Process for the preparation of derivatives of 4a, 5, 9, 10, 11, 12-hexahydro-6H-benzofuro(3a, 3, 2- ef)(2)benzazepine

(42) Date of commencement of the patent: 15.10.1995 (45) Date of issue: 25. 6.1996

<td>(56) Documents:</td><td>(73) Patent owner:</td>

<td>WO 8808708A1 US 3673177A</td><td>WALDHEIM PHARMAZEUTIKA SOCIETY MBH A-2491 NEUFELD ADLEITHA, BURGENLAND (AT).</td>

<td></td><td>(72) Inventor:</td>

<td></td><td>CZOLLNER LASZLO DIPL.ING. DR. NEUFELD, BURGENLAFC (AT). FRÖHLICH JOHANNES DIPL.ING. DR. VIENNA (AT). JORDIS ULRICH DIPL.ING. DR. VIENNA (AT). KÜENBURG BERNHARD DIPL.ING. DR. VIENNA (AT).</td>

(54) METHOD FOR PRODUCING DERIVATIVES OF 4A, 5, 9, 10, 11, 12, -HEXAHYDR0-6H-BENZ0FUR0 (3A, -3,2-EF) (2) BENZAZEPINE (57) For preparing derivatives of the

4a, 5,9,10,11,12, -hexahydro-6H-benzofuro [3a, 3,2-ef] [2] benzazepine (I) is a compound (III) with a compound (IV) to the compound (V ) condenses and reduces. &gt; ·

The compound (V) is cyclized oxidatively and then reduced to the compound (I). This is particularly suitable

Process for the preparation of galanthamine.

CQ

AT 401 058 ms eeraeiss

<img file="AT401058B_D0001.tif" />

<img file="AT401058B_D0002.tif" />

AT 401 058 Β

The invention relates to a process for preparing derivatives of the 4a, 5,9,10,11,12-hexahydro-6H-benzofuro [3a, 3,2-ef] [2] benzazepine of the general formula (I)

<img file="AT401058B_D0003.tif" />

or salts thereof, wherein R₂, R₄, Xi, X₂, Yi and Y₂ are either the same or different and are hydrogen, Fluorine, Chlorine, Bromine, Iodine, a hydroxy or alkoxy group, a lower, optionally branched and optionally substituted alkyl group, a lower, optionally branched alkene group, a lower, optionally branched alkyne group, an optionally substituted aryl, Aralkyl or aryloxyalkyl group, whose alkyl chain is optionally branched and whose aromatic nucleus is optionally substituted, a formyl, but also unsubstituted and substituted by one or more halogens, unbranched or branched alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, aralkylsulphonyl, arylsulfonyl, as well as Y, , Ϊ2 = 0 (ketone), where A is a benzene nucleus, optionally one or more times by at least one lower, optionally branched alkyl group, at least one lower, optionally branched alkene group, at least one lower, optionally branched alkyne group, at least one lower, optionally branched alkoxy group, by fluorine, Chlorine, Bromine, Iodine or by several identical or different halogens, at least one alkyl group substituted by one halogen or by several identical or different halogens, such as chloromethyl and trifluoromethyl, at least one optionally substituted aralkyl group and / or at least one hydroxy group, primary, secondary or tertiary amino group nitro group, nitrile, alkylamino, arylamino, aldehyde group, Carboxylic acid group, all derivatives of the carboxylic acid group, like esters, amides, halides, is substituted.

It further relates to a process for preparing derivatives of the 4a, 5,9,10,11,12-hexahydro-6H-benzofuro [3a, 3,2-ef] [2] benzazepine of the general formula (II)

<img file="AT401058B_D0004.tif" />

wherein R₂, R₄, Xi, X₂, Yi and Y₂ and A have the meanings given above for formula (I). T is an organic anion of a pharmaceutically acceptable acid such as tartrate, lactate, citrate, acetate, maleate or an inorganic anion such as fluoride, chloride, bromide, iodide, sulfate, phosphate, chlorate, Rs is hydrogen, a lower, optionally branched alkyl group Aryl group or an optionally branched in the alkyl chain aralkyl group.

Preferred meanings of the substituents R1-R6, Xi,₂, Y_1-2 are

Ri, R2, R3, Rg ^ hydrogen, unsubstituted and substituted by one or more halogens, unbranched or branched alkyl, alkenyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, or any combination of these radicals

AT 401 058 Β

Xi, X₂H, F, Cl, Br, J, t-butyl and any combination

Yi, Y₂: H, 0-R_6i as well as Yi andY₂= O,

R4., Rs = as Ri, R₂, R3, Rg, but also unsubstituted and substituted by one or more halogens, unbranched or branched alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl.

From WO 88/08 708 it is known to convert galanthamine by demethylation and, if desired, subsequent alkylation into derivatives of galanthamine. In WO 88/08 708, it is also proposed to prepare galanthamine derivatives substituted by an optionally substituted mercaptan group by converting the hydroxy group of galanthamine to an O-aryldialkylthiocarbamate group by reaction with dialkylthiocarbonylchlofld, followed by pyrolyzing the compound to arylthioalkylthiocarbamate and finally adding an arylmercaptan is hydrolyzed.

Finally, in WO 88/08708 it is proposed to obtain galanthamine derivatives by cyclizing an amide with the formula given on page 23 of WO 88/08708 by electrochemical oxidation according to the method described in US-A-4,921,862A ,

US 3,673,177A discloses novel, substituted 4- (anilinomethylene) -3-galanthamaninones and methods of making them. The process described in US 3,673,177 starts from 3Galanthamaninones (Narwedin) and involves reacting with ethyl formate in the presence of an alkali alkoxide, whereupon the enolate obtained with an aromatic amine either in glacial acetic acid or in an acidic medium in ethanol to the desired 4- (anilinomethylene ) -3-galanthamaninone.

Galanthamine is an alkaloid with high pharmacological activity, occurring predominantly in plants of the Amaryllidaceae type. Of particular note is its action as a selective acetylcholinesterase inhibitor and the associated use in Alzheimer's disease. To date, galanthamine is isolated in quantities of a few kilograms per year from the Caucasian snowdrop Galanthus Voronoyi at a cost of more than US $ 30,000 / kg. Galanthamine syntheses have been known in principle since the late sixties, although long, uneconomic pathways with poor overall yields have been used.

The synthesis of some compounds of the general formulas (I) and (II) given above is known per se and described in the literature. Thus, N- (3-hydroxy-4-methoxyphenyl) N-methyl-4-hydroxy-phenylethylamine was oxidatively cyclized with the aid of various oxidizing agents to give narwedin derivatives (narwedin is the precursor to galanthamine, but already has the galanthamine ring structure) [Lit. 1-2], the yields were usually less than 1% of theory. Although this was the structure proved, but galanthamine not be produced in pharmaceutically interesting kg quantities.

Optimized procedures (especially Kametani, Lit. 3-7,22) described this ring closure to N-methylbenzamide or Phenylacetamide derivatives in yields up to 40%, but the poor overall yields make an industrial use impossible. Furthermore, in the literature, the cyclization of Ν, Ν-disubstituted phenylethylamine derivatives (ref. 8) and electrochemical (ref. 9-12), microbiological, enzymatic (ref. 8) as well as biomimetic methods (Ref. 14-15). In lit. 23 the production of narwedine from isovanillin in 44% overall yield is described, but the use of equimolar amounts of palladium and tallium trifluoroacetate make this synthesis uneconomical. On this way (Lit. 23) (+ / -) narwedine is described in Ref. 24 enriched in the desired (-) narwedine and converted into galanthamine with L-selectride in good yield.

In reference 8, a synthesis is proposed in which the oxidative cyclization is described as 21%, but the separation of the enantiomers is lacking. Also known is the reduction of Bromnarwedin with LiAlH «. in THF to give a 53:31 diastereomeric mixture of (+ / -) galanthamine and (+ / -) epigalanthamine.

The invention has for its object to develop a synthesis method by which larger amounts of the title substances can be prepared in a reproducible manner and in improved yields of both the individual steps and the overall yield.

This object is achieved according to the invention by the method according to claim 1 and 2, wherein the dependent claims have preferred and advantageous embodiments of the invention to the object. In particular, the following measures of the invention have proved to be advantageous:

Replacement of halogenated solvents, eg chloroform, with toluene. Halogenated solvents are nowadays hardly used as technical solvents due to toxicity, difficulties in disposal and ecological concern. Toluene, however, does not have these disadvantages.

The work-up by extraction requires organic solvents. With the invention, the work-up of most stages can be optimized so that the reaction product can be obtained mostly in crystalline form from the solution. Thus, chromatographic purification stages or

AT 401 058 Β

Extractions are largely avoided.

Further, in the invention, by improving the parameters, the yields can be reproduced in a very narrow range, and the purity of the main products and the proportion of by-products after these reactions can be defined. With the methods of the invention improved and reproducible yields of the individual stages and the overall yield are possible. The invention provides inter alia a method in which Bromformylnarwedin is reduced with reducing agents. As a reducing agent, L-Selektride can be used, the reduction diastereoselective to N-demethylbromogallamine in high yield (eg 85%), which can be converted into (±) galanthamine by N-methylation according to Eschweiler-Clark and debromination. Epigalanthamine could not be detected in the reaction product (+ / -) by chromatographic methods. Galanthamine and galanthamine derivatives can be prepared by the process according to the invention on an industrial scale via intermediates which are not described in the literature (see the compounds mentioned in claims 64 to 67).

The processes of the present invention which are substantially improved and industrially feasible in terms of yield and purity of the products obtained compared to the prior art can be exemplified as follows:

For the synthesis of derivatives of the 4a, 5,9,10,11,12-hexahydro-6H-benzofuro [3a, 3,2-ef] [2] benzazepines of the general formula (I)

<img file="AT401058B_D0005.tif" />

or of salts thereof, wherein R2, R4, Xi, X2, Y1 and Y2 are either the same or different and are hydrogen, Fluorine, Chlorine, Bromine, Iodine, a hydroxy or alkoxy group, a lower, optionally branched and optionally substituted alkyl group, a lower, optionally branched alkengtuppe, a lower, optionally branched alkyne group, an optionally substituted aryl, Aralkyl or aryloxyalkyl group, whose alkyl chain is optionally branched and whose aromatic nucleus is optionally substituted, a formyl, but also unsubstituted and substituted by one or more halogens, unbranched or branched alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, aralkylsulphonyl, arylsulfonyl, and Y1 Λ2 = 0 (ketone), where A is a benzene nucleus, optionally one or more times by at least one lower, optionally branched alkyl group, at least one lower, optionally branched alkene group, at least one lower, optionally branched alkyne group, at least one lower, optionally branched alkoxy group, by fluorine, Chlorine, Bromine, Iodine or by several identical or different halogens, at least one alkyl group substituted by one halogen or by several identical or different halogens, such as chloromethyl and trifluoromethyl, at least one optionally substituted aralkyl group, at least one hydroxy group, primary, secondary or tertiary amino group, Nitro group, nitrile, Alkylamino group or arylamino group, aldehyde group, Carboxylic acid group and all derivatives of the carboxylic acid group, like esters, amides, halides, is a condensation step followed by reduction, an N-formylation or imports of an N-protecting group, a bromination (which can already be carried out at the isovanillin stage according to the overall formula scheme), an oxidative cyclization, a reduction, depending on the nature of the reducing agent also an N-methylation and Debromierung, and a separation of the optical isomers containing method used. If necessary, individual of the mentioned process steps can also be omitted.

The present invention also relates to the preparation of salts.

The compounds of the general formula (I) can be embedded in salts with organic and inorganic acids, for example:

AT 401 058 Β of mineral acids such as hydrochloric and hydrobromic acid, sulfuric acid and phosphoric acid, perchloric acid, or pharmaceutically acceptable organic acids such as lactic acid, substituted and unsubstituted tartaric acid, acetic acid, salicylic acid, citric acid, benzoic acid, ε-naphthoic acid, adipic acid, etc. are transferred ,

The processes of the invention lead in part to new compounds. New connections include:

Bromgalanthamine of the formula

<img file="AT401058B_D0006.tif" />

Epibromgalanthamine of the formula

<img file="AT401058B_D0007.tif" />

N-demethylbromo-galantamine of the formula

<img file="AT401058B_D0008.tif" />

and

N-demethyl-epibromgalanthamine of the formula

<img file="AT401058B_D0009.tif" />

The preparation of salts of the substituted derivatives of the 4a, 5,9,10,11,12-hexahydro-6H-benzofuro [3a, 3,2-ef] benzazepine of the general formula (II)

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<img file="AT401058B_D0010.tif" />

in the R₂, FU, Xi, X₂, Yi and Y₂ and A have the meanings given above for formula (I) and Z - is an organic anion of a pharmaceutically acceptable acid, like tartrat, lactate, citrate, Acetate, Maleate etc., or an inorganic anion, like a fluorine, Chlorine-bromine or iodine anion, is a sulphate or phosphonate or chlorate anion, Rs is a hydrogen atom, a lower, is a linear or non-linear alkyl radical or a branched or unbranched aryl radical in the alkyl chain, The method described above by way of example is likewise the subject of the invention.

The compounds obtainable according to the invention and their salts have at least two asymmetric centers and therefore occur in several stereoisomeric forms. The invention also includes the separation of the resulting diastereomers or racemates in the optically pure antipodes and mixtures thereof.

The above steps can be generally and exemplarily carried out as follows:

1. Condensation and reduction.

<img file="AT401058B_D0011.tif" />

For the preparation of the compounds of the general formula (I) and (II) substituted derivatives of the general formula (V) with R₄ = H prepared by adding a substance of general formula (III) (wherein Ri, R₂ = Hydrogen, a lower linear or non-linear alkyl or a branched or unbranched aryl or aralkyl in the alkyl chain and also alkylcarbonyl, arylcarbonyl and aralkylcarbonyl, or common (Ri = R₂ = -CH₂-) alkyl group or a combination of these radicals, Xi = H, fluorine, chlorine, bromine, iodine, t-butyl) with tyramine or substituted tyramine (R₃ = Hydrogen atom, a lower linear or non-linear alkyl or a branched or unbranched aryl or aralkyl and alkylcarbonyl, arylcarbonyl and aralkylcarbonyl) in the alkyl chain. This can be done as follows:

An equimolar solution of (III) and (IV) in toluene, xylene or benzene or mixtures of these solvents with higher alcohols, predominantly toluene with n-butanol in ratios of 9: 1 to 1: 9, predominantly 1: 1, in concentrations of 1-30%, is reacted at reflux temperature and water is separated off. The solvent is then separated by distillation and recovered to&gt; 95%, the residue in alcohol, such as methanol, ethanol, n-propanol, i-propanol, methyl glycol, ethyl glycol, water, glacial acetic acid, or mixtures of these solvents, mainly methanol, in concentrations of 130% and by portion addition of from 0.6 to 5 equivalents, preferably from 0.65 to 0.7 equivalents of reducing agent such as sodium borohydride, potassium borohydride, sodium cyanoborohydride, LiAlHa. and mixtures of these, but mainly sodium borohydride as a powder or granules at temperatures from -30 to reflux temperature. The condensation product (V) is filtered off in yields of 80 to 85% as the first fraction by filtration from the alcoholic solution. Work-up of the alcoholic solution by distillation to 15 to 30% of the volume and filtration of the 2. Fraction increases the yield to 90 to 95% d.Th .. Alternatively, the reaction solution can be poured onto water, wherein

AT 401 058 Β crystalline product (V) precipitates and is obtained after suction and drying in yield up to 95%.

Second N-formylation or N-protective group:

Starting compounds for the oxidative cyclization of the formula (V) with Ra = formyl, but also unsubstituted and substituted by one or more halogens, unbranched or branched aralkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, aralkylsulphonyl, Arylsulfonyl are prepared by reacting the compounds (V) with R &lt;= H with the appropriate acids, esters, anhydrides, halides, azides, Carbonates or other reactive derivatives of these protecting groups produced.

In particular, a compound of the general formula (V) with R₄ = H in solvents such as THF, dioxane, DMF, toluene, xylene or all mixtures of these solvents with the equimolar to 50-fold molar amount of ethyl formate and catalytic amounts of formic acid (0.001 to 1 equivalent) at temperatures from 0 to reflux to a compound of general formula (V) with R₄ = CHO be implemented. The solvents are removed by vacuum distillation in this process, the distillation residue is crystallized by adding portions of water and ice, and the product is recovered by filtration in yields of&gt; 90% at a content of&gt; 95%.

Third bromination:

When in compounds of general formula (V) with R1.R2.R3 = a lower unbranched or branched alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, Xi, X₂ = H, R₄ = Formyl, but also unsubstituted and substituted by one or more halogens, unbranched or branched aralkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, aralkylsulphonyl, Arylsulfonyl containing from 90 to 100% in solvent mixtures of halogenated hydrocarbons, such as chloroform or methylene chloride with alcohols (methanol, ethanol, methyl glycol, ethyl glycol, ethylene glycol, n-propanol, i-propanol) in ratios of 9: 1 to 1: 9, preferably 3: 2 to 2: 3, as well as pure alcohols (methanol, ethanol, Methylene glycol, ethyl glycol, Ethylene glycol, n-propanol, i-propanol) and mixtures thereof, preferably ethanol / methyl glycol, in ratios of 9: 1 to 1: 9, preferably 3: 2 to 2: 3 with water fractions of 0 to 5%, preferably 0 to 0.2%, at a temperature of -80 to + 60'C, preferably -40 to O'C, in a concentration of 0.5 g to 20 g / 100 ml of solvent with 1.0 to 3.0, preferably from 1.4 to 1.7 equivalents of a bromine reagent is reacted, which by adding elemental bromine in the specified solvent in a concentration of 1 to 90%, preferably 2 to 10%, is obtained with addition times of the bromine reagent from 10 minutes to 4 hours, preferably 15 to 30 min. After a reaction time of 0.5 to 24 hours, preferably 30 to 60 minutes, obtained after work-up (concentration by distillation to 10 to 25% by volume and pouring on the 10- to 50-fold amount of ice water, filtration and drying) yields from 90 to 96% of theory of the product of formula (V) with Xi = Br at a content of 80 to 82% d.Th ..

Preparation of Intermediate (V) with Xi = Br, R₄ = CHO or multiply brominated intermediates:

Route 1 (see page 11, overall formula). Becomes intermediate (V) with Xi, X₂ = H and R₄ = CHO brominated according to the specified optimized procedures, so 82% product, 6% starting material, 8% by-product with X.₂= Br and 5% higher brominated products. (HPLC, Lichrosorb RP 18, 5u, 300/4 mm, eluent MeOH / H₂O 6: 4 at 280 nm). If the bromination method is changed, the ratios of the indicated products change as well (in most cases a larger proportion of higher brominated products is formed). After the oxidative cyclization, in addition to the desired product of general formula (I) with Xi = Br, R₄= CHO and Y_t= Y₂= O and the product of general formula (I) with Xi = X₂ = Br, R₄ = CHO, Y, = Y₂ = 0 in yields corresponding to the precursor detected (HPLC, Lichrosorb Si 60, 10 u, 300/4 mm, eluent: CHCb / MeOH 95: 5 at 254 nm) and by prep. Chromatography (silica gel 60, CHCb: MeOH 1-5%) are isolated. After reduction with L-selectride or with other reducing agents, more highly brominated narwedine (Xi = X₂= Br) either also reduced to galanthamine or separated by preparative chromatography.

Way 2: (see page 11, overall formula). Starting from 6-bromo-isovanillin, condensation and N-formylation give intermediate (V) with Xi = Br, R₄= CHO without higher brominated by-products.

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4th Oxidative cyclization:

For the oxidative cyclization of compounds of general formula (V) with R₂ Is hydrogen, a lower linear or nonlinear alkyl or a branched or unbranched aryl in the alkyl chain or Aralkyl and alkylcarbonyl, Arylcarbonal and aralkyl-carbonyl or a combination of these radicals Xi = H, fluorine, chlorine, bromine, iodine, t-butyl, Rt = formyl, but also unsubstituted and substituted by one or more halogens, nich-branched or branched aralkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, R3 = hydrogen to give a compound of the general formula (I) with R₂. R4, Xi = as above, Yi, Y2 = O (ketone) and X2 = H, Br is in solvents, like chloroform, Methyienchlorid, ethyl acetate, THF, dioxane, glacial acetic acid, Water, their mixtures with alcohols (methanol, ethanol, Methylene glycol, ethyl glycol, Ethylene glycol, n-propanol, i-propanol) in ratios of 9: 1 to 1: 9, as well as toluene, xylene, Benzene, predominantly xylene and toluene in a concentration of 0.05 g to 10 g / 100 ml of solvent with bases, like sodium bicarbonate, potassium carbonate, NaOH, KOH, pyridine, preferably potassium carbonate, in a concentration of 0.1% to saturated solutions, predominantly 5 to 20% and oxidizing agent, like Pb (OAc) 4, KMnÜ4, FeCl, potassium, H2O2, preferably potassium ferricyanide, 4-10 equivalents, preferably 5.5-6 equivalents, if necessary with the addition of phase transfer catalysts such as aliquat or crown ether as well as ascorbic acid, CuCl or trifluoroacetic acid at a temperature from -40 ° C to reflux temperature, mainly 50 to 80'C, and by rapid or portionwise addition of the educt as a solid, as a solution or as a suspension in a solvent, preferably as a solid, at a reaction time of 10 minutes to 72 hours, mainly 15 to 45 minutes under heavy, mechanical stirring, preferably in the form of an agitator and an additional homogenizer, at most under inert gas, such as N₂, CO2, argon, predominantly argon, implemented. Working up by filtration, phase separation and vacuum distillation of the toluene phase gives the crude product in yields of 5 to 65%, from which by purification of Zyklisierungsprodukte yields of 5 to 50% are obtained.

5th Reduction:

For the reduction of compounds of general formula (I) in the R₂ a low unbranched or branched alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, Xi, X2 fluorine, Chlorine, Bromine, Iodine, t-butyl, Yi Ύ2 = O, R4 formyl, but also unsubstituted and substituted by one or more halogens, unbranched or branched aralkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, aralkylsulphonyl, Arylsulfonyl and Y1, Y2 = O, (Bromine-narwedene type) with hydride reagents such as DiBAL-H, DiBAL-H / ZnCl, Al isopropylate, RedAl, K-selectrides, L-selectrides, KS-selectrides, LS-selectrides, Li-tri-t-butoxy-AIH, Li-tri-ethoxy-AIH, 9-BBN, Superhydride, NaBH₄, Zn (BH₄) 2, AIH3 AICI2H or any combination of these reducing agents can be carried out in such a way that by addition of the reducing agent in equimolar amounts or in excess of the starting material or inverse addition of the starting material to the reducing agent in an inert solvent such as diethyl ether, THF, dioxane, toluene, Xylene, benzene at temperatures of -50'C to reflux temperature is reduced. After alkaline (mainly NH4OH) or acidic (predominantly 2n HCl) workup and subsequent extraction with solvents such as toluene, xylene, benzene, ethyl acetate, ether, chloroform or methyl chloride, the crude product is purified by chromatographic techniques and if necessary, the diastereomers isolated or the crude products reacted directly.

In particular, by reduction of bromine-N-formylnarwedine (in contrast to reference 24, where narwedin is used) with L-selectride or K-selectride diastereoselectively N-demethylbromo-galantamine in yields of 70-85% of theory. after purification by column chromatography. No epi-N-demethylbromogallamine could be detected by chromatographic methods.

N-Demethylbromgalanthamin by N-methylation, for example by boiling for 10 minutes to several hours in 5- to 50-fold excess of formic acid and aqueous formaldehyde solution in yields of 80-90% of theory converted into bromogallanthamine.

Bromgalanthamine, for example, by refluxing for 1-12 hours with a 5- to 50-fold molar excess of formic acid and triethylamine in the presence of 0.1 to 15% palladium-activated carbon catalyst with elimination of bromine in galanthamine converted. Yield: 70 to 80% of theory: The reaction steps can also be carried out without isolation and purification of the intermediates.

By reduction of the educt with Li-tri-t-butoxy-AIH, a mixture of N-Demethylbromgalantham and Epi-N-demethylbromgalanthamine in the ratio of about 1: 1 is obtained.

Reduction with DiBAL-H gives 43% bromogallanthamine and 41% epibromogallanthamine.

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Reduction with LiAlH 2 / anhydrous H 2 SO 4 also gives bromogallanthamine and epibromogallanthamine in a ratio of about 3: 1.

The reduction may be carried out as indicated below, for example:

For the reduction of a compound of the general formula (I) with R₂ = Alkyl, Xi = Br, R4 = CHO, X₂ = H, Yi, Y₂ = 0 (ketone), the educt is dissolved in a solvent such as THF, dioxane or other ethers, mainly THF, in concentrations of 0.1 to 20 g / 100 ml by heating. Then, at a temperature of -50 ° C. to reflux temperature, predominantly 0-20 ° C. 3 to 5, predominantly 3.5 equivalents of LSelectride are added, predominantly as a 1 molar solution in THF, and the reaction at 0-20 ° C. for 20 minutes to 48 ° Hours, mostly stirred for 1 hour. The complex formed with the reducing agent is destroyed by addition of water and ammonium hydroxide and excess organic solvent is evaporated in vacuo with heating to a maximum of 30'C. Extraction with solvents such as ethers (eg Diethyl ether), ethyl acetate, butyl acetate, chloroform, methylene chloride, toluene, benzene or xylene gives NDemethylbromgalantham in crude yields of 90 to 100% d.Th ..

For monomethylation of N-demethylbromo-galantamine, a solution of N-demethylbromo-galanthamine in a 5-30 molar excess of formic acid and aqueous formaldehyde solution (37%) with or without organic solvent is refluxed for 10 minutes to 2 hours, preferably 15-20 minutes heated.

For bromobromamine or epibromgalanthamine to be brominated bromine or epibromogallanthamine is dissolved in a 5-50 fold molar excess of formic acid and triethylamine with or without organic solvent in the presence of 0.1 to 15% palladium-carbon catalyst for 1 to 12 hours, heated to reflux for a maximum of 2.5 hours.

For reducing a compound of general formula 1 with R₂ = Alkyl, Xi = Br, FL = CHO, X₂ = H, Y1, Y₂ = O (ketone), the educt is suspended in an inert organic solvent, such as benzene, toluene or xylene, predominantly toluene in a concentration of 0.1 to 20 g / 100 ml and at a temperature of - 50'C to reflux temperature, predominantly 0 to 20'C 3 to 5, predominantly 3.5 equivalents of DiBAL-H added dropwise as a predominantly 1.5 molar solution in toluene. Now 20 min to 12 hours, mainly stirred for 30 min to 1.5 hours at this Teperatur, destroys the complex formed with water and ammonium hydroxide, extracted with toluene and the crude product (90 to 100% of theory) by column chromatography (silica gel , Acetone / hexane 1: 1) in 43% bromogallanthamine and 41% epibromogallanthamine.

6th Separation of the optical isomers:

To obtain chiral 4a, 5,9,10,11,12-hexahydro-6H-benzofuro [3a, 3,2-ef] [2] benzazepines of general formula (I), (Y1 = H, OH; Y₂ = H, OH) in the A, R₂, Rt, Xi and X₂ which have the meaning initially given to separate into the enantiomerically pure antipodes, a fractional crystallization can be applied. The separation of the (+) and (-) isomers of the narwedene type compounds by fractional crystallization takes place in the manner in that a solution or suspension of the optical isomer mixture contains from 5 to 50 times the amount of a solvent, like water, methanol, ethanol, propanol, isopropanol, Acetone or mixtures of these solvents, predominantly methanol, with the equimolar amount or an excess of a chiral acid (unsubstituted, singly or multiply substituted + or - tartaric acid, Citric acid, Lactic acid, α-methoxyphenylacetic acid, Camphorsulfonic acids and their derivatives, preferably di-p-tolyl (+) tartaric acid), which is dissolved in one of the abovementioned solvents, is added or submitted - and the solution or suspension of the optical isomer mixture is added, that the solution is composed of the natural (-) galanthamine derivative and chiral organic acids, such as di-p-tolyl (+) tartaric acid, inoculated crystals and at -40 to + 20'C, preferably O'C is allowed to stand for 2 to 24 hours or longer, that the crystals formed are filtered and dried, then treated with excess NHaOH and with organic solvent, like chloroform, Methylene chloride, ethyl acetate, butyl acetate, diethyl ether, t-butyl methyl ether, dibutyl ether, petroleum ether, xylene, Benzene, Toluene or similar solvents and isolated by distillation of the solvent, the corresponding (-) galanthamine derivative is isolated.

Concentration of the mother liquor, absorption in excess of NH 4 OH, extraction with an organic solvent (as indicated above) and evaporation of the mixture results in further fractions of galanthamine, from which analogously to the above with the aid of chiral organic acids, such as di-p-tolyl (-) tartaric acid the (+) galanthamine derivatives can be obtained.

The products obtained according to the invention can be purified by a conventional method in chemistry, for example fractional distillation, crystallization or chromatography.

AT 401 058 Β

Reaction schemes of the processes according to the invention are reproduced below, and subsequently the invention is explained in more detail by way of examples:

tjesamtreaKtionsscriema h₂n

Way 1

Way 2:

<img file="AT401058B_D0012.tif" />

AT 401 058 Β

Reductions of Bromnarwedin - Overview

OH

<img file="AT401058B_D0013.tif" />

Reduction with L-selectride

Galanrhsunin ^CH'

<img file="AT401058B_D0014.tif" />

OH OH

<img file="AT401058B_D0015.tif" />

<img file="AT401058B_D0016.tif" />

AT 401 05S Β

Chiral separation of galanthamine

<img file="AT401058B_D0017.tif" />

<img file="AT401058B_D0018.tif" />

<img file="AT401058B_D0019.tif" />

AT 401 058 Β

Example 1:

N- (4-hydroxyphenethyl) - (3-hydroxy-4-methoxy) benzylamine (general formula (V) with: Ri = R3 = FL = Xi = X₂ = H, R₂ = Me)

In a glass 5 l jacketed vessel, 217.5 g (1.43 mol) of isovanillin and 200 g (1.45 mol) of tyramine are suspended in 2.5 l of toluene / n-butanol (1: 1) and heated to reflux temperature with removal of water , After 4 hours, the solvent is distilled off in vacuo, the residue taken up in 2.5 l of methanol and the clear solution with 25 g of NaBH₄ (0.66 mol) added. The reaction mixture is stirred at 0xC for 4 hours, the precipitate which has precipitated is filtered off, washed with methanol and dried. Yield: 332.3 g (85.1%)

Melting point: 176-178'C

Molecular weight: Ci6HigNC&gt; 3: 273.32

Example 2:

N- (4-hydroxyphenethyl) - (6-bromo-3,4-dimethoxy) benzylamine (general formula (V) with R₃ = R₄ = X2 = H, R · = R₂ = Me, Xi = Br)

In a 100 ml round bottom flask 2.45 g (10 mmol) of 6-bromo-3,4-dimethoxybenzaldehyde, 1.37 g (10 mmol) of tyramine are suspended in 50 ml of toluene / n-butanol (1: 1) and with separation of water heated to reflux temperature. After 3 hours, the solvent is distilled off in vacuo, the residue taken up in 50 ml of methanol and the clear solution with 0.8 g NaBH₄ added. The reaction is stirred at O'C for 4 hours, the solvents distilled off in vacuo, the residue in 100 ml of CH₂CI₂ taken and washed the organic phase with twice 10 ml of water. The organic phase is over Na₂SO₄dried, filtered and the solvent removed in vacuo. The remaining residue is chromatographed on 150 g of silica gel with hexane: ethyl acetate = 2: 8.

Yield: 2.95 g (80.6%) of viscous oil

Molecular weight: Ci 7 H₂₀BrNO3: 366.23

Example 3:

N- (4-hydroxyphenethyl) - (4-methoxy-3-methoxymethoxy) benzylamine (general formula (V) with Ri = MeOCH₂O, R₂ = Me, Xi = X₂ = X₃ = X₄ = R₃ = R₄ = H)

In a 100 ml round bottomed flask, 0.83 g (4.2 mmol) of 4-methoxy-3-methoxymethoxybenzaldehyde [Lit. 16-17] 0.55 g (4.0 mmol) of tyramine were suspended in 50 ml of toluene / n-butanol (1: 1) and heated to reflux with water separation. After 4 hours, the solvent is distilled off in vacuo, the residue taken up in 50 ml of methanol and the clear solution with 0.35 g NaBH₄ staggered :. The reaction is stirred at O'C for 4 hours, the solvents distilled off in vacuo, the residue in 100 ml of CH₂CI₂ taken and washed the organic phase with twice 10 ml of water. The organic phase is over Na₂SO₄ dried, filtered and the solvent removed in vacuo. The remaining residue is chromatographed on 65 g of silica gel with ethyl acetate: methanol = 7: 3.

Yield: 1.12 g (83.4%) of viscous oil

Molecular weight: Ci3H₂₃NO₄ : 317.37

AT 401 058 Β

Example 4:

N- (4-hydroxyphenethyl) - (6-bromo-3-hydroxy-4-methoxy) benzylamine (general formula (V) with Ri = Rs = FL = Η, X₂ = H, R₂ = Me, Xi = Br)

Method 1:

In a 50 ml round bottomed flask, 1.0 g (4.3 mmol) of 6-bromo-4-methoxy-3-hydroxybenzaldehyde [Lit. 18] 0.6 g (4.3 mmol) of tyramine in 20 ml of toluene / n-butanol (1: 1) suspended and erwächt with water separation to reflux. After 90 min, the solvent is distilled off in vacuo, the residue taken up in 20 ml of methanol and the clear solution with 0.33 g of NaBH »added. The reaction is stirred at 0 ° C for 4 hours, the solvent distilled off in vacuo, the residue in 50 ml of CH₂CI₂ taken and washed the organic phase with twice 10 ml of water. The organic phase is over Na₂Dried, filtered and the solvent removed in vacuo. The remaining residue is chromatographed on 60 g of silica gel with ethyl acetate: methanol = 97: 3-95: 5.

Yield: 1.43 g (93.8%)

Method 2:

53.38 g (231 mmol) of 6-bromo-4-methoxy-3-hydroxybenzaldehyde [Lit. 18], 31.7 g (231 mmol) of tyramine in 530 ml of toluene / n-butanol (1: 1) and heated with the precipitation of water to reflux. After 90 min, the solvent is distilled off in vacuo, the residue taken up in 350 ml of methanol and the suspension with 12 g NaBH »added. The reaction is stirred at 0 * C for 1 hour and added dropwise to 3 l of ice water. After stirring for 30 minutes, the precipitated product is filtered, washed with water twice and dried in a vacuum oven at 60'C. Yield: 70.2 g (86.3%)

Melting point: 122-125 ° C

Molar weight: Ci 6 HisBrNO₃ : 352.21

IR / KBr): 655.76w; 800.45 m, 824.97 m; 1022,56m; 1165,88m; 1245,88s; 1409,83s; 1448,40s; 1510,79s; 1554,48s; 3200-3370br.

'H-NMR (DMSO-ds): 7.0-6.60 (m, 6H); 6.73 (m, 2H); 3.77 (s, 3H); 2.75-2.58 (m, 4H); 2.88 (s, 2 OH).³C NMR (CDCI₃ + DMSO-ds): 155.46 s, 147.28 s, 145.95 s, 130.56 s, 129.68 s, 129.12 2 d, 116.93 d, 115.61 d, 114.99 2 d , 110.95 s, 55.85 q, 51.76 t, 50.16 t, 34.50 t.

Example 5:

N- (4-hydroxyphenethyl) - (4-methoxy-3-t-butylcarbonyloxy) benzylamine (general formula (V) with Ri = Me₃CCO, R₂ = Me, Xi = X₂ = R₃ = R »= H)

In a 50 ml round bottom flask, 3.63 g (16.5 mmol) of (4-methoxy-3-t-butylcarbonyloxy) benzaldehyde 2.06 g (15 mmol) of tyramine are suspended in 32 ml of toluene / n-butanol = 1: 1 and heated to reflux with water separation. After 3 hours, the solvent is distilled off in vacuo, the residue taken up in 32 ml of methanol and the clear solution with 1.32 g NaBH »added. The reaction is stirred at 0 ° C for 4 hours, the solvent distilled off in vacuo, the residue in 50 ml of CH₂CI₂taken and washed the organic phase with twice 10 ml of water. The organic phase is over Na₂SO "dried, filtered and the solvent removed in vacuo. The remaining residue is chromatographed on 140 g of silica gel with ethyl acetate: methanol = 9: 1-8: 2.

Yield: 1.7 g (28.8%) of viscous oil

Molecular weight: Ο₂ιΗ₂₇ΝΟ »: 357.43

AT 401 058 B

Example 6:

N-formyl-N- (4-hydroxyphenethyl) - (3-hydroxy-4-methoxy) benzylamine (general formula (V) with: Ri = R3 = Xi = X2 = H, R₂ = Me, R »= CHO)

In a 10 l 3-necked flask (dropping funnel reflux condenser, bubble counter, Gaseinleitrohr) 370 g (1.35 mmol) 5 (Ri = R3 = FU = Xi = X2 = H, R₂ = Me), 5 l technical dioxane and 370 ml technical DMF submitted. The dropping funnel is filled with a mixture of 1100 ml (13.66 mol) of HCOOEt and 10 ml of HCOOH, the suspension is stirred magnetically under argon and heated to boiling. The internal temperature rises to 100 to 103'C whereby the suspension becomes homogeneous. To this solution, the solution is added from the dropping funnel in 20 to 30 min. The internal temperature drops to 87 to 89'C. The cloudy reaction mixture is stirred for 4 hours at reflux temperature. The solvent is removed in vacuo and the residue is added in portions with 8 l of ice water. The precipitated crystals are filtered, washed three times with 2 l of water and dried in vacuo for 12 hours.

Yield: 360.5 g (88.6%)

Melting point: 144 to 148 ° C

Molecular weight: Ci7Hi9NO4: 301.33

Example 7:

N-formyl-N- (4-hydroxyphenethyl) - (6-bromo-3,4-dimethoxy) benzylamine (general formula (V) with: R3 = X₂ = Η, Xi = Br, Ri = R₂ = Me, Rt = CHO)

In a 250 ml 3-necked flask (dropping funnel, reflux condenser, bubble counter, gas inlet) is a mixture of 4.53 g (12.2 mmol) 5 (R3 = R4 = X2 = H, Xi = Br, Ri = R₂= Me), 100 ml of technical dioxane 10.0 ml (122.0 mmol) of HCCOEt and 0.1 ml of HCOOH are refluxed. After 68 hours, the solvent is removed in vacuo and the residue is crystallized from 40 ml of MeOH.

Yield: 3.61 g (75%)

Melting point: 160 to 162 ° C

Molecular weight: CisH2oBrNOt: 394.24

Example 8:

N-formyl-N- (4-hydroxyphenethyl) - (4-methoxy-3-t-butylcarbonyloxy) benzylamine (general formula (V), where R i = Me 3 CCO, R₂ = Me, Xi = X₂ = R3 = H, R4 = CHO)

In a 500 ml 3-neck flask, a mixture of 1.7 g (4.7 mmol) of the compound of formula (V) (Ri = MesCCO, R₂= Me, Χ_Ί = X₂ = R₂ = R4 = H), 7.5 ml of technical dioxane, 7.5 ml of HCOOEt and one drop of HCOOH refluxed. After 15 hours, the solvent is removed in vacuo and the residue is chromatographed on 30 g of SiO 2 with AcOEt.

Yield: 1.5 g (81.8%) of oil

Molecular weight: C22H27NO5: 385.44 ¹H-NMR (CDCl3): 8.20 and 7.80 (2s, 1H); 7.16-6.80 (m, 7H); 4.30 (d, 2H); 3.78 (s, 3H); 3.35 (m, 2H); 2.70 (m, 2H); 1.38 (s, 9H).

¹³C-NMR (CDCl 3): 176.69 s; 163,24 and 162,90 d; 155.36 and 154.99 s; 150.99 and 150.70 s; 140.35 and 140.18 s; 129.67 to 112.30 m; 55.85 q; 50.94 and 48.46 t; 44.60 and 43.61 tons; 38.94 s; 33.60 and 32.24 t; 27.05 3q.

AT 401 058 B

Example 9:

N-formyl-N- (4-hydroxyphenethyl) - (6-bromo-3-hydroxy-4-methoxy) benzylamine (general formula (V) with Ri = R₃ = X₂ = H, Xi = Br, R₂ = Me, R »= CHO)

Method 1:

In a 500 ml 3-necked flask (dropping funnel, reflux condenser, bubble counter, Gaseinleiter) is a mixture of 27 g (76.6 mmol) of the compound (V) (Ri = R₃ = Ra = X₂ = H, Xi = Br, R₂= Me), 300 ml of technical dioxane, 30.0 ml (37.2 mmol) of HCOOEt and 0.1 ml of HCOOH are boiled under reflux. After 72 hours, the solvent is removed in vacuo and the residue is crystallized from 50 ml of chloroform. Yield: 23.95 g (82.3%)

Method 2:

300 g of the compound (V) (Ri = R₃ = Xi = X₂ = H, R₂ = Me, R₄ = CHO), was dissolved in 2000 ml of anhydrous ethanol and 2000 ml of methyl glycol (H₂O &lt;0.1%) by heating to 40'C, then cooled to -20'C and 14 ml of bromine in 1000 ml of ethanol / methyl glycol (1: 1) was added dropwise during 15 min, so that the temperature -20'C not above. The mixture was then stirred at -20 ° C. for 30 minutes, then the solution was concentrated to about 1000 ml and poured onto 30 l of ice / water with vigorous stirring. The mixture was stirred at 0 ° C. for 4 hours, filtered off with suction and the colorless, crystalline substance was dried in vacuo (60 ° C.).

Yield: 370.2 g (96% of theory); Content (HPLC) 82%

Melting point: 162 to 164'C

Molecular weight: Ci 7 HisBrNOt: 380.22

Example 10:

N-formyl-N- (4-hydroxyphenethyl) - (4-methoxy-3-methoxymethoxy) benzylamine (general formula (V) with Ri = MeOCH₂O, R₂ = Me, Xi = X₂ = R₃ = H, Rn. = CHO)

In a 50 ml 3-necked flask (dropping funnel, reflux condenser, bubble counter, gas inlet), a mixture of 4.9 g (15.4 mmol) of compound (V) (Ri = MeOCH₂O, R₂ = Me, Xi = X₂ = R₃ = R »= H), boiled 60 ml of HCOOEt and one drop of HCOOH under reflux. After 18 hours, the solvent is removed in vacuo and the residue is crystallized from AcOEt / hexane.

Yield: 3.95 g (74%)

Melting point: 102 to 104'C

Molecular weight: Ci₃H₂₃NOs: 345.38'H-NMR (CDCls): 8.23 ​​and 7.83 (2s, 1H); 7.05 to 6.70 (m, 7H); 5.20 (s, 2H); 4.46 and 4.28 (2s, 2H); 3.87 (s, 3H); 3.52 (s, 3H); 3.38 (m, 2H); 2.70 (m, 2H).

¹³C NMR (CDCl 3): 163.20 and 162.86 d; 155.41 and 155.05 s; 149.53 and 149.30 s; 146.53 and 146.33 s; 129.66 and 129.59 s; 129.52 d; 128.56 and 128.02 s; 122.40 d; 121.64 d; 116.71 d; 115.88 d .; 115.60 and 115.33 d; 111.75 d; 95.39 t; 56.13 q; 55.79 q; 51.44 and 48.62 tons; 45.10 and 43.71 t; 33.72 and 32.27 t.

Example 11:

4a, 5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-formyl-6H-benzofuro [3a, 3,2-ef] [2] benzazepin-6-one (general formula ( I) with: R₂ = Me R »= CHO, Xi = Br, X₂ = Η, Y1, Y₂ = O)

To a suspension of 16 lit toluene, 600 g K₃[Fe (CN&gt; 6] and 2 lit 10% K₂CO₃Solution at 70'C 120 g (0.316 mol) of finely pulverized compound (V) (Ri = R₃ = X₂ = H, Xi = Br, R₂ = Me, Ri = CHO) added at once. Subsequently, the reaction is stirred vigorously at the same temperature for 30 minutes with the addition of a homogenizer, whereby an insoluble polymer precipitates. The reaction mixture is filtered, the organic phase over Na₂Dried SO4, filtered and the solvent removed in vacuo. Yield: 59.6 g (49.9%). If starting material used for the cyclization, prepared according to Example 9, Method 2, was used, then, after separation by column chromatography (silica gel 60, CHCl₃/ MeOH (1-5%))

AT 401 058 Β

By-product of the general formula (I) with R2 = CH₃, Xi = Χς = Br, Ra = CHO; Yi, Y₂ = 0 in 6% yield.

'H-NMR (CDCI₃): 8.23 ​​(d, 1H), 7.30 (s, 1H), 6.98 (s, 1H), 5.85-3.95 (m, 3H), 4.70 (s, 1H ), 3.80 (s, 3H), 3.35 (m, 2H), 2.95 (m, 1H), 2.15 (m, 2H).

¹³C-NMR (CDCI₃ + DMSO d₆): 185.31 and 185.25 s, 162.43 and 161.43 d; 147.12 and 146.84 s; 144.61 and 144.37 s; 142.33 and 141.97 d, 129.27 and 129.13 s, 126.62 and 126.40 s, 123.40 and 123.25 s, 116.67 and 116.46 d, 114.27 and 112 , 74 s, 87.00 and 86.86 d, 56.01 q, 52.38 and 51.55 s, 46.18 and 45.80 t, 40.58 t, 37.68 and 36.86 t, 34.26 t.

Example 12:

(4a6β) -4a, 5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro [3a, 3,2-ef] [2] benzazepine-6-ol (galanthamine) ( general formula (I) with: R2 = Ra = Me, X, = X₂ = Y2 = Η, Y1 = OH)

Method 1:

In a 1 I 3-necked flask is placed 4.6 g (121.21 mmol) of LiAlHa in 80 ml of abs. THF and cooled to 0 ° C. 7.36 g (19.47 mmol) of compound (V) (Ri = H, Ra = CHO, Xi = Br, X2 = H, YiY2 = O) in 460 ml of abs. THF was added dropwise in 5 min, stirred for 1 hour at 0'C and refluxed for 21 hours. The reaction mixture is then transferred to a 1 l one-necked flask, cooled to 0 ° C., excess LiAlHa is decomposed with a few drops of H 2 O and the solvent is removed in vacuo. The residue is treated with H₂O is added and the pH is adjusted to 1 with 2N HCl solution. The reaction solution is shaken and warmed until the precipitate is dissolved. The pH is then adjusted to pH 9 with 2N NaOH, the turbid solution is combined with ethyl acetate, shaken well and the precipitate which has precipitated out is filtered off. The organic phase is separated and the aqueous phase extracted with ethyl acetate. The combined organic phases are washed over Na₂SOA dried, filtered and the solvent removed in vacuo. Chromatographic purification of the residue (300 g SiO₂, with CHCI₃: MeOH = 97: 3-95: 5) gives colorless crystals.

Yield: 2.23 g (40.03%)

Method 2:

To a suspension of 240 mg (6.3 mmol) LiAlHa in 4 ml abs. THF is added a solution of 365 mg (1.0 mmol) of compound (I) (R.₂= RA = Me, Xi = Br, X₂= Y₂= H, Yi = OH) in 4 ml abs. THF was added dropwise at 0 ° C, stirred at room temperature for one hour and then at reflux temperature for 23 hours. Now the reaction mixture is cooled to 0'C, excess reducing agent with H₂O decomposed, with 50 ml of ethyl acetate and 50 ml of cc. Diluted NHaOH. After shaking, the precipitate which precipitated out is filtered, the organic phase is separated and the aqueous phase is washed with ethyl acetate. The combined organic phases are washed over Na₂SOA dried, filtered and the solvent removed in vacuo. Chromatographic purification of the residue (25 g SiO₂, CHCI₃: MeOH = 99: 1-96: 4) gives 140 mg (49%) of compound (I) (R.₂ = Ra = Me, X, = X₂ = Y₂ = Η, Υ_Ί = OH).

Method 3:

To a suspension of 100 mg (0.27 mmol) of compound (I) (R.₂ = Ra = Me, Xi = Br, X₂ = Η = Y₂ = H, Yi = OH) and 10 mg 10% Pd / C in 3 ml Et₃N is added dropwise to 1.0 ml HCOOH. After stirring for 2.5 hours at reflux temperature, the Pd / C is filtered through Celite, the solvent removed in vacuo and the residue in CH₂Cl2 added. The organic solution is washed twice with sat. NHACI solution, once with H₂O washed, with Na₂SOA dried and the solvent evaporated in vacuo. The residue is separated by column chromatography (9 g SiO₂, CHCI₃: MeOH = 95: 5). Yield: 62 mg (79%) Compound (I) (R2 = R4 = Me, Xi = X₂ = Y₂ = H, Yi = OH)

Melting point: 119 to 121 ° C

Molecular weight Ci 7 H₂1 NO3: 287.34

AT 401 058 Β

Example 13:

(4a6 $) - 4a, 5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-methyl-6H-benzofuro [3a, 3,2-ef] [2] benzazepine-6 ol (bromogallanthamine) (general formula (I) with: R₂ = R₄ = Me, Xi = Br, X₂ = Y₂ = H, Yi = OH) and (4a6a) -4a, 5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-methyl-6H-benzofuro [3a, 3,2-ef] [2] benzazepine-6-ol (epibromogallanthamine) (general formula (I) with: R₂ = R₄ = Me, Xi = Br, X₂ = Yi = H, Y₂ = OH)

To a suspension of 8.0 g (21 mmol) of compound (V) (R₂ = Me, R₄= CHO, Xi = Br, X2 = H, Yi, Y₂= O) in 150 ml of toluene is added dropwise 10 ml (36 mmol) of 1.5M DIBAL-H solution in toluene at 0'C. The reaction is stirred for 1 hour at RT, the residual reducing agent with H₂O decomposes and then 12 ml of concentrated NH₄OH added. After stirring for 20 minutes at room temperature, the precipitated material is filtered off, the organic phase separated and the aqueous phase washed with 50 ml of toluene. The combined organic phases are washed over Na₂SO₄ dried, filtered and the solvent removed in vacuo. The residue (7.7 g) is separated by column chromatography.

Yield: 3.2 g (45.1%) of compound (I) with (R₂ = R₄ = Me, Xi = Br, X₂ = Y₂ = H, Yi = OH) and 0.8 g (20.7%) of compound (I) (R.₂ = R₄ = Me, Xi = Br, X₂ = Y, = H, Y₂ = OH)

Data of Bromogallamine (Compound (I) with R₂ = R₄ = Me, Xi = Br, X₂ = Y₂ = H, Yi = OH):

Molecular weight: CwHigBrNOs: 365.23

IR (KBr): 689.03m; 778,57m; 839,37m; 989,86m; 1050,66s; 1212,43s; 1279,87s; 1434,08s; 14,72s; 1613,99s; 2667,39m; 3370 to 3778 br 'H-NMR (CDCb): 6.9 (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, 1 H).

'³C NMR (CDCb): 145.32 sec; 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; 58.56 t; 55.95 q; 53.26 t; 48.56 s; 42.06 q; 33.47 t; 29.69 t.

Data from Epibromgalanthamine (Compound (I) with R₂ = R₄ = Me, Xi = Br, X₂ = Yi = H, Y₂ = OH):

Molecular weight: CizHigBrNOg: 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 to 3575br.

'H NMR (CDCb): 6.85 (s, 1H); 5.96 (AB, 2H); 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 3 H); 2.15 (td, 1H); 1.69 (m, 2H).

'³C-NMR (CDCb + DMSO-ds): 145.84 s; 143.49 s; 133.89 s; 133.14 d; 126.12 s; 124.35 d; 115.04 s; 113.01 s; 88.26 d; 61.10 d; 57.44 t; 55.58 q; 52.84 t; 47.86 s; 41.20 q; 33.35 t; 31.43 t.

Example 14:

(4a6a) -4a, 5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro [3a, 3,2-ef] [2] benzazepine-6-ol (epigalanthamine) (general formula (I) with: R₂ = R₄ = Me, Xi = X₂ = Yi = H, Y₂ = OH)

To a suspension of 240 mg (6.3 mmol) LiAlH₄ in 4 ml abs. THF is added a solution of 365 mg (1.0 mmol) compound (I) (R.₂ = R₄ = Me, Xi = Br, X₂ = Yi = H, Y₂ = OH) in 4 ml abs. THF was added dropwise at 0 ° C, stirred at room temperature for one hour and then at reflux temperature for 23 hours. Now the reaction mixture is cooled to 0 * C, excess reducing agent with H₂O decomposed, with 50 ml of ethyl acetate and 50 ml of ethyl acetate and 50 ml of cc. NH₄OH diluted. After shaking, the precipitate which precipitated out is filtered off, the organic phase is separated off and the aqueous phase is washed with ethyl acetate. The combined organic phases are washed over Na₂SO₄ dried, filtered and the solvent removed in vacuo. The residue is separated by column chromatography (25 g SiO₂), CHCb: MeOH = 99: 1-96: 4).

Yield: 140 mg (49%) 1 (R.₂ = R₄ = Me, Xi = X₂ = Yi = H, Y₂ = OH)

Melting point: 199 to 201 ° C

Molecular weight: Ci 7 H₂ , NO3: 287.34

AT 401 058 Β

Example 15:

(406jS) -4a, 5,9,10,11,12-hexahydro-1-bromo-3-methoxy-6H-benzofuro [3a, 3,2-ef] [2] benzazepine-6-ol (N-demethyl bromo galanthamine) (general formula (I) with: R 2 = Me X, = Br, Ra = X 2 = Y 2 = H, Y 1 = OH)

To a suspension of 10 g (26.4 mmol) of (I) (R2 = Me, Ra = CHO, Xi = Br, X2 = H, Y: = Y2 = 0) in 200 ml of THF is added 100 ml (100 mmol) 1 M solution of L-Selektride at O'C added dropwise in 30 min. After stirring at O'C for 60 minutes, the complex formed with the reagent is decomposed with H2O and the reaction mixture is mixed with 100 ml of 25% NHAOH solution. After stirring for 30 minutes at RT, the LM is concentrated by half in vacuo, transferred to a separatory funnel, treated with 100 ml of 25% NHAOH solution and extracted with 3 × 200 ml of CH 2 Cl 2. The combined organic phases are dried with Na 2 SO, filtered and the LM evaporated in vacuo. Chromatographic purification of the residue (650 g of SiO 2 silica gel CJCb: MeOH = 95: 5-9: 1) gives colorless foam.

Yield: 7.3 g (75.8%)

CigHigBrNOs: 352.21

IR (KBr): 748.19 m; 793.11 meters; 828,59m; 927,62w; 991,65w; 1058,8s; 1214,79s; 1281,61s; 14,29s; 1488,49s; 1571,11w; 1616,51s; 2912,36s; 3280 to 3420br.

UV (MeOH): X_Max: 225.0 and 297.5 nm.

'H-NMR (CDCb): 6.85 (s, 1H); 6.02 (AB, 2H); 4.53 (s, 1H); 4.81 and 4.48 (AB, 2H); 4.10 (m, 1H); 3.78 (s, 3H); 3.22 (m, 2H); 2.63 (dd, 1H); 2.29 (s, br, 2H); 2.00 (m 1H); 1.78 (m, 2H).

'³C-NMR (CDCl 3): 145.79 s; 143,96s; 134,06s; 131,64s; 127,87d; 126,83d; 115,46d; 113,02s; 88,44d; 61,67d; 56,04q; 52,65t; 49,23s; 46,59t; 39.81 tons; 29,71t.

Example 16:

(4a6jS) -4a, 5,9,10,11,12-hexahydro-1-bromo-3-methoxy-6H-benzofuro [3a, 3,2-ef] [2] benzazepine-6-ol (N-demethyl bromo galanthamine) (general formula (I) with: R2 = Me, X, = Br, Ra = X2 = Y2 = H, Y1 = OH) and (4a6a) -4a, 5,9,10,11,12-hexahydro 1-bromo-3-methoxy-6H-benzofuro [3a, 3,2-ef] [2] benzazepine-6-ol (N-demethyl-epibromogallanthamine) (general formula (I) wherein: R2 = Me, Xi = Br, Ra = X2 = Y1 = Η, Y2 = OH)

To a suspension of 1.0 g (2.6 mmol) (I) (R2 = Me, R₄= CHO, Xi = Br, X2 = H, Yi = Y₂= O) in 5 ml of THF is added dropwise 3.0 g (11.8 mmol) of LiAlH (* BuO) 3 in 15 ml of THF O'C in 30 min. After stirring at O'C for 30 minutes, the reaction mixture is refluxed. After boiling for 22 hours, the complex formed with the reagent is decomposed with H 2 O and 10 ml of 25% NH 4 OH solution are added to the reaction mixture. After stirring for 30 minutes at RT, the LM is concentrated by half in vacuo, transferred to a separatory funnel, treated with 10 ml of 25% NHAOH solution and extracted with 3 × 20 ml CH 2 Cl 2. Dry the combined organic layers with Na 2 SOA, filter, and evaporate the LM in vacuo. Chromatographic purification of the residue (60 g of SiO 2 silica gel CHCb: MeOH = 95: 5-9: 1-8: 2) gives two products. 300.0 mg (32.2% N-demethyl-bromgalanthamine (general formula (I) where R2 = Me, Xi = Br, Ra = X2 = Υς ⁼H, Yi = OH) as a colorless foam and 270 mg (29.0% N-demethyl-bromgalanthamine (general formula (I) where R2 = Me, Xi = Br, Ra = X2 = Y; = H, Υί = ΟΗ) as a colorless foam.

Data of N-demethyl-epibromo-galanthamine:

Molecular weight: CigHisBrNOa: 352.21

IR (KBr): 781.60w; 834,28w; 976,63w; 1050,28m; 1179,73m; 1211,87m; 1280,07m; 1435,24m; 1486,10m; 1616,37m; 2923,54w; 3700-2900mbr.

'H-NMR (CDCb): 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).

'³C-NMR (CDCb): 146.73s; 143,91s; 134,10s; 132,17s; 132,17d; 131,48d; 126,34d; 115,34d; 112,44s; 88,51d; 62,81d; 56,10q; 52,34t; 49,25s; 46,82t; 40,52t; 32,07t.

AT 401 058 Β

Example 17:

(4a6 $) - 4a, 5,9,10,11,12-hexahydro-1 -bromo-3-methoxy-11-methyl-6H-benzofuro [3a, 3,2-ef] [2] benzazepine-6 ol (N-demethyl-bromogallanthamine) (general formula (I) with: R₂ = R₄ = Me, Xi = Br, X₂ = Y₂ = H, Yi = OH)

Method 1:

To a solution of 2.0 g (5.6 mmol) of (I) (R.₂= Me, Xi = Br, R₄= X₂= Y₂ = H, Yi = OH) in 20 ml H₂0 5 ml of 89% HCOOH, 5 ml of 37% CH₂0 given and boiled under reflux. After 15 minutes of cooking, the reaction mixture is treated with H₂O diluted, the pH with 25% NH₄OH adjusted to 9 and with 3 x 20 ml CH₂CI₂ extracted. The combined organic phases are washed with Na₂SO₄dried, filtered and the LM evaporated in vacuo. Chromatographic purification of the residue (150 g SiO₂ Silica gel CHCI₃: MeOH = 97: - »95: 5) gives colorless foam.

Yield: 2.0 g (96.4%)

Method 2:

To a suspension of 10 g (26.4 mmol) of (I) (R.₂ = Me, R₄ = CHO, Xi = Br, X₂ = H, Yi = Y₂ = 0) in 200 ml of THF is added dropwise 100 ml (100 mmol) of 1 M solution of L-Selektrid at O'C in 30 min. After stirring at O'C for 60 minutes, the reagent is treated with H₂O decomposes and the reaction mixture with 100 ml of 25% NH₄OH solution offset. After stirring for 30 minutes at RT, the LM is concentrated by half in vacuo, transferred to a separatory funnel, with 100 ml of 25% NH₄OH and with 3 x 200 ml CH₂CI₂ extracted. The combined organic phases are washed with Na₂SO₄ dried, filtered and the LM evaporated in vacuo. To the residue 50 ml H₂O, 30 ml 98% HCOOH, 30 ml 37% CH₂Added O solution and the reaction mixture was refluxed. After 15 minutes of cooking, the reaction with NH₄OH neutralized and with 3 x 200 ml CH₂CI₂ extracted. The combined organic phases are converted over Na₂SO₄ dried, filtered and the LM evaporated in vacuo. Chromatographic purification of the residue of the residue (600 g SiO₂ Silica gel CHCI₃: MeOH = 9: 1- »8: 2) gives colorless foam.

Yield: 6.4 g (66.2%).

Example 18:

Optical separation of (t) galanthamine

A solution of 500 mg (±) galanthamine (1.74 mmol) Compound (I) (R.₂ = R₄ = Me, Xi = X₂ = Y₂ = H, Yi = OH) in 1.0 ml of MeOH is added a solution of 672.2 mg (1.74 mmol) of (+) di-p-toluyl-D-tartaric acid in 4 ml of MeOH at RT. After standing in the refrigerator for 24 hours, the precipitated crystalline substance is filtered and washed with MeOH. The mother liquor is released for the other isomer. Recrystallization from EtOH gives 450 mg of (-) galanthamine (+) di-p-toluyl tartrate (compound (II) R₂ = R₄= Me, R₅= Xi = X₂= Y₂ = H, Y, = OH, Z = (+) di-p-toluyl tartrate), m.p .: 182 to 184'C. The free base is mixed with CHCl₃/ NH₄OH released from the salt [a]_D = -101.8 '.

The methanolic mother liquor is evaporated, the base with CHCl₃/ NH₄OH, dissolved in 0.5 ml of MeOH and treated with a solution of 215 mg (0.55 mmol) of (-) di-p-toluyl-L-tartaric acid. After standing in the refrigerator for 24 hours, the precipitated material is filtered and washed with MeOH. Recrystallization from EtOH gives 242 mg of (+) galanthamine - (-) di-p-toluyl tartrate (Compound (II) R₂ = R₄= Me, Rs = Xi = X₂= Y₂ = H, Yi = OH, Z = (-) di-p-toluyl tartrate), m.p .: 144 to 148'C. The salt is added to the free base with CHCl₃/ NH₄OH has been converted. [A]_D = + 98.9 '.

Explanation of abbreviations used in the above description:

DiBAL-H: diisobutylaluminum hydride

Red-AI^R: Sodium bis (2-methoxyethoxy) aluminum dihydride

Superhydrides ": lithium triethylborohydride

9-Borabicyclo (3.3.1) nonane lithium tri-sec-butylborohydride (Aldrich)

Potassium tri-sec-butylborohydride (Aldrich)

Lithium trisiamylborohydride (Aldrich)

9-BBN:

L-selectrides^R:

K-selectrides^R:

LS-selectrides ":

AT 401 058 B

KS-selectrides^R: Potassium trisiamylborohydride (Aldrich)

Abbreviations:

<td>LM:</td><td>solvent</td>

<td>ML:</td><td>mother liquor</td>

<td>TTHF:</td><td>tetrahydrofuran</td>

<td>DMF:</td><td>dimethylformamide</td>

<td>EtOAc:</td><td>ethyl acetate</td>

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

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