NO142075B - PROCEDURE FOR ASYMMETRIC HYDROGENERATION - Google Patents

Description

When an olefin, which in its saturated form is optically active, is hydrogenated, the usual end product is optically inactive mainly because an equivalent amount of both enantiomorphs (racemic mixture) is formed. In order to obtain the desired enan-

thiomorph, the mixture must be separated into its optical components.

This method is laborious and expensive, and results

often in the destruction of the unwanted enantiomorph. Because of

these difficulties, a keen attention has been devoted to the asymmetric syntheses, whereby essentially one of the enantiomorphs is obtained.

It has now been found that excellent yields of a desired enantiomorph of α-amino acids can be obtained from the olefinic compounds which are (3-substituted-α-acrylamido-acrylic acids and/or their salts by hydrogenation of the olefinic bond in the presence of an optically active coordinated metal complex as hydrogenation catalyst. Such a reaction is illustrated using the following equation:

wherein the P substituent is phenyl.

(The 3-substituent can be exemplified by such groups as hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, amino, benzylamino, dibenzylamino, nitro, carboxyl and carboxyl ester, etc. Those skilled in the art will also recognize that the substituent can be selected from a large number of groups , and that these are only limited by the α-amino acid which is the desired end product.

Examples of α-amino acids, whose enantiomorphs can be rapidly prepared in accordance with the method according to the present invention, are alanine, p-chlorophenylalanine, tryptophan, phenylalanine, 3-(3,4-dihydroxyphenyl)-alanine, 5-hydroxytryptophan, lysine, histidine, tyrosine, leucine, glutamic acid and valine.

The acyl group can be substituted or unsubstituted acyl, and examples of such groups are acetyl, benzoyl, formyl,

propionyl, butyryl, toluyl, nitrobenzoyl, or other acyl variants used as blocking groups in peptide synthesis, etc.

It is preferred that such a catalytic hydrogenation of P-substituted-oc-acylamido-acrylic acids is carried out in the presence of a base.

P-substituted-α-acylamido-acrylic acids and/or their salts are precursors of the substituted and unsubstituted alanines.

Compounds represented by the following structural formula give excellent results with the method according to the present invention, and are therefore compounds which are particularly suitable for the method according to the present invention.

where T is selected from the group consisting of hydrogen, carboxyl, unsubstituted and substituted alkyl, thienyl, P-indolyl, (3-imidazolyl, furyl, piperonyl and

where B, C and D are independently selected from groups consisting of hydrogen, alkyl, carboxyl, hydroxyl (and their metal salts), alkoxy, halogen, acyloxy, aryloxy, aralkyloxy, amino, alkylamino, nitro and cyano,

Z is selected from the group consisting of substituted

or unsubstituted acyl, accordingly. described above,

and p, q and r are integers from 0 to 5 provided that the sum of p, q and r does not exceed 5.

A particularly preferred embodiment, which also illustrates the method according to this invention, is the preparation of substituted and unsubstituted phenylalanines by catalytic asymmetric hydrogenation according to the present invention. Unsaturated precursors of such α-amino acids can be prepared

by means of the Erlenmeyer-azlactone synthesis, whereby a substituted or unsubstituted benzaldehyde is allowed to react with an acylglycine, such as e.g. acetylglycine, and acetic anhydride to form azlactone, which is hydrolyzed to form the unsaturated precursor. Such a reaction is illustrated by means of the following equations (using benzaldehyde and acetylglycine as illustrative reactants):

In such reactions, the substituents on the phenyl group can be chosen from a large number of groups, and they are only limited by the phenylalanine which is the desired end product. Moreover, it may occur that such substituent groups are themselves precursors of substituents which are desired in the final product, and which can easily be converted into such desired substituents. If the substituted benzaldehyde e.g. is vanillin, and one wishes to produce 3-(3,4-dihydroxyphenyl)-alanine, the unsaturated precursor can be α-acetamido-4-hydroxy-3-methoxy-cinnamic acid, which will give N-acetyl-3-(4- hydroxy-3-methoxyphenyl)-alanine by hydrogenation, and which can then be converted to 3-(3,4-dihydroxyphenyl)-alanine by simple hydrolysis. The L-enantiomorph of such phenylalanines is particularly undesirable. E.g. is 3-(3,4-dihydroxyphenyl)-L-alanine ("L-DOPA") well known for its utility in treating symptoms of Parkinson's disease. Likewise, L-phenylalanine has found use as an intermediate product in the production of alkyl esters of L-aspartyl-L-phenylalanine, which has recently proven to be an excellent synthetic sweetener.

The optically active hydrogenation catalysts, which are applicable according to this invention, are soluble, coordinated complexes, which contain a metal selected from the group consisting of rhodium, iridium, ruthenium, osmium, palladium and platinum in combination with at least one optically active phosphine or arsine ligand. These catalysts are soluble in the reaction mass, and are therefore referred to as "homogeneous" catalysts. 5 6 7 Phosphine or arsine ligands can e.g. be of the formula AR R R , 5 6 7

where A means phosphorus or arsenic and R , R , and R are independently selected from the group consisting of hydrogen; alkyl or alkoxy, having at least one carbon atom and a maximum of 12 carbon atoms; substituted alkyl whereby, by said substitution, groups consisting of amino, carbonyl, aryl, nitro and alkoxy are selected, whereby said alkoxy has a maximum of 4 carbon atoms$ aryl5 aryloxy; phenyl5 substituted phenyl, whereby groups consisting of alkoxy are selected by said substitution

and alkyl, hydroxy, aryloxy, amino and nitro, and that less than 3 substituents occur in said substitution; cycloalkyl of at least 3 carbon atoms; substituted cycloalkyl; pyrryl; thienyl; furyl; pyridyl; piperidyl; and 3-cholesteryl.

The optical activity of the metal complex is due to the phosphine or arsine ligand. This optical activity is due either to three different groups on the phosphorus or arsenic atom or to an optically active group being bound to the phosphorus or arsenic atom.

Illustrative coordinated metal complexes can be represented by

1 2 l

the formulas M XnL3 or M X^ , where M means a metal selected from the group consisting of rhodium, iridium, ruthenium and osmium: M 2 is selected from the group consisting of palladium and platinum;

X is selected from the group consisting of hydrogen, fluorine, bromine, chlorine and iodine; 1 is phosphine or arsine ligand as previously defined and n is the numbers 1 or 3.

In the above coordinated metal complex formulas, needs

only one ligand (L) to be optically active to make the reaction and process feasible.

If the optical activity of the ligand is due to an optically active group bound to phosphorus or the 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 R 5 , R 6 or R 7 needs to be optically active, whereby the remaining

two groups can be equal or inactive.

Catalysts which can be used include, but are not limited to, coordinated metal complexes with the formulas below.

In the formulas, a star indicates asymmetry and thus optical activity. The asterisk indicates an asymmetric atom or a dissymmetric group. As an example, R shows that phosphorus or arsenic is asymmetric. When no star is found, this indicates that there is no optical activity.

where M1, M~, X, A, KJ, \ib and R7 have previous anqilU meanings.

It appears from the above-mentioned catalysts that the dissymnium r ik<' group can be RJ, or R7 and not limited to just one group. Besides, it can. occur a combination of the part that is bonded to the metal.

It appears that the above formulas do not only represent

the coordinated metal complexes, which contain two or three ligands as in the formulas M 2 ^■ 2L2 or M 1xnL3' but that they °9so represent coordinated metal complexes in which the number of ligand-metal coordinated bonds is described by the number of L in the formulas, and whereby these bonds are determined by the ligands of multidentate type. Although it e.g. can only be two ligands in a particular coordination metal complex, the formula M 1X will still stand for the complex if one or two ligands are bidentate, i.e. they give two coordination bonds. In the same way, the formula M"Sc also represents those complexes in which there is only one ligand present and if this ligand is tridentate it will give three coordination bonds.

The substituents on the phosphorus or arsenic atoms include, but are not limited to: methyl, ethyl, propyl, isopropyl, butyl and its isomers, pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers isomers, nonyl and its isomers, decyl and its isomers, undecyl and its isomers, dodecyl and its isomers, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, acetoxyphenyl, methylphenyl, ethylphenyl, propylphenyl, butylphenyl, dimethylphenyl, trimethylphenyl, diethylphenyl, hydroxyphenyl, phenoxyphenyl, o-anisyl, 3-cholesteryl, benzyl, pyrryl, furyl, pyridyl, thienyl, piperidyl, menthy1, borny1 and pinyl.

A list of optically active phosphine and arsine that may be used includes, but is not limited to, the following: methylethylphosphine, methylisopropylphosphine, ethylbutylphosphine, isopropylisobutylphosphine, methylphenylphosphine, ethylphenylphosphine, propylphenylphosphine, butylphenylphosphine, phenylbenzylphosphine, phenylpyrrolephosphine, ethylisopropylisobutylphosphine, methylphenylphosphine -4-methylphenylphosphine, ethylphenyl-4-methylphenylphosphine, methylisopropyl-phenylphosphine, ethylphenyl-2,4,5-trimethylphenylphosphine, phenylbenzyl-4-dimethylaminophenylphosphine, phenylpyridylmethylphosphine, phenylcyclopentylethylphosphine, cyclohexylmethylisopropylphosphine, o-methoxy-phenylmethylphenylphosphine, o-methoxyphenylcyclohexylmethylphosphine and analogues arsenic compounds of the above.

The optically active phosphines and arsines contain at least one phenyl group which has a substituent in the ortho position, such as e.g. hydroxy; Alkoxy with at least one carbon atom and a maximum of 12 carbon atoms and aryloxy are particularly preferred compounds for use according to the present invention. Excellent results have been obtained with methylphenyl-o-anisylphosphine and methylcyclohexyl-o-anisylphosphine. The latter compound, prepared together with the optically active coordinated metal complex as "hydrogenation catalysts" are new compounds. It has been found that the desired enantiomorphs of substituted and unsubstituted phenylalanines can be easily prepared with excellent yield by using such optically active ligands in the process according to the invention.

Although only one optically active group or ligand is required

in the coordination metal complex catalyst, it is preferred for reasons of ease of preparation that all three ligands are the same in the formula described above, M^X^^- It is also preferred that the asymmetry be attributed either to phosphorus or the arsenic atom.

It has been found that excellent yields of the desired en-antimorphs can be obtained not only by means of the optically active hydrogenation catalysts described above, which consist of coordination metal complexes of a metal selected from the group consisting of rhodium, iridium, ruthenium, osmium, palladium and platinum, it is believed that these good yields can also be obtained by hydrogenation in the presence of a catalyst containing a solution of a metal selected from the group consisting of rhodium, iridium, ruthenium, osmium, palladium and platinum and at least one equivalent of a phosphine and/or arsine -ligand per mole of metal, provided the ligand is optically active. E.g. the catalyst can be prepared by dissolving a soluble metal compound in a suitable solvent together with a ligand,

in that the ratio of ligand to metal is at least one equivalent of the ligand per mole of metal, preferably two equivalents of the ligand per moles of metal. Likewise, it has been found that the catalyst can be formed in situ by adding a soluble metal compound to the reaction mass together with the addition of an appropriate amount of the optically active ligand to the reaction

sion mass either before or during the hydrogenation.

The preferred metal used is rhodium. Soluble rhodium compounds that can be used include rhodium trichloride hydrate, thodium tribromide hydrate, rhodium sulfate, organic rhodium complexes with ethylene, propylene, etc., and bis-olefins, such as 1,5-cyclooctadiene and 1,5-hexadiene, bicyclo-2,2 ,lhepta-2,5-diene and other dienes which can form bidentate ligands,

or an active form of metallic rhodium and which can be easily dissolved.

It has been found that the method according to this invention is preferably carried out in the presence of an optically active phosphine or arsine ligand, the ligand occurring in a ratio corresponding to 1.5 to approx. 2.5 (preferably 2.0) equivalents of ligand per moles of metal. In practice, it is preferred to have the optically active catalyst in solid form due to handling and storage. This can be achieved with solid cationic coordination metal complexes.

Cationic coordination metal complexes, containing 2 equivalents of phosphine or arsine per moles of metal and a chelate-forming bis-olefin, can be used as catalysts according to the present invention. E.g. by using the organic rhodium complexes, as described above, such cationic coordination rhodium complexes can be prepared by adding

prepare a slurry of organic rhodium complex in an alcohol,

like for example. ethanol, and adding 2 equivalents of the optically active phosphine or arsine so that an ionic solution is formed, after which a suitable anion is added, such as e.g. tetrafluoroborate, tetraphenylborate or some other anion which can cause precipitation or crystallization of a solid, cationic coordination metal complex, either directly from the solution or after 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(methyl-cyclohexyl-1-anisylphosphine)rhodium tetraphenylborate and bicyclo-2.2.1-hepta -2,5-diene-bis(methylcyclohexyl-o-anisylphosphine) thodium tetrafluoroborate .

Without affecting the present invention, it can be mentioned that it is intended that the catalyst is actually present as a catalyst precursor, and that the catalyst is converted into an active form upon contact with hydrogen. This conversion can of course be carried out during the actual hydrogenation of the olefin bond, or it can be carried out by exposing the catalyst (or precursor) to hydrogen before the addition to the olefin material for hydrogenation.

The hydrogenation reaction is usually carried out in a solvent, such as e.g. benzene, ethanol, toluene, cyclohexane, and mixtures of these solvents. Almost any solvent of aromatic or saturated alkane or cycloalkane, and which is inactive to the hydrogenation conditions during the reaction, can be used. As the hydrogenation process according to the present invention has been found to be special, solvents such as e.g. nitrobenzene is used. The preferred solvent is methanol.

As mentioned above, the catalyst is added to the solvent either as a compound per see or in the form of its components which then form the catalyst in situ. When the catalyst is added in the form of its components, it can be added before or simultaneously with the β-substituted oc-acylamido-acrylic acid. Components for producing the catalyst in situ are soluble metal compounds and optically active phosphine or arsine ligands.

The catalyst can be added in a catalytically effective amount, which is usually in the range from approx. 0.0001% to approx. 5 weight-% metal content based on (3-substituted-oc-acylamido-acrylic acid and/or the content of its salts.

Within practical limits, methods should be provided to

avoid contact between the catalyst or the reaction mass and the oxidizing substances. In particular, you should avoid contact with

oxygen. It is preferred to carry out the hydrogenation reaction and other relevant reactions in gases (not H2) which are inert to both reactants and catalysts, such as e.g. nitrogen or carbon dioxide.

As previously mentioned, it has been found that the asymmetric hydrogenation is enhanced in the presence of a base in the reaction mass. Although the asymmetric hydrogenation can be carried out in a reaction mass that is free of base, and even if it can be carried out under acidic conditions, the hydrogenation is enhanced by the addition of small amounts, which can amount to one equivalent basic material per moles of acrylic acid. It is surprising that a small amount of basic material added to even an acidic reaction mass will result in an enhanced asymmetric hydrogenation, and in fact it has been found that the formation of a small amount of salt of acrylic acid is sufficient to achieve these improved results.

Some bases that can be used are tertiary bases, such as e.g. triethylamine, NaOH, and almost any basic material that can form a salt with the carboxylic acids.

After adding the components to the solvent, hydrogen is added to the mixture until approx. 1 to approx. 5 times the molar amount of P-substituted-oc-acylamido-acrylic acid, or in an amount ratio necessary to complete the hydrogenation to the desired point. The pressure of the reaction system will necessarily vary depending on the type of β-substituted-oc-acylamido-acrylic acid, catalyst type, the size of the hydrogenation apparatus, the proportion of the components and the amount of solvent and/or base. Lower pressures, which include atmospheric or subatmospheric pressure, can be used as well as higher pressures.

The reaction temperatures can be in the range of approx. -20°C to approx. 110°C. Higher temperatures can be used, but are normally not necessary and can lead to an increase in side reactions.

After completion of the reaction, as determined by conventional methods, the solvent is removed, and the products and catalyst are separated by conventional methods.

Many naturally occurring products and drugs exist in an optically active form, whereby only one of the L or D forms is usually effective. Synthetic preparations of these compounds in the past have required an additional step to separate the products into their enantiomorphs. This procedure is expensive and time-consuming. The method according to the present invention allows the formation of optically active products, thereby eliminating much of the time-consuming and expensive separation of the enantiomorphs, and whereby the yield of the desired enantiomorphs is improved and the yield of the desired enantiomorphs is reduced.

The desired enantiomorph of the α-amino acids can be prepared by hydrogenation of the appropriate P-substituted-α-acylamido-acrylic acid according to the present invention, after which the acyl group is removed from the α-amino and other blocking groups by conventional methods, thereby obtaining the desired enantiomorph connection.

It has been found that α-amino acids prepared from (3-substituted t-α-acylamido-acrylic acids and/or their salts can be easily prepared with a large preponderance of the desired enantiomorphic compound. This makes the present invention particularly valuable.

The following examples shall illustrate in detail the execution of the method according to the invention. In the following, "parts" means parts by weight unless otherwise stated. In the examples, % optical purity is determined using the following equation, (the optical activities expressed as specific rotations are measured in

me solvent):

MANUFACTURE 1

The optically active phosphines and arsines can be prepared according to the method of Mislow and Korpiun, J. Am. Chem. Soc. 89, 4784 (1967).

250 parts of phenyldichlorophosphine, 240 parts of pyridine and; 495 parts hexane. The solution was cooled to approx. 5 - 10°C

and a mixture consisting of 96 parts methanol and 27 parts hexane was added with stirring and over a period of approx. 1 - 1/2 hour. The resulting mixture was further stirred for 2 - 1/2 hours while heating to approx. 25°c. The reaction then took place in an inert nitrogen atmosphere.

Pyridine hydrochloride, which was formed during the reaction, was removed by filtration, and the filtrate was concentrated. The yellow residue was distilled while collecting a colored fraction boiling at 95.5 - 97°c/17 mm (82% yield dimethyl-phenylphosphonite). [Harwood and Grisley, J. Am. Chem. Soc, 82, 423 (1960)].

11 parts of dimethylphenylphosphonite, 2.5 parts of methyl iodide and 9 parts of toluene were added to a suitable container which was equipped with a refrigerating device, a temperature measuring instrument and material coating devices. The solution obtained was heated slowly. The reaction is exothermic and the temperature increases from approx. 110°C, the reaction mixture is kept at a temperature of approx. 100 - 120°C and a further 185 parts of dimethylphenylphosphonite are added slowly. Additional quantities of methyl iodide, i.e. quantity reductions of approx. 1 part, is added occasionally during the phosphonite addition. The reaction mixture was maintained at approx. Il0°c for a further 1 hour followed by the addition of the components. The reaction mixture was then distilled, and the fraction boiling at 148-149°c/17 mm was collected. (96% yield methylphenylmethylphosphinate.) [Harwood and Grisley J. Am Chem. Soc., 82, 423 (1960)].

187 parts of methylphenylmethylphosphinate and 1600 parts of carbon tetrachloride were added to a suitable container equipped with a refrigerating device, a condensing device, a temperature measuring instrument and a material deposition device. To this mixture were added 229 parts of phosphorus pentachloride divided into three portions of 50 parts each and one portion of 79 parts. A temperature increase was observed during the addition of the first three portions. The mixture was stirred at approx. 60°C for two hours, and then carbon tetrachloride and phosphorus oxychloride were removed by distillation. The residue was distilled and the fraction boiling at 138 - 141°c/17 mm was collected (95% yield methylphenylphosphine chloride). [Method according to organic chemistry (Houben-Weyl) vol. XII/I p. 243].

To a suitable container equipped with a refrigerating device, a condensing device, a temperature measuring instrument and a material coating device, 78 parts of 1-menthol were added

([oOq5 = -50° in ethanol) and 72 parts of diethyl ether. 119 parts of triethylamine were added to the resulting solution, and the resulting mixture was cooled at approx. 0°C. To this mixture, 87 parts of methylphenylphosphine chloride were added with stirring over a period of time of approx. 1 - 1/2 hour and at a temperature of approx. 0°c. The mixture was allowed to heat to approx. 25°c and was then heated under reflux approx. 10 - 1/2 hour.

To remove the triethylamine hydrochloride, the mixture was filtered and the filtrate concentrated. The concentrated filtrate gave a solid yield which melted at 50-65°C, and which constitutes a mixture of diastereoisomers of 1-methylyl-methylphenylphosphinate (60% S and 40% R).

The above-prepared mixture of diastereoisomers of 1-menthyl-methylphenylphosphinate was purified by crystallization several times in hexane followed by crystallization in diethyl ether and gave a solid melting at 78 - 82°C, which is in the S form of 1-methyl-methylphenylphosphinate .

Under an inert nitrogen atmosphere, 9.5 parts magnesium, 7 parts diethyl ether and a quantity of iodine were added to a suitable container equipped with a freezing device, temperature measuring instrument, material coating device and condensation device, which set the reaction in motion. A small amount of bromopropane was added to initiate the reaction, and the mixture, which consisted of 47 parts of bromopropane and 123 parts of diethyl ether, was then added slowly so that a suitable reflux of the reaction mixture could be maintained. The reaction mixture was then heated to approx. 25°C and stirred for a further two hours.

To this mixture was added a mixture consisting of 12 parts of the S-form of 1-menthyl-methylphenylphosphinate (prepared as above) and 88 parts of benzene. The diethyl ether was then removed and the resulting mixture heated at 78°C for 64 hours.

The reaction product of the magnesium complex was decomposed in a solution of ammonium chloride and then filtered. The precipitate was extracted with hot benzene, and the extract mixed with the filtrate. The organic layer was dried over sodium sulfate, and the solvents removed. Thereby a yellow oil residue was obtained. The oil was chromatographed using a silica gel column and using a hexane:benzene:diethyl ether (3:1:1) mixture, thereby obtaining an optically active phenylmethylpropylphosphine oxide with a 61% yield.

Under an inert nitrogen atmosphere, 16 parts of trichlorosilane and 88 parts of benzene were added to a suitable container, which was equipped with stirring devices, a temperature measuring instrument and a material coating device, at a temperature of approx. 0°C. For this mixture and at a temperature of approx. 4 - 6°C, a mixture consisting of 22 parts triethylamine and 44 parts benzene was added. The resulting mixture was then heated to approx. 25°c and a mixture consisting of 8.2 parts of optically active phenylmethylpropylphosphine oxide (prepared according to the above) and 2 2 parts of benzene was added. The mixture was then heated to approx. 60°C over a two-hour period, and then cooled to approx. 25°c.

The reaction product of the silicone complex was decomposed in 75 parts of a 20% solution of sodium hydroxide followed by 35 parts of water. The resulting mixture was allowed to stand for approx. 15 hours, and the layers were thereby separated. The organic layer was then extracted with 5% hydrochloric acid, twice with water and then dried over sodium sulfate. The solvent was then removed by distillation, and methylpropylphenylphosphine was obtained in 95% yield and with 69% optical purity.

Preparation of rhodium-III-chloride-tris-(methyl-propylphenylphosphine) is as follows: Under a nitrogen atmosphere, 0.342 g (0.0013 mol) rhodium-III-chloride trihydrate and 10 ml of methanol are added to a suitable container. To this was added dropwise over a 15 minute period 0.76 g (0.0046 mol) of optically active methyl-propylphenylphosphine, which had been prepared according to the above, in 3 ml of methanol. The mixture was allowed to stand for 1 hour, and this resulted in a yellow precipitate that separated from the solution. The precipitate was removed by filtration to give 0.21 g of rhodium complex with a specific rotation of [oc]^ = -69.2° (benzene-ethanol, 1:1 v/v).

Concentration of the filtrate gave an additional 0.13 g of product

with a specific rotation of [cc]^<5> = -56.4° (benzene-ethanol,

1:1 v/v).

MANUFACTURE 2

The same general procedure as in Example 1 was followed with the mixture of 1-menthyl-methylphenylphosphinate diastereoisomers, which were dissolved and crystallized in hexane and/or hexane-ether. This resulted in an S form, which melts at 78 - 82 C, and which has a specific rotation [cc]^<5> = -94° (benzene) and an R form, which melts at 86 - 87°c and which has a specific rotation [oc]^ = -17° (benzene).

To a suitable container equipped with a refrigerating device, temperature measuring instrument, material deposition device and condenser,

18.3 parts of magnesium shavings, 13 parts of diethyl ether and an amount of iodine necessary to initiate the reaction were added under an inert nitrogen atmosphere. A small amount of o-anisyl bromide was added to initiate the reaction, and then a mixture consisting of 138 parts of o-bromoanisole and 400 parts of diethyl-

ether added so slowly that a suitable reflux of the reaction mixture could be maintained. After the mixture was added everything

it was kept under reflux for a further 2 hours.

To this mixture was added a mixture consisting of 74 parts of either the R- or S-form of 1-menthyl-methylphenylphosphinate (the choice of the S- or R-form depends on the enantiomorph obtained after the asymmetric hydrogenation) and 450 splits benzene. The diethyl ether was then removed and the resulting mixture heated for 64 hours at 78°C.

The reaction product of the magnesium complex was decomposed in a solution of ammonium chloride, and the product extracted from the aqueous phase with benzene. After removal of benzene, the residual oil was distilled, whereby after a pre-fraction consisting of menthol a product with a boiling point of 180 - 190°C was obtained

at 0.5 mm pressure. The crude methylphenyl-o-anisylphosphine oxide was obtained in 60% yield. By using the R form, a product with a specific rotation [oc] 25 = +27 o (methanol) was obtained. By using the S-shape, a product with the opposite rotation was obtained.

Under an inert nitrogen atmosphere, 16 parts of trichlorosilane and 100

splits benzene at approx. 5°C. A mixture of 12 parts triethylamine and 50 parts benzene was added to this mixture at 4 - 6 C. The resulting mixture was heated to 70°C and a mixture consisting 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 reaction product consisting of the silicone complex was de-

composed by adding under a nitrogen atmosphere 75 parts of 20% sodium hydroxide at 25 o c under cooling. From the organic layer, the desired methylphenyl-o-anisylphosphine was obtained, which

had a specific rotation [oc]D 25 = +41 o (methanol) when the above-mentioned prepared phosphine oxide with a specific rotation [a]D 25 = +2 7 o (methanol) was used. With the opposite enantio-

morph e the phosphine oxide, a phosphine with opposite rotation was obtained.

MANUFACTURE 3

Preparation of methylcyclohexyl-o-anisylphosphine

To a 1 liter autoclave were added 143 parts of (+)-methylphenyl-o-anisyl phosphinoxide (prepared according to the above), 28 parts of 5% rhodium on carbon and 250 parts of methanol. The batch was heated to 75°C and stirred under 56 kg/cm 2 of hydrogen. After completion of hydrogen absorption, nmr analyzes showed that the reaction,

as illustrated by the above equation, 75% was complete. A further 7.0 parts of catalyst were added, after which a

pressure corresponding to 56 kg/cm was imposed and the rate was allowed to go to 96% reaction.

The catalyst was filtered and methanol removed in vacuo. Raw-

the oil was taken up in 200 parts of dibutyl ether and cooled to 0 oC. The crystals, which were separated, were filtered and washed with hexane. 63 parts of methylcyclohexyl-o-anisyl-phosphine oxide were obtained, which melts at 108-110°C and has a specific rotation [ccjD 20 = +63 (methanol).

The above phosphine oxide can be reduced to methylcyclohexyl-o-anisylphosphine with a 95% yield by using HSiCl3 and triethylamine, and which has been described previously for methylphenyl-o-anisylphosphine. The resulting methylcyclohexyl-o-anisylphosphine is a solution with the specific rotation [cc]^° = +98.5° (methanol).

EXAMPLE 1

Asymmetric hydrogenation of g-benzamido-4-hydroxy-3-methoxy-cinnamic acid

To a hydrogenation apparatus equipped with a pressure gauge, temperature measuring instrument and heating device, 25 parts of α-benzamido-4-hydroxy-3-methoxy-cinnamic acid and 186 parts of methanol and 64 parts of 5% sodium hydroxide were added. The batch was carefully purged to remove any trace of air, and finally the pressure was regulated to 3.5 kg/cm 2 with hydrogen at 25°C.

A catalyst solution was prepared by dissolving 0.0059 g of rhodium-1,5-hexadiene chloride ([Rh (1,5-hexadiene)Cl]2)

J. Am. Chem. Soc. 86, 217 (1964) in 2 ml of benzene under a nitrogen atmosphere. Then 0.0139 g of (+)-methylphenyl-o-anisylphos-

fine in 1.3 ml of benzene added. Hydrogen was then allowed to flow through the mixture for 5 minutes. The resulting catalyst solution was then pressed into an autoclave using hydrogen pressure. The hydrogenation starts immediately and is complete after 3-4 hours at 25°C and 3.5 kg/cm^.

A sample of the obtained solution shows an optical purity of 56.4%, and this corresponds to 78/22 L/D bilayering of the sodium salt of N-benzoyl-3-(4-hydroxy-3-methoxyphenyl)-alanine.

The N-benzoyl-substituted amino acid can be obtained in 95% yield by evaporating away the methanol and neutralizing the sodium salt with hydrochloric acid.

The obtained L-enantiomorph can be converted to L-DOPA by means of simple hydrolysis, which thereby removes the blocking groups, benzoyl and methyl in the 3-substitution position in phenyl.

EXAMPLE 2

25.0 g of α-benzamido-4-hydroxy-3-methoxy-cinnamic acid, 300 ml of methanol and 0.6 ml of 5% aqueous NaOH were added to a 1 liter autoclave. The batch was stirred at 25°C under 2.8 kg/cm 2 of pure hydrogen until it was ensured that there was no leakage. After that, approx. 1 ml (0.01% Rh, 0.05% phosphine) of the following catalyst solution added by means of a membrane so that the pressure is not affected. [the catalyst solution was prepared by dissolving under nitrogen atmosphere 0.0050 g [Rh (1,5-hexadiene)Cl]0 in 0.33 ml solution of methylphenyl-o-anisylphosphine with a specific rotation [<x]D 25 = +42 o (methanol) in benzene,

which contained 0.041 g/ml and diluted to 1 ml with methanol].

A stirring speed of 1400 rpm. kept in the reaction mass,

and hydrogen begins to absorb after a 2-5 minute induction period and the hydrogenation is finished in 2 hours.

Methanol is evaporated and the acid is dissolved in one mole of aqueous NaOH. The neutral catalyst is extracted with benzene and set aside for recovery. The free amino acid is then precipitated using concentrated HCl during crystallization. 24 g of N-benzoyl-3-(4-hydroxy-3-methoxyphenyl)-alanine are obtained, which contains 73% L-enantiomorph and 27% D-enantiomorph. The L-enantiomorph can be converted to L-DOPA by hydrolysis as shown in example 4.

EXAMPLES 3-17

Other optically active α-amino acids prepared according to a method similar to the methods described in Examples 4 and 5, together with the hydrogenated olefin compounds, the phosphine ligand used in the rhodium catalyst and the optical purity obtained are as follows:

EXAMPLE 18

To an autoclave was added 25.0 g (0.085 mol) of α-acetamido-4-hydroxy-3-methoxy-cinnamic acid acetate, 300 ml of methanol and 0.36

ml of 50% NaOH. The autoclave was put under 2.5 kg/cm 2 pressure with a 50/50 mixture of and H2.

A catalyst solution was prepared by dissolving 0.0050 g

(0.023 meq.) of [Rh(1,5-hexadiene)Cl]2 in 0.5 ml of benzene and

under a nitrogen atmosphere to add 0.051 meq. (+)-methylcyclohexyl-o-anisyl-phosphine (optical purity = about 90%) in 2.4 ml of benzene. Hydrogen was bubbled through the solution for 10 minutes.

The catalyst solution was then added to the autoclave. The hydrogenation was carried out at 60°C and finished in 4 hours.

The product obtained by evaporation of the solvent

was N-acetyl-3-(4-hydroxy-3-methoxyphenyl)-alanine acetate,

which had a specific rotation [oc]D 25 = +38.2 (Na salt in water).

Pure N-acetyl-3-(4-hydroxy-3-methoxyphenyl)-L-alanine acetate,

as well as a sodium salt in water, had a specific rotation [a]<25> = +54.0°:

Thus was the optical purity of the hydrogenation product

70.7% or better than 85% of L-enantiomorph and 15% of D-enantiomorph.

By using a similar procedure and with (-)-methylcyclohexyl-o-anisylphosphine (optical purity = approx. 80%), a hydrogenation product containing mainly D-enantio-

morph (optical purity of the reaction product mixture was 65%).

Thus, by suitable choice of (+)- or (-)-phosphine, mainly one enantiomorph could be prepared.

EXAMPLE 19

A similar method as described in example 18 was used

on (-)-methylcyclohexyl-o-anisylphosphine, as optically active ligand and α-benzamido-4-hydroxy-3-methoxy-cinnamic acid as (3-substituted-oc-acylamido-acrylic acid.

The hydrogenation product obtained was N-benzoyl-3-(4-hydroxy-3-methoxyphenyl)-alanine which contained mainly the D-enantiomorph (the optical purity of the reaction product mixture =

about. 65%).

Claims (2)

1. Procedure for asymmetric hydrogenation of an unsaturated compound containing the group to give a non-racemic mixture of a compound containing the group characterized in that the unsaturated compound is hydrogenated in the presence of a catalyst which is: or where M is a metal selected from the group consisting of rhodium, ruthenium, iridium and osmium, M 2 is a metal selected from the group consisting of palladium and platinum, X is selected from the group consisting of hydrogen, chlorine, fluorine, bromine and iodine, L means a phosphine or arsine ligand, provided that at least one L group is optically active and n means the number one or three, or (c) a solution of a metal selected from the group consisting of rhodium, iridium, ruthenium, osmium, palladium and platinum and at least one equivalent phosphine or arsine ligand per moles of metal in the solution, assuming the ligand is optically active; or (d) cationic coordination rhodium complexes containing two equivalents of an optically active phosphine or arsine ligand per moles of rhodium and a chelating bis-olefin. 2. Method according to claim 1, characterized in that the hydrogenation is carried out in the presence of a base.