CS225271B1 - The asymmetrical hydrogenation of the dehydroamine acid - Google Patents

Description

The present invention relates to a process for the asymmetric hydrogenation of dehydroamino acids catalysed by transition metal complexes.

With amino acids, it is known to generally be obtained in three ways:

1) separation from hydrolysed proteins,

Fermentation; and

3) chemical synthesis, of which, in particular, the catalytic asymmetric synthesis represents a significant technological advance.

Furthermore, it is known that in the presence of transition metal complexes that contain ehiral ligands in their coordination sphere, reactions of the prochiral unsaturated compounds containing the O = C bond proceed to form enantiomers that are formed in amounts significantly different from the equilibrium distribution. This enantioselective process was also carried out in the preparation of amino acids by hydrogenation of carboxylic acid N-enamides. The transition metal complexes VIII were used as catalysts for this reaction. groups, in particular rhodium and ruthenla, with tertiary phosphines such as ligands containing an ehalal phosphorus atom (NSR Publication Nos. 2,210,938 and 2,456,937) or carbon, in this case, and by chirality in the substituent attached to the phosphorus atom (NSR Publication No. WO 02/32711). 2,161,200), ehiral phosphinites and aminophoefins (Aspecte of Homogeneoue

225 271

225 271

Catalysla, Vol. 4, pp. 145-222, Rledel Co., Dordrecht 1981).

The above catalyst systems make it possible to carry out asymmetric hydrogenation with a β enantiomeric excess in the range of 60 to 95%. The known reaction methods are to dissolve the o-enamide of the carboxylic acid, its ester or salt in a suitable solvent and react with hydrogen in the presence a chiral transition metal complex. The mixture of enantiomers resulting from this reaction is then isolated from the reaction mixture by evaporating the solvent, converting the resulting amino acid into an aqueous alkali metal hydroxide solution, and separating the precipitated catalyst by filtration; the amino acid precipitated from the filtrate by acidifying it is then shaken into an organic solvent, usually ether (J. Amer. Chem. Soc. 94, 6429 (1972)) or separated by filtration from solution and crystallized from an alcohol, preferably methanol (Homogeneous catelysls, Volume II, pp. 275-282). Although in the asymmetric hydrogenation of α-enamides of carboxylic acids, an enantiomeric excess in the range of 60-95% can be achieved in the presence of some of the known catalyst systems using very favorable reaction conditions (20-50 ° C, normal or slightly elevated hydrogen pressure). The process of isolation and treatment of the resulting mixture of enantiomers is necessary and is associated with yield losses. Moreover, in this way the enaneomer is obtained in optical purity, which is usually insufficient for its direct use and needs to be further purified by multiple crystallization.

Some of the above drawbacks can be overcome by the process of carrying out the reaction in excess of the hydrogenated substance described in the description of the invention to U.S. Pat. Certificate No. 185974.

It has now been found that a significantly higher efficiency of the hydrogenation process in terms of the amount of hydrogenated product formed in a unit of time can be achieved by the process of the invention, consisting in the asymmetric hydrogenation of dehydroamino acids RCH = C (NHCCR ') COOH where R is phenyl. 3-methoxy, 3-methoxy-4-hydroxyphenyl or 3-methoxy-4-ecethoxy, and R 'is methyl or benzyl, ketalylated with T11 transition metal complexes. groups, in particular rhodium compounds, are carried out in a solvent, preferably methanol, ethanol, isopropanol, mixtures thereof with water or aromatic hydrocarbons, preferably benzene, toluene, at a temperature of 10 to 60 ° C under hydrogen pressures from normal to 1.5 MPa and using dehydroaminoacid in an amount ensuring preferential crystallization of the enantiomers resulting from this reaction in excess.

The lowest amount of dehydroaminokyeelines is given by exceeding the solubility limit of the hydrogenation product in a given solvent system under the reaction conditions used, and its maximum amount is theoretically limited by:

max (100 - e _a ) e _f

M _s / M _p )

10 ’

225 271 where represents

G_ _o ^. the maximum amount of dehydroaminokyeelines usable by the process of the invention mex in grams,

A p limit of solubility of the resulting hydrogenation product while achieving equilibrium distribution of enantiomers in the reaction mixture expressed in g / ml,

V _r total volume of the liquid phase of the reaction mixture in ml, e enantiomeric excess corresponding to the enantiomeric composition in the actual asymmetric hydrogenation in%, enantiomeric excess in the hydrogenation product separated in crystalline form from the reaction mixture to achieve equilibrium distribution of enantiomers (racemic composition) mixtures in%,

Mg molecular weight of substrate a

Mp molecular weight of the hydrogenation product.

Under these reaction conditions, it is advantageous to work in the manner described with amounts of the substrate which are close to the upper limit given by the above relationship, without substantially reducing the optical purity of the product separated by its crystallization during hydrogenation. In the case of the formation of a supersaturated solution of the product, it is also possible to work at amounts exceeding the theoretical limit given by the above expression. The asymmetric hydrogenation process according to the invention can be carried out intermittently and continuously both with respect to the substrate feed and the final product withdrawal. All the chiral transition metal complexes catalytically active in the hydrogenation of the above compounds can be used as catalysts. Suitable solvents for the process according to the invention are alcohols, preferably methanol, ethanol and isopropanol, mixtures thereof with aromatic hydrocarbons, preferably benzene, or alcohols or mixtures thereof with the addition of water. The above process is particularly advantageous for the preparation of phenylalanine and 3,4-dihydroxyphenylalanine derivatives by hydrogenation of 1-acetamidicinnamic acid, 1N-acetyl-3-methoxy-4-hydroxycinnamic acid, 1N-acetyl-3-methoxy-4-acetoxycinnamic acid and asymmetric hydrogenation of 1- N-Aethylaminoacrylic. For example, while the asymmetric hydrogenation of Z1-acetamidocinnamic acid in the presence of a catalytic system consisting of a di- (4-chloro-bis (N-ethylene)) rhodium complex and (2R, 3R) -2,3-O-isopropylidene-2,3-dihydroxy- 1,4-bis (diphenylphosphino) butane gave (R) -N-acetylphenylalanine with an optical purity of 81% (J. Amsr. Chem. Soc. 94, 6429 (1972)), using the same catalyst system using the same catalyst system. a product having an optical purity greater than 99% by simply filtering off the resulting crystalline material from the reaction mixture.

According to the process of the present invention, the optically active amino acid can be produced in high optical purity without multi-stage treatment of the reaction mixture and subsequent recrystallization, reducing product loss on isolation, solvent consumption per kg of product produced, increasing product per unit time and reducing catalyst. it becomes ineffective during the reaction due to its deactivation.

225 271

The following examples illustrate the invention without limiting or restricting it. The weights are given in parts by weight.

Example 1

220 parts of 1-acetamido cinnamic acid were charged to a hydrogenation reactor equipped with a stirrer and hydrogen inlet, the reactor was evacuated and purged with argon and charged with hydrogen containing 10 ppm oxygen. Then 840 parts of a 1: 2 mixture of benzene-ethanol and 60 parts of a solution of 0.175 parts of di-ju-chloro-β-β (β-ethylene) rhodium complex and 0.47 parts (2R, 3R) -2,3-O-cyclopentylidene-2,3-dihydroxy-1,4-bis (diphenylphosphino) butane in the same solvent. The reaction mixture was kept under stirring at 25 ° C and hydrogenation was performed at a partial hydrogen pressure of 1 bar. After completion of the reaction, the reaction product was filtered from the reaction mixture. 76 parts of (R) -N-acetylphenylalanine having an optical purity of 99.5% (? -46.0 ° (c = 1, ethanol)) were obtained. The filtrate was evaporated to dryness, dissolved in 2000 parts of 0.5 M aqueous sodium hydroxide solution, the solution was filtered off, acidified with hydrochloric acid and the product was shaken into ether. Evaporation of the solvent gave 13.3 g of (R) -N-acetylphenylalanine with an optical purity of 70.0%.

Example 2

Following the procedure of Example 1, hydrogenation of 646 parts of 1-acetamidoacetic acid in the presence of 0.52 parts of di-β-chloro-bis (d-ethylene) rhodium complex and 1.4 parts of (2R, 3R) -2.3-0 was carried out. cyclopentylidene-2,3-dihydroxy-1,4-bia (diphenylfoefino) butene dissolved in 180 parts of benzene and ethanol (1: 2) at 25 ° C for 4 hours. As described in Example 1, 501 parts of crystalline (R) -N-acetylphenylalanine having an optical purity of 99.4% were obtained and the filtrate was treated with 120 parts of (R) -N-acetylphenylalanine having an optical purity of 18.1%.

Example 3

Example 2 was repeated except that the reaction was carried out in the presence of 1.2 parts of perchlorate / 2R, 3R-2,3-O-cyclopentylidene-2,3-dihydroxy-1,4-bia (diphenylfoefino) butane 5-cyclooctadiene) at a temperature of 40 ° C and a hydrogen pressure of 175 kPa. The reaction was complete in 30 minutes. Treatment of the reaction mixture of Example 1 gave (R) -N-acetylphenylalanine with an optical purity of 98.5% in 72% yield.

Example 4

Example 1 was repeated except that the hydrogenation was carried out at a temperature of 60 ° C and a hydrogen pressure of 1.5 MPa for 20 minutes. Working up the reaction mixture of Example 1 yielded 72 parts of (R) -N-acetylphenylalanine with an optical purity of 99.0% and from the filtrate 135 parts of (R) -N-acetylphenylalanine with an optical purity of 72.3%.

225 271

Example 5

Example 1 was repeated except that (2S, 3S) -2- was substituted for (2R, 3R) -2,3-O-cyclopentylidene-2,3-dihydroxy-1,4-bis (diphenylphosphino) butane. 3-O-cyclohexylidene-2,3-dihydroxy-1,4-bis (diphenylphosphino) butane. In contrast to the (R) -enantiomer obtained in Example 1, (S) -N-acetylphenylalanine was obtained in the same yield of 1 optical purity using the above-mentioned phosphine.

Example 6

Example 1 was repeated except that the same amount of 1N-acetylamino-3-methoxy-4-acetoxycinnamic acid was used in place of 1-acetamidicinnamic acid. Filtration yielded 71 parts of (R) -N-acetyl-3-methoxy-4-acetoxyphenylalanine with an optical purity of 97.9% (c). D ^{2 _22 »θ} ° ^{(c = 1>} acetone) /.

Claims (2)

object of the invention A process for the asymmetric hydrogenation of dehydroamino acids of the formula RCH = C (NHCCR ') COOH, wherein R is phenyl, 3-methoxy, 3-methoxy-4-hydroxyphenyl or 3-methoxy-4-ethoxy and R ^# is methyl or benzyl, catalyzed transition metal complexes VHI. The reaction is carried out in a solvent at a temperature of 10 DEG to 60 DEG C., a hydrogen pressure of from 1 to 50 bar, using a dehydroamino acid in an amount ensuring preferential crystallization of the enantiomer resulting from the reaction in excess. 2. Process according to claim 1, characterized in that the solvents used are alcohols, preferably methanol, ethanol, isopropanol, mixtures thereof with aromatic hydrocarbons, preferably benzene, or these solvents with the addition of water.