Catalytic asymmetric hydrogenation and catalyst therefor

When an olefin, which in its saturated form is optically active, is hydrogenated, an optically inactive product is usually obtained, mainly due to the formation of an equal amount of the two enantiomers (racemic mixture). To obtain the desired enantiomer, the racemic mixture must be divided into its optical components. This process is laborious, costly and often results in destruction of the unwanted enantiomer. Due to these difficulties, extensive attempts have been made to enable asymmetric synthesis, which yields a major amount of the desired enantiomer.

It has now been found that excellent yields of the desired enantiomer of β-amino acids can be obtained from the olefin compounds which are substituted α-acylaminoacrylic acids and / or salts thereof by hydrogenation of the olefin bond in the presence of an optically active coordination metal complex. Such a reaction is illustrated in the following reaction scheme, where_z the substituent is phenyl:

<img file="SE400552B_D0001.tif" />

COOH

NH

IN

Acyl

<img file="SE400552B_D0002.tif" />

CH - COOH I

NH

IN

Acyl

The β-substituent may be, for example, hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, amino, benzylamino, dibenzylamino, nitro, carboxyl and carboxylic ester, etc. The person skilled in the art can select the β-substituent from a large number of groups and in this selection it is only necessary to ensure that the desired amino acid is obtained as the end product.

Examples of α-amino acids whose enantiomers according to the invention can be easily prepared include alanine, p-chlorophenylalanine, tryptophan, phenylalanine, 3- (3,4-dihydroxyphenyl) -alanine, 5-hydroxytryptophan, lysine, histidine, tyrosine, leucine , glutaric acid and valine.

The acyl group may be substituted or unsubstituted and as examples may be mentioned acetyl, benzoyl, formyl, propionyl, butyryl, toluyl, nitrobenzoyl and other acyl variants, which are used as protecting groups in peptide synthesis, etc.

It is preferred that such catalytic hydrogenation of β-substituted α-acylamidoacrylic acids be carried out in the presence of a base.

N -substituted-acylamido-acrylic acids and / or salts thereof are precursors to the substituted or unsubstituted alanines.

The compounds of the following structural formula give excellent results in the process of the invention and therefore represent compounds which are particularly suitable for the present invention.

T - C = C - COOH ii H NH

IN

Z where T represents hydrogen, carboxyl, unsubstituted or substituted alkyl, thienyl, β-indolyl, _{/ f}? -imidazolyl, furyl, piperonyl or

Bp

Cq

<img file="SE400552B_D0003.tif" />

//

Dr and each of the symbols B, C and D, one independently representing hydrogen, alkyl, carboxyl, hydroxyl (and metal salts thereof), alkoxy, halogen, acyloxy, aryloxy, aralkyloxy, amino, alkylamino, nitro or cyano , Z represents substituted or unsubstituted acy.1 of the above kind and p, q and r are. integer 0-5, where the sum p + q + r is at most 5.

7106040-4

An especially preferred embodiment, which is also illustrative of the process of the invention, is the preparation of the substituted and unsubstituted phenylalanines by catalytic asymmetric hydrogenation according to the invention. Unsaturated precursors for such β-amino acids can be prepared according to Erlenmeyer's azlactone synthesis, wherein a substituted or unsubstituted benzaldehyde is reacted with an acylglycine, for example acetylglycine, and acetic anhydride to azlactone, which is hydrolyzed to the unsaturated pair of precursors. Such a reaction is illustrated by the following reaction scheme in which men use benzaldehyde and acetylglycine as examples of reactants:

(1)

<img file="SE400552B_D0004.tif" />

O

CHO + CH₃C-NH-CH₂COOH

ΊΟ

O (C-CH₃)₂

<img file="SE400552B_D0005.tif" />

(2)

S = \

W

CH = CC = 0 'I Ν OW /

C

IN

CH, hydrolysis

<img file="SE400552B_D0006.tif" />

In such reactions, the substituents on the phenyl group can be selected from a large number of groups and the choice is limited only by the phenylalanine which is the desired end product. In addition, such substituent groups may themselves be precursors. to substituents which are desired in the final product and can be readily converted to such desired substituents. For example, if the substituted benzaldehyde is vanillin and it is desired to produce 3- (3,4-dihydroxyphenyl) -alanine, the unsaturated precursor may be α-acetamido-4-hydroxy-3-methoxy-cinnamic acid, which would give N-acetyl-3- (4-hydroxy-3-methoxyphenyl) -alanine by hydrogenation. It can then be converted to 3- (3,4-dihydroxyphenyl) -alanine by simple hydrolysis.

The L-enantiomer of such phenylalanines is particularly desirable. Thus, for example, 3- (3,4-dihydroxyphenyl) -L-alanine (L-DOPA) is well known for its utility in treating the symptoms of Parkinson's disease. Likewise, L-phenylalanine has been found to be useful as an intermediate for the preparation of the alkyl esters of

7106040-4

L-aspartyl-L-phenylalanine, which has recently been shown to be an excellent synthetic sweetener.

The optically active hydrogenation catalysts useful in the process of the invention are soluble coordination complexes containing a metal from the group of rhodium, iridium, ruthenium, osmium, palladium and platinum in combination with at least one catalytically active phosphine or arsine ligand. These catalysts are soluble in the reaction mass and are therefore referred to as homogeneous catalysts.

The phosphine or arsenic ligand may, for example, have the formula AR θ ', where A is phosphorus or arsenic and each of the symbols

R “

7

R 0 and R one independently of one another represent a hydrogen atom; an alkyl or alkoxy group having 1-12 carbon atoms; a substituted alkyl group in which the substituents are selected from the following, namely amino, carbonyl, aryl, nitro and alkoxy, which alkoxy contains at most 4 carbon atoms; an aryl group; an aryloxy group; a phenyl group; a phenyl group substituted with less than 3 substituents, the substituents being selected from the following, namely alkoxy and alkyl, hydroxy, aryloxy, amino and nitro; cycloalkyl having at least 3 carbon atoms; substituted cycloalkyl; pyrryl; thienyl; furyl; pyridyl; piperidyl; and 3-cholesteryl.

Optical activity of the metal coordination complexes of the invention lies in the phosphine or arsine ligand. This optical activity can be due either to the fact that there are three different groups on the phosphorus or arsenic atom or to the fact that an optically active group is attached to the phosphorus or arsenic atom.

As illustrative examples of coordination metal complexes can

M¹ is one of those mentioned by the formula or wherein the metals are rhodium, iridium, ruthenium or osmium; M² is palladium or platinum; X is hydrogen, fluorine, bromine, chlorine or iodine; L, as indicated above, is the phosphine or arsine ligand; and n is an integer 1 or 3.

In the above formulas for coordination metal complexes, only one ligand (L) needs to be optically active for the method of the invention to work.

If the optical activity of the ligand consists in that an optically active group is attached to the phosphorus or arsenic atom, there need only be one such group and the other two groups may be the same or inactive. In this case, only one of the groups c needs A * 7

R, R or R may be optically active and the remaining two groups may be identical or inactive.

7106040-4

Useful catalysts fall under the following formulas for coordination metal complexes but are not limited thereto.

The formulas indicate an asterisk asymmetry and thus optical activity.

Asterisk denotes the asymmetric atom or the dissymmetric group. By way of example, A 'suggests that the phosphorus or arsenic atom is asymmetric. No asterisk means no optical activity.

(AiA⁶R⁷) (ar⁵r⁶r⁷)₂ . 10 r ~ -

<td>(IN)</td><td>M \ (A * k⁵R⁶R⁷)³</td><td>(WE)</td>

<td> (11)</td><td>M ^ X (A * k⁵R⁶R⁷ )₂ (ARE⁵R⁶R⁷)</td><td>(VII)</td>

<td> (111)</td><td>M¹X (A^&gt;^?⁵R⁶R⁷) (ar⁵r⁶r⁷)₂</td><td>(VIII)</td>

<td>(IV)</td><td>m¹x (ar '^⁵r⁶r⁷)₃</td><td>(IX)</td>

<td>(V)</td><td>lAx (AR⁵^⁵R⁶R⁷) ₂ (ARE⁵R⁶R⁷ )</td><td>(X)</td>

<td>(Xl)</td><td>M¹X3 (ar^s^⁵r⁶r⁷ ) 2 (AR^SR⁶R⁷)</td><td>(XIV)</td>

<td>(XXI)</td><td rowspan="2">lAx (AR ^^SR⁶R⁷) (AR⁵R⁶R⁷ ) ₂iAx (a4r⁵r⁶r⁷)</td><td>(XV)</td>

<td>(XIII)</td><td>(XVI)</td>

ΐΑί (A * k⁵R⁶R⁷) &lt;3&lt;

S &lt;

&lt;2&lt;

&lt;2&lt;

dar M

OF

X, A, R '', R ° and r 'have the meanings given above.

In the above list of catalysts, the dimetric group may be R⁵, R⁶ or R⁷ and is not limited to any single group. In addition, there may be one

Kombination ~~ combination of groups attached to the metal.

Of course, the above formulas do not only represent the coordination metal complexes containing two or three ligands, as in the formulas and M ', respectively.^lX_nL₃, but also the coordination metal complexes in which the number of ligand-metal coordination bonds is described by the number L in the formula and in which these bonds are provided by multi-toothed ligands. Thus, for example, although there may be only two ligands in a given coordination metal complex, the formula 1Ai_nL₃ still complex, if one of the two ligands is bidentate, i.e. provides two coordination bonds. Likewise, the formula represents M₍L₃ also the complexes, in which only one ligand is included, namely if this is tridentate, ie. provides three coordination bonds.

The substituents on the phosphorus and arsenic atoms include methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, acetoxyphenyl, methylphenyl, methylphenyl, , propylphenyl, butylphenyl, dimethylphenyl, trimethylphenyl, diethylphenyl, hydroxyphenyl, phenoxyphenyl, o-anisyl, 3-cholesteryl, benzyl, pyrryl, furyl, pyridyl) thienyl, piperidyl, mentyl, bornyl and pinyl. Among the above-mentioned substituents from butyl tom

7106040-4 dodecyl, of course, includes isomers thereof. However, the substituents are not limited to those listed above.

For the purpose of the invention, the following optically active phosphines and arsines used, but the invention is of course not limited to these: metyletylfosfin, metylisopropylfosfin, etylbutylfosfin, isopropylisobutylfosfin, methylphenylphosphine, etylfenylfosfin, propylfenylfosfin, butylfenylfosfin, fenylbensylfosfin, fenylpyrrolfosfin, etylisopropylisobutylfosfin, metylfenyl4-methylphenylphosphine, ethylphenyl- 4-methylphenylphosphine, methylisopropylphenylphosphine. ethylphenyl-2,4,5-trimethylphenylphosphine, phenylbenzyl-4-dimethylaminophenylphosphine, phenylpyridylmethylphosphine, phenylcyclopentylethylphosphine, cyclohexylmethylisopropylphosphine, o-methoxyphenylmethylphenylphosphine, o-methoxyphenylmethoxyphenylceneylcenycenophenylcenylcene.

For the purpose of the invention, particularly preferred are the optically active phosphines and arsines which contain at least one phenyl group which bears a substituent in the ortho position, for example hydroxy; alkoxy having 1-12 carbon atoms; and aryloxy. Good results have been obtained with methylphenyl-o-anisylphosphine and methylcyclohexyl-anisylphosphine. and with the corresponding arsenic analogues. Methylcyclohe, xyl-o-anisylphosphine. and the optically active coordination metal complex hydrogenation catalysts thus prepared are new, and it has been found that the desired enantiomers of substituted and unsubstituted phenylalanines are readily prepared in excellent yields when using such optically active ligands in the manner described below.

Although only one optically active group or ligand is required in the coordination metal complex catalyst, it is preferred to facilitate the preparation that all three ligands in the above-described formula L₃ are equal to each other. It is also preferred that the asymmetry be with the phosphorus or arsenic atom.

It has been found that excellent yields of the desired enantiomers can be obtained not only with the optically active hydrogenation catalysts described above, which are coordination metal complexes of one of the metals rhodium, iridium, ruthenium, osmium, palladium and platinum, but good yields can also be obtained. , when the hydrogenation is carried out in the presence of a catalyst consisting of a solution of the metals rhodium, iridium, ruthenium, osmium, palladium and platinum and at least one equivalent of one phosphine and / or arsine ligand per mole of metal, provided that the ligand is optically active. By way of example, the catalyst may be prepared by

Dissolving a soluble metal compound in a suitable solvent together with a ligand, the ligand: metal ratio being at least one equivalent of ligand per mole of metal, preferably two equivalents of ligand per mole of metal. Likewise, it has been found that the catalyst can be prepared in situ by adding a soluble metal compound to the reaction mass together with an addition of the appropriate amount of the optically active ligand to the reaction mass either before or during the hydrogenation.

Rhodium is preferred as the metal. Useful, soluble rhodiura compounds include rhodium trichlorohydrate, rhodium tribromide hydrate, rhodium sulfate, organic rhodium complexes with ethylene, propylene, etc. and bisolefins, such as 1,5-cyclooctadiene and 1,5-hexadiene, bicyclo2,2,1-hepta-2,5-diene and other dienes, which may form bidentate ligands, or an active form of metallic rhodium, which is readily solubilized.

It has been found that the method of the invention is preferably carried out in the presence of an optically active phosphine or arsine ligand, the ligand being present in a ratio of about 1.5 to about 2.5 (preferably 2.0) equivalents of ligand per mole of metal. In practice, for handling and storage, it is preferred to use the optically active catalyst in solid form. It has been found that these results can be achieved with solid, cationic coordination metal complexes.

Cationic coordination metal complexes containing two equivalents of phosphine or arsine per mole of metal and a chelating bis-olefin can be used as catalysts for the purpose. according to the invention. Thus, using the above-described organic rhodium complexes, such cationic coordination rhodium complexes can be prepared by suspending the organic rhodium complex in an alcohol, for example ethanol, adding two equivalents of the optically active phosphine or arsine to form an ionic solution, whereupon a suitable anion added, for example tetrafluoroborate, tetraphenylborate or any other anion which precipitates or crystallizes a solid, cationic coordination metal complex either directly from the solution or by treatment in a suitable solvent.

Examples of cationic coordination metal complexes are cyclooctadiene-1,5-bis (methylcyclohexyl-o-anisylphosphine) rhodium tetrafluoroborate, cyclooctadiene-1,5-bis (methylcyclohexyl-anisylphosphine) -rodium tetraphenylborate and bicyclo-60-2,5-2,2 4 diene-bis (methylcyclohexyl-o-anisylphosphine) -rodium tetrafluoroborate.

Without tying the invention to any particular theory, it is believed that the catalyst is in the form of a precursor which, upon contact with hydrogen, is converted to active form. This conversion can of course be carried out during the actual hydrogenation of the olefin bond or the catalyst or its precursor can be hydrogenated before the addition to the olefin material to be hydrogenated.

The hydrogenation is usually carried out in a solvent such as benzene, ethanol, toluene, cyclohexane or a mixture of two or more of these. Almost any aromatic, saturated alkane or cycloalkane which is inert to the hydrogenation conditions of the process of the invention can be used as a solvent. Since the hydrogenation according to the invention has been found to be specific, such solvents as nitrobenzene can also be used. However, methanol is preferred as the solvent.

As stated above, the catalyst is added to the solvent either in the form of a compound as such or in the form of the components of the compound, which in that case form the catalyst in situ. When the catalyst is added in the form of its components, these may be added before or at the same time as the β-substituted acylamidoacrylic acid. Components for the preparation of the catalyst in situ are the soluble metal compound and the optically active phosphine or arsine ligand.

The catalyst may be added in any effective catalytic amount, usually in an amount between about 0.0001 and about 5% by weight of metal contained in the catalyst based on the amount of α-substituted = α-acylamidoacrylic acid and / or salt thereof.

Measures should be taken within practical limits to avoid contact between the catalyst or the reaction mass and the oxidizing material. In particular, precautions should be taken to avoid contact with oxygen. It is preferred to prepare the hydrogenation reaction and carry out the hydrogenation itself in gases (other than H 2) which are inert to both reactants and the catalysts, for example nitrogen or carbon dioxide.

As pointed out above, it has now been found that the asymmetric hydrogenation is increased by the presence of a base in the reaction mass. Although the asymmetric hydrogenation can be carried out in a reaction mass which is free from base and even in an acidic reaction mass, the yield is improved if small amounts of a basic material are added to the reaction mass, namely up to a maximum of one equivalent per

7106040-4 moles of acrylic acid. It is surprising that a small amount of base added to an empty acidic reaction mass gives improved asymmetric hydrogenation and it has been found that the formation of a small amount of salt of acrylic acid is sufficient to obtain improved results.

Useful bases include tertiary bases, such as triethylamine, further NaOH and almost any other basic material which forms a salt with carboxylic acids.

After adding the components to the solvent, hydrogen is added to the mixture, until between about 1 and about 5 times the molar amount / substituted oe-acylamido-acrylic acid or an amount required for complete hydrogenation to the desired level is added. The pressure in the system necessarily varies, as it depends on the type / substituted α-acylamido-acrylic acid, the type of catalyst, the dimensions of the hydrator, the amount of components and the amount of solvent and / or base. Lower pressures, including atmospheric pressure and subatmospheric pressure can be applied as well as higher pressures.

The reaction temperature can be between about -20 and about 110 ° C Higher temperatures can be applied but are not normally required and can lead to side reactions being accelerated.

When the reaction is complete, as determined in a conventional manner, the solvent is removed and the products and the catalyst are separated by ordinary means.

Many naturally occurring products and medicines occur in an optically active form. In this case, usually only the L- or D-shape is effective. Synthetic preparation of these compounds has hitherto required further steps, namely separation of the products into their enantiomers. This is time consuming and expensive. The method according to the invention enables the production of optically active products, whereby said time-consuming and expensive separation is eliminated at the same time as the yields of the desired enantiomers are increased and the amount of undesired enantiomer is reduced.

Desired enantiomers of β receives the desired enantiomer.

It has now been found that &lt;x-aminoacrox produced by the

The 7-acylamidoacrylic acids and / or salts thereof can be easily prepared with a large predominance of the desired enantiomer, which makes the present invention particularly valuable.

The following examples show in more detail how the method according to the invention is carried out. Of course, however, the invention is not limited to these details. Parts refer to parts by weight, unless otherwise expressly stated. In the examples,% optical purity has been determined by the following equation (the optical activities are of course expressed as the specific rotations, which have been determined in one and the same solvent):

% optically observed optical activity of the mixture X 100 purity optical activity of the pure enantiomer

Example 1: The optically active phosphines and arsines can be prepared in the manner described by Mislow and Korpiun, J. Am.

Chem. Soc., 89, 4784 (1967).

PhPCl_O + 2 CH₃OII -&gt; Ph-P (0CH₃)₂

A suitable vessel equipped with a stirrer, temperature measuring device and loading device was coated with 250 parts of phenyldichlorophosphine, 240 parts of pyridine and 495 parts of hexane. The solution was cooled to about 5-10 ° C and a mixture of 96 parts of methanol and 27 parts of hexane was added with stirring over about 1.5 hours. The mixture thus obtained was stirred for a further 2.5 hours while heating to about 25 ° C. The reaction was carried out in an inert nitrogen atmosphere.

Pyridine hydrochloride formed during the reaction was filtered off and the filtrate was concentrated. The yellow residue was distilled, collecting a colorless fraction with a distillation range of 95.5-97 ° C / 17 mm Hg (82% yield of dimethylphenylphosphonite). (Harwood and Grisley J. Am. Chem., Soc., 82, 423 (1960))

O

PhP (0CH₃)₂ + CH₃I -&gt; PhP-0CH₃

CH, ³

A suitable vessel equipped with a stirrer, temperature measuring device and loading device was charged with 11 parts of dimethylphenylphosphonite, 2.5 parts of methyl iodide and 9 parts of toluene.

The solution thus obtained was slowly heated. The reaction was exothermic and the temperature rose to about 110 ° C. The reaction mixture

7106040-4 was maintained at a temperature of about 100-120 ° C and an additional 185 parts of dimethylphenylphosphonite was added slowly. Additional amounts of methyl iodide in portions of about 1 part each were added time after time during the phosphonite addition. The reaction mixture was kept at about 110 ° C for an additional 1 hour after the components were added. The reaction mixture was then distilled and a portion with a distillation range of 148-149 ° C / 17 hg was collected (96% yield of methylphenylmethylphosphinate). (Harwood and Grisley J. Am. Chem. Soc., 82, 423 (1960)).

^CH3 O ^CH3 O \ I! 'K II p-och₃ + pci_s-------&gt;; p - ci

Ph

Ph

A suitable vessel equipped with a stirrer, condenser, temperature measuring device and loading device was charged with 187 parts of methylphenylmethylphosphinate and 1600 parts of carbon tetrachloride. To this mixture was added 229 parts of phosphorus pentachloride in three portions of 50 parts each and a portion of 79 parts. An increase in temperature was observed during the addition of the first three portions. The mixture was stirred at about 60 ° C for two hours and then the carbon tetrachloride and phosphorus oxychloride were distilled off. (95% yield of methylphenylphosphine chloride). (Methods of Organic Chemistry (Houben-Weyl) Vol.

XII / I p. 243).

<img file="SE400552B_D0007.tif" />

A suitable vessel equipped with a stirrer, condenser, temperature measuring device and loading device was charged with 78 parts of // '- menthol (^]²⁵= -50 ° in ethanol) and 72 parts of diethyl ether. To the solution thus obtained was added 119 parts of triethylamine and the mixture was cooled to about 0 ° C. To the mixture was added with stirring 87 parts of methylphenylphosphine chloride over a period of about 1.5 hours while maintaining the temperature at about 0 ° C.

7106040-4

The mixture was allowed to stand until the temperature rose to about 25 ° C, after which it was heated under reflux for about 10.5 hours.

The triethylamine hydrochloride was filtered off from the mixture and the filtrate was concentrated. This gave a solid which melted at 50-65 ° C and which was found to be a mixture of / -methylmethylphenylphosphinate diastereoisomers (60% S and 40% R).

The mixture of 7-menthyl-methylphenylphosphinate diastereoisomers prepared as above was decomposed into its components by crystallization several times in hexane and crystallization in diethyl ether to give a solid which melted at 78-82 ° C and which was found to be S -form of / -mentyl-methylphenylphosphinate.

<img file="SE400552B_D0008.tif" />

CH₃CH₂CH₂MgBr

Ph

CH

<img file="SE400552B_D0009.tif" />

^CH2^CH2^CH3

A suitable vessel equipped with a stirrer, a temperature measuring device, a charging device and a condenser was charged with an inert nitrogen atmosphere and then with 9.5 parts of magnesium, 7 parts of diethyl ether and a reaction initiating amount of iodine. A small amount of bromopropane was added to initiate the reaction, whereupon a mixture consisting of 47 parts of bromopropane and

123 portions of diethyl ether were slowly added at such a rate that mild refluxing of the reaction mixture was maintained. The reaction mixture was then cooled to about 25 ° C and stirred for an additional two hours.

To this mixture was added one mixture consisting of S-form parts of β-menthyl methylphenylphosphinate (prepared as above) and 88 parts of benzene. The diethyl ether was then removed and the mixture thus obtained was heated at 78 ° C for 64 hours.

The magnesium complex reaction product was decomposed with a solution of ammonium chloride and then filtered. The precipitate was extracted with hot benzene and the extract was combined with the filtrate. The organic layer was dried over sodium sulfate and the solvents were removed to give a yellow oil. This was chromatographed on a silica gel column but a mixture of

7106040-4 hexane: benzene: diethyl ether (3: 1: 1) to give an optically active phenylmethylpropylphosphine oxide in 61% yield.

Ph 0 Ph 0 \^hrsx) \! ix)

P ^ I-CH₂-CH₂-CH₃ + HSiCl₃ + Et₃N -5&gt; -CHgCHgCH 2

CH₃ CH₃

A suitable vessel, charged with an inert nitrogen atmosphere and equipped with a stirrer, temperature measuring device and loading device, was charged with 16 parts of trichlorosilane and 88 parts of benzene at a temperature of about 0 ° C. To this mixture was added at a temperature of about 4-6 ° C a mixture consisting of 22 parts of triethylamine and 44 parts of benzene.

The mixture thus obtained was then heated to about 25 ° C and a mixture of 8.2 parts of optically active phenylmethylpropylphosphine oxide (prepared as above) and 22 parts of benzene were added. The mixture was then heated to about 60 ° C over two hours and then cooled to about 25 ° C.

The silica complexes obtained as a reaction product were decomposed with 75 parts of a 20% solution of sodium hydroxide and then with 35 parts of water. The mixture thus obtained was allowed to stand for about 15 hours, after which it was divided into layers. The organic layer was extracted with 5% hydrochloric acid, twice with water and then dried over sodium sulfate. The solvent was distilled off, and methylpropylphenylphosphine was obtained in 95% yield with 69% optical purity.

A method of preparing rhodium (II) cloxide tris- (methylpropylphenylphosphine) is described below:

A suitable vessel containing a nitrogen atmosphere was charged with 0.342 g (0.0013 mol) of rhodium (III) chloride trihydrate and 10 ml of methanol, then 0.76 g (0.0046 mol) of the optically active methylpropylphenylphosphine prepared in the above manner in 3 ml of methanol was added dropwise over 15 minutes. The mixture was allowed to stand for one hour, during which time a yellow precipitate formed. This was filtered off to give 0.21 g of the rhodium complex with specific rotation -69.2 ° (a mixture of benzene and ethanol in a volume ratio of 1: 1).

Concentration of the filtrate gave an additional 0.13 g of the product with specific rotation -56.4 ° (a mixture of benzene and ethanol in a volume ratio of 1: 1).

7106040-4

Example 2: The general procedure described in Example 1 was repeated and the mixture of / rotation -94 ° (benzene) and an R-shape, which melted at 86-87 ° C and had specific rotation f / lp⁵- -17 ° (benzene).

<img file="SE400552B_D0010.tif" />

A suitable vessel equipped with a stirrer, temperature measuring device, loading device and condenser was charged with an inert nitrogen atmosphere and with 18.3 parts of magnesium turnings, parts of diethyl ether and a reaction initiating amount of iodine. A small amount of o-anisyl bromide was added to initiate the reaction, and then a mixture of 138 parts of o-bromoanisole and 400 parts of diethyl ether was slowly added at such a rate that mild refluxing was maintained. After the addition was added, the mixture was refluxed for a further two hours.

To the mixture was added a mixture consisting of 74 parts of either the R or S form of / -methyl methylphenylphosphinate (choice of the S or R form depends on which enantiomer is desired to be obtained by the asymmetric hydrogenation) and 450 parts of benzene. The diethyl ether was then removed and the mixture was heated at 78 ° C for 64 hours.

The magnesium complex obtained as a reaction product; was decomposed with a solution of ammonium chloride and the product was extracted from the aqueous phase with benzene. After the benzene was removed, the remaining oil was distilled off, first removing a menthol fraction. Finally, the product distilled over at 180-190 ° C / 0.5 mm Hg. The crude methylphenyl-o-anisylphosphine oxide was formed in 60% yield. Using the R-form, a product with a specific rotation of + 27 ° (methanol) was obtained. Using the S-shape, a product with opposite rotation was obtained.

7106040-4

<img file="SE400552B_D0011.tif" />

A suitable vessel containing an inert nitrogen atmosphere and equipped with a stirrer, temperature measuring device and loading device was charged with 16 parts of trichlorosilane and 100 parts of benzene at a temperature of about 5 ° C. To the mixture was added at 4-6 ° C a mixture of 12 parts of triethylamine and 50 parts of benzene. The mixture thus obtained was heated to 70 ° C and a mixture of 7.5 parts of optically active methylphenyl-o-anisylphosphine oxide in 30 parts of benzene was added. The mixture was heated to 70 ° C for one hour and then cooled to 25 ° C.

The silicon complexes obtained as a reaction product were decomposed by the addition under nitrogen of 75 parts of a 20% sodium hydroxide solution at 25 ° C while cooling. The desired methylphenyl-anisylphosphine was obtained from the organic layer. It had specific rotation + 41 ° (methanol) when the phosphine oxide produced in the above-mentioned manner with specific rotation te ·]²+ 27 ° (methanol) was used. Using the opposite enantiomer of the phosphine oxide, phosphine with opposite rotation was obtained.

Example 3: Preparation of methylcyclohexyl-o-anisylphosphine

<img file="SE400552B_D0012.tif" />

A one liter autoclave was charged with 143 parts of the (+) - methylphenyl-o-anisylphosphine oxide prepared as above, 28 parts of 5% rhodium on carbon and 250 parts of methanol. The batch was heated to 75 ° C and stirred under a hydrogen atmosphere at a pressure of 56 kp / cm² overpressure. When the hydrogen uptake ceased, the NMR spectrum showed that the reaction described in the equation given above proceeded to 75%. An additional 7.0 parts of catalyst was added, the batch was refilled under hydrogen pressure 56 kp / cm gauge and the reaction was continued to a 96% conversion. The catalyst was filtered off and the methanol was evaporated in vacuo. The crude oil was taken up in 200 parts of dibutyl ether and cooled to 0 ° C. The precipitated crystals were filtered off and washed with

7106040-4 hexane. 63 parts of methylcyclohexyl-o-anisylphosphine oxide were obtained in this way, which melted at 108-110 ° C and had a specific rotation of + 63 ° (methanol).

The phosphine oxide prepared as above can be reduced to methylcyclohexyl-o-anisylphosphine in 95% yield using HSiCl 2 and triethylamine as indicated above for methylphenyl-o-anisylphosphine. The resulting methylcyclohexyl-anisylphosphine is a liquid with specific rotation = + 98.5 ° (methanol).

Example 4: Asymmetric hydrogenation of β-benzamido-4-hydroxy-3-methoxy-cinnamic acid

A hydrator equipped with a pressure gauge, temperature measuring device and heating device was charged with 25 parts of pc-benzamido-4-hydroxy-3-methoxy-cinnamic acid, 186 parts of methanol and 64 parts of 5% sodium hydroxide. The batch was carefully blown to remove each trace of air and the hydrogen pressure was finally set at 3.5 kp / cm² overpressure and the temperature of 25 ° C.

A catalyst solution was prepared by dissolving 0.0059 g of rhodium-1,5-hexadienochloricyl (Rf (1,5-bexadien) ₂)

J. Am. Chem. Soc. 86,217 (1964) in 2 ml of benzene under a nitrogen atmosphere. Then 0.0139 g of (+) - methylphenyl-o-anisylphosphine in 1.3 ml of benzene was added, after which hydrogen was passed through the mixture for five minutes. The catalyst solution thus obtained was then pressed into an autoclave with hydrogen pressure. The hydrogenation started immediately and was completed after 3-4 hours at 25 ° C and 3.5 kp / cm² overpressure.

Analysis of the solution thus obtained showed an optical purity of 56.4% corresponding to an L / D mixture of the sodium salt of N-benzoyl-3- (4-hydroxy-3-methoxyphenyl) -alanine in a ratio of 78:22.

The N-benzoyl-substituted amino acid can be prepared in 95% yield by evaporation of the methanol and neutralization of the sodium salt with hydrochloric acid.

The L-enantiomer thus obtained can be converted to L-DOPA by simple hydrolysis to remove the blocking groups benzoyl and methyl on the substituent in the 3-position of the phenyl group.

Example 5: One liter of autoclave was charged with 25.0 g of c The batch was stirred at 25 ° C under 2.8 kp / cm (gauge pressure) of pure hydrogen gas, until it could be established with certainty that no leakage occurred. Approximately 1 ml (0.01% Kh, 0.05%

7106040-4 phosphine) of the following catalyst solution was added through a partition without relieving the pressure. The catalyst solution had been prepared by dissolving under N₂ of 0.0050 g [_Rh (1,5-hexadiene) Cl]₂in 0.33 ml of a solution of methylphenyl-o-anisylphosphine with specific rotation + 42 ° (methanol) in benzene containing 0.041 g / ml and dilution to 1 ml with methanol.

Stirring at 1400 rpm was maintained in the reaction mass and hydrogen began to be absorbed after 2-5 minutes of induction time. The hydrogenation was completed in 2 hours.

The methanol was evaporated and the acid was dissolved in one mole of an aqueous solution of NaOH. The neutral catalyst was extracted with benzene and set aside for recovery. The free amino acid was then precipitated by the addition of concentrated HCl with abundant inoculation. 24 g of N-benzoyl-3- (4-hydroxy-3-methoxyphenyl) -alanine were obtained, containing 73% of the L-enantiomer and 27% of the D-enantiomer. The L-enantiomer can be converted to L-DOPA by hydrolysis in the manner set forth in Example 4.

Examples 6-21: Other optically active β-amino acids were prepared in a manner similar to those given in Examples 4 and 5. These are listed in the table below together with the hydrogenated olefin compound in each case, the phosphine ligand used in the rhodium catalyst and the optical purity of the product. '.z—

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K

Example Olefin -Product Catalyst (Ligand) Optical Purity, \ O

N cn

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E i

K

E

O w

E

O

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O

E OE II &lt;NEO

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O i

~ EX Οι &lt;n

E

U §

O o

io—

II

CM

E

U

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Example 1 Olefin Product Catalyst Optical purity

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island)

Λ

C

M

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W • H

hrs

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rM

Φ

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Example Olefin Product Catalyst Optical purity

<img file="SE400552B_D0024.tif" />

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Example 19 Olefin Product Catalyst Ligand Optical Purity

LO it

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O in

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O

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Ol

OH

Ol

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Ol

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Example 22- An autoclave was charged with 25.0 g (0.085 mol) of acetamido-4-hydroxy-3-methoxy-cinnamic acid acetate, 300 ml of methanol and 0.36 ml of 50% NaOH. The autoclave was placed under a pressure of 2.46 2 kp / cm gauge with a mixture of N₂ and H₂ (50:50).

A catalyst solution was prepared by dissolving

0.0050 g (0.023 mech.) ^ Rh (1,5-hexadiene) ClJ₂ in 0.5 ml of benzene, then 0.051 meq was added under a nitrogen atmosphere. (+) - methylcyclohexyl-o-anisylphosphine (optical purity about 90%) in 2.4 ml of benzene.

Hydrogen was bubbled through this solution for 10 minutes.

The catalyst solution was then introduced into the autoclave and the hydrogenation was carried out at 60 ° C. It was completed in 4 hours. The product, namely N-acetyl-3- (4-hydroxy-3-methoxyphenyl) -alanine acetate, which was recovered by evaporation of the solvent, had specific rotation 5 + = +38.2 (Na salt in water). Pure N-acetyl15 3- (4-hydroxy-3-methoxyphenyl) -L-alanine acetate, also in the form of sodium salt in water, had a specific rotation of + 54.0 °. Thus, the optical purity of the obtained hydrogenation product was 70.7% or better than 85% of the L-enantiomer and 15% of the D-enantiomer.

The procedure described above was repeated with (-) - methyl20 cyclohexyl-o-anisylphosphine (optical purity about 80%). A hydrogenation product containing a major amount of the D-enantiomer was obtained (optical purity of the reaction product mixture was 65%). By appropriate selection of the (+) - or (-) - phosphine, one can thus prepare the respective enantiomers in large yield.

Example 25: The procedure described in Example 22 was repeated with the (-) - methylcyclohexyl-o-anisylphosphine as the optically active ligand and α-benzamido-4-hydroxy-3-methoxy-cinnamic acid as the β-acylamidoacrylic acid. The resulting hydrogenation product was N-benzoyl-3- (4-hydroxy-3-methoxyphenyl) -alanine containing a major amount of the D-enantiomer (optical purity of the reaction product mixture about 65%).

Example 24: In a pressure flask purged with nitrogen, Xbenzamido-4-hydroxy-3-methoxy-cinnamic acid (1.67 g, 5.0 mol), cyclooctadiene-1,5-bis (methylcyclohexyl-o-anisylphosphine) was charged iridiuratefetrafluoroborate³⁵ (21.7 mg, 0.025 mol), and 20 ml of anhydrous methanol. The mixture was stirred and bubbled with nitrogen for 15 minutes. The pressure in the pressure flask was raised to 7 kp / cm gauge by blowing hydrogen, and the mixture was stirred and heated at 100 ° C for 4 hours 20 minutes. A portion of this reaction mixture was subjected to NMR spectrometry risk analysis, which showed that 59% of the starting material had

7106040-4 converted to the product N-benzoyl-3- (4-hydroxy-3-methoxyphenyl) alanine. By polarimetric analysis of the reaction mixture after neutralization according to standard packaging, it was found that the product was optically active with²⁴= 9,3°.

Example 2: In a solution of 2.005 g of N-acetyl-indolyl-OC-acetamidoacrylic acid in 60 ml of methanol was added 0.0074 g of cyclooctadiene-1,5-bis (methylcyclohexyl-o-anisylphosphine) rhodium tetrafluoroborate. The mass thus obtained was carefully blown clean, first with nitrogen and then with hydrogen, and then stirred under a hydrogen overpressure of 2.7 kp / fcm 'at 25 ° C. The hydrogenation to N, N * -diacetyl-tryptophan was completed in 2.5 hours. The solution was diluted to 100 ml and analyzed for optical torsion. The solution had a temperature of 20.1 °. Theoretical value for the pure optical enantiomoXfen is 25.9 °. Thus, an optical purity of 77.5% had been obtained. The product can be isolated by evaporating the solvent and crystallizing the residue

Example 26: Optically active methylpropylphenylarsine was prepared as described by Mislow and co-workers in JACS 95, 953 (1973).

A catalyst solution was prepared by mixing 2 ml of methanol, 0.2 g of methylpropylphenylarsine (80%, 0.16 mmol) and 0.025 g of rhodium (cyclooctadiene-1,5) -acetonylacetonate (0.08 mmol).

After stirring for 10 minutes under a nitrogen atmosphere, the entire amount of solids had gone into solution. A solution of 1.0469 g of α 1 -acetamido-4-hydroxy-3-methoxy-cinnamic acid acetate in 25 ml of methanol was thoroughly purged with nitrogen and then added under a hydrogen overpressure of 3.9 kp / cm² at 50 ° C. To the reaction mixture was added through a septum 1.0 ml of the above catalyst solution. The hydrogenation began and was completed in 2.5 hours, as evidenced by a pressure drop of 0.8 kp / cm². The resulting mass was diluted to 50 μl and tested for specific optical torque, which was found to be⁰⁼ -2.53 °. A test solution using pure N-acetyl-3- (4-hydroxy-3-methoxy-phenyl) -L-alanine acetate and the same amount of catalyst gave a correction of this torque for the catalyst of 0.7 °. The hydrogenation thus gave a net rotation of -1.8 °. The pure optical enantiomorph had Jjxj θ ° = -40.8 °. The optical purity was thus 4.4%.

Evidence that the arsine was not optically pure was obtained by its conversion to the sulfide (Mislow and co-workers in JACS 95).

953 (1973)) and measurement of the optical unit with a Caesian shear reagent (NMR Chiral Shift Reagent, Whitesides and co-workers JACS 96. 1038 (1974)).

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<img file="SE400552B_D0029.tif" />

the methylpropylphenylarsine had an optical purity of only 45%. Thus, if the hydrogenation had been carried out with the optically pure arsine, an optical purity of 9.5% would have been achieved. By evaporation of the methanol and recrystallization from the concentrated solution, the product was recovered.

Example 271 Preparation of cyclooctadiene-1,5-bis (methylcyclohexyloanisylphosphine) rhodium tetrafluoroborate. In a one-liter flask, 300 ml of methanol and 15.4 g (0.031 mol of rhodium (cyclooctadiene-1.5) chloride) were charged under nitrogen.₂30.3 g (98%, 0.12 mol) of methylcyclohexyl-anisylphosphine were added to the solution and the whole was stirred for one hour, whereby a red / orange solution was obtained. The solution of sodium tetrafluoroborate (13.7 g, 0.12 mol) in 160 ml of water was added over one hour. Orange crystals separated and were collected. They were washed with water (2 x 30 ml). The product was dried under vacuum at 25 ° C and weighed. 45 g of product with a melting point of 170-175 ° C were obtained in this way. This material was about 96% optically pure.

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Patent claims