CH625204A5 - Process for the preparation of enantiomorphs of alpha-amino acid derivatives - Google Patents

Description

The invention relates to a process for the preparation of enantiomorphs of a-amino acid derivatives by 55 homogeneously catalyzed asymmetric hydrogenation of the geometric Z isomers of corresponding olefin derivatives.

Homogeneous catalysis, i.e. those catalyzed reactions in which both the reactants and the catalysts are soluble in the reaction mass are known to be particularly valuable in processes in which an asymmetrical result is obtained. For example, it was found that in the homogeneous catalytic hydrogenation of an olefin which is capable of forming a racemic mixture, one of the two possible optically active enantiomorphs in a larger amount and the other optically active in the presence of an optically active catalyst Enantiomorphs obtained in a smaller amount. It has also been found that certain such olefinic sub-

3rd

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strate, for example the precursors of a-amino acids containing a-acylamido and carboxyl substituents optionally present as salts, esters or amides, are particularly suitable for hydrogenation under homogeneous catalysis with optically active catalysts. Such asymmetric catalytic hydrogenations enable the production of large amounts of the desired optical enantiomorph. It has also recently been found that certain optically active catalysts which contain optically active bis-phosphine ligands give excellent optical purity levels of 80% and more in the homogeneously catalyzed asymmetric hydrogenation of such a-amino acid precursors.

Other olefinic substrates which give en-antiomorphs which can be converted into a-amino acids during hydrogenation and which have such excellent optical purity levels would be particularly desirable. The present invention relates to the asymmetric hydrogenation of such olefinic substrates. The desired enantiomorphs can be obtained in large quantities.

BE-PS No. 822 848 describes the optically active catalysts used according to the invention, but only the hydrogenation of acidic olefinic substrates is mentioned. Thus, the hydrogenated olefins of formula B according to the invention are neither mentioned nor even suggested.

The method according to the invention is defined in claim 1. The enantiomorphs can be obtained with excellent optical purity.

It has been found that the constitution (geometry) of the compound of formula B which is hydrogenated affects the results obtained. It is necessary to hydrogenate the geometric Z-isomer in order to achieve the desired excellent optical purity. It was found that the geometric E isomer and the geometric Z isomer give the same optically active enantiomorph in the hydrogenation using the same catalyst, but the optical purity is different. The E / Z system of the nomenclature of geometric isomers (cis-trans nomenclature) is e.g. in "The Journal of Organic Chemistry", Vol. 35, No. 9, September 1970, pages 2849 to 2867. It was introduced by the Chemical Abstracts Service.

R, R1, R4, R5, R6, R7 and R8 can mean, for example, methyl, ethyl, propyl etc. and phenyl. Such substituent groups are sometimes precursors of substituents that one actually desires.

The optically active enantiomorphs which can be prepared by the present process are particularly desirable since optical activity is an advantageous property of a "amino acids because normally only one of the optically active enantiomorphs can be used in living organisms. For example, those optically active enantiomorphs obtainable according to the invention are those in which R or R1 means phenyl or substituted phenyl, convertible into valuable L-phenylalanine derivatives.

The compounds of the formula:

R1, CN

V /

vS nh-r3

deliver excellent results in the process according to the invention and are therefore particularly suitable for the invention.

Particularly preferred embodiments of the process according to the invention are the catalytic asymmetric hydrogenation of the geometric Z isomers of

2- (N-ethoxycarbonylamino) -3-phenyl-2-propenoic acid ethyl ester and 2-benzamido-3-phenyl-2-propenenitrile. The L-en-5 antiomorphic phenylalanine can easily be obtained from the hydrogenation products obtained.

The hydrogenation reactions according to the invention are usually carried out in a solvent such as benzene, ethanol, 2-propanol, toluene, cyclohexane or mixtures of these solvents. Almost any aromatic alkane-lo or cycloalkane solvent which is inert under the conditions of the process according to the invention can be used. The preferred solvents are alcohols, especially methanol, ethanol and 2-propanol.

The optically active catalysts used according to the invention preferably contain at least 0.5 mol of bisphosphine ligand per gram atom of metal. These catalysts are soluble in the reaction mass and are therefore referred to as “homogeneous” catalysts. Preferred bis-phosphine ligands of the formula I contain two different 20 aryl groups on each phosphorus atom, those in which such an aryl group has an alkoxy substituent in the ortho position are particularly preferred.

More preferred bis-phosphine ligands correspond to the formula:

xtch2ch2-px y • y in which X denotes an optionally substituted phenyl group and Y is an optionally further substituted 2-alkoxyphenyl group, the alkoxy radical of which has 1 to 6 carbon atoms, the substituents not substantially disrupting the steric conditions around the phosphorus atom may cause and X and Y are different. 35 Particularly preferred optically active bis-phosphine ligands correspond to the formula:

M-P-CH0CH -P-M I 2 2 |

40 Q

where M is a group of the formula:

q

(iii)

45

-CT

50

and Q is a group of the formula: R "'l

R "

55, wherein R 'and R ", which are the same or different, each represent hydrogen, a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms and R'" is an n-alkyl group having 1 to 6 Carbon atoms means that M and Q are different.

A particularly preferred optically active bis-phosphine ligand is 1,2-bis (o-anisylphenylphosphino) ethane.

Further examples of suitable optically active bisphosphine ligands are: 65 1,2-bis- (o-anisyl-4-methylphenylphosphino) -ethane 1, 2-bis- (o-anisyl-4-chlorophenylphosphino) -ethane 1 , 2-bis- (o-anisyl-3-chlorophenylphosphino) -ethane 1,2-bis- (o-anisyl-4-bromophenylphosphino) -ethane

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4th

1,2-bis - [(2-methoxy-5-chlorophenyl) phenylphosphino] ethane

1,2-bis- [(2-methoxy-5-bromophenyl) phenylphosphino] ethanol 1,2-bis (2-ethoxypheny! Phenylphosphino) ethanol 1,2-bis- [o-anisyl- (p- phenylphenyl) -phosphmo] -ethane l, 2-bis - [(2-methoxy-4-methylphenyl) -phenylphosphino] -ethane l, 2-bis- (2-ethoxyphenyl-4-chlorophenylphosphino) -ethane l, 2-bis - (o-anisyl-2-methylphenylphosphino) ~ ethanol l, 2-bis- (o-anisyI-4-ethylphenylphosphino) -ethane l, 2-bis- (o-anisyl-3-ethylphenylphosphino) -ethane l, 2- Bis (o-anisyI-3-phenylphenylphosphino) ethane.

These bis-phosphine ligands, as stated in claim 1, must be optically active and therefore must not be in the meso form.

The optical activity of the catalysts used according to the invention derives from the bis-phosphine ligand and results from the fact that the ethane bridge and two different groups (A and D) are bonded to the phosphorus atoms.

Examples of suitable coordination complexes can be represented by the formula MeTL, in which Me is at least one of the transition metals rhodium, iridium and ruthenium, T is hydrogen, fluorine, bromine, chlorine or iodine and L is the optically active bisphosphine ligand defined above is.

It has been found that excellent optical purities of the desired optical enantiomorphs can be achieved, not only with the catalysts of the formula MeTL described above, but also when carrying out the hydrogenation in the presence of at least one of the transition metals rhodium, iridium in solution from a solution and ruthenium and at least 0.5 mole of the optically active bis-phosphine ligand per gram atom of metal formed catalyst. For example, such catalysts can be obtained by dissolving a soluble compound of the corresponding metal together with an optically active bis-phosphine ligand of the formula I in a suitable solvent, at least 0.5 mol of ligand per gram atom of metal, preferably 1 mol Ligand per gram atom of metal can be used. It has been found that the catalyst can be formed in situ by adding a soluble metal compound to the reaction mass along with an appropriate amount of the optically active bis-phosphine ligand either before or during the hydrogenation.

The catalyst is preferably a coordination complex of rhodium. Soluble rhodium compounds which can be used to prepare such complexes include a. Rhodium trichloride hydrate, rhodium tribromide hydrate, rhodium sulfate and organic rhodium complexes with ethylene, propylene, etc. and dienes, such as 1,5-cyclooctadiene, 1,5-hexadiene, bicyclo-2,2, l-hepta-2,5-diene and other dienes that can form bidentate ligands or active forms of metallic rhodium that can be easily solubilized.

In a preferred embodiment of the invention, the ratio of optically active bis-phosphine ligand to metal is about 0.5 to about 2.0 moles, preferably 1.0 mole, per gram atom. In practice it is preferred

that the optically active catalyst is in solid form with regard to its handling and storage. It was found that excellent results can be obtained with fixed, cationic coordination complexes.

Cationic coordination complexes containing one mole of the optically active bis-phosphine ligand per gram atom of metal and a chelating diene are preferred as catalysts. For example, using organic rhodium complexes of the type described above, such cationic coordination complexes of rhodium can be prepared by slurrying the organic rhodium-5 complex in an alcohol such as ethanol, adding one mole of the optically active bis-phosphine ligand per gram atom of rhodium, so that a solution is formed and then a suitable anion, for example the tetrafluoroborate, tetraphenylborate or any other anion, is added, so that a solid, cationic coordination complex either precipitates directly from the solvent or crystallizes out or after treatment in one suitable solvent precipitates or crystallizes out.

Examples of suitable cationic coordination complexes 15 are

Cyclooctadiene-1,5- [1,2-bis- (o-anisylphenylphosphino) -

ethane] -rhodium tetrafluoroborate, cyclooctadiene-l, 5- [l, 2-bis- (o-anisylphenylphosphino) -ethane] -rhodium tetraphenylborate and 20 bicyclo-2,2, l-hepta-2,5-diene [1,2 -bis- (o-anisylphenyl-phosphino) -ethane] -rhodium tetrafluoroborate.

Without prejudging the present invention, it is believed that the catalyst is actually present as a catalyst precursor and that it is converted to an active form upon contact with water. This conversion can of course either take place during the actual hydrogenation or can be brought about by bringing the catalyst (or the precursor) into contact with hydrogen before the addition to the reaction mass to be hydrogenated. As mentioned above, the catalyst can be added to the solvent either as such or in the form of its components which then form the catalyst in situ. If the catalyst is added in the form of its components, it can be added before or after the addition of the olefini-35 see substrate. The components for the preparation of the catalyst in situ are the soluble metal compound and the optically active bis-phosphine ligand. The catalyst can be added in any catalytically effective amount; it is generally used in an amount in the range of 0.001 to 5% by weight of metal, based on the olefinic substrate to be hydrogenated.

As far as practically possible, it should be avoided that the catalyst or the reaction mass comes into contact with oxidizing materials. In particular, care should be taken to ensure that any contact with oxygen is avoided. Preferably, the preparation of the reaction mass and the actual reaction should be carried out in gases other than hydrogen which are inert with respect to the two reaction partners and the catalyst, such as nitrogen or argon.

The procedure is preferably as follows: after the addition of the reactants and the catalyst to the solvent, hydrogen is added to the mixture, 55 to about 0.5 to 5 moles of hydrogen being present per mole of the olefinic substrate. The pressure in the system depends on the type of reactants, the type of catalyst, the size of the hydrogenation device, the amount of reactants and catalyst and the amount of solvent 60. Low pressures, including atmospheric and vacuum, as well as higher pressures can be used.

The reaction temperatures can range from about 65-20 to about 110 ° C. Higher temperatures can be used, but are usually not required and can increase side reactions.

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After the end of the reaction, which can be determined using conventional methods, the product can be obtained using conventional methods.

Many naturally occurring substances and medicines exist in optically active forms. In these cases, usually only the L or only the D form is effective. In the synthetic preparation of these compounds it was previously necessary to split the products into their enantiomorphs in an additional step. This split is expensive and time consuming. The method according to the invention enables the direct formation of the desired optical enantiomorphs with excellent optical purity, which largely eliminates the very time-consuming and expensive separation of the optical enantiomorphs. Furthermore, the method according to the invention provides the desired optically active enantiomorph in higher yield, while at the same time the yield of the undesired optically active enantiomorph is reduced.

The process according to the invention is particularly advantageous because it not only provides an unusually high optical purity of the desired optically active enantiomorph, but also results in a high hydrogenation rate at low catalyst concentrations.

In the examples, the percent optical purity (% OR) is determined according to the following equation (the optical activities, expressed as specific rotation, of course, all being determined in the same solvent):

OA of the mixture of isomers

% OR =: ^ x 100

OA of the pure isomer where OA means the observed optical activity.

example 1

A. Preparation of the Z-isomers of ethyl 2- (N-ethoxy-carbonylamino) -3-phenyl-2-propenate To a solution of 21.0 g (0.12 mol) of ethyl N-ethoxycarbonyl) glycine, 10, 08 g (0.095 mol) of benzaldehyde and 200 ml of ethyl ether, which was kept at 5 ° C., were added to 3.0 g (0.13 mol) of metallic sodium. The mixture was stirred at room temperature for 18 hours and filtered to remove the solid precipitate. The ethereal filtrate was washed with water and dried. The ether was driven off and the solid residue was recrystallized from toluene. The yield was 4.9 g from melting point 102 to 107 ° C. The product was identified as the Z-isomer of 2- (N-ethoxycarbonylamino) -3-phenyl-2-propenoic acid ethyl ester by NMR, gas liquid chromatography and UV analysis.

B Preparation of ethyl 2- (N-ethoxycarbonylamino) -3-phenyl-propanoate A solution of 2.29 g of the Z-isomer of ethyl 2- (N-ethoxycarbonylamino) -3-phenyl-2-propenate and 0.0105 g

Cyclooctadiene-l, 5- [l, 2-bis- (o-anisylphenyl-phosphino) -

äthan] -rhodiumtetrafluoroborat in 30 ml of ethanol was at 3 Atm. and hydrogenated at 50 ° C. After 2.5 hours the solvent was stripped from the solution on a rotary evaporator. NMR analysis found that the hydrogenation was complete.

The hydrogenation product, namely ethyl 2- (N-ethoxycarbonylamino) -3-phenylpropanoate, can be converted to phenylalanine, which is largely derived from the L-

Enantiomorphs exist, are hydrolyzed: a solution of the residue obtained after the ethanol has been driven off in 30 ml of acetic acid at 75 ° C. was slowly bubbled with hydrogen bromide gas for 1 hour. After the solution was kept for several hours, the acetic acid was removed on a rotary evaporator. The residue obtained was added to 25 ml of water containing 2 ml of 48% aqueous hydrogen bromide. The mixture was heated to reflux for 3.5 hours, cooled to 25 ° C and extracted with chloroform to remove the non-hydrolyzed organic substances. The aqueous solution containing phenylalanine hydrobromide and 1 ml of the acetic acid added was brought to pH 3 with a 50% NaOH solution. The optical rotation of the phenylalanine solution obtained (100 ml) was determined using a polarimeter: [a] D20 = -27.95 ° (C = 1 in water), optical purity = 88.7%.

Example 2

A. Preparation of N-Benzamidoacetonitrile

0.108 mol of sodium carbonate was added to a solution of 20 g (0.216 mol) of aminoacetonitrile hydrochloride in 150 ml of water. The solution was cooled to 5 ° C. and 18.1 g (0.216 mol) of sodium bicarbonate were added. 30.4 g (0.216 mol) of benzoyl chloride were added dropwise to the cold aqueous solution over the course of about 1.5 hours, forming a solid. The mass obtained was left on

Heat 20 ° C; then the solid was isolated and washed thoroughly with water. The dry weight of the substance obtained, which was crude N-benzamidoacetonitrile, was 33 g (96% yield) from the melting point 137 to 139 ° C. This substance was recrystallized from 100 ml of methanol to obtain 29 g of the product.

B. Preparation of the Z-isomer of 2-benzamido-3-phenyl-2-propenenitrile

Hydrogen chloride gas was bubbled into a solution of 4 g (0.037 mol) of benzaldehyde and 6 g (0.037 mol) of N-benzamido-doacetonitrile in 100 ml of diethyl ether, the solution being kept at 0 to 5 ° C. A solid precipitated after about 1.5 hours of storage. 10.4 g of this solid was isolated by filtration.

The 10.4 g of the solid obtained above was added to a solution of 4 g of sodium carbonate in 100 ml of cold (0 to 5 ° C.) water. The mixture was stirred at 5 ° C. for 1 hour and then 10 ml of acetone were added; the mass obtained was allowed to warm to 20 ° C. The product, which was the crude Z isomer of 2-benzami-do-3-phenyl-2-propenenitrile according to the NMR data, was isolated and washed with water. The dry weight of the isolated substance was 8.5 g (92% yield). This 8.5 g was recrystallized from 85 ml of ethanol. 6.8 g of melting point 164 to 165 ° C. were obtained.

C. Preparation of 2-benzamido-3-phenyl-propanenitrile

1. A solution of 0.9956 g of the Z isomer of 2-benzamido-3-phenyl-2-propenenitrile, 0.0046 g of cyclooctadiene-1,5- [1,2-bis- (o-anisylphenylphosphino) -

äthan] ~ rhodium tetrafluoroborate and 0.5 ml acetic acid in 30 ml methanol was hydrogenated in a Hoke bomb at 27 atmospheres and 50 ° C. The hydrogenation was complete after 3 hours. The solution was diluted to 200 ml with methanol; a rotation of -0.359 °, [a] D20 = -72.1 °, was observed. The pure enantiomorph of 2-benzamido-3-phenylpropanenitrile has a rotation [a] D20 = -84.3 ° in a solution of comparable composition. The optical purity was therefore 85.5 cc.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

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2. A solution of 0.9924 g of the Z isomer of 2-benzamido-3-phenyl-2-propenenitrile, 0.0153 g of cyclooctadiene-1,5- [1,2-bis- (o-anisylphenylphosphino) -

äthan] -rhodium tetrafluoroborate and 2 drops of acetic acid in 30 ml of methanol was at 50 ° C.

exposed to a hydrogen pressure of 3 atmospheres. After about 24 hours the solution was diluted to 200 ml with methanol. The rotation observed was -0.372 °, [a] D20 = -75 °. The optical purity was therefore 89%.

s

Claims (2)

625 204 2 PATENT CLAIMS 1. Process for the preparation of enantiomorphs of compounds of the formula: R1 R2 \ * / CH-CH (A) R ^ NH-R3 in which C * denotes an asymmetric carbon atom and also the carbon atom to which R and R1 are bonded are asymmetric if R and R1 are different, R and R1, which are the same or different, each represent alkyl or aryl, R2 is cyano or a group of the formula: 0 I! -C-N. / RV or -C-0-R, where R4 and R5, which are the same or different, each represent hydrogen, alkyl having 1 to 5 carbon atoms or aryl and R6 is hydrogen, alkyl having 1 to 5 carbon atoms, aryl or an alkali metal , and R3 is a group of the formula: 0 1 7 -C-O-R ' 0 8 8 -C-R or means, wherein R7 and R8 each represent alkyl having 1 to 5 carbon atoms or aryl, where R2 is cyano when R3 is a group of the formula: 0 »8 -C-R , characterized in that the geometric Z isomer of a corresponding compound of the formula: R1 B2 R NH-R3 (B) asymmetrically hydrogenated under homogeneous catalysis in the presence of a coordination complex of rhodium, iridium and / or ruthenium, which has an optically active bis-phosphine ligand of the formula: A-P-CELCH -P-A I 2 2 | D D X-P-CH ^ CH_-P-X 1 2 2 I used, wherein X represents an optionally substituted phenyl group and Y represents an optionally further substituted 2-alkoxyphenyl group, the alkoxy group of which contains 1 to 6 carbon atoms, the substituents not being allowed to cause any significant disturbance of the steric conditions around the phosphorus atoms and X and Y are different. 3. The method according to claim 1, characterized in that a bis-phosphine ligand of the formula: M-P-CH-CH -P-M I 2 2 I Q Q where M is a group of the formula: (III) 15 -O" 20th and Q means a group of the formula: RtM0 25th R " 30 means where R 'and R ", which are the same or different, each represent hydrogen, a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms and R" is an n-alkyl group having 1 to 6 carbon atoms means that M and Q are different. 4. The method according to claim 1, characterized in that 1,2-bis (o-anisylphenyl-phosphino) -ethane is used as the bis-phosphine ligange. 5. The method according to claim 1, characterized in that 40 is used as the metal in the catalyst complex rhodium. 6. The method according to claim 1 for the hydrogenation of the Z isomer of 45- 2- (N-ethoxycarbonylamino) -3-phenyl-2-propenoic acid. 7. The method according to claim 2 for the hydrogenation of the Z-isomer of 2-benzamido-3-phenyl-2-propenenitrile. 50 (I) contains, as a catalyst, wherein A and D, which are different, each represent an optionally substituted alkyl group having 1 to 12 carbon atoms, an optionally substituted cycloalkyl group having 4 to 7 carbon atoms or an optionally substituted aryl group, the substituents being no significant disruption to the steric conditions around the phosphorus atoms may cause. 2. The method according to claim 1, characterized in that a bis-phosphine ligand of the formula: (II)