HU193202B - Process for preparing alpha-/acetyl-amino/-beta-phenyl-propionic acid enantiomers - Google Patents

Abstract

L-Phenylalanine D-N-benzoyl-phenylalanine salt, D-phenylalanine L-N-benzoyl-phenylalanine salt, D-phenylalanine O,O-dibenzoyl-L-tartrate, D-phenylalanine O,O-di-p-toluoyl-L-tartrate, L-N-formyl-phenylalanine D-2-benzylaminobutanol salt, and L-N-acetyl-phenylalanine D-phenylglycinamide salt are new. - Optical resolution of racemic phenylalanine cpds. of formula (I) or their salts is effected by reaction with an optically active cpd. of formula (II) in a polar solvent and/or a solvent mixt. comprising at least one nonpolar solvent and opt. an achiral acid or base, followed by sepn. of the crystalline diastereomeric salt and release of optically active (I) from the sepd. salt or mother liquor by treatment with an achiral acid or base: R=H or acyl, pref. formyl or acetyl; R1=COOH, NH2 or benzylamino; R2=CH2OH, benzoylamino, CONH2, or benzoyloxy-carboxymethyl opt. ring-substd. by alkyl; R3=alkyl, phenyl, phenylalkyl, or benzoyloxy opt. substd. by alkyl.

Description

The present invention relates to a process for the preparation of optical isomers of α-acetylamino-β-phenylpropionic acid (hereinafter acetylphenylalanine).

The L-isomer of racemic acetylphenylalanine, an important industrial intermediate of Lp-phenylalanine, such as one of the intermediates in the preparation of the dipeptide used as the sweetener Aspartam (Aspartame: L-aspartyl-Lp-phenylalanine methyl). ester).

The preparation is carried out by industrial synthesis and in each case the corresponding racemic compound is formed which, by resolution, racemization of the D-enantiomer and subsequent resolution of the racemic compound thus obtained, affords L-acetylphenylalanine. Many methods for resolving DL-acetylphenylalanine are described in the literature, including the separation of isomers with L - (- {-) - threo-2-amino-1- (4-nitrophenyl) -propanediol-1. , 3 in water and various alcohols (J, Prakt. Chem. 9, 104 (1959j) α-fenchylamine in water (J. Am. Chem. Soc. 73, 3363 (1951)), optically active with leucine amide in ethanol. (Agr. Bioi. Chem. 26, 467 (1962)) and 2- (2,5-dimethylbenzylamino) butanol in water (U.S. Pat. No. 4,151,198, 1979).

However, it can be noted that these methods generally employ a very expensive resolving agent which is often difficult to access and not available in sufficient quantities for resolution. The most preferred process known to date is known as L- (+) -treo-2-amino-1- (4-nitrophenyl) -propanediol-1,3, which is known as an intermediate in the production of Chlorocid, but has a high molecular weight. the resolving agent is used in molar amounts to the racemic material, but its regeneration potential is not described, and the resolution yield is only about 75% and does not provide further purification options for the enantiomers obtained, although they are not optically obtained from the diastereomeric salt or mother liquor. pure products.

It is therefore an object of the present invention to provide a resolution of racemic acetylphenylalanine using a resolving agent not previously used for resolution.

Unexpectedly, our research has found that D-phenylglycine amide hydrochloride, which can be prepared in a manner known per se, has not yet been used as a resolving agent, but is well suited for the resolution of racemic acetylphenylalanine enantiomers as a resolving agent. after resolution, it can be regenerated in a suitable manner for repeated resolution.

However, it is also possible to further hydrolyze the amide from D-phenylglycine amide hydrochloride used as a resolving agent in the resolution steps to isolate the valuable D-phenylglycine under acidic conditions. In this way, the production of D-phenylglycine 2 can be modified by hydrolyzing D-phenylglycine nitrile hemitartrate obtained in the synthesis in two steps rather than one step. The D-phenylglycine amide hydrochloride obtained as the product of the first hydrolysis is also used for resolving racemic acetylphenylalanine before further hydrolysis.

The racemic acetylphenylalanine is resolved into the enantiomeric signal by suspension in water and dissolved by addition of a base under heating and stirring, preferably at pH

After adjusting to 6.5-7, the resulting solution is mixed with half an equivalent of the solid D-phenylglycine amide hydrochloride, preferably 0.55 mol, based on the racemic compound. During addition, the resolving agent is temporarily dissolved in solution and, unexpectedly, the D-phenylglycine amide-L-acetylphenylalanine diastereomeric salt precipitates crystalline. to produce an optically pure enantiomer than from the remaining mother liquor. Therefore, this recognition only enhances the applicability of our procedure.

The diastereomeric salt isolated by filtration is recrystallized from water, if necessary, and decomposed by addition of acid or base in aqueous medium. D-phenylglycine amide precipitates from the solution upon basic addition, which is isolated by filtration and converted into concentrated resin for re-use with concentrated hydrochloric acid, or by further hydrolysis to D-femylglycine. After isolation of the resolving agent, L-acetylphenylalanine is precipitated from the mother liquor by addition of acid.

If the resulting L-acetylphenylalanine has an inadequate optical purity, the former precipitation is carried out in several steps and the precipitates are separated by filtration. In this way, the racemic moiety can be selectively separated from L-acetylphenylalanine, which is used for repeated resolution.

However, it is also possible to dissolve L-acetylphenylalanine from the mother liquor obtained in the decomposition of the diastereomeric salt with a base in water and proceed from this solution to carry out the selective release in several steps.

If the diastereomeric salt is decomposed by the addition of aqueous acid, the use of dilute hydrochloric acid (not more than 5%) results in the crystallization of crude L-acetylphenylalanine, which is filtered off and the mother liquor is regenerated. When decomposed with 20% hydrochloric acid, both acetylphenylalanine L and the resolving agent are precipitated. The precipitate is separated and the resulting mixture is suspended in water, the insoluble L-acylphenylalanine is filtered off and the resolving agent is regenerated from the mother liquor. The resulting crude L-acetylphenylalanine is purified as described above and the racemic fraction is regenerated. The crude is L-acetylphenylalanine

Purification of -2193202 can also be carried out by recrystallization with acetone in a known manner. The d-acetylphenylalanine was precipitated from the mother liquor after filtration of the diastereomeric salt by the addition of acid. If the release is done in several portions or the crude enantiomer is purified as described for the other enantiomer, then the racemic product is regenerated. The following examples illustrate our process:

Example 1

Racemic acetylphenylalanine (15.7 g, 0.076 mol) was suspended in water (35 ml), and concentrated ammonium hydroxide was added under stirring and heating until a pH of 7 was obtained. D-phenylglycine amide hydrochloride (8 g, 0.042 mol) was added in solid state. After crystallization began, the solution was allowed to cool to room temperature with stirring and then cooled with ice water for 12 hours. The precipitated L-acetylphenylalanine D-phenylglycine amide salt was filtered off, washed with water (2 x 3 mL) and dried; Yield: 11.7 g (86.1%).

Example 2

10.0 g (0.028 mol) of the diastereomer obtained in Example 1 are mixed with 20 ml of water and 2 ml of 5 molar sodium hydroxide are added and stirred for 30 minutes. The precipitated D-phenylglycine amide was filtered off, washed with water (2 x 3 mL), dried, and weighed 3.6 g (85.7%).

The mother liquor was acidified with 10 ml of 5 M hydrochloric acid, the precipitated L-phenylalanine was filtered off, washed with water and dried to give 5.4 g (93.1%) of [a]? ⁵ : + 43.2 ° (c: 1, ethyl alcohol).

Example 3

10.0 g (0.028 mol) of the diastereomer obtained in Example 1 are stirred with 30 ml of 5% hydrochloric acid for 2 hours, the insoluble L-acetylphenylalanine is filtered off, washed with a little water, dried, 2 g (yield: 89.6%) [α] ³⁵ : + 42 ° (c: 1, ethyl alcohol).

Example 4

10.0 g (0.028 mol) of the diastereomer obtained in Example 1 are stirred with 20 ml of 20% hydrochloric acid for 30 minutes and then filtered. The wet material was stirred with 20 mL of water for 1 hour, and the insoluble L-acetylphenylalanine was filtered, washed, dried, and weighed 5.0 g (yield: 86.2%) [a], * ⁵ : -U45 ^o (c: 1, ethyl alcohol).

Example 5

In the same manner as in Example 1, the mother liquor of the diastereoisomeric salt was acidified with 5 ml of concentrated hydrochloric acid, the precipitated D-acetylphenylaniline was filtered off, washed with a little water and dried to give 8.1 g of [α] ³⁵ D = -35.2 °. c: 1, ethyl alcohol).

The material (8.1 g) was suspended in water (20 ml) and concentrated ammonium hydroxide under heating. the resulting solution was cooled and 2.3 ml of 5 M hydrochloric acid was added dropwise with stirring, followed by stirring for 30 minutes, the precipitated acetylphenylalanine was filtered off, washed with water, dried and weighed 2.3 g. [a] £ ^5: -3 ° (c 1, ethanol). Concentrated hydrochloric acid (3 ml) was added to the mother liquor, the precipitated D-acetylphenylalanine was filtered off, washed with a little water and dried to give 5.2 g [a] ³⁵ : -45 ° (c: 1, ethyl alcohol).

Example 8

41.4 g of racemic acetylphenylalanine are suspended in 100 ml of water and concentrated ammonium hydroxide is added with stirring until heated to a pH of 7. Then 18.5 g of D-phenylglycine amide are added to the solution. Hydrogen chloride is sprayed and allowed to crystallize with stirring and then cooled in ice water for 10 hours. The precipitated L-acetylphenylalanine D-phenylglycine amide salt was filtered off and washed with water (2 x 6 mL).

The nucleated wet salt was stirred in 100 ml of water at 80 ° for one hour, cooled in ice-water and stirred for two hours, and finally the recrystallized salt of L-acetylphenylalanine-D-phenylglycine amide was dried. 7 g (77.3% yield). The recrystallized salt was worked up as in Example 2.

Claims (3)

PATENT CLAIMS l. A process for preparing α- (acetylamino) -β-phenylpropionic acid enantiomers by resolution of their racemic modifications comprising reacting a suspension of water-racemic α- (acetylamino) -β-phenylpropionic acid with a sufficient amount of a water-soluble inorganic base to purify the suspension. The neutral salt thus obtained is reacted with 0.5 to 0.6 equivalents of the solid Dphenylglycine amide hydrochloride resolving agent per racemic compound, the reaction mixture is cooled to -10 to 10 ° C, and the crystallized diastereomeric salt is filtered, recrystallizing the diastereomeric salt from water if desired, the. the diastereomer is reacted with 15-40% by weight of water-soluble inorganic base, the crystallization is filtered off with D-phenylglycine amide, the filtrate is acidified to pH 1 with the inorganic acid, the crystallized La (acetylamino) -β-phenylpropionic acid or b. acidifying the diastereomeric acid with 3 to 5% by weight of inorganic acid, filtering the crystalline L-a-acacylamino-β-phenylpropionic acid, or c. / the diastereomeric acid is acidified with 15-40% by weight of inorganic acid, filtered and the crystals are suspended in water, the crystalline L-α- (acetylamino) -β-phenylpropionic acid is filtered off, and the diastereoisomeric salt is filtered to pH I with an inorganic acid acidified, the crystallized Da- (acetyl3 -3193202 -amino) -β-phenylpropionic acid is filtered off and, if desired, crystallized by fractional crystallization. 2. The process of claim 1, wherein the crystalline Da- (acetylamino) -β-phenylpropionic acid is dissolved in water with an equivalent amount of inorganic base, cooled to -10 to 10 ° C. acidified with an inorganic acid equivalent to a racemic fraction, the crystallized racemic α- (acetylamino) -β-phenylpropionic acid is filtered off and recycled to the first step of the resolution, the filtrate is acidified to pH 1 with the crystallized Da- (acetylamino) ) p-phenylpropionic acid is filtered off. 3. A process according to claim 1, characterized in that the crystalline L-α- (acetylamino) -β-phenylpropionic acid is optionally precipitated fractionally according to claim 2.