HU193201B - Process for preparing optically active alpha-/formyl-amino/-beta-phenyl-propionic acids - 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 separation of racemic α- (boiling 1-amino) -β-phenylpropionic acid enantiomers. The L-isomer of the racemic compound is an intermediate for the industrial preparation of L-phenylalanine and is, for example, one of the starting materials for the preparation of the sweetener Aspartam (L-aspartyl-L-3-phenylalanine methyl ester). Resolution of the racemic compound can be accomplished with α-fenchylamine or α-phenylethylamine in water (J. Am. Chem. Soc. 73, 3363 (1951)), with brucine in methanol (Liebigs Ann. Chem. 357, 1 (1907). ) and 2-aminobutanol in n-butyl alcohol (J. Am. Chem. Soc. 76, 2801 (1954)). These resolving agents are extremely expensive and can be regenerated with poor efficiency.

The aim of our work was to develop a process which enables the separation of α- (formylamino) -β-phenylpropionic acid enantiomers using a significantly cheaper, well-regenerable resolving agent.

It has now been surprisingly discovered that L- and D-2- (benzyl) intermediates in the manufacture of the drug Ethambutol (2,2'-ethylenediamino) di-1-butanol) and its unused benzylated derivatives -amino) -butanol can be used to separate enantiomers of α- (formylamino) -β-phenylpropionic acid.

Unexpectedly, our work has found that when the optically active 2-benzylamino-butanol and the racemic compound are heated to a molar or different ratio to dissolve in acetone, the diastereomeric salt of one of the enantiomers precipitates, the other enantiomer, or a salt thereof, remains in solution. D-2- (Benzylamino) -butanol precipitates the salt of L-α- (formylamino) -β-phenylpropionic acid which, after filtration, leaves D-α-formylamino-β-phenylpropionic acid in solution. , with the L-2- (benzylamino) butanol, the D-isomer crystallizes out and the L-enantiomer remains in solution.

After addition of water, the diastereomeric salt is liberated with an acid, preferably hydrochloric acid, and the enantiomers bound by the resolving agent are precipitated. If necessary, the diastereomeric salt, D-2- (benzylamino) -butanol-L-α- (formylamino) -β-phenylpropionic acid salt, is recrystallized before precipitation. The precipitated enantiomers are isolated by filtration and the mother liquor is set aside to regenerate the resolving agent.

The acetone mother liquor of the diastereomeric salt is evaporated, the residual oil to which is added water and an acid, preferably hydrochloric acid, and the mirror image of the isomer precipitated from the diastereomeric salt crystallizes out. The optically active α-formylamino-β-phenylpropionic acid thus precipitated is filtered off and the mother liquor is set aside to regenerate the resolving agent.

If the resolution is performed with L-2- (benzylamino) butanol, the diastereomeric salt of the crude L-α- (formylamino) -β-phenylpropionic acid is left on evaporation of the mother liquor, but 2 an amount of D-enantiomer-resolving agent salt is formed which can be isolated to purify the L-isomer. In this way, L-α- (formylamino) -β-phenyl-p'opionic acid of sufficient optical purity is again obtained.

The resolving agent is precipitated from the discarded solutions by strong alkalization, but it can also be regenerated by extraction and evaporation of the extraction solvent to provide a regenerated resolving agent for repeated resolving.

The following examples illustrate our process:

Example I

19.3 g (0.1 mol) of DL-α-formylamino-4-phenylpropionic acid and 17.9 g (0.1 mol) of D-2- (benzylamino) butanol ([< A mixture of ¹⁵ ', -24.9 ° (c: 1, ethyl alcohol) was heated to reflux with 100 ml of acetone. A clear solution is formed which, upon cooling, begins to crystallize upon scrubbing or inoculation with the L-α- (formylamino) -β-phenylpropionate salt of D-2- (benzylamino) butanol. After standing overnight at 0-5 ° C, the next day the crystals were filtered, washed with a little ice-acetone, weighing 17.1 g.

Yield: 92% (calculated on the L-isomer-D-2- (benzylamine) butanol salt of the racemate which is a long-lived compound).

Example 2

The salt obtained in Example 1 is triturated with a mixture of 50 ml of water and 20 ml of concentrated hydrochloric acid, which forms a solution which begins to crystallize by scraping, cooling in ice, filtering and washing with water the precipitated La-formylamino-β-phenylpropionic acid. weighing 8.5 g.

Yield: 88% [a] J ^5: + 62.3 ° (c 2, EtOH).

Example 3

The acetone mother liquor of the salt obtained in Example 1 was evaporated to dryness. The resulting oil was triturated with water (30 ml) and concentrated hydrochloric acid (20 ml), cooled in ice, and the precipitated crystalline D-α-formylamino-β-phenylpropionic acid was filtered off, washed with water (9.5 g).

Kbermelés: 98% [JP ^5: -5b, 1 ° (c 2, EtOH).

Example 4

The hydrochloric acid mother liquors obtained in Examples 2 and 3 were adjusted to pH 11 with 40% aqueous sodium hydroxide solution, cooled in ice, filtered, and washed with water to crystallize D-2- (benzylamino) butanol. 14.9 g.

Yield: 83% (with respect to the measured resolving agent), [a] ^ ^5: -24.8 ° (c 2, EtOH).

-2193201

Example 5

The mother liquors obtained in Examples 2 and 3 were combined, adjusted to pH 11 with 40% aqueous sodium hydroxide solution and extracted with 3 x 50 ml 1,2-dichloroethane. The combined organic phases were washed with water (2 x 50 mL), dried over anhydrous sodium sulfate and evaporated to dryness to give 16.7 g of D-2- (benzylamino) -butanol.

Yield: 93% 10

-24.9 ° (c: 2, ethyl alcohol).

Example 6

19.3 g (0.1 mol) of DL-α- (formylamino) + phenylpropionic acid and 17.9 g (0.1 mol) of L-2- 15

- (benzylamino) butanol ([a] £ ^5: + 24.8 ° (c 2, ethanol)) in 100 ml of acetone was heated until dissolved and further treated as described in Example 1. The crystalline product obtained is D-α- (formylamino) -β-phenylpropionic acid L-2- 20.

- (Benzylamino) butanol salt, weight 16.4 g. Yield: 88%.

Example 7 ₍

The mother liquor obtained in Example 6 is evaporated to dryness, the precipitated crystals are filtered off from the resulting oily residue, washed with a little ice-acetone and combined with the salt obtained in Example 6. The product D-α-formylamino-β-phenylpropionic acid L-2- (benzylamino) butanol 30 salt weighed 0.93 g.

Yield: 5%.

Example 8

The oil obtained in Example 7 is further processed as in Example 3. The product weighed 9.6 g of L-α-formylamino-p-phenylpropionic acid.

Yield: 99.5%, [a] p ^5: + 58.3 ° (c 2, ethyl alcohol). 40

Example 9

The salt obtained in Example 6 is processed as in Example 2. The product weighed 8.6 g of D-α-formylamino-β-phenylpropionic acid. ₄₅

Yield: 89% [a] p ^5: -62.5 ° (c 2, EtOH).

Example 10 g The L-α- (boiled-in form) -β-phenylpropionic acid D-2- (benzylanino) butanol salt prepared in Example 1 was heated in boiling water (100 ml) for 1 hour and then with ice-water. After cooling for two hours, the recrystallized material is filtered off, washed with a little ice-acetone and dried. The product was recrystallized from the salt of L-α-formylamino + phenylpropionic acid D-2- (benzylamino) butanol (22.7 g). Yield: 84%.

The salt was treated as in Example 2.

Claims (1)

PATENT CLAIMS CLAIMS 1. A process for the preparation of optically active α- (formylamino) -β-phenylpropionic acids by resolution of their racemic forms, comprising reacting an racemic α- (formylamino) + phenylprop'onic acid with an equivalent amount of D- or L- With 2- (benzylamino) butanol as a resolving agent in acetone at reflux temperature, the reaction mixture is cooled to -10 to 10 ° C, the crystallized diastereoisomeric salt is filtered off and, if desired, recrystallized from an organic solvent, c) dissolving the diastereomeric salt in 5-20% by weight hydrochloric acid, cooling to -10 to 10 ° C, and filtering the crystallized? -formylamino-β-phenylpropionic acid in the configuration appropriate to the resolving agent used, b. The diastereomeric salt filtrate was evaporated to dryness, the residue was taken up in 5-20% by volume hydrochloric acid, cooled to -10 to 10 ° C, and the crystallized α-formylamino-β-phenyl bound as diastereomeric salt filtering the enantiomer in the opposite configuration to the propionic acid, c. the filtrates obtained after the recovery of each isomer are combined, basified to pH 11, optionally extracted with an organic solvent, preferably 1,2-dichloroethane, the solvent is evaporated off, the crystallized resolution agent is filtered off and recycled to the next resolution.