1H, H-5 '); 2.35 (s, 3H, NCH3); 3.00 (ddd, 1H, H-10, J (0.10) = 11.6Hz); 3.30 (ddd, 1H, H-10 ', J (, oO') = 11.6 Hz); 3.60 (d, 1H, H-12, J_G2, 129 = 14.2Hz); 3.85 (s, 3H, OCH3); 4.15 (d, 1H, H-12 ', J (12 12- = 14.2 Hz); 4.25 (dd, 1H, H-6); 4.55 (dd, 1H, H-4a); 5 .85 (dd, 1H, H-8, J (7.8) = 9.8Hz); 6.10 (d, 1H, H-7, J_r, 8 = 9.8 Hz); 6.50; 6.60 (AB, 2H, Hl / 2, J_G., ₂&gt; = 8.0 Hz).

N-Allyl-C-Pfvetyl-Narvedine (41):

A solution of 100 mg (0.29 mmol) of pewterhydrate (15), 38 mg (0.31 mmol) of allyl bromide, 46 mg (0.31 mmol) of sodium iodide and 85 mg (0.62 mmol) of potassium carbonate in 10 ml of absolute acetone is refluxed for 12 hours. The solution is then evaporated, taken up in 2N hydrochloric acid, made alkaline with concentrated ammonia solution and extracted with hydrogen chloride. The combined organic layers were washed once with a saturated aqueous solution of sodium chloride, dried (Na2SO4), filtered and evaporated to give 50 mg of crude product which was purified by column chromatography (15 g silica gel, recycle: CHCl3: MeOH = 9 : 1), whereby 28 mg (25% of theory) of colorless crystals of compound 41 are obtained.

DC: CHCl3: MeOH = 9: 1

1 H-NMR (CDCl 3; δ (ppm)): 180-2.25 (m, 3H, H-5/9/9 '); 2.75 (ddd, 1H, H-5 '); 3.053.15 (w, 2H, H -10 / 10 '); 3.78 (s, 2H, NCH2); 3.84 (s, 3H, OCH3); 4.00 (d, 1H, H-12); 4.55 (d, 1H, H-12 '); 4.73 (b, 1H, H-4a); 5.18 (dd, 2H, = CH2); 5.90 (dP, 1H, = CH); 6.04 (P, 1H, H-8);

ΛΛ (0 H_T U 1. Π AΏ CA 1U U

1AA, AA “4 (,! ^AAA? aa- / J (6R) -4a, 5,9,10,11,12-hexahyPro-1-bromo-3-methoxy-11 - (ffdylmethyl) -6H-benzofuro [3a, 3,2-ef] [2] bedzoazepine-6 ​​(44):

A solution of 500 mg (1.43 mmol) of dfmethylbromonyrwfdrdy (15), 244 mg (1.43 mmol) of benzyl bromide, 214 mg (1.43 mmol) of sodium iodide and 400 mg (2.90 mmol) of potassium carbonate in 40 ml of absolute acetone is refluxed for 4 hours. Then the solution is evaporated, taken up in 2N hydrochloric acid,

190 032 is made alkaline with concentrated ammonia solution and extracted with trichloromethane. The combined organic layers were washed once with a saturated aqueous sodium chloride solution, dried (Na2SO4), filtered and evaporated to give 350 mg of crude product which was purified by column chromatography (15 g silica gel, recycle: EtOAc: PE = 1 : 1), whereby 280 mg (45% of theory) of colorless crystals of compound 44, mp 135-138 ° C, are obtained.

DC: CHCUMeOH = 9: 1.

1 H-NMR (CDCl 3; δ (ppm)): 1.88 (dd, 1H, H-9); 2.15 (ddd, 1H, H-9 '); 2.55-2.80 (m, 2H, H -5 / 5 '); 2.98-3.38 (m, 2H, H -10 / 10 '); 3.77 (s, 2H, NCH2); 3.86 (s, 3H, OCH3); 4.03 (d, 1H, H-12); 4.31 (d, 1H, H-12 '); 4.74 (b, 1H, H-4a); 6.04 (d, 1H, H-8); 6.93 (s, 1H, H -2); 7.08 (d, 1H, H-7); ? 21-7.46 (m, 5H, Ph).

^I3C-NMR (CDCl3; δ (ppm)): 31.6 (t, C-5); 37.0 (t, C-9); 49.4 (d, C-8a); 51.1 (t, C-10);

54.8 (t, NCH2); 56.1 (q, OCH3); 56.8 (t, C-12); 88.1 (d. C-4a); 114.1 (d, C-1); 116.4 (d, C-8); 127.1; 127.3 (2 d, C-7, Ph-4); 128.3 (d, Ph-1/2/6); 128.7 (2 d, Ph-3/5); 131.7 (s. C-12a); 138.1 (s, C-12b); 143.9 (s, C-3a); 144.6 (d. C-2); 146.6 (s. C-3); 193.3 (s, C-6).

(6R) -4a, 5,9,10,11,12-hexahy acetate &lt;dro-11-acetates 1- 1-bromine-O-methoxy-6H-benzofuro- [3a, 3,2-ef] [2] Benzoazepinol-6 (48):

A solution of 300 mg (0.85 mmol) of compound 4, 258 mg (2.55 mmol) of triethylamine in 15 ml of absolute acetone is slowly added at 0 ° C with 200 mg (2.55 mmol) of acetyl chloride and then overnight. Boil for 24 hours to reflux. The solution is evaporated to dryness, taken up in 2N hydrochloric acid and shaken three times with 30 ml of ethyl acetate. The combined organic layers were washed once with a saturated aqueous sodium chloride solution, dried (Na2SO4), filtered and evaporated. The crude product, which is contaminated with compound 59, was purified by MPLC (60 g silica gel, recycle medium: CHCUMeOH = 1: 1), yielding 190 mg (51% of theory) of the oily substance of compound 48.

DC: chloroform: MeOH = 9: 1 'H-NMR (CDCl 3; δ (ppm)): 1.70 (ddd, 1H, H-9); 1.80 (dd, 1H, H-9 '); 1.95 (ddd, 1H, H-5); 2.03; 2.12 (2s, 6H, 2COCH3); 2.02-2.18 (m, 1H, H-5 '); 2.68 (ddd, 1H, H-10, J (_IN 109 = 14.3 Hz); 3.20 (ddd, 1H, H-10 ', J (_IN 10 = 14.3 Hz); 3.85 (s, 3H, OCH3); 4.33 (d, 1H, H-12, J (i2.129 = 16.9 Hz); 4.55 (b, 1H, H-6, 1 (, 68) = 4.8 Hz); 5, 14 (d, 1H, H-12 ', J_G.2.12- = 16.9 Hz); 5.32 (dd, 1H, H-4a, J (4.5) = J (4a5 ') = 5.2Hz); 5.93 (dd, 1H, H-8, = 100.3 Hz, J (6.8) = 4.8 Hz); 6.15 (d, 1H, H-7,

J (7.8) = 10.3 Hz); 6.92 (s, 1H, H -2).

Alkylation of the Laotamine N-demethylbromog (4): (R7, = /, Z = N)

<td>Substance No .:</td><td>Radical Rg</td><td>Name</td><td>Summary formula:</td>

<td> 49</td><td></td><td>(6R) -4a, 5,9,10,11,12-hexahydro-1-broro-3-m-2 -toxy-11-hexyl-6H-benzofrester [3aa3,2-ef] [2] benzoazepinol-6</td><td>C22H30BrNO3 [436.40]</td>

<td> 52</td><td>\ ^ - CN</td><td>(6R) -4a, 5,9,10,11,12-hexahydr 0-1 ^^^ - 3-iuatoxy-11- (cyanorratyl) -6H-benzofuro [3a, 3,2-ef] ^ Ibenzoazepinol ^</td><td>C._laH.₁₉BrN; O₃ [391,27]</td>

<td> 51</td><td>\ ^ COOEt</td><td>(6R) -4a, 5,9,10,11,12-hexahydro-1-brfTOf-6-hydrfxy-3-ietfxy-6H-benzofuro [3a, 3,2-ef] [2] benzoazepinyl-11- acid ethyl ester fct</td><td>C.₂oH2₄BrNO5 [438.33]</td>

190 032 table continues:

<img file="PL190032B1_D0017.tif" />

(6R) -4a, 5,9,10,11,12-HexaHydro-1-bromo-6-Hydroxy-3-netoxy-6H-benzofu [3a, 3,2-ef] [2 ] benzoazepinyl-11-acetic acid (6R) -4a, 5,9,10,11,12-HexaHydro-1-bromine&gt; -3-roethoxy-11- [2- (1H-isoindoledione-1,3 (2H) yl -2) -ethyl-6H-benzofuro [3a, 3,2-ef]

[2] benzoazepinol-6 (6R) -4a, 5,9,10,11,12-HexaHydro-1-brono-3-netoxy-11- (2-propynyl) -6H-benzofuro [3a, 3,2- ef [22] benzoazepinol-6 (6R) 9,10,11,12-HeksaHydro-1-brono-3 ~

-ethoxy-11- ^ -vfolinoethyl) -6H-benzofuro [3a, 3,2-ef [22] benzoazepieol-6 (6R) -4a, 5,9,10,11,12-hexahydro-1-bro: mo -3-methoxy-11- (3-diumtylammopropyl) -6H-benzofuro (3a, 3,2-ef] ^ benzoazepinol-S (6R) -4a, 5,9,10,11,12-hexahy &lt;^ : c &amp; lt; ^ - 1-bromo ^ -3-methoxy-11- (S-piperidinopropyl) -6H-benzofuro [3a, 3,2-ef] [2] benzoazepinol-6 (6R) -4a, 5.9, 10,11,12-htxahydro-1-brono-3-methoxy-11- (2-plrollcyeottylo) -6H-beezo £ uro [3a, 3,2-ef] [Z] btezoaztpi.eol-6 (6R) - 4a, 5,9,10,11,12-hexah; ^ &lt;^:! ^ I: ^^ 1-bromine: ^ - 3-methoxy-11 - ^ -propenyl) -6H-benzofuro [3a, 3,2- ^ e: ^] [2] benzoazepinol-e (6R) -4a., 5,9,10,1L, 1Z-htxahydro-1-brono-3-methoxy-1- (phenylmethyl) -eH-benzofuro- [3a , 3,2-ef] [2] btezoaztplnol-6 ^C.18^H.21^BrN2^ABOUT4 (409229]

CjeHzsBrNiOs

[525,411

CC-UzoBrNCO

[390,28]

[465,33]

AT 20^1Z28^B

[437,39]

0224^13(11^^^235

[477,75]

C2oH2oBrN20 ;;

[449,40]

C.₁₉H »21: 1 (05 [392.30]

C2oH2o1lrN-3

[442,33]

Method:

A mixture of 500 mg (1.42 mmol) of N-desmethylbromogalanthamine (4), 391 mg (2.84 mmol) of potassium carbonate and 272 mg (1.70 mmol) of potassium iodide is carefully ground in a porcelain mortar and ground. Then this mixture in 20 ml of absolute acetone is mixed with 1.2 equivalents of a halide reagent and heated to reflux. After completion of the reaction (DC), the reaction mixture is evaporated, the residue is taken up in 100 ml of 2N hydrochloric acid, washed with ethyl acetate, made alkaline with concentrated aqueous ammonia solution and either the precipitate is filtered off under reduced pressure or it is extracted three times with 30 ml of ethyl acetate each time. The precipitate is dried at 50 ° C / 50 mbar, the combined organic layers are washed once with a saturated aqueous sodium chloride solution, dried (Na2SO4₄), activated carbon), filtered and evaporated. Further purification was carried out by column chromatography (15 g silica gel, circulating agent: CHCl2 -&gt; CHCl2 MeOH = 9: 1).

DC: CHCl3: MeOH = 9: 1.

190 032

<td rowspan="3">Subs- dance no .:</td><td rowspan="3">Reagent</td><td colspan="2" rowspan="3">Time reaction- tions</td><td>Performance</td><td rowspan="3">Tt. :</td>

<td></td>

<td></td>

<td> 49</td><td>1-bromohexane</td><td> 24</td><td>h</td><td>67% oily substance</td><td> -</td>

<td> 52</td><td>chloroacetic acid nitrile</td><td> 2</td><td>h</td><td>89% colorless crystals</td><td>150-153'C</td>

<td> 51</td><td>ethyl chloroacetate</td><td> 1</td><td>h</td><td>amount oily substance</td><td> -</td>

<td> 53</td><td>chloroacetic acid amide</td><td> 1</td><td>h</td><td>90% colorless crystals</td><td>164-165 ° C</td>

<td> 55</td><td>N- (2-bromoethyl) phthalimide</td><td> 48</td><td>h</td><td>Quantitative yellow crystals</td><td>88-89'C</td>

<td> 50</td><td>propargyl bromide</td><td> 4</td><td>h</td><td>57% oily substance</td><td> -</td>

<td> 54</td><td>N- (2-chloroethyl) morpholine * HCl</td><td> 24</td><td>h</td><td>98% oily substance</td><td></td>

<td> 56</td><td>(3-chloropropyl) dimethylamine * HCl</td><td> 72</td><td>h</td><td>46% oily substance</td><td></td>

<td> 58</td><td>N- (3-chloropropyl) piperidine * HCl</td><td> 30</td><td>h</td><td>85% oily substance</td><td> —</td>

<td> 57 42 45</td><td>N- (2-chloroethyl) -pyrrolidine * HCl allyl bromide benzyl bromide</td><td> 24</td><td>h</td><td>25% oily substance 80% 92%</td><td></td>

'H-NMRdCDCbt * in DMSO-dd; δ (ppm)):

<td>H- atom</td><td> 49</td><td> 52</td><td> 51</td><td> 53</td><td> 55</td>

<td>H-9</td><td>1.55 (d)</td><td>1.75 (ddd)</td><td>1.60 (ddd)</td><td>1.65 (ddd)</td><td>1.40 (dd)</td>

<td>H-9 '</td><td>2.05 (ddd)</td><td>2.05 (ddd)</td><td> 1,90-2,05</td><td> 1,90-2,10</td><td> 1,90-2,30</td>

<td>H-5</td><td>2.00 (dd)</td><td> 2,55-2,75</td><td> 1,90-2,05</td><td> 1,90-2,10</td><td> 1,90-2,30</td>

<td>H-5 '</td><td>2.65 (dd)</td><td> 2,55-2,75</td><td> 2,20-2,30</td><td>2.70 (ddd)</td><td>2.65 (ddd)</td>

<td>H-10</td><td>3.05 (dd)</td><td>3.10 (ddd)</td><td>2.65 (dd)</td><td>3.10 (ddd)</td><td>2.95 (dd)</td>

<td>H-10 '</td><td>3.30 (ddd)</td><td>3.25 (ddd)</td><td>3.15 (dd)</td><td>3.40 (ddd)</td><td>3.25 (dd)</td>

<td>NCH₂</td><td>2.50 (dd)</td><td>3.65 (s)</td><td>3.40 (s)</td><td>3.20 (d)</td><td> 1,90-2,30</td>

<td>oh₃</td><td>3.85 (s)</td><td>3.85 (s)</td><td>3.80 (s)</td><td>3.85 (s)</td><td>3.75 (s)</td>

<td>H-12</td><td>3.95 (d)</td><td>4.00 (d)</td><td>4.12 (d)</td><td>4.00 (d)</td><td>3.60 (d)</td>

<td>H-12 '</td><td>4.40 (d)</td><td>4.30 (d)</td><td>4.45 (d)</td><td>4.40 (d)</td><td>4.35 (d)</td>

<td>H-6</td><td>4.15 (dd)</td><td>4.15 (b)</td><td>4.16 (s)</td><td>4.15 (b)</td><td>4.05 (b)</td>

<td>H-4a</td><td>4.60 (b)</td><td>4.60 (b)</td><td>4.60 (b)</td><td>4.60 (b)</td><td>4.50 (b)</td>

<td>H-8</td><td>6.00; 6.10 (AB)</td><td>6.05 (b)</td><td>6.00 (dd)</td><td>6.05 (s)</td><td>6.10 (d)</td>

<td>H-7</td><td>6.00; 6.10 (AB)</td><td>6.05 (b)</td><td>6.10 (dd)</td><td>6.05 (s)</td><td>5.75 (dd)</td>

<td>H-2</td><td>6.90 (s)</td><td>6.90 (s)</td><td>6.90 (s)</td><td>6.90 (s)</td><td>7.00 (s)</td>

table continued H (Hz)

0.90 (t, 3H, O-CH₃); 1.20-1.35 (m, 6Η, γ / δ / ε-CH_;): 1.45-1.60 (m, 2Η, β-CH_WITH) (12.12 ') -16.9L, 30 (t, 3H,

OCH2CH3);

4.20 (a, 2H,

Oh₂CH₃)

5.70; 6.95 (2 * b, 2 * 1H lists DzO,

NH₂) (9,9')=14,0 (10,10')=13,6 (12,12')=15,8 (7,8)=10,3 (9,9')=13,4 (12,12')=16,1 (5,5)=16,2 (9,9')=16,9 (10,10')=11,6 (12,12')=16,0

1.90-2.30 (m 6H, H-5/9 '/ NCH₂-CH₂) ;

7.80-7.90 (m 4H, Ph) (6.8) = 4.5 (7.8) = 9.8

190 032

<td>H- atom</td><td> 50</td><td> 54</td><td> 56</td><td> 58</td><td> 57</td>

<td>H-9</td><td>1.70 (ddd)</td><td> 1,48-1,63</td><td>1.55 (ddd)</td><td>1.45 (d)</td><td>1.55 (ddd)</td>

<td>H-9 '</td><td> 1,95-2,01</td><td> 1,92-2,13</td><td>2.00 (ddd)</td><td>1.95 (dd)</td><td> 1,80-2,10</td>

<td>H-5</td><td> 1,95-2,01</td><td> 1,92-2,13</td><td> 1,65-1,85</td><td>1.95 (dd)</td><td> 1,80-2,10</td>

<td>H-5 '</td><td>2.63 (dd)</td><td> 2,45-2,95</td><td>2.65 (dd)</td><td>2.58 (dd)</td><td> 2,60-2,85</td>

<td>H-10</td><td> 3,10-3,35</td><td>3.12 (ddd)</td><td>3.10 (ddd)</td><td>3.00 (ddd)</td><td>3.15 (ddd)</td>

<td>H-10 '</td><td> 3,10-3,35</td><td>3.35 (ddd)</td><td>3.30 (ddd)</td><td>3.20 (ddd)</td><td>3.35 (ddd)</td>

<td>nch₂</td><td>3.48 (d)</td><td> 2,45-2,95</td><td>2.50 (dt)</td><td> 2,45(0</td><td> 2,60-2,85</td>

<td>OH</td><td>3.83 (s)</td><td> 3,82(3)</td><td>3.85 (s)</td><td>3.80 (s)</td><td> 3,80(3)</td>

<td>H-12</td><td>3.98 (d)</td><td>4, 01 (d)</td><td>3.95 (d)</td><td>3.95 (d)</td><td>4.00 (d)</td>

<td>H-12 '</td><td>4.36 (d)</td><td>4.39 (d)</td><td>4.45 (d)</td><td>4.35 (d)</td><td>4.40 (d)</td>

<td>H-6</td><td>4.18 (b)</td><td>4.12 (dd)</td><td>4.15 (dd)</td><td>4.13 (b)</td><td>4.13 (dd)</td>

<td>H-4a</td><td>4.59 (b)</td><td>4.59 (b)</td><td>4.60 (b)</td><td>4.58 (b)</td><td>4.60 (b)</td>

<td>H-8</td><td>6.02 (dd)</td><td>6, 02 (dd)</td><td>6.10 (d)</td><td>6, 08 (d)</td><td>6.00; 6.08 (AB)</td>

<td>H-7</td><td>6.08 (dd)</td><td>6.09 (d)</td><td>6.00 (dd)</td><td>5.98 (dd)</td><td>6.00; 6.08 (AB)</td>

<td>H-2</td><td>6, 92 (p&gt;</td><td>6.90 (s)</td><td>6.85 (s)</td><td> 6,90(3)</td><td>6.90 (s)</td>

<td>gave-</td><td>2.29 (t, 1H,</td><td>2.45-2.95 (m,</td><td>1.65-1.85 (m,</td><td>1.35 (ddd, 2H,</td><td>1.80-2.10 (m,</td>

<td>six H.</td><td> =^CH»^H.("CH, M:; H2)^=:</td><td>9H, H-5 '</td><td>3H, H-5, N-CH2-</td><td>Pi] p-4); 1, S5</td><td>6Η, Η - 59 '/ Ρχγ</td>

<td></td><td>= 2.4 Hz)</td><td>/ NCHCb / morf-</td><td>-CH₂) ;2,18;</td><td>(ddd, 4H, Pip-</td><td> -3/4);2,60-</td>

<td></td><td></td><td>-2/6); 3.72 (t,</td><td>2.22 (2 * s, 6H,</td><td>3/5; 1.68 (ddd,</td><td>2.85 µm, 9H, H-</td>

<td></td><td></td><td>4H, rm&gt; of-3/5,</td><td>N (CHak); 2.30</td><td>2H, N-CH2-CH2);</td><td>5 * / NCH2CH2 /</td>

<td></td><td></td><td>J (moo / s, mo2 / 6) =</td><td>(t, 2H, CH₂-</td><td>2.28 (dd, 2H,</td><td>Pir-2/5</td>

<td></td><td></td><td>= 4.8 Hz</td><td>NM &lt;e₂)</td><td>CH₂- e.g. p; 2.32 (dd, 2H)</td><td></td>

<td>, T ,. ~</td><td>(= CH, MCH₂)</td><td>(mo3, / 5, mo2 / 6)</td><td> (12,12')=16,0</td><td></td><td> (9,9' )=13,4</td>

<td>(Hz)</td><td> =2,4</td><td> =4,8</td><td></td><td> 7,3</td><td> (10,10')=12,5</td>

<td></td><td> (6,8)=4,5</td><td> (10,10') =13,4</td><td></td><td> (5,5')=10,6</td><td> (12,12')=16,0</td>

<td></td><td> (6,7)=1,3</td><td> (12,12')=16,1</td><td></td><td> (6, 8)=4, 6</td><td></td>

<td></td><td> (7,8)=10,0</td><td></td><td></td><td> (7, 8) =10, 4</td><td></td>

<td></td><td> (9,9')=13,4</td><td></td><td></td><td> (10,10')=14,3</td><td></td>

<td></td><td> (12,12' )=15,4</td><td></td><td></td><td> (12,12')=16,0</td><td></td>

<td>H- atoin</td><td> 42</td><td> 45</td>

<td>H-9</td><td>1.58 (ddd)</td><td>1.55 (ddd)</td>

<td>H-9 '</td><td> 1,90-2,10</td><td>2.01 (ddd)</td>

<td>H-5</td><td> 1,90-2,10</td><td> 2,60-2,73</td>

<td>H-5 '</td><td> 2,15-2,25</td><td> 2,60-2,73</td>

<td>H-10</td><td>2.65 (ddd)</td><td>3.50 (ddd)</td>

<td>H-10 '</td><td> 3,02-3,29</td><td>3.27 (ddd)</td>

<td>NCH₂</td><td>3.18 (d)</td><td>3.70 (s)</td>

<td>OCH3</td><td>3.82 (s)</td><td>3.82 (s)</td>

<td>H-12</td><td>3.92 (d)</td><td>4.00 (d)</td>

<td>H-12 '</td><td>4.35 (d)</td><td>4.34 (d)</td>

<td>H-6</td><td>4.11 (d)</td><td>4.14 (b)</td>

<td>H-4a</td><td>4.59 (b)</td><td>4.64 (b)</td>

<td>H-8</td><td>6.00 (dd)</td><td>6.02 (ddd)</td>

<td>H-7</td><td>6.09 (d)</td><td>6.14 (dd)</td>

<td>H-2</td><td>6.90 (s)</td><td>6.90 (s)</td>

<td>gave-</td><td>5.16 (dd, 2H,</td><td>7.22-7.35 (m,</td>

<td>six H.</td><td>= CH₂); 5.88 (ddt), 1H, = CH)</td><td>5H, Ph)</td>

<td>J (A, B)</td><td>(NCH₂, = CH)</td><td> (6,8)=4,8</td>

<td>(Hz)</td><td> =7,0 (9,9' )=14,0 (12,12')=16,5</td><td> (7,8)=10,3 (9,9' )=13,2 (10,10' )=13,0 (12,12' )=15,9</td>

190 032

1OC-NMR (CDC13 [* in DMSO-d6]; δ (ppm)):

<td>c- atom</td><td> 49</td><td> 52</td><td> 51</td><td> 53</td><td> 54</td>

<td>C-5</td><td>29.7 (t)</td><td>29.2 (t)</td><td>29.3 (t)</td><td>29.4 (t)</td><td>(t)</td>

<td>C-9</td><td>33.1 (t)</td><td>34.5 (t)</td><td>33.6 (t)</td><td>33.9 (t)</td><td>(t)</td>

<td>C-8a</td><td> 48,8(3)</td><td> 48,3(3)</td><td>48.4 (s)</td><td>48.3 (s)</td><td>(s)</td>

<td>C-10</td><td>51.5 (t)</td><td>51.6 (t)</td><td>51.2 (t)</td><td>51.8 (t)</td><td>(t)</td>

<td>Nch₂</td><td>52.5 (t)</td><td>53.7 (t)</td><td>53.4 (t)</td><td>51.8 (t)</td><td>(t)</td>

<td>OCH3</td><td>55.9 (q)</td><td>56.1 (q)</td><td>55.7 (q)</td><td>55.8 (q)</td><td>(q)</td>

<td>C-12</td><td>56.0 (t)</td><td>57.2 (t)</td><td>56, 3 (t)</td><td>56.9 (t)</td><td>(t)</td>

<td>C-6</td><td>61.7 (d)</td><td>61.6 (d)</td><td>61.3 (d)</td><td>61.3 (d)</td><td>(d)</td>

<td>C-4a</td><td>88.6 (d)</td><td>88.6 (d)</td><td>88.3 (d)</td><td>88.3 (d)</td><td>(d)</td>

<td>Cl</td><td> 114,3(5)</td><td>113.9 (s)</td><td> 113,9(3)</td><td>114.2 (s)</td><td>(s)</td>

<td>C-8</td><td>115.5 (d)</td><td>115.8 (d)</td><td>115.4 (d)</td><td>115.5 (d)</td><td>(d)</td>

<td>C-2</td><td>126.7 (d)</td><td>126.3 (d)</td><td>126.2 (d)</td><td>125.6 (d)</td><td>(d)</td>

<td>C-7</td><td>127.8 (d)</td><td>128.5 (d)</td><td>127.8 (d)</td><td>128.4 (d)</td><td>(d)</td>

<td>C-12a</td><td>128, l (s)</td><td>130.2 (s)</td><td>127.3 (s)</td><td> 126,5(3)</td><td>(s)</td>

<td>C-12b</td><td> 134,1(3)</td><td>134.0 (s)</td><td>133.7 (s)</td><td>133.7 (s)</td><td>(s)</td>

<td>C-3a</td><td>144.0 (s)</td><td>144.5 (s)</td><td>143.9 (s)</td><td> 144,2(3)</td><td>(s)</td>

<td>C-3</td><td>145.3 (s)</td><td>145.6 (s)</td><td>145.2 (s)</td><td>145.2 (s)</td><td>(s)</td>

<td>gave-</td><td>13.9 (q, ω-CH});</td><td>115.5 (s, CN)</td><td>13.8 (q, &lt;XH₂ęH₃);</td><td>173 (s, CO)</td><td></td>

<td>six H.</td><td>22.5 (t, e-CH₂);</td><td></td><td>60.3 (t,</td><td></td><td></td>

<td></td><td>26.9; 27.4 (2 * t,</td><td></td><td>OCH2CH3);</td><td></td><td></td>

<td></td><td>γ / δ- ^ ζ);</td><td></td><td>170.3 (s, CO)</td><td></td><td></td>

<td></td><td>31.6 (t, - 0¾)</td><td></td><td></td><td></td><td></td>

<td>C-</td><td> 56</td><td> 58</td><td></td><td> 57</td><td></td>

<td>atom</td><td></td><td></td><td></td><td></td><td></td>

<td>C-5</td><td>29.4 (t)</td><td>29.4 (t)</td><td>29.6 (t)</td><td>(t)</td><td>(t)</td>

<td>C-9</td><td>32, 8 (t)</td><td>32.8 (t)</td><td>33.2 (t)</td><td>(t)</td><td>(t)</td>

<td>C-8a</td><td>48.6 (s)</td><td>48.5 (s)</td><td>48.9 (s)</td><td> (3)</td><td>(s)</td>

<td>C-10</td><td>51.5 (t)</td><td>51.1 (t)</td><td>52.5 (t)</td><td>(t)</td><td>(t)</td>

<td>NCH2</td><td>55.6 (t)</td><td>55.68 (t)</td><td>54.7 (t)</td><td>(t)</td><td>(t)</td>

<td>OCH3</td><td>55.7 (q)</td><td>55.7 (q)</td><td>56.0 (q)</td><td>(q)</td><td>(q)</td>

<td>C-12</td><td>57.3 (t)</td><td>56.8 (t)</td><td>55.6 (t)</td><td>(t)</td><td>(t)</td>

<td>C-6</td><td>61.4 (d)</td><td>61.4 (d)</td><td>61.7 (d)</td><td>(d)</td><td>(d)</td>

<td>C-4a</td><td>88.3 (d)</td><td>88.3 (d)</td><td>88.7 (d)</td><td>(d)</td><td>(d)</td>

<td>C-1</td><td> 114,0(8)</td><td>113.9 (s)</td><td>114.3 (s)</td><td>(s)</td><td>(s)</td>

<td>C-8</td><td>115.4 (d)</td><td>11S, 4 (d)</td><td>115.7 (d)</td><td>(d)</td><td>(d)</td>

<td>C-2</td><td>126.6 (d)</td><td>126.4 (d)</td><td>126.3 (d)</td><td>(d)</td><td>(d)</td>

<td>C-7</td><td>127.6 (d)</td><td>127.6 (d)</td><td>128.1 (d)</td><td>(d)</td><td>(d)</td>

<td>C-12a</td><td>127.7 (s)</td><td>127.8 (s)</td><td>127.6 (s)</td><td>(s)</td><td>(s)</td>

<td>C-12b</td><td>133.8 (s)</td><td>133.8 (s)</td><td> 134,1(0</td><td>(s)</td><td>(s)</td>

<td>C-3a</td><td>143.8 (s)</td><td>143.7 (s)</td><td>144.3 (s)</td><td>(s)</td><td>(s)</td>

<td>C-3 further H.</td><td>145.1 (s) 25.3 (t, N-CHiCH; 45.0 (q, N (Ch7) 2); 53.4 (t, CH₂-N ^^ 2)</td><td>145.1 (s) 23.9; 24.2 (2 * t, NCH2CH2, Pip-4); 25.3 (t, Pip-3/5); 50.2 (t, CH2-Np_no); S4.1 (t)</td><td>145.5 (s) 23.2 (t, Pir-3/4); 53.7 (t, CH₂-No_lc); 54.4 (t, Pir-2/5)</td><td>(s)</td><td>(s)</td>

190 032

Acylow-anio N-dz-methylbromogalantamma (4): (R7 = /, Z = N)

Substance No .:

Rodtu-k Rs

Name ybf ° CH₃

ABOUT

ΊΓ ^ ° '(6R) -4a, 5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-acetyl-6H-benzofuro [3a, 3,2-ef] [2] benzoazepinol -6 (6R) -4a, 5,9,10,11,12-hexahydro-1-bromo-6-hydroxy-3-methoxy-6H-bennoofuo [3a, 3,2-ef] [2] benzoazepinyl-11 ethyl α-ketoacetate

Summary formula: C.głHoBzNO

[334.27] ϋ2 (! Η22θ ^ -ΝΟ (;

[452,: 331 (6R) -4a, 5,9,10,11,12-hexahydro-1-bromo-6-CnHaBrNO,

methyl-hydroxy-3-methoxy-6H-benzofu.ro [3a, 3, 2-ef] [441.22] ^ [benzoazepinyl-H-carboxylate methyl (6R) -4a, 5,9,10,11,12- hexahydro ~ 1-bromine 3-6-C_PLNH.₂4BrNO₆

-hydroxy-3-methoxy-6H-benzofuro [3a, 3,2-ef] [446.34]

[2] benzoazepinyl-11-methyl ketobutyrate

C15H31 (6R) -4a, 5,9,10,11,12-hexahydro-1-bromo-3-CjiHeBrNO, -matoxy-11- (1-ketohexadecyl) -6H-benzofuro [590,65] [3a, 3 , 2-ef] [2] benzoazepinol-6

A solution of 500 mg (1.42 mmol) of N-dimethylbromegalanthamine (4) and 156 mg (1.56 mmol) of triethylammonium in 20 ml of absolute acetone was added with 0.9 eq of an acid halide and refluxed. After completion of reaction (DC) the mizezau reaction is evaporated. The residue is taken up in 100 ml of 2N hydrochloric acid, washed with a little acetone, made alkaline with concentrated aqueous ammonia solution and either the precipitate is filtered off under vacuum or extracted three times with 30 ml of ethyl acetate each time. The precipitate is dried at 50 ° C / 50 mbar, the combined organic layers are washed once with saturated aqueous sodium chloride solution, dried (NaSO), activated carbon), filtered and evaporated. Further purification was carried out by column chromatography (7 g of silica gel, circulating agent: CHCl3: MeOH = 9: 1).

DC: CHCl3: MeOH = 9: 1.

<td>Subs- dance no .:</td><td>Reagent</td><td>Time reaction-^cjl</td><td>Performance</td><td>Tt. :</td>

<td> 59</td><td>acetyl chloride</td><td>3 h</td><td>84% yellow crystals</td><td>76-78'C</td>

<td> 60</td><td>ethyl oxalate chloride</td><td>1.5 h</td><td>54% yellow crystals</td><td>66-69 ° C</td>

<td> 62</td><td>methyl chloroformate</td><td>1 h</td><td>93% colorless crystals</td><td>158-159'C</td>

<td> 61</td><td>mtyl succinate chloride</td><td>1.5 h</td><td>35% colorless crystals</td><td>53-57Ύ</td>

<td></td><td>wego</td><td></td><td></td><td></td>

<td> 49</td><td>palmtoyl chloride</td><td></td><td> 99%</td><td></td>

190 032 * H-NMR (CDCl₃[* in DMSO-d₆]; δ (ppm)):

<td>H- atom</td><td> 59</td><td> 60</td><td> 62*</td><td> 61</td><td> 64</td>

<td>H-9</td><td>1.79 (ddd)</td><td>1.92 (dd)</td><td> 1,60-1,90</td><td>1.75 (ddd)</td><td>1.74 (ddd)</td>

<td>H-9 '</td><td>1.90 (ddd)</td><td>2.03 (ddd)</td><td> 1,60-1,90</td><td>1.94 (ddd)</td><td>2.24 (ddd)</td>

<td>H-5</td><td>1.97 (dd)</td><td>2.25 (ddd)</td><td>2.05 (dd)</td><td>2.06 (dd)</td><td>1.95 (ddd)</td>

<td>H-5 '</td><td>2.05 (dd)</td><td>2.68 (dd)</td><td>2.40 (dd)</td><td> 2,45-2,70</td><td>2, 45 (ddd)</td>

<td>H-10</td><td>2.67 (ddd)</td><td>3.38 (ddd)</td><td>3.40 (dd)</td><td>2.98 (ddd)</td><td>2.68 (ddd)</td>

<td>H-10 '</td><td>3.20 (ddd)</td><td>3.68 (ddd)</td><td>3.90 (dd)</td><td>3.22 (ddd)</td><td>3.20 (ddd)</td>

<td>oh₃</td><td>3.83 (s)</td><td>3.85 (s)</td><td>3.75 (s)</td><td>3.80 (s)</td><td>3.84 (s)</td>

<td>H-12</td><td>4.33 (d)</td><td> 4,25-4,45</td><td>4.20 (d)</td><td>4.33 (d)</td><td>4.31 (d)</td>

<td>H-12 '</td><td>5.13 (d)</td><td>5.20 (d, conf_AND), 5.75 (d, conf_B);</td><td>5.20 (d)</td><td>5.22 (d)</td><td>5.13 (d)</td>

<td>H-6</td><td>H-6</td><td>4.13 (b)</td><td>4.10 (b)</td><td>4.12 (dd)</td><td>4.13 (dd)</td>

<td>H-4a</td><td>4.60 (b)</td><td>4.45 (b, conf_AND), 4.60 (b, conf_s);</td><td>4.50 (b)</td><td>4.60 (dd)</td><td>4.60 (b)</td>

<td>H-8</td><td>6, 03 (dd)</td><td> 5,90-6,15</td><td>5.85 (dd)</td><td>6.02 (dd)</td><td>6, 05 (dd)</td>

<td>H-7</td><td>5.90 (d)</td><td> 5,90-6,15</td><td>6.00 (dd)</td><td>5.96 (d)</td><td>5.91 (d)</td>

<td>H-2 . table</td><td>6.94 (s)</td><td>6.90 (s)</td><td>6.85 (s)</td><td>6.90 (s)</td><td>6.90 (s)</td>

<td> 1- 2</td><td>., II (s, 3H,</td><td>4.25-4.45 (m,</td><td>3.55 (s, 3H,</td><td>2.45-2.70 (m,</td><td>0.89 (t,? -CHj);</td>

<td colspan="2">HOCHj,; 2.30 (b, 1H lists D₂Oh oh)</td><td>3H, H "12tonf. A / B / COOCH₂); l, 10 (t, 3H, OCH₂CH₃)</td><td>COOCHj)</td><td>5H, H-5 / COCH₂CH₂); 3.65 (S, 3H, COOCHj)</td><td>1.18-1.40 (m, 22H, CH₂^&lt;4¹⁴¹); 1.45-1.67 (m, 4H, CH₂^(WITH³'); 2.18 (t, 2H, COCH₂)</td>

¹³C-NMR (DMSO-d₆); δ (ppm) compound 59: 29.6 (q, COCH3); 30.3; 36.1 (t, Ck_hef_orrner a / b); 37.9; 43.4 (t, C-9 conformer a / b), 48.8 (t, C-1 conformer A / B) and 48.4 (s, C-8a); 51.4; 55.8 (t, C-12 conformer a / b), 55.9 (q, OCH₃); 86.3; 86.5 (d, C-4 conformer a / b); 115.4 (d, C-8); 126.3; 126.4 (d, C -2 conformer a / b); 127.7 (s, C-1); 128.5 (s, C-12a); 128.7 (d, C-7); 133.2; 133.4 (s, C-12 conformer a / b), 144.0; 144.3 (s, C-13former a / b); 146.6; 147.0 (s, C-3 conformer a / b), 168.9; 169.2 (s, COconformer A / B),

Compound 62: 30.2; 30.5 (t, C -5 conformer A / B); 36.5; 37.3 (t, C-9 conformer A / B), 44.7, 45.0 (t, C-1 conformer A / B) and 48.4 (s, C-8a); 49.7; 50.4 (t, C-12 conformer a / b); 52.2 (q, COÓCH3); 55.7 (q.0CH3); 59.7 (d, C-6); 86.8 (d. C-4a); 111.8; 112.1 (s, C-1 conformer a / b); 115.2 (d, C-8); 125.8; 126.0 (d, C -2 conformer A / b); 128.1; 128.3 (s, C-12a conformer A / B); 128.5; 128.6 (d, C -7 A / B conformer); 133.1 (s, C-12b); 143.9 (s. C-3a); 146.4 (s. C-3); 155.2 (s, CO).

Racemic N-Boc-bromogalanthamine (63):

To a solution of 1.0 g (2.44 mmol) of racemic N-demethibromogalanthamine (4) and 620 mg (2.84 mmol) of di-IU-is.-butyl pyrocarbonate in 50 ml of absolute tctrahydrofurun, 286 mg (2.84 mmol) of triethylamine and heated to reflux against the reflux. After 15 minutes, the tetrahydrofuran is stripped off in a rotary evaporator and the residue is taken up in 50 ml of ethyl acetate. The organic layer was washed once with portions of 2N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried (Na₂SO4) and evaporated, thereby obtaining quantitatively colorless crystals of compound 63.

190 032

DC: EtOAc: MeOH = 4: 1 'H-NMR (CDCl 3; δ (ppm): 1.45 (s, 9H, t-Bu); 1.80 (dd, 1H, H, 9); 2.05 (dd, 1H, H, 9 '); 2.30 (ddd, 1H, H-5); 2.65 (ddd, 1H, H-5'); 3.30 (ddd, 1H, H-10); 3 , 85 (s, 3H, OCH3): 4.054.30 (m, 2H, H-6/10 '); 4.10 (d, 1H, H-12, J (₁2, j2 ') = 15.1 Hz; 4.60 (dd, 1H, H-4a); 5.25 (d, 1H, H-12 ', J (2, and 2') = 15.1 Hz); 5.90 (d, 1H, H-8, J (7.8) = 8.9 Hz); 6.00 (dd, 1H, H-7, J (78) = 8.9 Hz); 6.90 (s, 1H, H -2).

Modifications of N-substituted galanthamine derivatives

<td>Subs- dance no</td><td>Educt no</td><td>) educt</td><td>R «product</td><td>R1</td><td>Me- toda</td>

<td> 66</td><td> 61</td><td>'γ ^ χ-ΌΟΟΜβ ABOUT</td><td>ABOUT</td><td>Br</td><td>AND</td>

<td> 67</td><td> 60</td><td>x ^ xCOOEt ABOUT</td><td>xyCOOH ABOUT</td><td>Br</td><td>AND</td>

<td> 71</td><td> 51</td><td>χ / COOEt</td><td>x ^ xCOOH</td><td>Br</td><td>AND</td>

<td> 68</td><td> 51</td><td>χ / COOEt</td><td></td><td>Br</td><td>B</td>

<td> 69</td><td> 51</td><td>\ / COOEt</td><td></td><td>H.</td><td>C.</td>

<td> 68</td><td> 60</td><td>x ^ COOMe ABOUT</td><td></td><td>Br</td><td>D</td>

<td> 70</td><td> 55</td><td></td><td>^X^ 'NH₂</td><td>Br</td><td>E.</td>

<td> 65</td><td> 59</td><td>Y 0</td><td>^ Et</td><td>H.</td><td>F.</td>

Method A:

An approximately 10% solution of educt in 2 N potassium hydroxide solution is heated to reflux. After 1-3 hours, the reaction is complete, the reaction solution is added dropwise to 2N hydrochloric acid and the amino acids are neutralized with a concentrated aqueous ammonia solution. The aqueous layer is then extracted three times with trichloromethane: ethanol 9: 1. The organic layer is evaporated and the crude product is optionally purified by column chromatography (15 g of silica gel of the G60 type, recycle: MeOH-CH2 Cl2 mixture).

DC: CHCl3: MeOH = 9: 1.

<td>Substance No.</td><td>Name</td><td>SF, MG</td><td>Performance</td><td>Tt .:</td>

<td> 66</td><td>(6R) -4a, 5,9,10,11,12-hexahydro-1-bromo-6-hydroxy-3-methoxy-6H-benzofuro [3a, 3,2-ef] [2] benzoazepinyl-11-Y- acid ketcbutter</td><td>^C.20^H.22^BrNO6 [452,31]</td><td>89% yellow crystals</td><td>107-109 ° C</td>

<td> 67</td><td>(6R) -4a, 5,9,10,11,12-hexahydro-1-bromo-6-hydroxy-3-methoxy-6H-benzofuro [3a, 3,2-ef] [2] benzoazepinyl-11-γ- acid ketoacetic</td><td>Ci8H₁₈BrNO₆ [424,26]</td><td>22% red crystals</td><td>schedule &gt; 120 ° C</td>

<td> 71</td><td>(6R) -4a, 5,9,10,11,12-hexahydro-1-broirc&gt; -6-hydroxy-3-methyloxy-6H-benzofuro [3a, 3,2-ef] [2] benzoazepinyl-11-acetic acid</td><td>CH ^ B ^ NO ^ [410.27]</td><td>quantitatively colorless crystals</td><td>schedule &gt; 200 ° C</td>

190 032

Method B:

About a 5% solution of the educate in absolute tetrahydrofuran is added with 2 equivalents of a 10% solution of lithium aluminum hydride in tetrahydrofuran. After 1.5 hours, hydrolysis is carried out with water: tetrahydrofuran 1: 1, the tetrahydrofuran is stripped off in a rotary evaporator and the residue is dissolved in 2N hydrochloric acid. After addition of 2.5 eq. Of tartaric acid, it is made basic with concentrated aqueous ammonia solution and extracted with ethyl acetate. The combined organic layers were washed once with a saturated aqueous sodium chloride solution, dried (Na2SO₄), filtered and evaporated. The crude product was purified by column chromatography (15 g of G60 type silica gel, circulating agent: CHCl: MeOH = 9: 1).

DC: CHCl3: MeOH = 9: 1

<td>Substance No.</td><td>Name</td><td>SF, MG</td><td>Delivery</td><td>Tt .:</td>

<td> 68</td><td>(6) -43,5,9,10,11,12-hexahydro-1-brim-3-IΓ.ethoxy-11 (2-hydroxyethyl) -3a, 3,2-ef] [2] -benzazepinol-6</td><td>C18H ^ EBNO ^ [09-_r8H]</td><td>quantitatively oily sutostasis</td><td></td>

Method C:

About a 5% solution of the educate in absolute tetrahydrofuran is mixed with four equivalents of a 10% solution of lithium aluminum hydride in tetrahydrofuran. After 15 minutes it is refluxed. After 24 hours, hydrolysis is carried out with water: tetrahydrofuran 1: 1, the tetrahydrofuran is stripped off in a rotary evaporator and the residue is dissolved in 2N hydrochloric acid. After adding five equivalents of tartaric acid, it is made basic with concentrated aqueous ammonia solution and extracted with ethyl acetate. The combined organic layers were washed once with a saturated aqueous sodium chloride solution, dried (Na2SO₄), filtered and evaporated. The crude product was purified by column chromatography (15 g of G60 type silica gel, circulating agent: CHCl: MeOH = 9: 1).

DC: CHCl3: MeOH = 9: 1

<td>Substance No.</td><td>Name</td><td>SF, MG</td><td>Efficiency</td><td>Tt .:</td>

<td> 68</td><td>(6) -! A, 5,9,10,11,18-hexahydro-3-matoxy-11 (2-hydrolkyethyl) -6Hbtnzofuri [0a, 3, 2-ef] [8] -benziazepinol -6</td><td>C18H2NO4</td><td>81%, oily substance</td><td></td>

Method D:

0.84 ml of a 10% solution of lithium aluminum hydride (2.20 mmol) in 10 ml of absolute tetrahydrofuran was refluxed. Then 100 mg (0.22 mmol) of the mt7 compound are dissolved in 5 ml of absolute tetrahydrofuran and added dropwise to the boiling solution. After 15 minutes, the reaction mixture was cooled to 0 ° C and hydrolysed with water. Tetrahydroiuran 1; 1. The tetrahydrofuran is then stripped off in a rotary evaporator, the residue is taken up in 50 ml of 2N hydrochloric acid, mixed with 0.80 g of tartaric acid, made alkaline with concentrated aqueous ammonia solution and extracted three times with 30 ml of ethyl acetate each time. The combined organic layers were washed once with a saturated aqueous sodium chloride solution, dried (Na2SO4₄), filtered and evaporated, giving 100 g of crude product, which it purifies

190 032 is carried out by column chromatography (15 g silica gel, circulating agent: CHCl ,:

Me-OH = 9: 1).

DC: CHCl3: MeOH = 9: 1.

<td>Substance No.</td><td>Name</td><td>SF, MG</td><td>Productivity</td>

<td> 68</td><td>(6R} -4a, 5,9,10 11,12-hexahydro-1-bromo-3-m3-oxy-11 (2-hydroxyethyl) -6H-benzofuro [3a, 3,2-ef] [2] -benzazepinol- 6</td><td>CDHzaBrNOą [396.29]</td><td>42%, an oily substance</td>

Method E:

170 mg (0.32 mmol) of the compound st80 and 80 mg (1.60 mmol) were refluxed in 10 ml of absolute ethanol. After 30 minutes, the reaction mixture is cooled and, after 1 hour, the precipitate formed is filtered off with suction. The precipitate is washed once with ethanol, then the ethanol layer is concentrated on a rotary evaporator. The crude product was purified by column chromatography (15 g of silica gel, circulating agent: CHCl3: MeOH = 9: 1).

DC: CHCl3: MeOH = 9: 1

<td>Substance No.</td><td>Name</td><td>SF, MG</td><td>Vitality Tt .:</td>

<td> 70</td><td>(6R) -4a, 5,9,10,11,12-hexahydro-1-b romo-4-methoxy-11- (2-a.mLnoethyl) -6H-benzofuo [3a, 3,2-ef] [ 2] -benzoazepinol-6</td><td>C ^ BrNA [393. ^ 0]</td><td>70%, colorless - 116-117 ° c ne crystals</td>

Method F:

To 2 ml of a 10% solution of lithium carbon hydride in tetrahydreferan (5.26 mmol) was added dropwise under reflux 50 mg (0.381 mmol) of St62 in 1.5 ml of absolute tetrahydrofuran. It is then heated to reflux for a further 90 minutes. Then the water: tetrahydreferan = 1: 1 is hydrolyzed at 0 ° C. and the mShezauine is concentrated to dryness in a rotary evaporator. The residue is then taken up in 2N hydrochloric acid, treated with 1.2 g of tartaric acid and made alkaline with concentrated aqueous ammonia solutions. After that, it was extracted three times with 40 ml of ethyl acetate each time, the combined organic layers were washed once with saturated aqueous sodium chloride solutions, dried (Na2SO4), filtered and evaporated. The crude product was purified by column chromatography (15 g silica gel, circulating agent: CHCl3 system: MzOH = 9: 1).

DC: CHCl3: MeOH = 9: 1.

<td>Substance No.</td><td>Name</td><td>SF, MG</td><td>Extant</td><td>Tt .:</td>

<td> 65</td><td>(6R) -4a, 5,9,10,11, N -hexahydro-1-bromine-3-iretoxy-11-ethyl-6H-benzofuro [3a, 3,2-ef] [2] -benzazepinol-6</td><td>CuIH7BrN7O4 [494.40]</td><td>76%, oily substance</td><td></td>

190 032'H-NMR (CDC1₃[* in DMSO-de]; δ (ppm);

<td>H- atom</td><td> 66</td><td> 67</td><td> 71</td><td> 68</td><td> 69</td>

<td>H-9</td><td> 1,70-2,10</td><td> 1,85-2,35</td><td> 1,80-2,10</td><td>1.60 (ddd)</td><td>1.60 (ddd)</td>

<td>H-9 '</td><td> 1,70-2,10</td><td> 1,85-2,35</td><td> 1,80-2,10</td><td> 1,90-2,10</td><td> 1,90-2,10</td>

<td>H-5</td><td> 2,40-2,80</td><td> 1,85-2,35</td><td>2.25 (dd)</td><td> 1,90-2,10</td><td> 1,90-2,10</td>

<td>H-5 '</td><td>2.90 (ddd)</td><td> 3,30-3,70</td><td>3.00 (ddd)</td><td> 2,60-2,75</td><td> 2,60-2,75</td>

<td>H-10</td><td>3.25 (ddd)</td><td> 3,30-3,70</td><td> 3,20-3,50</td><td>3.10 (ddd)</td><td>3.15 (ddd)</td>

<td>H-10 '</td><td>3.40 (d) 3.60 (dd)</td><td> 3,30-3,70</td><td> 3,20-3,50</td><td>3.45 (ddd)</td><td>3.40 (ddd)</td>

<td>NCHj</td><td> -</td><td> -</td><td>3.25 (s)</td><td> 2,60-2,75</td><td> 2,60-2,75</td>

<td>oh₃</td><td>3.80 (s)</td><td>3.80 (s)</td><td>3.75 (s)</td><td>3.80 (s)</td><td>3.82 (s)</td>

<td>H-12</td><td>4.35 (d)</td><td> 3,30-3,70</td><td>3.60 (d)</td><td>4.00 (d)</td><td>3.78 (ci)</td>

<td>H-12 '</td><td>5.20 (d)</td><td>4.10 (d)</td><td>4.20 (d)</td><td>4.40 (d)</td><td>4.17 (d)</td>

<td>H-6</td><td>4.15 (b)</td><td>4.60 (b)</td><td>4.08 (b)</td><td>4.12 (dd)</td><td>4.12 (dd)</td>

<td>H-4a</td><td>4.60 (b)</td><td>4.90 (b)</td><td>4.50 (b)</td><td>4.60 {b)</td><td>4.60 (b)</td>

<td>H-8</td><td>5.90 (d)</td><td>6.15 (d)</td><td>6, l0 (d)</td><td> 5,95-6,10</td><td>6.10 (d)</td>

<td>H-7</td><td>6.05 (dd)</td><td>5.90 (dd)</td><td>5.80 (dd)</td><td> 5,95-6,10</td><td>6.00 (dd)</td>

<td>H-2</td><td>6.90 (s)</td><td> 7,15</td><td>6.95 (s)</td><td> 6,90(3)</td><td> 6,55-6,70</td>

<td>gave-</td><td>2.40-2.80 (m,</td><td>9.15 (b, 1H ex-</td><td> -</td><td>2.45 (b, 2H yield-</td><td>2.50 (b, 2H</td>

<td>six H.</td><td>5H, H-5 / CO- CH₂-CH₂WHAT)</td><td>property of D.₂Oh COOH)</td><td></td><td>property E ^ O, OH): 3.55 (t, 2H, CH₂OH)</td><td>mentions D₂O, OH): 3.55 (t, 2H, CH_;OH! 6.55-6.70 (m, 2H, Hl / 2)</td>

<td>7 (A. B) (Hz)</td><td>(4a, 7) = 4.0 (6.8) = 7.1 (7.8 = 10.4) (12.12 ') = 17.0</td><td></td><td></td><td> (10,10')=14,3 12,12')=16,1</td><td> (9,9')=14,1 (10,10'1=15,1 (12,12')=15,6</td>

<td>d- atom</td><td> 70</td>

<td>H-9</td><td> 1,80-2,15</td>

<td>H-9 '</td><td> 1,80-2,15</td>

<td>H-5</td><td> 1,80-2,15</td>

<td>H-5 '</td><td> 2,40-2,70</td>

<td>H-10</td><td>3.20 (ddd)</td>

<td>H-10 '</td><td>3.60 (ddd)</td>

<td>NCH,</td><td> 2,40-2,70</td>

<td>Oh₃</td><td>3.80 (s)</td>

<td>H-12</td><td>3.95 (d)</td>

<td>H-12 '</td><td>4.50 (d)</td>

<td>H-6</td><td>4.10 (dd)</td>

<td>H-4a</td><td>4.55 (b)</td>

<td>H-8</td><td> 5,95-6,05</td>

<td>H-7</td><td> 5,95-6,05</td>

<td>H-2</td><td>6.90 (s)</td>

<td>gave-</td><td>2.40-2.70 (m,</td>

<td>six H.</td><td>5H, H-5 '/ NCH₂CH₂)</td>

<td>J | A, Bl (Hz)</td><td></td>

190 032 i3C-NMR (CDCfo [* in DMSO-d6]; δ (ppm)):

<td>C- atom</td><td> 66 *</td><td> 68</td><td> 69</td><td> 70</td><td> 65</td>

<td>C-5</td><td>28.8; 30.2 (t)</td><td>29, 4 (t)</td><td>29.7 (t)</td><td>(t)</td><td>(t)</td>

<td>C-9</td><td>36.0; 37.8 (t)</td><td>33.2 (t)</td><td>33.2 (t)</td><td>(t)</td><td>(t)</td>

<td>C-8a</td><td> 48,4(0</td><td>48.6 (s)</td><td>48.2 (s)</td><td>(s)</td><td>(s)</td>

<td>C-10</td><td>43.6-45.4 (t)</td><td>51.7 (t)</td><td>51.7 (t)</td><td>(t)</td><td>(t)</td>

<td>nch₂</td><td> -</td><td>54.9 (t)</td><td>52.0 (t)</td><td>(t)</td><td>(t)</td>

<td>OC-3</td><td>55.8 (q)</td><td>55.7 (q)</td><td>55.6 (q)</td><td>(q)</td><td>(q)</td>

<td>C-12</td><td>48.8; 5O.4 (t)</td><td>57.6 (t)</td><td>57.6 (t)</td><td>(t)</td><td>(t)</td>

<td>C-6</td><td>59.3 (d)</td><td>61.4 (d)</td><td>61.7 (d)</td><td>(d)</td><td>(d)</td>

<td>C-4a</td><td>86.4; 86.6 (d)</td><td>88.3 (d)</td><td>88.4 (d)</td><td>(d)</td><td>(d)</td>

<td>Cl</td><td>111.0, 112.1 (s)</td><td>114.3 (s)</td><td>121.8 (d)</td><td></td><td></td>

<td>C-8</td><td>115.3 (d)</td><td>115.4 (d)</td><td>110.9 (d)</td><td>(d)</td><td>(d)</td>

<td>C-2</td><td>128.4; 128.6 (d)</td><td>121.7 (d)</td><td>126.4 (d)</td><td>(d)</td><td>(d)</td>

<td>C-7</td><td>126.3 (d)</td><td>127.9 (d)</td><td>127.5 (d)</td><td>(d)</td><td>(d)</td>

<td>C-12a</td><td>127.4 (s)</td><td>127.3 (s)</td><td>128.8 (s)</td><td>(s)</td><td>(s)</td>

<td>C-12b</td><td>133.2; 133.4 (s)</td><td>133.7 (s)</td><td>132.8 (s)</td><td>(s)</td><td>(s)</td>

<td>C-3a</td><td>143.8; 144.2 (s)</td><td>144.0 (s)</td><td>144.0 (s)</td><td>(s)</td><td>(s)</td>

<td>C-3</td><td>146.5; 146.9 (s)</td><td>145.2 (s)</td><td>145.5 (s)</td><td>(s)</td><td>(s)</td>

<td>further</td><td>27.4 (t, NCOCH2);</td><td>56.6 (t, CH₂OH)</td><td>56.7 (t, CH₂OH)</td><td></td><td></td>

<td>C.</td><td>27.9 (t, CH2COOH;</td><td></td><td></td><td></td><td></td>

170.0; 170.4 (s,

CON); 173.6; 173.8 (s, COO)

General procedure for bromine implantation with zinc and calcium chloride:

<td>Subs- dance no</td><td>Educt no</td><td>R4</td><td>R5</td><td>Re</td><td>SF,</td><td>MG</td>

<td> 112</td><td> 4</td><td>OH</td><td>H.</td><td>'-H</td><td>C._ieH1903</td><td> [273,22]</td>

<td> 73</td><td> 52</td><td>OH</td><td>H.</td><td></td><td>^C.18^H.20^N2^ABOUT3</td><td> [312,37]</td>

<td> 74</td><td> 54</td><td>OH</td><td>H.</td><td rowspan="2"></td><td>C22H30N2O3</td><td> [386,50]</td>

<td> 43</td><td> 42</td><td>OH</td><td>H.</td><td>^C.19^H.23^WELL3</td><td> [313,40]</td>

<td> 46</td><td> 45</td><td>OH</td><td>H.</td><td>-jO</td><td>C;₃H25NO₃</td><td> [363,46]</td>

<td> 72</td><td> 64</td><td>OH</td><td>H.</td><td>^ χΌ · | 5Η31 about</td><td>C32H49NO4</td><td> [511,75]</td>

<td> 47</td><td> 44</td><td> =0</td><td></td><td>uO</td><td>C23H23NO3</td><td> [361,44]</td>

A solution of 500 ml of educate and 1.0 g of calcium chloride in 50 ml of 50% ethanol are added with 2.0 c of freshly activated-oe2o pints: ^ .- n ^ t ^ qO ^ f ^ oe n acrvwa sir in the state of reflux . The excess zinc is then filtered off, washed with methanol and the remaining solution is concentrated on a rotary evaporator. The residue is taken up in 100 ml of 1N hydrochloric acid, made alkaline with concentrated aqueous ammonia solution and extracted three times with 50 ml of ethyl acetate each time. The combined organic layers were washed once with a saturated aqueous sodium chloride solution, dried (Na2SO4), filtered and evaporated. The crude product was purified by column chromatography (15 g silica gel, circulating agent: CHCl3: MeOH = 9: 1).

190 032

Substance No .:

112

Reagent (6R) -4a, 5,9,10,11,12-hexahydro-1-bromo-3-raetoxy-6H-benzofuro [3a, 3,2-ef] (2] benzoazepinol-6 (6R) -4a, 5,9,10,11, 12-hexahydro-3-methoxy-11- (cyanomethyl) -6H-benzofuro- [3a, 3,2-ef] (2] benzoazepinol-6 (6R) -4a, 5,9,10,11,12-hexahydro -3-methoxy-11- (roorfolinoethyl) -6H-benzofuro [3a, 3,2-ef] [2] benzoazepinol-6 (6R) -4a, 5,9,10,11,12-hexahydro-3-methoxy -ll- (ketohek3adecyl) -6H-benzofuro [3a, 3,2-ef] [2] benzoazepinol-6 (6R) -4a, 5,9,10,11,12-hexahydro-3-methoxy-11- ( 2-propenyl) -6H-benzofuro- [3a, 3,2-ef] [2] benzoazepinol-6 (6R) -4a, 5,9,10,11,12-hexahydro-3-methoxy-11- (phenylmethyl) -6H-benzofuro [3a, 3,2-ef] [2] benzoazepinol-6 (6R) - 4a, 5,9,10,11,12-hexa Time Reaction yield_

1.5 h 93% colorless crystals h 55% colorless crystals h 80% h 84% colorless crystals h 96% h 52%

236-240 ° C

68-70'C hydro-3-methoxy-11- (phenylmethyl) -6H-benzofuro [3a, 3,2-efJ (2] benzoazepinone-6

3.5 h quantitatively, orange crystals

159-162C ^lH-NMR (CDCl₃[* wEMSO-d₆]; δ (ppm)):

<td>H- atom</td><td> 112</td><td> 73</td><td> 74</td><td> 43</td><td> 46</td>

<td>H-9</td><td>1.70 (dd)</td><td>1.71 (ddd)</td><td>1.50 (ddd)</td><td>1.54 (ddd)</td><td>1.54 (ddd)</td>

<td>H-9 '</td><td>1.70 (dd)</td><td> 1,92-2,10</td><td> 1,93-2,12</td><td> 1,92-2,12</td><td> 1,94-2,20</td>

<td>H-5</td><td>2.05 (ddd)</td><td> 1,92-2,10</td><td> 1,93-2,12</td><td> 1,92-2,12</td><td> 1,94-2,20</td>

<td>H-5 '</td><td>2.30 (dd)</td><td>2.70 (ddd)</td><td>2.66 (ddd)</td><td> 2,60-2,75</td><td>2.71 | ddd&gt;</td>

<td>H-10</td><td> 3,00-3,20</td><td>3.12 (ddd)</td><td>3.16 (ddd)</td><td> 2,60-2,75</td><td>3.17 (ddd)</td>

<td>H-10 '</td><td> 3,00-3,20</td><td>3.38 (ddd)</td><td>3.39 (ddd)</td><td>3.25 (ddd)</td><td>3.40 (ddd)</td>

<td>nch₂</td><td> -</td><td>3.58 (s)</td><td> 2,40-2,66</td><td>3.16 (d)</td><td>3.68 (s)</td>

<td>OH</td><td> 3,70(5)</td><td>3.85 (a)</td><td>3.80 (s)</td><td>3.85 (s)</td><td>3.68 (s)</td>

<td>H-12</td><td>3.75 (d)</td><td>3.78 (d)</td><td>3.81 (d)</td><td>3.80 (d)</td><td>3.87 (s)</td>

<td>H-12 '</td><td>3.90 (d)</td><td>4.17 (d)</td><td>4.17 (d)</td><td>4, 08 (d)</td><td>4.13 (d)</td>

<td>H-6</td><td>4.10 (b)</td><td>4.14 (b)</td><td>4.12 (b)</td><td>4.13 (b)</td><td>4.15 (dd)</td>

<td>H-4a</td><td>4.45 (dd)</td><td>4.60 (b)</td><td>4.58 (b)</td><td>4.61 (b)</td><td>4.66 (b)</td>

<td>H-8</td><td>5, S0 (dd)</td><td> 6,00-6,04</td><td>5.98 (dd)</td><td>6.00 (ddd)</td><td>6, 01 (ddd)</td>

<td>H-7</td><td>6.05 (dd)</td><td> 6,00-6,04</td><td>6.08 (d)</td><td>6.10 (dd)</td><td>6.12 (dd)</td>

<td>H-1</td><td>6.65 (AB)</td><td> 6,61-6,70</td><td>6.62 (AB)</td><td>6.64 (AB)</td><td>6, 66 (AB)</td>

<td>H-2</td><td>6, 55 (AB)</td><td> 6,61-6,70</td><td>6, 58 (AB)</td><td>6.57 (AB)</td><td>6, 50 (AB)</td>

<td>further H.</td><td></td><td></td><td>2.40-2.66 (m, 8H, NCH₂CH_WITH/ morph-2/6; 3.68 (t, morph-3/5)</td><td>5.12 (dd, 2H, = CH_WITH): 5.82 (ddt, 1H, = CH)</td><td>7.20-7.39 (m, 5H, Ph)</td>

<td>J (A, 8) (Hz)</td><td> (5,5')=13,4 (7,8)=9,8 (12,12')=15,1</td><td> (9,9')=12,7 (10,10')=14,0 (12,12')=15,9</td><td></td><td>(NCH_WITH(= CH) = 6,6 (6.7) = 1.2 (6.8) = 4.5 (7.8) = 10.3 (12.12′1 = 15.4</td><td> (1,2)=8,2 (5,5')=15,6 (6,81=4,8 (7,8)=10,2 (9,9')=13,6 (10,10' )=14,1 (12,12')=15,3</td>

190 032

<td>fi- atom</td><td> 72</td><td> 47</td>

<td>H-9</td><td>1.78 (ddd)</td><td>1.81 (ddd)</td>

<td>H-9 '</td><td>2.18 (ddd)</td><td> 2,16-2,48</td>

<td>H-5</td><td>1.95 (ddd)</td><td> 2,16-2,48</td>

<td>H-5 '</td><td>2.42 (ddd)</td><td>2.77 (dd)</td>

<td>H-10</td><td>2.68 (ddd)</td><td> 3,10-3,42</td>

<td>H-10 '</td><td>3.18 (ddd)</td><td> 3,10-3,42</td>

<td>nch₂</td><td> -</td><td>3.71 (s)</td>

<td>OH</td><td>3.82 (s)</td><td>3.86 (s)</td>

<td>H-12</td><td>3, 93 (d, conf_AND); 4.41 (d, conf_B)</td><td>3.81 (d)</td>

<td>H-12 '</td><td>4.68 (d, conf_AND); 5.28 (d, conf_B)</td><td>4.13 (d)</td>

<td>H-6</td><td>4.14 (b)</td><td> -</td>

<td>H-4a</td><td>4.57 (b)</td><td>4.79 (b)</td>

<td>H-8</td><td> 5,93-6,08</td><td>7.01 (dd)</td>

<td>H-7</td><td> 5,93-6,08</td><td>6.06 (d)</td>

<td>Hl</td><td> 6,64-6,70; 6,81-6,88</td><td>6.70 (d)</td>

<td>H-2</td><td> 6,64-6,70; 6,81-6,88</td><td>6.52 (d)</td>

<td>further H.</td><td>0.89 (t, co-CH₃): 1.18-1.38 (m, 22H, CH₂⁽⁴¹⁴'); 1.48-1.65 (t., 4H, CH2 '²'³¹); 2.06 (t, 2H, COCH2)</td><td>7.21-7.46 (m, 5H, Ph)</td>

<td>^J.(A, 8)</td><td> -</td><td>(1,2) = 8.1; (4a, 5/5 ') = 3</td>

<td>(Hz)</td><td></td><td>(4a, 8) = 1.9, - (5.5 ') = 17, (7.8) = 10.4; (12.12 ') = 1!</td>

¹³C-NMR (CDC1₃[* wDMSO-dc]; δ (ppm)):

C- 112 atom

<td>C-5</td><td>30.6 (t)</td><td>(t)</td><td>(t)</td><td>(t)</td><td>(t)</td>

<td>C-9</td><td>33.5 (t)</td><td>(t)</td><td>(t)</td><td>(t)</td><td>(t)</td>

<td>C-8a</td><td>48, l (s)</td><td>(s)</td><td>(S)</td><td>(s)</td><td>(s)</td>

<td>C-10</td><td>46.3 (t)</td><td>(t)</td><td>(t)</td><td>(t)</td><td>(t)</td>

<td>nch₂</td><td> -</td><td></td><td></td><td></td><td></td>

<td>oh₃</td><td>55.5 (q)</td><td>(q)</td><td>(q)</td><td>(q)</td><td>(q)</td>

<td>C-12</td><td>52.8 (t)</td><td>(t)</td><td>(t)</td><td>(t)</td><td>(t)</td>

<td>C-6</td><td>59.7 (d)</td><td>(d)</td><td>(d)</td><td>(d)</td><td>(d)</td>

<td>C-4a</td><td>86.7 (d)</td><td>(d)</td><td>(d)</td><td>(d)</td><td>id)</td>

<td>C-8</td><td>111.1 (d)</td><td>(d)</td><td>(d)</td><td>(d)</td><td>(d)</td>

<td>C-7</td><td>119.5 (d)</td><td>(d)</td><td>(d)</td><td>(d)</td><td>(d)</td>

<td>C-2</td><td>121.0 (d)</td><td>(d)</td><td>(d)</td><td>(d)</td><td>(d)</td>

<td>C-1</td><td>127.4 (d)</td><td>(d)</td><td>(d)</td><td>(d)</td><td>(d)</td>

<td>C-12a</td><td>132.9 (s)</td><td>(s)</td><td>(s)</td><td>(s)</td><td>(s)</td>

<td>C-12b</td><td>133.8 (s)</td><td>(s)</td><td>(s)</td><td>(s)</td><td>(s)</td>

<td>C-3a</td><td>142.9 {s)</td><td>(s)</td><td>(s)</td><td>(s)</td><td>(s)</td>

<td>C-3</td><td>146.3 (s)</td><td>(S)</td><td>(s)</td><td>(s)</td><td>(s)</td>

further

C.

190 032

C- 47 at-cn

<td>C-5</td><td>(t)</td><td>(t)</td><td>(t)</td><td>(t)</td><td>32.5 (t)</td>

<td>C-9</td><td>(t)</td><td>(t)</td><td>(t)</td><td>(t)</td><td>36.9 (t)</td>

<td>C-8a</td><td>(s)</td><td>(s)</td><td>(s)</td><td>(s)</td><td>48.8 (s)</td>

<td>C-10</td><td>(t)</td><td>(t)</td><td>(t)</td><td>(t)</td><td>51.5 (t)</td>

<td>NCH2</td><td></td><td></td><td></td><td></td><td>56.4 (s)</td>

<td>OCH3</td><td>(q)</td><td>(q)</td><td>(q)</td><td>(q)</td><td>55.6 (q)</td>

<td>C-12</td><td>(t)</td><td>(t)</td><td>(t)</td><td>(t)</td><td>57.0 (t)</td>

<td>C-6</td><td>(d)</td><td>(d)</td><td>(d)</td><td>(d)</td><td>194.0 &lt;s)</td>

<td>C-4a</td><td>(d)</td><td>(d)</td><td>(d)</td><td>(d)</td><td>87.6 (d)</td>

<td>C-8</td><td>(d)</td><td>(d)</td><td>(d)</td><td>(d)</td><td>111.5 (d)</td>

<td>C-7</td><td>(d)</td><td>(d)</td><td>(d)</td><td>(d)</td><td>126.8 (d)</td>

<td>C-2</td><td>(d)</td><td>(d)</td><td>(d)</td><td>(d)</td><td>144.1 (d)</td>

<td>C-1</td><td>(d)</td><td>(d)</td><td>(d)</td><td>(d)</td><td>121.7 (d)</td>

<td>C-12a</td><td>(s)</td><td>(s)</td><td>(s)</td><td>(s)</td><td>129.3 (s)</td>

<td>C-12b</td><td>(s)</td><td>(s)</td><td>(s)</td><td>(s)</td><td>138.2 (s)</td>

<td>C-3a</td><td>(s)</td><td>(s)</td><td>(S)</td><td>(s)</td><td> 143,6(8)</td>

<td>C-3</td><td>(s)</td><td>(s)</td><td>(s)</td><td>(s)</td><td> 146,6(8)</td>

<td>further</td><td></td><td></td><td></td><td></td><td>126.7 (d, Ph-4);</td>

C 127.8 (s, Ph-1);

127.9 (d, Ph-2/6); 128.5 (d, Ph-3/5)

O-TOS-Narvedine Oxime (75):

A suspension of 1.05 g (3.51 vol.) Of narwedine oxime (compounds 76, 77) in 20 ml of absolute pyridine is mixed with 1.33 g (7.02 vol.) Of p-toluanesulfonyl chloride and stirred for 20 hours at temperature room. The reaction mixture was then poured into 100 ml of water and extracted three times with 50 ml of ethyl acetate each time. The combined organic layers are washed once with a saturated aqueous sodium chloride solution, dried (Na2SO4, activated carbon), filtered and evaporated. Purification was carried out by column chromatography (50 g silica gel, circulating agent: CHCl =&gt; CHCl3: MaOH = 9: 1), yielding 1.27 g (80% of theory) of yellow colored crystals of compound 75, m.p. 78 -79 ^.

DC: CHCl3: MeOH = 9: 1.

1 H-NMR (CDCl 3; δ (ppm)): 1.55-1.65; 1.80-1.95 (2 * m, 2H, H-9 / 9'conforkar a / b_}; 2.05-2.25 (m, 1H, H-5kenforkar a / e 2.40; 2.43 (2 * s, 6H, NCH3, Ph-CH3); 2.50-2.70 (m, 1H , H-5 confonner AAB) j 2.95-3.25 (v, iH, H-1 Okonforkar A / B) j 3.60-3.85 (v, 2H, H-10/12 konfonner AB); 4, 00-4.25 (v1H, Hd2kUmAB) 4.55 (b, 1H, H-4coofomer A / B 6.15; 7.10 (2 * d, 1H, H-8lkOlfovΓAB); 6.40; 7.65 (2 * d, 1H, b-7ooIlOorker A / B) j 6.50-6.70 (v, 2H, H-Uconfoomer a / b), 7.20-7.35 (m, 2H, Ph-35konfOover A / B) j 7.75-7.90 (v, 2H, Ph-k / conformer A / B) 'C-NMR (DMSO-d_ex; δ (ppm)): 21.1 (q, Ph-CH3); 23.9 (t, C-5); 31.6 (t, C-9); 40.6 (q, NCH3); 48.7 (s. C-8a); 52.9 (t, C-10); 55.5 (q, OCH3); 59.2 (t, C-12); 84.3 (d. C-4a); 111.9 (d, C-2); 118.6; 121.6 (d, C-Sm A / B); 125.5; 128.0 (d, C-7confoil AB); 128.4 (d, Ph-2/6); 130.0 (d, Ph-3/5); 131.8 (s. C-12a); 136.1 (s, Ph-1): 137.5 (s, C-12b); 138.7 (d, C-1); 143.1 (s. C-3a);

145.4 (s, C-3); 145.8 (s, Ph-4); 159.8 (s, C-6).

i - \ - Ra -e 'l-in_ok # atn1 -) - i (łr \ -7O - ^ \_andmv 7yV vivujlił yy X γ y xxxwvj xvsxxmx »» λ-λ-j yi s j.

A solution of 300 mg (1.05 mmol) of narwedine in 10 ml of ethanol is mixed with 88 mg (1.05 vol.) Of O-methylhydroxylamine and 53 mg (0.53 vol.) Of potassium bicarbonate and the mixture is refluxed for 4 hours. condensate return. The reaction mixture is then evaporated off, the residue is taken up in 50 ml of 1N hydrochloric acid, made basic with concentrated aqueous ammonia solution and extracted three times with 30 ml of ethyl acetate each time. The combined organic layers were washed once with saturated aqueous sodium chloride solution, dried (Na2SO4), filtered and evaporated to

190 032 quantitatively, a ductile amorphous substance of compounds 78/79 (with a rotation of a_D²⁰[CHCl3] = -152 ° for compound 78 or aD²0 [CHCl₃] = + 108 ° for compound 79).

DC: CHCl): MeOH = 9: 1 'H-NMR (CDCl ,; δ (ppm)): 1.70 (ddd, 1H, H-9); 2.20 (ddd, 1H, H-9 '); 2.30-2.45 (m, 1H, H -5): 2.40 (s, 3H, NCH5); 2.70 (ddd, 1H, H-5 '): 3.00-3.35 (m, 2H, H-10/10'); 3.65; 3.70; 4.00; 4.10 (4 * d, 2H, H -12conone, &lt;ra / b), 3.80 (s, 3H, OH,); 3.85; 3.90 (2 * s, 3H, NOCH3conormer a / b), 4.60 (b, 1H, H-4a): 6.15; 6.20; 6.75 (s, d, d, 2H, H-7/8confomer A / B), 6-55-6.70 (m, 2H, H-1/2.

Narvedinoimine (80):

A solution of 100 mg (0.35 mmol) of narwedine in 10 ml of a 7N methanolic ammonia solution in a glass autoclave was heated at 100 ° C for 10 hours. The excess methanol was then chased off on a rotary evaporator, thereby quantitatively obtaining colorless crystals of compound 80, mp 105-110 ° C.

DC: CHCtyMeOH = 9: 1 and H-NMR (CDCl3 [formation of narwedine and decomposition products during measurement], δ (ppm)): 1.80 (ddd, 1H, H-9); 2.00-2.35 (m, 2H, H -5 / 9 '); 2.45 (s, 3H, NCH5); 2.80 (ddd) 1H, H-5 '): 3.00-3.35 (m, 2H, H-10/10'), 3.70 (d, 1H, H-12), 3.80 (s, 2H, OCH1); 4.05 (d, 1H, H-12 '); 4.65 (b, 1H, H-4a); 6.15 (d, 1H, H-8); 6.45 (d, 1H, H-7); 6.55-6.70 (m, 2H, Hl / 2).

Racemic oxime (+) - or (-) - narwedine (76, 77):

1.0 g (3.51 mmoles) of the elorvaner, 266 mg (3.86 mm6 b) of hydroxylarroin chloride and 193 mg (1.93 mmoles) of potassium bicarbonate, are refluxed in 30 ml of 96% ethanol. After 3 hours, the reaction mixture is concentrated on a rotary evaporator, the residue is taken up in 50 ml of 2N hydrochloric acid and the product is precipitated with concentrated aqueous ammonia solution. After crystallization overnight, a first fraction of 0.81 g (81% of theory) is obtained. A second fraction is obtained by extraction of the mother liquor with three times 30 ml of ethyl acetate, whereby quantitatively colorless crystals of compounds 76, 77 having a melting point of 170-171 ° C are obtained.

<td></td><td>FROM²⁰[CHC1)]</td><td>above^junless errors according to CE * * CE = capillary electrophoresis</td>

<td>oxime (-) - narwedine (77)</td><td> -79°</td><td> 20%</td>

<td>oxime {-) - narwedine (76)</td><td> +126*</td><td> 12%</td>

<td>DC: CHCl): MeOH = 9: 1.</td><td></td><td></td>

iH-NMR (CDCl; δ (ppm)): 1.70 (dd, 1H, H-9, J (9 9) = 13.4 Hz); 2.20 (ddd, 1H, H-9 ', J (9') = 13.4Hz); 2.40 (s, 3H, NCH5); 2.45 (dd, 1H, H-5, J (5 ') = 16.9 Hz); 3.10 (m, 2H, H-5 ', J (s' 5) = 16.9 Hz); 3.30 (ddd, 1H, H-10, J (i₀ = 14.2 Hz); 3.75 (d, 1H, H12, J₀₂i R = 16.0 Hz);

3.80 (s, 3H, OCH₃); 3.85 (dd, 1H, "O, J" at 109 = 14.2 Hz); 4.10 (d, 1H, H-12 ', J₍u, '09 = 16/0 Hz); 4.65 (b, 1H, H-4a); 6.20 (b, 2H, H-7/8); 6.55-6.65 (m, 2H, Hl / 2).

1³C-NMR (DMSO-d (; δ (ppm)): 22,) (t, C-5); ) 2.8 (t, C-9); 41.2 (q, NCH3); 48.7 (s. C-8a); 53.1 (t, C-10); 55.5 (q; OCH1); 59.5 (t, C-12); 85.9 (d. C-4a); 111.6 (d, C-8); 121.1 (d, C-2);

nn 2 a, n \. 1 on ca /); Οι ^ i ^ c \ n (A ntc 1 ai 2 a ni ou \. 0 ao 1 ^ 4 1- / 7, 'c-LLiy, uv, / ^ 4 ν'17, ^ -, va.1z.u71 i-ru, i

150.1 ¢£-6).

190 032

Summary formula, MG

CiaHjjNjOj

[313,40]

Reaction of narwedine with hydrazides:

SUastance no

Radical

H.

<img file="PL190032B1_D0018.tif" />

H.

<img file="PL190032B1_D0019.tif" />

H * N.

NI

CH₃

NH

COOH

CH₃ '^NN ^ NH₂

H *^Nxnh,

<img file="PL190032B1_D0020.tif" />

Name

2-m; tylohydrazone 4a, 5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro [3a, 3,2-ff] Pjeenoaazepmon-e

Formic acid 2- (4a, 5,9,10,11,12-hexahydro-3-methoxy-11-mityl-6H-benzofuro [3a, 3,2-ef] [2] benzoazepinylidene-6] -hydrazide

2- (2-hydroxyethyl) -hydrazone 4a, 5,9,10,11,12-hex5ahydro-3-methok3y-11-imatyl-6H-benzofuro (3a, 3,2-ef] 22] benzoazepinone-6

4-Methylbenzenesulfonic acid 2- (4a, 5,9,10,11,12-hexahydro-3-methoxy-11-thyl-6H-benzofuro [3a, 3,2-ef] [2] benzoazepinylidene-6) -hydrazide

T- 2- (4a, 5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro [3a, 3,2-ef] [2] benzoazepinylidene-6) -hydrazide butyl

Pyrocarbonic acid 2- (4a, 5,9,10,11,12-hexahldro-3-methoxy-11-matyl-6H-benzofuro [3a, 3,2-ef] [2] benzoazepinylidene-6) -hydrazide

2,2-dimethylhydrazone 4a, 5,9,10,11,12-hexahydro-3-methoxy-11-roatyl-6H-benzofuro [3a, 3,2-ef] [2] benzoazepinone-6 2- (4a, 5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro [3a, 3,2-ef] [2] benzoazepvylidene-6) -hydrazinocarbonamidine hydrazone 4a, 5,9,10 , 11,12-hexahydro-3-m »toxy-11-TOityl-6H-benzofuro [3a, 3,2-ef] [2] benzoazepinone-6

Carbamic acid 2- (4a, 5,9,10,11, N -hexahydro-rioethoxy-H-methyl-SH-benzofurona, 3,2-ef] [2] benzoazepinylidene-6) -hydrazide ^C.18^H.2i^N3^ABOUT3

[327,39]

C ^ zsNO,

[343,43]

C2₄H.₂₁N3O₄S.

[453,56]

C22H29N3O4

[399,49]

CisHjit-LO ·;

[371,40]

C1.5H25N3O2

[327,43]

CHH23N5O;

[341,42]

C11H21N3O2

[299,38]

C._ieH22N₄ABOUT₃

[342,40]

Method: A solution of 500 mg (1.75 mmol) of narwedine and 1.1-1.2 equivalents of N-alkylhydrazone or acid hydrazide in 10 ml of ethanol is added with 0.25 equivalents (43 mg, 0.44 mmol) of concentrated acid. sulfuric acid and boils to reflux. The reaction mixture is then evaporated, the residue is taken up in 50 ml of 1N hydrochloric acid, made basic with concentrated aqueous ammonia solution and the precipitate formed is filtered off under vacuum, or the aqueous phase is extracted three times with 30 ml of ethyl acetate each time. The precipitate is dried at 50 ° C / 50 mbar, the combined organic layers are washed once with saturated aqueous sodium chloride solution, dried (Na2SO4) and evaporated.

DC: CHCl₃: MeOH = 9: 1.

190 032

<td>Subs- tan- tation no</td><td>Reagent; H2SO4 equivalents</td><td>Time reaction- tions</td><td>Delivery</td><td>Tt. :</td>

<td> 81</td><td>methylhydrazine; 0.25</td><td>4 h</td><td>76% yellow crystals</td><td>97-99'C</td>

<td> 84</td><td>formic acid hydrazide; 0.0</td><td>48 h</td><td>63% yellow crystals</td><td>145-148'C</td>

<td> 83</td><td>2-hydraoynoethanol; 0.0</td><td>30 h</td><td>61% yellow crystals</td><td>100-105'C</td>

<td> 86</td><td>p-toluenesulfonic acid hydrazide; 0.25</td><td>6 h</td><td>97% colorless crystals</td><td>210-212'C</td>

<td> 85</td><td>t-butyl carbazate; 0.25</td><td>4 h</td><td>quantitatively, colorless crystals</td><td>transformation at 155-160'C, decomposition&gt; 200'C</td>

<td> 89</td><td>ethyl oxalate hydrazide; 0.25</td><td>30 h</td><td>64% yellow crystals</td><td>189-191'C</td>

<td> 82</td><td>N, N-dimbylhydrazine; 0.25</td><td>12 h</td><td>78% oily substance</td><td> —</td>

<td> 88</td><td>aminoguanidine bicarbonate; 0.0</td><td>20 h</td><td>ίΐοζεύον ^, yellow crystals</td><td>112-113'C</td>

<td> 90</td><td>10 eq. hydrazine hydrate; 2.5</td><td>2 h</td><td>94% oily substance</td><td></td>

<td> 87</td><td>Semlcarbazide Hydrochloride; 0.5 eq. KHCO3</td><td>4 h</td><td>88% colorless crystals (Lit. []% of theory</td><td>decomposition from 225'C (Lit. [] decomposition from 'C)</td>

¹H-NMR (CDCl₃[* in DMSO-d6]; δ (ppm)):

<td>H - atom</td><td> 81</td><td> 84</td><td> 83</td><td> 86</td><td> 85</td>

<td>H-9</td><td>1.75 (ddd)</td><td>1.7Ο ((()</td><td>1.70 (ddd)</td><td>1.80 (&lt;ddd)</td><td>1.70 (ddd)</td>

<td>H-9 '</td><td> 2,10-2,35</td><td>2.20 (dd)</td><td>2.20 (ddd)</td><td>2.15 (ddd)</td><td>2.20 (ddd)</td>

<td>H-5</td><td> 2,10-2,35</td><td>2.50 {dd)</td><td>2.35 (dd)</td><td>2.50 (b)</td><td> 2,35-2,45</td>

<td>H-5 '</td><td> 2,90-3,30</td><td> 3,00-3,30</td><td>2.70 (OD</td><td>3.25 (dd)</td><td>2.75 (ddd)</td>

<td>H-10</td><td> 2,90-3,30</td><td> 3,00-3,30</td><td> 3,00-3,40</td><td> 3,25-3,45</td><td> 3,00-3,35</td>

<td>H-10 '</td><td> 2,90-3,30</td><td>3.407ddl</td><td> 3,00-3,40</td><td> 3,25-3,45</td><td> 3,00-3,35</td>

<td>nch₃</td><td>2.45 (s)</td><td>2.45 (s)</td><td>6.65 (s)</td><td>2.40 (s)</td><td>2.40 (s)</td>

<td>ocH₃</td><td>3.85 (s)</td><td>3.35 (s)</td><td>3.80 (s)</td><td>4.10 (s)</td><td>3.80 (s)</td>

<td>H-12</td><td>3.70 (d)</td><td>3.70 (d)</td><td>3.68 (d)</td><td>3.58 (d)</td><td>3.70 (d)</td>

<td>H-12 '</td><td> 4,10(0</td><td>4, N57dl</td><td>4, 07 (d)</td><td>4.30 (d)</td><td>4.10 (d)</td>

<td>H-4a</td><td>4.70 (b)</td><td>4.70 (b)</td><td>4.70 (b)</td><td>4.60 (b)</td><td>4.15 (b)</td>

<td>H-8</td><td>5.96 (d)</td><td> 6,10-6,40</td><td>6.16 (d)</td><td>6.00 (d)</td><td>6.35 (d)</td>

<td>H-7</td><td>6.98 (dd)</td><td> 6,10-6,40</td><td>5.98 (dd)</td><td>6.32 (d)</td><td>6.20 (dd)</td>

<td>Hl / 2</td><td> 6,48-6,68</td><td> 6,50-6,70</td><td> 6,55-6,65</td><td> 6,55-6,78</td><td> 6,55-6,70</td>

<td>further</td><td>2.50 (s, 3H, N-</td><td>8.65 (b, 1H,</td><td>3.00-3.40 (m.</td><td>3.70 (s, 3H, FH-</td><td>1.50 (s, 9H,</td>

<td>H.</td><td>NCH.); conformer B: 5.80-6.06 (m, 2H, H-7/8)</td><td>CHO): 10.40 (b, 1H listed by D₂Oh, NH)</td><td>6H, H-10/10 ', N-CH2-CH2-O); conformer B: 4.07; 4.14 (2 * d, 2H, H12 / 12 '); 6.38 (dd, 1H, H-8); 6.70 (dd, 1H, H-7)</td><td>CH3); 7.36 (d, 2H, Ph-3/5; 7.76 Td, 2H, Ph-2/6)</td><td>C ^ Ha) ;,); 7.70 (b, 1H according to D₂Oh, NH)</td>

<td>J (A, 8) (Hz)</td><td> (7,8)=10,2</td><td> (12,12')=14,2</td><td> (7,8)=14,4; (12,12' )=15,2</td><td> (7,8)=10,2; (12,12' )=16,0</td><td>(7.8i = 8.9; (12.12 ') = I3.4</td>

(12_and,128')=7,2

190 032

Hatom

<td>H-9</td><td>1.86 (ddd)</td><td>1.80 (ddd)</td><td>1.65 ·; Ρ (Ρ |</td><td>1.70 (dd)</td><td>1.65 (dd)</td>

<td>H-9 '</td><td>2.30 (ddd)</td><td>2.20 (ddd)</td><td> 2,00-2,40</td><td> 2,15-2,40</td><td>2.20 (ddd)</td>

<td>H-5</td><td>2.75 (dd)</td><td> 2,35-2,50</td><td> 2,00-2,40</td><td> 2,15-2,40</td><td>2, 50 (dd)</td>

<td>H-5 '</td><td> 3,05-3,35</td><td>2.75 (ddd)</td><td>2.75 (ddd)</td><td>2.65 (ddd)</td><td>2.70 (Pd)</td>

<td>H-10</td><td> 3,05-3,35</td><td> 3,00-3,35</td><td>2.95 (dd)</td><td>3.05 (ddd)</td><td> 2,95-3,20</td>

<td>H-10 '</td><td> 3,05-3,35</td><td> 3,00-3,35</td><td> 3,10-3,30</td><td>3.25 (ddd)</td><td> 2,95-3,20</td>

<td>NCHi</td><td>2.45 (s)</td><td> 2,55(8)</td><td>2.25 (s)</td><td>2.40 (s)</td><td>2.35 (s)</td>

<td>OH</td><td>3.85 (s)</td><td>3.85 (s)</td><td>3.70 (s)</td><td>3.80 (s)</td><td>3.75 (s)</td>

<td>H-12</td><td>3.75 (d)</td><td>3.70 (d)</td><td>3.58 (d)</td><td>3.70 (d)</td><td> 3,55-3,70</td>

<td>H-12 '</td><td>4.10 (d)</td><td>4.10 (d)</td><td>4.06 (d)</td><td>4.08 (d)</td><td> 3,95-4,15</td>

<td>H-4a</td><td>4.70 (b)</td><td>4.65 (b)</td><td>4.58 (b)</td><td>4.20 (b)</td><td>4.60 (b)</td>

<td>H-8</td><td>6.05 (d)</td><td> 6,15-6,40</td><td> 6,00-6,15</td><td>6.05 (d)</td><td>5.95 (d)</td>

<td>H-7</td><td>6.95 (d)</td><td> 6,15-6,40</td><td> 6,00-6,15</td><td>6.20 (d)</td><td>6.90 (d)</td>

<td>H-1/2</td><td> 6,60-6,75</td><td> 6,5596,70</td><td>6, 55, - 6.68 (AB)</td><td> 6,55-6,70</td><td> 6,50-6,65</td>

<td>further</td><td></td><td> 2,40;2,50(2*</td><td>ó-5S-5.90 (b,</td><td>5.30 (b, 2H yield-</td><td>conformer B:</td>

<td>H.</td><td></td><td>s, 6H, N (CH₃) 2)</td><td>4H D ^ NH); koldfoJndeb B: 6.95 (d, 1H, H-7)</td><td>rnenia D₂O Nj); confonner B: 6.35 (d, 1H, H8); 6.95 (d, 1H, H-7)</td><td>3.55-3.70 (w. 1H, H-12ab); 3, 95-4.15 (w, 1Η, Η-12'α8); 4.65 (b, 1H, H4a_B); 6.10 (s, 1H, H-8a); 6.506.65 (w, 3H, H- 1/2/7 »)</td>

<td>(Hz)</td><td> (5,5')=17,8 (7, 8)=10,5; (9, 9' )=13,7; (12,12') =15, 4</td><td> (12,12' ) =16,0</td><td> (1,2)=8,2 (12,12')=15,3</td><td> (12,12')=15,1</td><td>(5.5 ') = 16.9 &lt;7a, 9y) = 9.8</td>

13C-NMR (CDCla [* in DMSO-di]; δ (ppm):

86: 24.8 (t, C-5); 31.7 (t, C-9); 41.2 (q, NCH₃); 53.0 (t, C-10); 47.8 (s, C-8a); 55.5 (q, OCH3), 58.8 (t, C-12); 85.5 (d. C-4a); 111.9 (d, C-8), 122.3 (d, C-2); 125.0 (d, C-7); 125.2 (s, Ph-1); 127.5 (d, Ph-2/6); 129.5 (d, Ph-3/5); 132.2 (d. C-1); 132.3 (s. C-12a); 136.2 (s, C-12b);

143.3 (s. C-3a); 143.8 (s, Ph-4); 145.8 (s, C-3); 149.8 (s, C-6)

85 *: 24.5 (t, C-5); 28.1 (q, C (CH3) 3); 32.4 (t, C-9); 41.2 (q, NCHj); 48.2 (s. C-8a); 53.1 (t, C-10); 55.5 (q, OCH3); 59.3 (t, C-12); 79.4 (s E (CH3b); 86.0 (d, C-4a); 111.7 (d, C-8);

121.5 (d, C-2): 125.5 (P, C-7); 131.2 (d, Cl; 128.5 (s, C-12a): 132.5 (s, C-12b); 143.3 (s, C-3a); 145.6 (s, C-3 ); 145.8 (s, C-6); 153.0 (s, CO).

(-) - Alkylgalanti-linear halide

<td>Pro- track</td><td>Summary formula</td><td>Name</td><td>R</td>

<td></td><td>C.₂₂ B, t BrNOj [401.95]</td><td>bromide (-) - pentylgalantamnine</td><td>- ^ ck₃</td>

<td> 91</td><td>These ^ days [358.49]</td><td>(-) -2-dimethylininoethyl galataamine chloride</td><td>, ch₃'ch₃</td>

<td> 92</td><td>CjjHjjCINA [419.97]</td><td>(-) - 2-pyrrolidine-N-ethyl galantammonium chloride</td><td></td>

<td> 93</td><td>C.₂oH3₂C1C2O3 [435.97)</td><td>(-) -2-morpholine-N-ethylgalanamic chloride</td><td>- &lt;! - \ '-N 0</td>

<td> 94</td><td>C.₂4H_3lC1N2O3 [434.0]</td><td>(-) - 2-piperidine-N-ethyl galanthus chloride</td><td>-ΜΓ)</td>

<td> 95</td><td>C._^oH3iC1C2OJ [448.03]</td><td>(-) - 3-piperidine-N-propylgalanthamine chloride</td><td></td>

<td></td><td>C.₂, H.₂₅BrNO₂ [407,33]</td><td>bromide (- [- nllylogalantamlrium</td><td></td>

190 032

General rule of procedure

800 mg (2.78 mmol) of (-) - allanthamine and 3.84 g (27.8 mmol) of potassium carbonate are placed in 100 ml of acetone. After 1.5 equivalents of the halide and a pinch of potassium iodide had been added, the reaction mixture was stirred under reflux for 24-36 hours. Then the potassium carbonate was filtered off under reduced pressure and the filtrate was evaporated. The oily residue is finally purified by column chromatography in a mixture trichloromethane: ammoniacal methanol (9: 1).

DC: CHCl₃: MeOH (10% NH3) = 9: 1.

<td>Product</td><td>Produce [% of theoretical efficiency]</td><td>* Ooh (25^eC, c = 1)</td><td>Tem^er^at- melting point [° C]</td>

<td></td><td> 71</td><td> -83,7°</td><td> 130-132</td>

<td> 91</td><td> 72</td><td> -46,6°</td><td> 148-150</td>

<td> 92</td><td> 43</td><td> -62,5°</td><td> 120-125</td>

<td> 93</td><td> 94</td><td> -52,8°</td><td>285-22H</td>

<td> 94</td><td> 48</td><td> -70,8°</td><td> 136-140</td>

<td> 95</td><td> 70</td><td> -71,5°</td><td> 126-131</td>

<td></td><td> 41</td><td> -31,0·</td><td> 188-192</td>

* H-NMR [DMSO-d6; δ (ppm)]:

<td>Pro- tone</td><td></td><td> 91</td><td> 92</td><td> 93</td>

<td>Ka-5</td><td>2.10; m</td><td>2.10; m</td><td>2.00; m</td><td>2.00; m</td>

<td>H.-1</td><td> 2,20,^</td><td> 2,30^</td><td>2.50; m</td><td> 2,20^</td>

<td>H.-5</td><td>2.30; m</td><td>2.45; m</td><td>2.55; m</td><td>2.50; m</td>

<td>ch₃-n-</td><td>3.50; p</td><td>2.85; p</td><td>2.95; pp</td><td>3.00; pp</td>

<td>H-1</td><td> 2,70,-(31.0</td><td>2.50; m</td><td>2.65; m</td><td>2.90; m</td>

<td>Hb-6</td><td> 4,^5.;^</td><td>3.10; m</td><td>3.10; m</td><td>3.50; m</td>

<td>H._and- 6</td><td>4.30; m</td><td>3.25 m</td><td>3.80; m</td><td>3.60; m</td>

<td>H-8</td><td>4.90; this year</td><td>4.50; this year</td><td>4.15; this year</td><td>4.15; this year</td>

<td>CH3-O-</td><td>3.85; p</td><td>3.80; p</td><td>3.75; p</td><td>3.80 '; p</td>

<td>Ha-8</td><td>5.85; this year</td><td>5.05; this year</td><td>5.15; this year</td><td>5.10; this year</td>

<td>H-12a</td><td></td><td>4.70; t</td><td>4.65; t</td><td>4.70; t</td>

<td>H-2</td><td> 4,20^</td><td>4.10; m</td><td>3.90; m</td><td>3.90; m</td>

<td>H-3</td><td>6.15; dd</td><td>5.95, -dd</td><td>6.00; dd</td><td>6.05; dd</td>

<td>H-4</td><td>6.45; d</td><td>6.20; d</td><td>6.15; d</td><td>6.20; d</td>

<td>H-9</td><td>6.70; d</td><td>6.80; d</td><td>6, 70; d</td><td>6.75; d</td>

<td>H-10</td><td>7.10; d</td><td>6.90; d</td><td>6.85; d</td><td>6.85; d</td>

cd table

<td rowspan="6">various H.</td><td>0.95 (t, 3H, CH3-)</td><td rowspan="2">3.35 (s, 6H, 2 x CH3-N-)</td><td>1.75 (m, 4) 2x0 *)</td><td rowspan="2">2.50-2.60 (m, 6H, 2 x -ON- *)</td>

<td rowspan="2">1.35-1.50 (m, 4H, 2 x -CH-)</td><td>2.60 (m, 2H, -ON-)</td>

<td>3.40 (t, 2H, -CH-N-)</td><td rowspan="2">3.10 m, 02 x -CH-N- *)</td><td>2.55 (m, 2H, -CH₌-N-)</td>

<td>1.70 (m, 8H, -CHo-)</td><td> 3, 90()2)-1--0-)</td><td rowspan="2">3.0-3.20 (m, 6H, 3 x -OO- *)</td>

<td>2.0 (t, 2H, -N-CH, -)</td><td></td><td>3.80 (m, 2H, -NO-)</td>

<td></td><td></td><td> ’^lpyrilidcela</td><td>'' mirfolina</td>

190 032

<td>Proton</td><td> 94</td><td> 95</td><td></td>

<td> ^,-5</td><td>2.00; m</td><td>1.45; m</td><td> 2,13,-51</td>

<td>h, -1</td><td>7.70; m</td><td>2.00; m</td><td> 2,25,-51</td>

<td>Ht-S</td><td>2.50; m</td><td>2.15 m</td><td>2.50; m</td>

<td>CH3-N-</td><td>3.15; p</td><td>2.85; p</td><td>2.75; p</td>

<td>Hb-1</td><td>2.65; this year</td><td>2.45; this year</td><td>2.50; m</td>

<td>H-6</td><td>3.00; m</td><td>3.30; m</td><td> 3,35,^</td>

<td>H-6</td><td>3.10: m</td><td>3.60: m</td><td>3.35: m</td>

<td>Hb-8</td><td>5.15; this year</td><td>4.45, -br.d</td><td>4.50; m</td>

<td>CH3-O-</td><td>3.85; p</td><td>3.80; p</td><td>3.75; p</td>

<td>H._and-8</td><td>5.40; this year</td><td>5.05, this year</td><td>5.05; this year</td>

<td>H-12a</td><td> 4,65,-6</td><td>4.65, -t</td><td>4.65; t</td>

<td>H-2</td><td>4.15; m</td><td>4.10; m</td><td>4.15, m</td>

<td>H-3</td><td>6.15; dd</td><td>5.95, -dd</td><td>5.90, -dd</td>

<td>H-4</td><td>6.40; d</td><td>6.20; d</td><td>6.20; d</td>

<td>H-9</td><td>6.70; d</td><td>6.75; d</td><td>6.85, -d</td>

<td>H-10</td><td>7.05; d</td><td>6.85; d</td><td> 6,90,0</td>

<td rowspan="5">various H.</td><td>1.40-1.60 (m, 6H, 3x- ^ CH2- *)</td><td>1.50-1.65 (m, 3 x -C ^ - *)</td><td>4.35 (d, 2 ^ -14-0 ^ -)</td>

<td>2.40 (m, 2 x -CH2-N- *)</td><td>2.50 (m, 2H, -C 1 -CH — C 4 -)</td><td>5.70 (m, 1H, - CH 2 H, '</td>

<td>2.95 (m, 2H, -N-Cfc-CHr-N-)</td><td>3.10-3.45 (m, 6H, 3x -C1 -N- *)</td><td>6.30 (m, 1H, -CH2 Kg</td>

<td>4.35 (m, 2H, -N-CH-CH 2 N-)</td><td>3.75 (t, 2H, -NC2 -C2 -C2-)</td><td></td>

<td>'' piperidine</td><td>'' piperidine</td><td></td>

1³C-NMR [DMSO-d₆; 5 (ppm)]:

<td>C- atom</td><td></td><td> 91</td><td> 92</td><td> 93</td>

<td>C-1</td><td>27.9; t</td><td>41.0; t</td><td> 30,8</td><td>28.0; t</td>

<td>C-5</td><td>74.6; t</td><td> 32,1,6</td><td> 31,9</td><td>30.6, t</td>

<td>CH3-N-</td><td> 46,2,^</td><td>44.5, -q</td><td> 43,6</td><td>52.8, q</td>

<td>C-4a</td><td> 46,2^</td><td>4 5, 9, p</td><td> 45,9</td><td>45.9, pp</td>

<td>C-6</td><td>60, l, t</td><td> 51,6,6</td><td> 49,2</td><td>50.2, t</td>

<td>CH.gC</td><td>55.7, -q</td><td>55, 6, -q</td><td> 55,6</td><td>66.0, q</td>

<td>C-8</td><td>60, l, t</td><td>60.3, t</td><td> 60,1</td><td>59, 7, vol</td>

<td>C-2</td><td>60.8, -d</td><td>59.5, d</td><td> 59,5</td><td>59.7, -d</td>

<td>C-12a</td><td>88.0, d</td><td>86.5, -d</td><td> 86,6</td><td>86.8, d</td>

<td>C-3</td><td>112.0, d</td><td>121.1; d</td><td> 112,0</td><td>111.8, d</td>

<td>C-4</td><td> 124,9,^</td><td>123.8, -d</td><td> 123,9</td><td>123.8, d</td>

<td>C-9</td><td>13 (^, 0, d</td><td> 125,2^</td><td> 125,1</td><td>124.8, -d</td>

<td>C-10</td><td>132.3, d</td><td>130, 1: d</td><td> 129,8</td><td>130.0, d</td>

<td>C-8a</td><td>116.0, p</td><td>117.9, p</td><td> 118,0</td><td>117.5, s</td>

<td>C-11b</td><td>132.3; p</td><td>132.7, p</td><td> 132,6</td><td>132.5, pp</td>

<td>C-11a</td><td>146.0, s</td><td>145.4, p</td><td> 145,4</td><td> 145,5,^</td>

cd table

<td>C-11</td><td>146.1, p</td><td>146.4, p</td><td> 146,3</td><td>146.2, p</td>

<td rowspan="5">various C.</td><td>13.5 (q, CH :) -)</td><td>27.5 (q, CH3-N-)</td><td>23.1 ^^, C-3 * iC-4 *)</td><td>51.8 (t,&gt; T-CHz-CHH</td>

<td>21.9 (tCH j-CHa-)</td><td>29.5 (q, CH₃-N-)</td><td>53.4 ί ^ -ΐ · '^^ *)</td><td>55, 4 (ti ^ J-CMz-N- *)</td>

<td>21.9 ° TCH 3 -CH₂-CH₂-)</td><td>49.7 (t, CHN-)</td><td>65.0 (t, -C ^ -N-)</td><td>58.5 and c, -N-CH₂-CH [-)</td>

<td>22.3 (t, -N-CHj-CH, -)</td><td>64.9 (t, -NCH2-)</td><td>6 ^, 9 (t, -Ν ^ Η-)</td><td>60.1 (t ^ -OH- *)</td>

<td>60.1 (t, -N-CH-CH-)</td><td></td><td>'' pyrrolidine</td><td>'' morpholine</td>

190 032

<td>c-</td><td> 94</td><td> 95</td>

<td>c-1</td><td>25.9) t</td><td>30.8; t</td>

<td>C-5</td><td>30.0; t</td><td>40.0; t</td>

<td>CH3-N-</td><td>46.6; q</td><td>45.9; q</td>

<td>C-4a</td><td>46.6; pp</td><td> 54,8)5</td>

<td>C-6</td><td>53.8; t</td><td>55.6) t</td>

<td>CH3-0</td><td>56.2; q</td><td>53.6, -q</td>

<td>C-8</td><td>60.8) t</td><td>59.6; t</td>

<td>C-2</td><td>61.4; d</td><td>59.9) vol</td>

<td>c-12a</td><td> 88,5),</td><td>-6.7) d</td>

<td>C-3</td><td>112.4) d</td><td> 112,0),</td>

<td>C-4</td><td>123.4; d</td><td>123.9) d</td>

<td>C-9</td><td>125.4; d</td><td>125.0) d</td>

<td>C-10</td><td>129.8; d</td><td> 125,0),1</td>

<td> 0-8-</td><td>117.6; p</td><td> 130,0)5</td>

<td>c-iib</td><td>133.0) s</td><td> 132,5)3</td>

<td>C-Iia</td><td>146, i; pp</td><td>145.4; p</td>

<td>C-11</td><td>146.4; p</td><td>146.4; p</td>

<td rowspan="6">various C.</td><td>23.15t, C-4 *;</td><td>19.3 (t, H-CH2-CH2-CH2-H-)</td>

<td>23.9 (t, C-3 * and 0-5 *)</td><td>23.5 (t, C-4 *)</td>

<td>2 4.7 (t, -N-CH₂-CH₂-N-)</td><td>25.0 (,, Ο-3 * from C-5 *)</td>

<td>54.5 (t, C-2 * and C-6 *)</td><td>53.6 (t, C ^ 2 * and C-6 ')</td>

<td>6 0.8 (t, -N - H2-CH2-N-)</td><td></td>

<td>'piperidine</td><td>'' piperidine</td>

(+) - Alkylgalanthamine halide

<td>Product</td><td>Sunaric formula</td><td>Hazwa</td><td>R</td>

<td> 96</td><td>C.₂3H₃₂C1N: O4 [435.97]</td><td>(-) - 2-wrfoline-N-ethylgalanthirninium chloride</td><td>Ά_Ν^/—'D</td>

<td> 97</td><td>C.₂5H36C1H₂O3 [448.03]</td><td>(-) - 3-pyridine-H-propylgalantamino chloride</td><td></td>

General rule of procedure:

800 mg (2.78 g) of (-) - galyntavine and 3.84 g (27.8 g) of potassium carbonate are placed in 100 ml of acetone. After 1.5 equivalents of the halide and a pinch of potassium iodide had been added, the reaction mixture was stirred under reflux. Then the potassium carbonate was filtered off under reduced pressure and the filtrate was evaporated. The oily residue is finally purified by column chromatography in a mixture of trichloromethane and yvoniαkαl methanol (9: 1).

and'"/'''.

In run..M ^ nunMZ. _;

VAiVljUUW.Ł10V / VA ^ AA = y

Q-1

<td>Product</td><td>Capacity [% of theoretical efficiency]</td><td>* ao (25^eC, c = 1)</td><td>Topmeni tenperature [° C]</td>

<td> 96</td><td> 44</td><td>r48.6 °</td><td> 185-190</td>

<td> 97</td><td> 65</td><td>r64.0 °</td><td> 118-124</td>

190 032

N-propargyl galanthamine bromide (99)

IR (Kbr): 3489 s br; 3218 s; ) 014 w: 2915 br; 2133 w; 1619 s; 1507 m; 1440 s; 1274 s; 120) m; 1070 s; 1012 m; 951 m; 865 w; 791s cm'H-NMR (DO) δ: 6.95 (m, 2H); 6.12 (m, 2H); 5.08 (d. 1H); 4.70 (m, 2H); 4.46 (m, 2H); 4.29 (m, 22H) 4.11 (m, 10H) 3.80 ts, 3) H 3.69) (m UH 3.00 ts, 3IH 2.41 (m, 2H); 2.20 ) 0 22,

i) C-NMR (DO) δ: 148.1 (s), 047.9 (s); 134.5 (s); 1) 0.2 (d); 127.7 (d); 127.0 (d); 119.4 (q); 114.7 (d); 89.6 (d); 85.0 (d); 72.0 ss); 67.5 (t); 63.3 ()); 62.0 (d); 61.0 ()); 58.1 (φ; 48.1 ss);

46.3 (q); ) 3.5 (t); 31,) (t).

N-acetamido-galanthamine bromide (100) ¹ H-NMR. (DO) δ: 6.95 (m, 2H); 6.1) (m, 2H); 5.18 (d. 1H); 4.70-4.28 (m, 7H); 3.83 ((f, 1H); 3.08 (s, 3H); 2.50 (d, 1H) - 2.39 (d, 1H);

and³C-NMR (D20) δ: 168.7 (s); 048.2 (s); 048.0 (s); 134.7 (s); 130.2 (d); 128.2 (d); 127.2 (d);

119.5 ¢); 114.3 (d); 89.7 (d); 6, 3 t)); 64.0 ¢); 62.3 (d); 59.6 t)); 58.2 (φ; 4.2.2 (φ; 33.0 tH) 1.3 (t); 18.9 (q).

(-) - galanthamine N-oxide (98):

1.5 g (4.08 ππήο8β) m ^ oia ^ o ^ o ^ o (-) ^ 1 (n-6mayt8 is cleaned with 50 ml of water, mixed with concentrated aqueous ammonia solution and extracted three times with 25 ml of trichloromethane each time. concentrated to a volume of 0-50 ml and treated with 1.4 g (4.08 mmol) of 50% metachloroperbenzoic acid. After 30 minutes, the reaction mixture was evaporated and loaded onto a drill column. The greater part of the metachloroperbenzoic acid is then separated off with trichloromethane, and the N-oxide is eluted with the aid of the system (chloromethane: methanol · = 1: 1. This N-oxide is further purified by MPLC chromatography (60 g SiO ', circulating agent: CHCtyMeOŻ ^). l), whereby colorless crystals of compound 98, mp 80-85 ° C, rotation cd&gt; [MeOH] = - 102.9 ° are obtained.

DC: CHCl): MeOH = 8: 2 ¹ H-NMR (DMSO-to δ (ppm)): 1.75-1.95 (m, 1H, H-9): 2.00-2.40 (m,) H, H-5/5/9 '), 2.95 (s, 3H, NCH₃); 3.) O-), 75 (m, 2H, H -10 / 10 '); 3.75 (s, 3H, OCH); 4.10 (b, 1H, H-12); 4.35 (d, 1H, H-12 '); 4.60 (b, 1H, H-6); 4.95 (broad d, 1H, H-4a); 5.90 (dd, 1H, H-8); 6.15 (b, 1H, H-7); 6 75-6.90 (m, 2H, Hl / 2)¹³C-NMR (DMSO- to δ (ppm)): 31.2 (t, C-5); 34.3 (t, C-9); 45.6 (s, C-8a); 52.5 (q, NCH3): 55.5 (q, OCH3); 59.5 (d. C-6); 69.0 (t, C-10); 73.9 (t, C-12); 86.6 (d. C-4a); 112.0 (d, C-8); 120.0 (s, C-12a); 122.9 (d, C-7); 125.1 (d, C-2); 130,) (d, C-1); 1) 2.0 (s, C-12b); 144.9 (s, C-) a); 146.5 (s, C-3).

(6R) -4a, 5,9,10,11,12-hexahydro-1 bromo -) - methoxy-11-methyl-12-keto-6H-benzofuro - [) a, 3,2-ef] [2] benzoazepinol-6 (102):

A suspension of 450 mg (1.19 mmol) of 4a, 5.9, i0.11, i2-hexahs'dro-i-bromo-3-methoxs'-11-methyl-12-keto-6H-benzof5ro [3a,), 2ef] [2] beneazepmon-6 (101) in 10 ml of absolute tetrαhcdrhfUrαnu is added at 0 ° C with 3.6 ml (3.6 mmol) of a 1N solution of L-Selectrid in tetrahcdrof5ran. After 30 minutes, hydrolysis is carried out with 1: 1 aquabactrahydrofuran. The reaction mixture is then evaporated, the residue is taken up in 80 ml of 2N hydrochloric acid and stirred for 1 hour at room temperature. After that it is extracted three times with 40 ml of ethyl acetate each time. The combined organic layers were washed once with a saturated aqueous solution of sodium chloride, dried (Na2SO4), filtered and evaporated to give quantitatively the crude product which was purified by column chromatography (15 g silica gel, white: fresh? 0 ° C to give compound 1θ2, mp 188-189 ° C.

DC: CHCl): MeOH = 9: 1 ¹H-NMR (CDCl; δ (ppm)); 1.73 (ddd, 1H, H-9, J [beta] = 15.1 Hz); 2.03 (ddd, 1H, H-9 ', J (999 = 15.1Hz); 2.27 (ddd, 1H, H-51, J (₅ 59 = 14. Hz); 2.64 (ddd, 1H, H-5 ', J (5 59 = 14.3 Hz; 3.18 (s, 3H, NCH3); 3.19 (ddd, 1H, H-10, Jpo, 09 = 14.8 Hz); 3.75 (ddd, 1H, H-10 ', Jno 109 =' 4.8 Hz);

190 032

3.86 (s, 3H, OCH₃3; 4.1 (0 (b, 1, H-6); 4, 6-9 (b, 1, H-4a-; 5.48 (d, 1H, H-8, J₍(₈₎= 10.0 Hz);

5.88 (dd, 1H, H-7, J (78) = 10.0 Hz); 7.10 (s, 1H, H -2) &amp; lt; 1 &amp; gt; -NMR -CDClb; Δ (ppm)): 29.8 (1, C-5); 34.1 (q, NCH3); 38.2 (t, C-9): 48.3 (s, C-8a): 48.8 (t, C-10); 56.3 (q, OCH₃); 60.9 (d, C-6); 89.9 (d. C-4a); 113.8 (s, Cl); (118.0 (d, C-8);

123.3 (s, C-12. A), 126.3 (d, C-7); 130.8 (d, C-2), 132.1 (s, C-12b); 144.8 µs, C-3); 146.2 (s. C-3a); 165.1 (s, C-12)

Manufacture of products 105, 107

Method: A mixture of 500 mg (1.42 mmol) of N-desmethylbramogalanthamine2 (4), 391 mg (2.84 mmol) of potassium carbonate and 272 mg (1.70 mmol) of potassium iodide is carefully ground and ground in a porcelain mortar. The mixture is then mixed in 20 ml of absolute acetone with 1.2 eq of the halide reagent and heated to reflux. After completion of the reaction (DC), the reaction mixture is evaporated, the residue is taken up in 100 ml of 2N hydrochloric acid, washed with ethyl acetate, made basic with concentrated aqueous ammonia solution and the precipitate is either filtered off under reduced pressure or extracted three times with 30 ml of ethyl acetate each time. The precipitate is dried at 50 ° C / 50 mbar, the combined organic layers are washed once with a saturated aqueous sodium chloride solution, dried (m 2 SO 4, activated carbon), filtered and evaporated. Further purification was carried out by column chromatography (15 g silica gel; circulating agent: CHCl3 → CHCl2: MeOH = 9: 1.

DC: CHCl₃: MeOH = 9: 1

105:

educt: (4) and (136). Yield: 62.3% of the theoretical amount of a colorless foam.

¹H-NMR (CDCl 2; δ (ppm)): 2.36-1.36 (m, 12H); 2.62 (ddd, 1H); 2.89-3.35 (m, 7H); 3.60 (2H, m); 3.80 (s, 3H); 3.85 (d. 1H); 4.10 (dd. 1H); 4.29 (H, b); 4.48 (d, 1H); 4.56 (b, 1H); 5.90- 6.05 (m, 2H); 6.85-6.69 (4H, m), 7.23 (2H, m)

107:

educt: (4) and (137). Yield: 44.9% of the theoretical amount of a colorless foam.

'H-NMR (CDC'3; δ (ppm)): 1.65-1.85 (4H, m); 2.20-1.90 (m, 6H); 2.60-2.28 (2H, m); 2.62 (ddd, 1H); 2.89-3.35 (m, 5H); 3.60 (2H, m); 3.80 (s, 3H); 3.85 (d. 1H); 4.10 (dd. 1H); 4.20 (H, b); 4.48 (d. 1H); 4.56 (b, 1H); 5.90-6.05 (m, 2H); 6.65-6.30 (4H, m); 7.05-6.83 (2H, m).

Procedure for product 109:

1.25 g of dry THF (139) is heated in 10 ml of 0% to 3 ml of liquid and then refluxing for 30 minutes, the excess thionyl chloride is distilled off, the residue is taken up in 40 ml of anhydrous THF and a spray to a solution of 2.0 g of the compound (4) in 20 ml of THF and stirred for 1 hour under reflux. The reaction solution was evaporated and the crude product was purified by column chromatography (CHCl2 / MeOH 2-5%): 1.75 g (57% of theory) of colorless pieoxS (109).

* H-NMR (CDCl 2; δ (ppm)): 1.65-1.85 (m, 4H); 1.98 (ddd, 1H); 2.25 (b, 2H); 2.67-2.58 (m, 3H); 2.75-2.71 (2H, m); 2.87 (H, dd); 3.05-3.35 (m, 5H); 3.55 (2H, m); 3.67-3.74 (2H, d); 3.80 (s, 3H); 3.85 (d. 1H); 4.10 (dd, 1HH; 4.40 (d, 1H); 4.56 (b, 11T); 5, ^^^^. ^^ (m, 2H): 6.85 (s, 1H), 7.30 (5H, m)

ProgressomeoSa recipe for product 108:

1.0 g of the compound is heated and the water is heated to a state of water in 100 ml of thionyl chloride for 2 hours, the excess of thionyl chloride is distilled off, the rosurome residue is 20 ml of bnzmodongo THF and dropwise onto rostmor 1.33% compound (4) in 20 ml of THF and stirred for 1 hour at room temperature. x 40 ml). The ether layer is odueromized and the suramy product is purified by column 3hromethoaraphy (CHCl₃(MeOH 5%): 1.22 g (56% m2 of theory) of colorless ^ -ο ^ (108).

* H-NMR (CDCl 2; δ (ppm)): 1.63-1.80 (m, 4H); 1.98 (ddd, 1H); 2.20 (b, 2H); 2.61-2.48 (m, 3H); 2.69-2.74 (2H, m); 2.90 (H, dd); 3.02-3.45 (m, 3H); 3.59 (2H, m); 3.60-3.72 (2H, d);

190 032

3.87 (s, 3H); 3.95 (&amp; lt; d, 1H); 4.22 (dd, IIH) M5 (d, 1H); 4.76 ((^, UH) 5.68-6.00 (rn, 2H); 6.95 (s, 1H); 7.10-7.42 (5H, m) "Maritidinone type" 4 , 4a-dihydro-7-bromo-9-methoxy-3-keto (3H, 6H) (5,10b) ethanophenanthridinol-10 (113):

A solution of 4.70 g (13.4 mmol) of N-desmethylbromonarredine (15) and 2.35 g of calcium chloride in 200 ml of 70% ethanol is refluxed for 3.5 hours. The reaction mixture is then concentrated on a rotary evaporator, the residue is taken up in 80 ml of 1N hydrochloric acid and the product is precipitated with concentrated aqueous ammonia solution. After cooling (+ 4 ° C) overnight, the precipitate was filtered off with suction and dried at 50 ° C / 50 mbar. The aqueous layer is extracted three times with ethyl acetate, the combined organic layers are washed once with saturated aqueous sodium chloride solution, dried (Na2SO4₄), filtered and evaporated to give a total of 4.37 g (93% of theory) of colorless crystals of compound 113, mp 185-190 ° C.

DC: EtOAc: MeOH = 8: 2 ¹ H-NMR (DMSO-d ,; δ (ppm)): 1.95 (ddd, 1H, H-11); 2.15 (ddd, 1H, H-11 '); 2.30 (dd, 1H, H-4, J (4 = 16.0 Hz); 2.65 (dd, 1H, H-4 ', J (₄ 4 ') = 16.0 Hz); 2.80 (ddd, 1H, H-12, J₀₂ 120 = 15.1 Hz); 3.05 (ddd, 1H, H-12 ', J_a2 12) = 15.1 Hz); 3.30 (dd, 1H, H-4a); 3.55 (d, 1H, H-6, J (o₆) = 16.9Hz); 3.75 (s, 3H, O-CH3); 3.90 (d, 1H, H-6 ', J (J) = 16.9 Hz); 5.80 (d, 1H, H -2, J (1.2) = 9.3 Hz); 7.00 (s, 1H, H-8); 7.90 (d, 1H, H -1, J_about2), = 9.3 Hz) ¹³C-NMR (DMSO-d ,; δ (ppm)): 38.0 (t, Cl 1); 39.8 (t, C-4); 42.8 (5, C-10b): 53.1 (t, C-12); 55.9 (t, C-6); 56.0 (q, OCH3); 64.1 (d. C-4a); 109.6 (s, C-7); 113.6 (d, C-2); 123.2 (s. C-6a); 126.6 (d, C-8); 129.1 C-10a): 142.9 (s, C-10); 147.5 155.3 (d, C-1); (s, C-3).

3S-4,4a-dihydro-7-bromo-9-methoxy-10-hydroxy- (3H, 6H) (5, 10b) -ethan-phenanthridinol-3 (114):

To a suspension of 1.0 g (2.86 mmol) of a compound of the Maritidinone type (113) in 5 ml of absolute tetrahydrofuran was added dropwise at 0 ° C 10 ml of a 1N solution of L-Selectrid in tetrahydrofuran, followed by rapid heating. to boil against the return of condensate. After 1.5 hours, hydrolysis is carried out at 0 ° C. with 10 ml of tetrahydrofuran-water 1: 1 and the tetrahydrofuran is stripped off in a rotary evaporator. The residue is taken up in 80 ml of 1N hydrochloric acid, made alkaline with concentrated aqueous ammonia solution and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried (Na2SO₄), filtered and evaporated to give quantitatively yellow-colored crystals of compound 114, mp 165-167 ° C.

DC: CHCl₃: MeOH = 9: 1

114 and 3R-2,3,4,4a-tetrahydro-7-bromo-9-methoxy-10-hydroxy- (1H, 6H) (5, 10b) ethanophenanthridinol-3 (116):

1 ml of a solution of L-Selectride in tetrahydrofuran was added dropwise at 0 ° C to a suspension of 100 mg (0.29 mmol) of a Maritidinone compound (113) in 1 ml of absolute tetrahydrofuran and stirred at 0 ° C. After 1 hour, 1 ml of a solution of L-Selectride in tetrahydrofuran was added dropwise, stirred for 2.5 hours at 0 ° C. and for 3.5 hours at room temperature. Then it is hydrolyzed with 2 ml of a 1: 1 mixture of tetrahydrofuran and water, taken up in 50 ml of 2N hydrochloric acid, after brief stirring it is made alkaline with concentrated aqueous ammonia solution and extracted with ethyl acetate. The combined organic layers are washed with a saturated aqueous sodium chloride solution, dried (Na2SO4), filtered and evaporated. Both products were purified by brdiimrirvirAi chromatography (Ίη, "1u iTwminnlrnuipan g / cciikenate C.HCMMeOH = 8: 2). thanks to₄vvn * i 1 ιιχν τ τ wj - —- ςρ— j - /&gt; *. * 30 mg (30% of theory) of colorless crystals of compound 114 and 20 mg (20% of theory) of colorless crystals of compound 116 are obtained.

DC: CHCl3: MeOH = 9: 1

114:

¹H-NMR (CDClb; δ (ppm)): 1.50 (ddd, 1H, H-4); 1.80 (ddd, 1H, H-11); 2.20 (ddd, 1H, H-II); 2.45 (ddd, 1H, H-40; 2.60-2.80 (m, 2H, H-4a / 12); 3.30 (ddd, 1H, H-12 '); 3.60 (d . 1H,

190 032

H-6, J (6 = 17.8 Hz); 3.75 (s, 3H, OCH3); 4.00 (d, 1H, H-6 ',₆₇ = 17.8 Hz); 4.30 (dd, 1H,

H-3); 5.55 (dd, 1H, H -2, J (2.3)) = 98Hz); 6.75 (dd, 1H, -3, J52 3) = 9.8 Hz); 6.80 (s, 1H, H-8). C-NMR (CDCl 3; δ (ppm)): 26.9 (t, C-11); 35.7 (t. 0-4); 37.7 (s. 0-Wb); 47.7 (t, 0-12); 50.7 φ C-6); 51.0.0 ((q OCH₃3; 58.8 (d, C-4a); 62.8 (d, C-3); 1053 (s. C-7); 11 ^^, - 4 (d, C-2); 118.3 (s, C-6a); 124.8 (d, C-8); 125.5 (s, C-10a); 127.4 (d, C-1); 137.9 (s, C-10); 141.3 (s, C-9)

116:

¹H-NMR (CDCl3; δ (ppm)): 1.55-1.95 (v, 4H, H-1/174/11); 2.15 (m, 1H, H-11 '); 2.35 (m, 1H, H -2); 2.60 (dd, 1H, H-4 '); 2.75-2.95 (m, 2H, H-4- / 12); 3.15 (dd, 1H, H -2 '); 3.40 (ddd, 1H, H-120; 3.70 (d, 1H, H-6, J (₆T = 6.2 Hz); 3.85 (d, 3H, OCII3); 4.00 (d, 1H, H-6 ', J (6 g = 6.2 Hz); 4.15 (ddd, 1H, H-3); 6.90 (s, 1H, H-8).

OS-4,4α-dihydro-9-methoxy-10-hydroxy- (3H, 6H) (5, 10b) ethinophenan.tridinol-3 (115):

A solution of 1.0 g (2.84 vol.) Of the compound of the Marititin.u (1i4) type and 2.0 g of calcium chloride in 50 ml of 50% ethanol was added with 4.0 g of freshly activated zinc powder and heated for 2 hours. boils due to condensation return. The excess zinc is then filtered off, washed with methanol and the residue solution is concentrated on a rotary evaporator. The residue is taken up in 80 ml of 1N hydrochloric acid, made alkaline with a concentrated aqueous solution of yvoniic and extracted three times with 50 ml of ethyl acetate each time. The combined organic layers were washed once with a saturated aqueous solution of sodium chloride, dried (Na2SO4, activated carbon) and evaporated to give 450 mg of crude product, which was purified by column chromatography (7 g of silica gel, recycle agent first CHCUMeOH = 8: 2, then CHCl3: MeOH: NH4OH = 49.9: 49.9: 0.2), yielding 270 mg (35% of theory) of red colored crystals of compound 115, m.p.

DC: CHCl3: MeOH = 9: 1 ¹H-NMR (DMSO-d6) δ (ppm)): 1.40 (ddd, 1H, H-4); 1.65 (ddd, 1H, H-11); 2.00 (ddd, H, H-11 '); 2.20 (ddd, 1H, H-4 '); 2.65 (dd, 1H, H-4a); 3.10 (ddd, 1H H, 12); 3.30-3.50 (m, 1H, H-120; 3.45 (d, 1H, H-6, J (6.67 = 15.1 Hz); 3.75 (s, 3H, OCH3 ); 4.05 (d, 1H, H-6 ', J (₆ ') = 15.1 Hz); 4.20 (dd, 1H, H-3); 5.45 (d, 1H, H -2, J₀2) = 8.9 Hz); 6.40 (d, 1H, H -1, J2,) = 8.9 Hz); 6.65-6.75 (v, 2H, H -? F); 8.40 (b, 1H lists D, O, Ph-OH)ⁿO-NMR (DMSO-d; δ (ppm)): 32.2 (t, 0-11); 41.1 (t. 0-4); 42.7 (s, 0-10b); 52.3 (t, 0-12); 54.6 (t, C-6); 55.8 (q, OCH₃); 64.1 (d. C-4a); 67.1 (d. C-3); 109.4 (d, 0-7); 115.8 (d, 0-2); 124.9 (s, C-6a); 129.9 (s, C-10a); 130.2 (d, 0-8); 132.5 (i, 0-1)) 143.7 (s, C-10); 146.0 (s, C-9).

[4aS- (4aa, 6p, 8aR *)] -4a, 5, 9, i0,1i, i2-he ^ a ^; ^ (Ł ^ i ^^ - ^ '^^ i ^ to ^^^ ii- metyi ^^ 1-nitro-6H-benzofuro ^ a, 3, 2-ef] [2] benzoazepinol-6 (117):

A mixture of 0.5 ml of fuming nitric acid and 2 ml of glacial acetic acid is added dropwise to a solution of 250 mg (0.87 vol) of gynthyltin in 10 ml of glacial acetic acid at 15-20 ° C. After 1 hour of stirring at room temperature, a further 0.25 ml of fuming nitric acid in 1 ml of glacial acetic acid was added dropwise and stirring was continued for 1 hour. Then it is poured into 80 ml of water and made alkaline with 40% sodium hydroxide solution. The aqueous layer is extracted three times with 30 ml of ethyl acetate each time. The combined organic layers were washed once with a saturated aqueous sodium chloride solution, dried (Na2SO4), filtered and evaporated to give 252 mg (87% of theory) of yellow colored crystals of Compound 117, mp 48-50 ° C.

DC: CHChpMeOH = 9: 1

ZH-NMR (ODCl3; δ (ppm)): 1.67 (ddd, 1b, H-9); 1.95-2.30 (v, 2H, H-5/91; 2.20 (ddd, 1H H-5 ') 2 44 (s. 3H NCH3 2.91 (ddd. 1H, H-10); 3.18 (ddd. 1H. H-10 '); 3.87 (s, 3H, OCH3); 4.01' (0.1H, H-12); 4.16 (dd, 1H, H-6)) 4.32 (d, 1H, H-12 '); 4.68 (b, 1H, H-4a); 6.04 (dd, 1H, H-8); 6.16 (d, 1H, H-7); 7.35 (s, 1H, H -2)¹³C-NMR (CDCl · j; [delta] (ppm)): 29.6 (t, C-5); 33.3 (t, C-9); 43.6 (q, NOH3); 48.5 (s, Ο -, -);

53.4 (t, 0-10); 54.4 (t, 0-12); 56.1 (q, OOH 3); 61.4 (d, 0-6); 89.6 (s, 0-4a); 108.9 (d, C-8);

126.5,)), 126.9,)), 1283 (d, 0 --- 7), 134.8 Q, Q, 143.4 QO

[4aS- (4a, α, 6β, 8yR *)] - 4y, 5,9,10,11,12-hexyhydro-1-yvmo-O-vethoxy-11-methyl-6H-benzofuro [3 a3,2- ef] [2] benzoazepinol-6

190 032 (Π8):

To a solution of 200 mg (0.60 mmol) of compound 117 in 10 ml of methanol, a solution of 420 mg (2.41 mmol) of sodium dithionite in 10 ml of water was added dropwise at room temperature and stirred for 1 hour. The methanol is then stripped off in a rotary evaporator, the residue is taken up in 50 ml of water, made basic with concentrated aqueous ammonia solution and extracted five times with 30 ml of trichloromethane each time. The combined organic layers were washed once with a saturated aqueous sodium chloride solution, dried (Na₂SO₄), filtered and evaporated to give 148 mg (82% of theory) of yellow-colored crystals of compound 118, mp 151-153 ° C.

DC: CHCl₃: MeOH = 9: 1 'H-NMR (CDCl₃; δ (ppm)): 1.59 (ddd, 1H, H-9); 1.90-2.10 (m, 2H, H-6 '); 2.43 (s, 3H, NCH₃); 2.62 (ddd, 1H, H-50 2.96 (ddd, 1H, H-1O); 3.20 (ddd, 1H, H-10 '); 3.70 (d, 1H / H-12) 3.79 (s, 3H, OCH₃); 4.10 (d, 1H, H-12 '); 4.52 (b, 1H, H-4a); 5.98 (dd, 1H, H-8); 6.08 (d, 1H, H-7); 6.16 (s, 1H, H -2).

New substituted rules bridged:

<img file="PL190032B1_D0021.tif" />

<td>Substitution No.</td><td>J-No.</td><td>Bj2</td><td></td>

<td></td><td></td><td></td><td></td>

<td> 120</td><td></td><td>benzyl</td><td>p-nitrophenyl</td>

<td> 121</td><td></td><td>benzyl</td><td>p-aitu.no phenyl</td>

<td> 122</td><td></td><td>benzyl</td><td>p-chlorophenyl</td>

<td> 123</td><td></td><td>benzyl</td><td>p-hydroxyphenyl</td>

<td> 124</td><td></td><td>benzyl</td><td>o-mtrophenyl</td>

<td> 125</td><td></td><td>benzyl</td><td>o-arM.no phenyl</td>

<td> 126</td><td></td><td>benzyl</td><td>o-chiorophenyl</td>

<td> 127</td><td></td><td>benzyl</td><td>o-dimethylarino phenyl</td>

<td> 128</td><td></td><td>p-Ts</td><td>phenyl</td>

<td> 129</td><td></td><td>H.</td><td>phenyl</td>

<td> 130</td><td></td><td>p-Ts</td><td>p-methyl phenyl</td>

<td> 131</td><td></td><td>H.</td><td>p-methyl phenyl</td>

<td> 132</td><td></td><td>p-Ts</td><td>p-chlorophenyl</td>

<td> 133</td><td></td><td>H.</td><td>p-chlorophenyl</td>

<td> 134</td><td></td><td>p-Ts</td><td>p-fluorophenyl</td>

<td> 135</td><td></td><td>H.</td><td>p-fluorophenyl</td>

<td> 136</td><td></td><td>-ch_;-ch₂-ch₂-ci</td><td>phenyl</td>

<td> 137</td><td></td><td>-ch₂-ch₂-ci</td><td>p-fluorophenyl</td>

<td> 138</td><td></td><td>-ch₂-ch₂-oh</td><td>t-BOC</td>

<td> 139</td><td></td><td>-CH.-CH.-OH</td><td>benzyl</td>

<td> 140</td><td></td><td>-ch₂-cn</td><td>benzyl</td>

<td> 141</td><td></td><td>-ch₂-ch₂-nh₂</td><td>benzyl</td>

<td> 142</td><td></td><td>-ch₂-ch₂-cn</td><td>benzyl</td>

<td> 143</td><td></td><td>-ch₂-ch₂-ch₂-nh₂</td><td>benzyl</td>

<td> 144</td><td></td><td>-CH₂-COOEt</td><td>benzyl</td>

<td> 145</td><td></td><td>t-BOC</td><td>-CH (Ph)_with</td>

190 032

5-benzyl-2-74-oStrophenyl) -2,5-diezebicycph [2.2.0] hnpteo (120)

To a solution of 5.30 g of 2-bonzyl-2,5-di-sabScycle [2.2 g] heptαou x 2 Hbr in 20 ml of anhydrous DMSO are added 3.97 g of dried, fine K2CO3 and 2.03 g of 4-fluoroitrabenzene. Then, for 3 hours, megoet23zoSe is stirred at 80 ° C, poured into 100 ml of water, the precipitated crystals are filtered off under reduced pressure, washed with dmuizouropylamate ether and dried under vacuum: 4.10 g of compound (120) in the form of colorless crystals⁷ (92% of theory). Water temperature: 170-173 ° C. DC: toluoo / acotoo (1: 1) or CHCb.

1 H-NMR (CDCl 3): 8.10 (2H, d); 7.35-7.2 (5H, m); 6.45 (2H, d); 4.40 (1H, m); 3.75 (2H, s); 3.65 (1H, b); 3.45 (2H, dd); 2.95-2.30 (2H, dd); 2.10; 1.85 (2H, dd) i'C-NMR (CDCl3): 151.14; 139.01; 136.55; 128.26; 126.97; 126.35; 110.42; 60.42; 58.28; 58.191; 53.17; 35.78.

5-bnnzyl-2- (4-eminophenyl) -2,5-diezebi3ykfo [2.2.1] heuten (121):

4.1 g of the compounds (I20) in 36, ml of Caml and 20 nd holy carbonate were intensively converted to reflux with 5 g of NH4Cl and 7 g of iron powder for 4 hours in meruokas of mechanical agitation. The reaction solution is filtered through a mixture of η-ϋΐο Celito and activated carbon, evaporated, taken up with 100 ml of water, adjusted to pH 10 with K2CO3 and extracted with diethyl ether (4 x 50 ml). The combined organS3SOo mersties are dried over N-2SO4, evaporated and distilled under a reflux condenser (frost α: 160-170 ° C / 5 mbar): 3.0 g (81% of theory) of Compound (121) as a colorless oil.

DC: CHCL / meteool (9: 1).

U-NMPRjCDCl2): 7.35-7.15 (5H, m); 6.65 (2H, d); 6.45 (2H, d); 4.15 (1H, m); 3.70 (2H, s); 3.50 (H1 m) 3.40; 3.30 (2H, dd); 3.20 (2H, b); 2.90; 2.70 (2H, dd); 2.05-1.85 (2H, dd)

-boozyl-2- (4-3-chlorophenyl) -2,5-diazabicyclo [2.2,1] hoptene (122)

1.5 g of the concentric (121) is present in 2% soaked HCl in the femwrtatkpor 0 ^ 0 μm dripped into a solution of 0.38 g of NaNOz in 3 ml of water, so that the temperature is kept below 5 ° C. Then this solution was poured into a CuCl solution prepared from 1.61 g of CuSO, x 5H2O, 0.41 g of NaCl, 0.39 g of N-HSO3 and 0.23 g of NaOH in 10 ml of HCl and heated at temperature for 4 hours. 50 ° C. It is then poured into 100 ml of water, made alkaline with K2CO₃ and extr-Hujo to ethyl ethers (5 x 100 ml). As a result of R-Romani and condensation distillation. ball (glass temperature 135 ° C / 5 mbar), 0.6 g (37% of theory) of the compound (122) is obtained in uoste3S colorless oil.

DC: CHCl3 / meteool (9: 1).

¹H-NMR 7 CDCl 3): 7.40-7.15 (7H, m); 6.90; 6.50 (2H, m); 4.25 (1H, m); 3.70 (2H, s); 3.60-3.45 (H1 m); 3.45-3.30 (2H, m); 2.95; 2.70 (2H, dd); 2.10-1.80 (2H, m).

5-beoz-2lo-Ζ- (4-hydrox2fonyl) -2,5-di-zabicyclop.i. ^ Hept-o (123)

0.35 g is slowly added dropwise to a 'Hg solution of compound (122) in 17 ml of concentrated HCl

NamO2 in 5 ml of water such that the temperature is kept below 5 ° C. The m-ntouoio is stirred for 2 hours at 60 DEG C. geruhrt, this solution is neutralized with NaHCO3 and extracted with ethyl ether (4 x 50 ml). The combined organic merstm2 is dried with NazSOr, adperomajo and distilled under a ball condenser (temperature 140 ° C / 0.05 hPa): 0.1 g of compound (123) as a natural oil (7.5% of theory) .

DC: CHCl3 / meteool (9: 1).

1 H-NMR (CDCl) b): 7.50-7.00 (8H, m); 6.85-6.40 (2H, m); 4.25 (1H, m); 3.80-3.30 (5H, m); 3.05-2.65 (2H, m); 2.05; 1.90 (2H, dd)

-υνι. ^^. ιν^-^^ χ «'ΐ ^ ιιν ± νΆΐ) χν ^'

17.6 g of dried, finely triturated K2CO3 and 9.0 g of β-fluorooitrobeozone are added to a solution of 22.3 g of 2-beoz2lo-2,5-diazebS3yclo [2.Ζ.1] heptαou x 2 HBr in 110 ml of anhydrous DMSO . Then it is magnetically stirred at the temperature for 3 hours at 80 ° C, ml is poured into 300 ml of water, the precipitated crystals are filtered off under reduced pressure, washed with disopropyl ether and dried in vacuo: 19.1 g of compound64

190 032K (124) as colorless crystals (96.9% of theory), mp: 107-108 ° C.

DC: toluene / acetone (1: 1) or I WANT to:

'Η-NMR (CDC1₃): 7.75 (H, d); 7.35 (H, d); 7.30-7.15 (5H, m); 6.85-6.70 (2H, m); 4.30 (H1 m); 3.65 (2H, s); 3.55 (2H, m); 2.90 (2H, dd), 2.85 (H, m), 2.00 (2H, dd).

5-benzyl-2- (2-aminophenyl) -2,5-diazabicyclo [2.2.1] heptane (125)

5.0 g of compound (124) in 360 ml of ethanol and 20 ml of water are refluxed with 4 g of NH4Cl and 6.7 of powdered iron under mechanical stirring. The reaction solution is filtered through a pad of Celite and activated charcoal, evaporated, quenched with 100 ml of water, adjusted to pH 10 with K2CO3 and extracted with diethyl ether (4 x 50 ml). The combined organic layers are dried over Na₂SO4, evaporates and distills under a ball condenser (boiling point: 160-170 ° C / 5 mbar): 2.20 g (48.8% of theory) of the compound (121) as a colorless oil.

DC: CHCl2 / methanol (9: 1).

&amp; Lt; 1 &amp; gt; -NMRiCDCb): 7.45-7.20 (5H, m); 7.05-6.65 (4H, m); 3.95-3.65 (5H, m); 3.60-3.40 (2H, m); 3.20-3.00 (H1 m); 2.95-2.75 (2H, m), 2.00-1.85 (2H, m).

5-benzyl-2- (2-chlorophenyl) -2,5-diazabicyclo [2.2.1 jheptane (126)

Provision of conduct by analogy to the association (122)

Yield after distillation under a ball condenser (bp 135 [deg.] C / 5 mbar): 0.60 g (37.5% of theory) of the compound (126) as a colorless oil.

DC: CHCl2 / methanol (9: 1).

1 H-NMR 1 CDCl 2): ​​7.50-7.20 (6H, m); 6.85-6.55 (3H, m); 4.25 (H5 m); 3.85-3.70 (2H, s); 3.65-3.50 (H, b); 3.45-3.30 (2H, m); 3.00; 2.75 (2H, dd); 2.15-1.80 (2H, m).

5-benzyl-2- (2-dimethylaminophenyl) -2,5-diazabicyclo [2.2.1 jheptane (127) 5-benzyl-2- (2-methylaminophenyl) -2,5-diazabicyclo [2.2.1 jheptane (127- and)

0.95 g of compound (125) is heated for 2 hours at 160-180 ° C with 0.5 g

PO (OMe) 3, cooled, hydrolyzed with 5ml 30% NaOH, added 10ml water and extracted with ether (3x10ml). Evaporation and column chromatography (CHCl2; methanol 3%) gave 0.15 g of a colorless oil (compound 127-a) (15.6% of theory) and 0.09 g of a colorless oil (compound 107) (8.5 % of theory).

^ -NMR (CDC1₃) (127-b): 74.5-7.20 (5H, m); 7.10-6.95 (2H, t); 6.80-6.00 (2H, dd); 3.90-3.65 (4H, m); 3.65-3.40 (2H, dd); 3.50-2.60 (6H, m); 2.0-1.80 (2H, m). 1 H-NMR (CDCl 2) (127): 7.40-7.20 (5H, m); 6.70-6.55 (3H, m); 6.40 (H1 m); 3.75 (2H, s); 3.80-3.65 (H, m), 3.60-3.55 (2H, dd); 3.45-3.20 (3H, m); 2.90-2.75 (6H, s, s); 2.30-2.15 (2H, dd).

Preparation of phenyl-substituted 2,5-diazabicyclo [2.2.1 jheptanes:

<td>No</td><td>Performance</td><td>Melting point / / Boiling point</td><td>DC</td><td>Method</td>

<td> 128</td><td> 62,5%</td><td> 139-143*0</td><td>petroleum ether / EtOAc (7: 3)</td><td>AND</td>

<td> 129</td><td> 71%</td><td>120-130'C / O, 05 hPa</td><td>DC: CHCl3 / methanol (9: 1)</td><td>B</td>

<td> 130</td><td> 46%</td><td>149-151'C</td><td>DC: Petroleum Ether / EtOAc (7: 3)</td><td>AND</td>

<td> 131</td><td> 65%</td><td>130-140 * C / 0.05 hPa</td><td>DC: CHCl3 / methanol (9: 1)</td><td>B</td>

<td> 132</td><td> 69%</td><td>214-217'C</td><td>DC: Petroleum Ether / EtOAc (7: 3)</td><td>AND</td>

<td>them</td><td>cca «/ v 0</td><td>120-130 * 0 / 0.05 hPa</td><td>nC: CHCl3 / methanol (9: 1)</td><td>B</td>

<td> 134</td><td> 55%</td><td>180-184'C</td><td>DC: Petroleum Ether / EtOAc (7: 3)</td><td>AND</td>

<td> 135</td><td> 74%</td><td>120-130 * C / 0.05 hPa</td><td>DC: CHCl₃/ methanol (9: l)</td><td>B</td>

190 032

Method (A) for cyclization of tritosyl-4-hydroxyprolinol:

g (35 mmol) of tritosyl-4-hydroxyprolinol are heated with 75 ml of toluene, 9.8 g (100 mmol) of triethylamine and 35 mmol of an appropriately substituted aniline (freshly distilled or cross-crystallized) in a steel autoclave for 3 hours at 160-170 ° C. After cooling and opening the autoclave, the product is rinsed from the autoclave with 100 ml of toluene, shaken once with 100 ml of saturated NaCl solution and once with 100 ml of saturated NaHCO solution.₃and the organic layer is dried over Na2SO4 and evaporated. The crystalline product is leached warm with isopropanol, filtered and dried.

Method (B) for cleaving the p-Ts protecting group 2.5 g of educt is stirred at 80 ° C for 2 hours in 40 ml of glacial acetic acid and 20 ml of concentrated sulfuric acid. Then poured into 200 mL of ice water, extracted with EtOAc (2 x 100 mL) (the EtOAc layer was discarded), the aqueous layer was quenched with 30% NaOH until pH = 12 and extracted with EtOAc ( 6 x 50 ml). This layer in ethyl acetate is evaporated and distilled under a ball condenser: a colorless oil.

NMR spectra:

5-phenyl-2-p-tosyl-2,5-diazabicyclo [2.2.1] heptane (128)

1 H-NMR (CDCl₃): 7.68 (2H, d); 7.29 (2H, d); 7.18 (2H m); 6.72 (H, t); 6.4 (2H, dd); 4.51 (H, b); 4.32 (H, b); 3.52 (2H, dd); 3.24 (2H, dd); 2.42 (3H, s); 1.86 (H, d); 1.40 (H, d).

13 C-NMR (CDCl 3): 146.18; 143.49; 135.27; 129.66; 129.10; 127.18; 116.84; 112.39; 59.98; 56.91; 56.52; 52.25; 36.50; 21.37.

2-phenyl-2,5-diazabicyclo [2.2.1] heptane (129) 1 H-NMR (CDCl₃): 7.23 (2H1 m); 6.71 (3H, m); 4.30 (H, b); 3.78 (H, b); 3.66 (H, dd); 3.18-2.89 (3H, m); 2.06-1.78 (3H, m).

'3 C-NMR (CDCl 3): 146.92; 129.09; 116.08; 112.41; 59.78; 56.62; 56.22; 49.65; 37.18 5- (4-methylphenyl) -2-p-tosyl-2,5-diazabicyclo [2.2.1] heptane (130) 1 H-NMR (CDCl 3): 7.68 (2H, d); 7.27 (2H, d); 7.00 (2H, d); 6.36 (2H, d); 4.49 (H, s);

4.25 (H, s); 3.53 (H, d); 3.46 (H, dd); 3.26 (H, dd); 3.17 (H, d); 2.41 (3H, s); 2.24 (3H, s); 1.83 (H, d); 1.38 (H, d).

13 C-NMR (CDCl 3): 144.09; 143.44; 135.35; 129.63; 127.30; 125.96; 112.55; 60.02; 57.06; 56.73; 51.99; 36.46; 21.36; 20.16.

2- (4-methylphenyl) -2,5-diazabicyclo [2.2.1] heptane (131):

^]H-NMR (CDCl3): 7.05 (2H, d); 6.48 (2H, d); 4.25 (H, s); 3.77 (H, s); 3.68 (H, dd); 3.16 (H, dd); 3.02 (H, dd); 2.92 (H, dd); 2.24 (3H, s); 1.95 (H, d); 1.82 (H, b); 1.80 (H, d).

5- (4-chlorophenyl) -2-p-tosyl-2,5-diazabicyclo [2.2.1] heptane (132) 1 H-NMR (CDCl 3): 7.52 (2H, d); 7.13 (2H, d); 6.96 (2H, d); 6.22 (2H, d); 4.38 (H, s);

4.12 (H, s); 3.40-3.29 (2H, m); 3.12 (H, dd); 3.03 (H, dd); 2.30 (3H, s); 1.73 (H, d); 1.28 (H, d).¹³C-NMR (CDCl3 / DMSO): 144.70; 143.30; 134.58; 129.44; 128.40; 126.77; 120.58;

113,34; 59,60; 56,73; 56,44; 51,81; 36,09; 21,00.

2- (4-chlorophenyl) -2,5-diazabicyclo [2.2.1] heptane (133) ¹H-NMR (CDCl3): 7.14 (2H, d); 6.45 (2H, d); 4.23 (H, s); 3.76 (H, s); 3.62 (H, d); 3.08 (H, d); 3.00 (H, d); 2.89 (H, d); 1.92 (H, d); 1.81 (H, d); 1.56 (H, b).

13 C-NMR (CDCl 3): 145.53; 128.78; 120.56; 113.44; 59.77; 56.83; 56.19; 49.50; 37.26. 5- (4-fluorophenyl) -2-p-tosyl-2,5-diazabicyclo [2.2.1] heptane (134) 1 H-NMR (CDCl 3): 7.68 (2H, d); 7.27 (2H, d); 6.82-6.95 (2H, m); 6.40-6.29 (2H, m);

4.49 (H, s); 4.23 (H, s); 3.52 (H, d); 3.46 (H, dd); 3.25 (H, dd); 3.13 (H, d); 2.41 (3H, s);

O ^ / TTJ \. 1 4 1 / TT ι, ου^AND&gt;^on k^AA&gt;

1³C-NMR (CDCl2): 157.63; 152.96; 143.56; 142.80; 142.77; 135.21; 129.65; 127.17; 115.73; 115.29; 113.20; 113.05; 59.97; 57.35; 56.93; 51.79; 36.60; 21.34.

2- (4-fluorophenyl) -2,5-diazabicyclo [2.2.1] heptane (135). 1 H-NMR (CDCl 3): 7.05-6.83 (2H, m); 6.52-6.28 (2H, m); 4.20 (H, s); 3.76 (H, s);

3.64 (H, dd); 3.10 (H, d); 3.00 (H, dd); 2.88 (H, d); 1.96 (H, d); 1.81 (H, d); 1.76 (H, b).

190 032

1³C-NMR (CDCl3): 157.27; 152.63; 143.61; 115.67; 115.32; 113.13; 112.98; 60.21; 57.04; 56.27; 49.21; 37.29.

- (3-chlorosropyl) -2-fouyl-2,5-diazabicyclo [2.2.1 phteptane (136):

1.0 g (5.7 mmol) of compound (129), 0.23 g (5.7 mmol) of sodium amide and 20 ml of toluene are refluxed for 1 hour. Then 0.93 g (5.7 mmol) of 1-brome-3-chloropropau in 10 ml of toluene was added dropwise over 20 minutes and refluxed for 2 hours, after cooling it was extracted with 2N HCl. (2 x 50 mL), the aqueous layer is analyzed with 30% NaOH and extracted with toluene (3 x 40 mL). Evaporation and distillation under a condenser (boiling point: 120-130 ° C / 0.05 mbar) gave 0.97 g (70.4% of theory) of the compound (136) as a colorless oil.

DC: CHCl3 / methanol (9: 1)

1 H-NMR (CDC 3): 7.19 (2H, m); 6.69 (3H, m); 4.27 (H, b); 3.68 (H, b); 3.60 (H, dd); 3.18-2.89 (5H, m); 2.36-1.36 (7H, m).

5- (2-chloroethyl) -2- (4-fluorophenyl) -2,5-diazabicyclo [2.2.1] heptane (137):

1.0 g (5.2 mmol) of compound (135), 0.21 g (5.3 mmol) of sodium amide and 20 ml of toluene are refluxed for 1 hour. Then 0.77 g (5.2 mmol) of 1-bromo-3-chloroethane in 10 ml of toluene is added dropwise over 20 minutes and refluxed for 2 hours, after cooling it is extracted with 2N HCl. (2 x 50 mL), the aqueous layer was basified with 30% NaOH and extracted with toluene (3 x 40 mL). As a result of evaporation and distillation under the condenser. ball (boiling point: 100-120 ° C / 0.05 mbar), 0.76 g (56.7% of theory) of the compound (137) is obtained as a colorless oil.

DC: CHCl3 / methanol (9: 1)

1 H-NMR (CDCl 3): 7.05-6.83 (2H, m); 6.52-6.28 (2H, m); 4.20 (H, s); 3.76 (H, s); 3.64 (H, dd); 3.10 (H, d); 3.00 (H, dd); 2.88 (H, d); 2.66-2.28 (2H, m); 2.20-1.90 (2H, m); 1.96 (H d)) 1.81 (H, d)) 1J6 (H, b).

2-t-Boc-5- (2-hydroxyethyl) -2,5-diazabicyclo [2.2.1 ^ eptane (138)

To a solution of 2.5 g of 2-t-Boc-2,5-dSacabicyclo [2.2.1] heptane in 50 m of methanol under stirring at 20 ° C, gaseous ethylzium oxide is slowly introduced over 1.5 hours, the the temperature rises to 35 ° C. This solution is evaporated and the crude oily product is distilled (boiling point: 90-100 ° C / 0.05 hPa) under a condenser: 1.60 g of compound (138) as a colorless oil (52.5% of theory) .

¹H-NMR (CDCl3): 4.31 (H, d); 3.54 (2H, t); 3.40 (H, d); 3.18 (H, dd); 2.92 (H, dd); 2.73 (2H, m); 2.56 (H, d); 1.84 (H, d); 1.72 (H, d); 1.54 (9H, s)

13 C-NMR (CDCl 3): 157.80; 79.21; 61.76; 61.24; 59.82; 59.68; 56.40; 56.09; 55.73; 55.43; 49.95; 49.21; 36.01; 35.36; 28.27.

2-bzucyl-5- (2-hydroxyethyl) -2,5-diazabicyclo [2.2.1) heptau (139)

Recipe for dealing: see relationship (138).

Yield: 83.3% of theory of Compound (139) as a colorless oil, bp 120-130 ° C / 0.005 mbar.

1 H-NMR (CDCl 3): 7.30 (5H, m); 3.67-3.74 (2H, d); 3.55 (2H, m); 3.30 (2H, b); 3.20 (H, b); 2.87 (l ^, ddj) 2, ^^ (H, dc ^ j) 2.71 (H, ()) 2.67 (22i, m)) 1/778 (H, m)) 1166 ( H, m).

13 C-NMR (CDCl 3): 139.63; 128.29; 128.09; 126.65; 62.49; 61.16; 59.80; 58.19; 56.45; 56.26; 56.19; 33.64.

2-bonkyl-5-cyanomethio-2,5-diazabicykio12.2.1] hzptau (140)

To a solution of 3 g of 2-benzyl-2,5-dacabicyclo [2.2.1] heptane in 40 ml of anhydrous toluene, 3 g of dried, finely triturated K2CO3 and 1.3 ml of freshly distilled chloroacetyl is added, and the mixture is heated to reflux against reflux for 10 hours under vigorous stirring. This solution is cooled, filtered and evaporated. Distillation under a ball condenser (boiling point: 110-120 ° C / 0.01 mbar) gives 3.57 g of the compound (140) as a colorless oil (97% of theory).

190 032 ¹H-NMR (CDO13): 7.41-7.18 (5H, v); 3.65; 3.75 (2H, d); 3.53) 3.46 (2H, d); 3.45 (H, b); 3.37 (H, b); 3.04 (H, d); 2.73 (H, d); 2.71 (H, dd); 2.68 (H, d); 1.82 (H, d); 1.77 (H, d).

¹³C-NMR (ODCl3): 139.41; 128.08; 127.92; 126.51; 117.03; 62.47; 61.39; 57.97; 57.09; 55.97; 41.23; 33.00.

2-benzyl-5- (2-yvinoethyl) -2,5-dizybicyclo [2.2.1] heptyne (141)

A solution of 5.74 g (25.3 vol) of compound (140) and 50 ml of NH3 in methanol was hydrogenated with 2 g of Raney nickel in a steel autoclave at 100 ° C under 10 MPa of hydrogen for 2 hours. The catalyst is filtered off under reduced pressure, the solution is evaporated and distilled under a ball condenser (boiling point: 135-145 ° C / 0.01 mbar): 5.02 g of the compound (i4i) as a colorless oil (7% of theory).

Ή-NMR 50 DCtο): 7.18 (5H, v); 3.70 (2H, d); 3.23 (2H, b); 2.69-2.42 (8H, v); 1.71 (H, ddd); 1.65 (H, ddd); 1.70 (2H, b).

i3C-NMR (CDO13): 139.62; 127.92; 127.65; 126.19; 62.15; 61.15; 57.92; 57.30; 56.19; 55.91; 40.80; 33.32.

1-benzyl-5-cyanoethyl-2,5-diazabicyclo [2.2.1] heptane (142)

2.5 g of freshly distilled acrylonitrile are added to a solution of 3 g of 2-benzyl-2,5-diazibicyclo [2.2 η] heptyne in 40 ml of anhydrous toluene and the mixture is refluxed for 24 hours under vigorous stirring. This solution is cooled, filtered and evaporated. Distillation under a ball condenser (boiling point: 120-130 ° C / 0.01 hPa) gives 3.43 g of compound (142) as a colorless oil (88% of theory) .

³H-NMR (OD013): 7.39-7.17 (5H, m); 3.70 (2H, d); 3.30 (H, b); 3.26 (H, b); 2.88-2.59 (4H, v); 2.74 (H, d); 2.63 (H, dd); 2.42 (2H, t); 1.75 (H, dd); 1.64 (H, dd ,.

¹³O-NMR (OD01.0): 139.50; 128.17; 127.99; 126.57; 118.64; 62.40; 61.15; 58.68; 56.59; 55.91; 49.77; 00.66; 18.21.

2-benzyl-5- (2-avinopropyl) -2,5-diizabicyclo [2.2.1] heptane (143)

Analogous to the relationship (141)

Yield: 83.7% of the theoretical capacity of a colorless oil, boiling point 120-130 ° Ο / 0.01 hPa.

¹H-NMR (OD013): 7.18 (5H, m); 3.70 (2H, d); 3.31 (H, b); 3.16 (H, b); 2.91-2.48 (8H, m); 2.22 (2H, b); 1.71 (2H, v); 162 (H, d), 149 (H, d) i³O-NMR (OD013): 139.46; 127.76; 127.54; 126.03; 61.55; 60.90; 57.76; 56.08; 55.32; 51.58; 39.99; 33.05; 31.97.

2- (5-benzyl-2,5-dizybicyclo [2.2.1] heptyl) ethyl acetate (144)

To a solution of 3 g of 2-benzyl-2,5-dizybicykte [2.2.1] heptane in 40 ml of anhydrous toluene, 2.5 g of ethyl brovoacetate and 3 g of dried, finely ground K2OO3 are added and the mixture is heated to reflux for 8 hours to reflux under vigorous stirring conditions. This solution is cooled, filtered and evaporated. Distillation under a ball condenser (boiling point: 125-130 ° C / 0.01 mbar) gives 1.79 g of the compound (144) as a colorless oil (40% of theory) and³O-NMR (OD013): 170.96; 139.44; 128.14; 128.03) 126.62; 62.31; 61.64; 60.36; 58.06; 56.90; 55.47; 55.33; 33.74; 14.03.

2-t-Boc-5-diphenylvethyl-2,5-dizybicyclo [2.2.1] heptane (145)

0.8 g of triethyloyvinyl and 1.55 g of diphenylmethyl chloride are added to a solution of 1.5 g of 2-t-Boc-2,5-diazabicyclo [2.2.1] hepane in anhydrous THF, and the mixture is stirred for 4 hours while in anhydrous state. boiling against reflux. The THF is then evaporated off, dispersed_init is loaded with 50 ml of saturated NaHCO2 solution and extracted three times with 30 ml of diethyl ether each time. Evaporation gives 2.2 g of yellowish crystals of compound (145) (78% of theory).

Ή-NMR (OD0tο): 7.48-7.11 (10H, m); 4.81 (H, b), 4.31 (H, d); 3.40 (H, d); 3.18 (H, dd); 2.92 (H, dd); 2.56 (H, d); 1.84 (H, d); 1.12 (H, d); 1.54 (9H, s).

190 032

Literature references

1) SY Han, JE Sweeney, ES Bachmann, EJ. Schweiger, JT Coyle, BM Davis, MM Joullie, Eur. J. Med. Chem. 27,673-687 (1992)

2) T. Kametani, K. Yamaki, S. Yaki, K. Fukumoto, J. Chem. Soc. (C), 2602 (1969)

3) T. Kametani, K. Shishido, E. Hayashi, J. Org. Chem., 36, 1259 (1971)

4) T. Kametani, C. Seino, K. Yamaki, S. Shibuya, K. Fukumoto, J. Chem. Soc., 1043-1047 (1971)

5) T, Kametani, K. Yamaki, T. Terui, S. Shibuya, K. Fukumotor, J. Chem. Soc. Perkin I, 513- ^ 51 ^ (1972)

6) T. Kametani, K. Yamaki, T. Terui, J. Het. Chem. 10, 35-37 (1973)

7) J. Szewczyk, A. Lewin, FI Caroll, J. Het. Chem 25, 1809-1811 (1988)

8) R. Vlahov, D. Krikorian, G. Spassov, M. Chinova, I. Vlahov, G. Parushev, G. Snatzke, L. Emst, K. Kieslich, W. Abraham, W. Shedrick, Tetrahedron 45, 3329 (1989)

9) P. Strehlke, GA Hoyer, E. Schroder, E. Arch, Pharm. 388 (2), 94-109 (1975)

10) M. Ishizaki, K. Ozaki, A. Kanematsu, T. Isoda, O. Hoshino, J. Org. Chem. 58, 3817-3885 (1993)

11) C. Nogueiras, W. Dopke, G. Lehmann, Tetrahedron Letters 35, 3249-3250 (1911)

12) HH Wassermann, RJ Gambale, Tertrahedron 48 (35), 7059-7070 (1992)

13) JM Pons, A. Pommier, J. Lerpiniere, P. Kocienski. J. Chem. Soc., Perkin Trans 114, 1549-1551 (1993)

14) T. Kioshi, Yakugaku Zhassi, 104, 1009 (1984)

15) BM Davsis. Pat WO 88/08708 AI (1988)

16) Stichting Biomed. Res., Pat NL 88000350 AI (1989)

17) J. Bastida, F. Viladomat, JM Llabres, S. Quiroga, C. Codina, M. Rubiralta,

Planta Med. 56,123. 1990

18) SJ Han, SC Mayer, EJ Schweiger, BM Davis, MM Joullie, Boorg. Med. Chem. Lett. 1, 579. 1991

19) D. Albrigt, N. Goldmann, Pat. 64,219 (1968)

20) HG Boit, W. Dopke, AW Beitner, Chem. Ber. 90, 2197 (1957)

21) R. Matusch, M. Kreh, U. Muller, Helv. Chim. Acta 77, 1611 (1994)

22) HM Fales, LD Gioffrida, WC Wildmann, J. Am. Chem. Soc. 78, 4145 (1956)

23) S. Kobayasbi, K. Satoh, S. Numata, T. Hingu, M. Kihara, Phytochemistry 30, 675 (1991)

24) RW Kosley, L. Davis, V. Ilberna, Pat. EP A53427 A1 (19957, US 93.137440

25) RW Kosley, L. Davis, Vl T ^ ema, Pt, EP 64 P84E Al (1994 (El S 93137444

26) RW Kosley, L. Davis, T ^ aem ,, Pat. EP 6, P77E Pl (19752, US 13 ^^ 1 ^ U ^ 43

27) WSK Kaiiha, EP 399400 ((990 (JP 82321 ((9899) JP 238064 (19899

28) DL Romero ey, Pat WO 91-09849 (2491), US 90-07390 (1990)

29) JE Arrowsmith, Pat. EP 324543 (1999), GB 8800694 (1488)

30) DG Hutchinson. Stalemate. WO 9923384 (1399), US 95-980435 (1945)

31) PS Portoghese, AA Mikhail, J.Org. Chem. 31, 1059 (1966)

32) TF Braish, DE Fox, J. Org. Chem., 55, 1699-1687 (1490)

99) S. Ziklova, K. Ninov, Tr Nauchniozsled. Khim. Farm.Inst. 12, 35-46 (1992)

34) K. Fujii, K. Tomino, H. Watanabe, J. Pharm. Soc. Japan 74.10 ^ 4 ^ 9-51 (^ H)

35) HG Morren, R. Danayer, R. Linz, J. Mathieu, H. Strubbe, S. Trolin, Ind. Chim. Beige 22, 4C3-416 (1957)

36) DC Jones, MA Winter, KS Hirsch, N. Stamm, H.M. Taylor, J. Med. Chem. 33 (1), 916-429 (1390)

190 032

37) GL Rogoier, CG Guillonneeu, JL Duheult, FP Tisserand, G. Saiot-Romes,

SM Holstorp, Eur. J. Med. Chem 22. 243-250 (1987)

38) GE Martin oe, J. Mod. Chem. 32.1056 (1Z8Z)

39) Z. Budei, Hp-t. HU 61737 (1991)

40) DW Smith, Pet. EP 345808 (1988), US 204845 (1988), US 338253 (1Z8Z)

41) 1. P. YevicH, EP 400661 (1990), US 360657 (1989), US 503197 (1990)

42) TF Breish, Pet. EP 397351 (1990), US 350423 (1989), US 423063 (1Z8Z)

43) published on October 15, 1995, Austrian petontame '980/94 of October 21 ^^ 94

44) GL Ellmeoo, KD Courtney, V. Aodros, RM Feethorstone, Biochom, Pharmacol. 7, 88 (1961).