CS263987B1 - Process for producing chiral highly pure N-acetyl-L-a-amine or N-acetyl-D-a-alanine - Google Patents

Abstract

The present invention relates to a process for the preparation of chiral highly pure N-acetyl-L-α-alanine or N-acetyl-D-α-alanine by acetylation of L- or D-α-alanine with acetic anhydride in an aqueous alkaline medium. The principle of the improved process is that the acetylation is carried out in an aqueous solution containing a stoichiometric amount of an inorganic base such as sodium hydroxide, based on free carboxyl groups, with acetic anhydride in an excess of 1.1 to 1.5 moles added simultaneously with the aqueous solution at at a temperature of -10 to -25 ° C and a pH of 9.0 to 11.5. The process described is simple and economical, suitable for industrial scale production, where the racemization of the starting L- or D-α-alanine is minimal. N-acetyl-L-α-alanine and its antipodes, respectively, is an important intermediate in peptide synthesis.

Description

The invention relates to a process for the preparation of chiral highly pure N-acetyl-L-α-alanine or N-acetyl-D-α-alanine of the formula

H3'C — CH — COOH

NH

HsC — CO

Chirally pure acetyl-L-alanine with characteristic constants:

[Α] -125 ° C * [α-] _D ²ⁿ = -66.2 ° C (c = 2; water) was prepared by resolution of racemic α-cetyl-D, L-alanine by porcine kidney acylase (SM Birnbaum, L). Levintow, RB Kingsley, JP Greenstein, J. Biol. Chem., 194, 455-470 (1952). Previously attempted synthesis starting from chirally pure reactants resulted in partially racemic products. Thus, acetylation of L-alanine with acetic anhydride in aqueous sodium hydroxide solution, a product was obtained of mp 116 ° C, [a] _D = -45.6 ° ^IE '(c = 5; water] (P. Karrer and K. Escher, R Widmer: Helv. Chim. Acta 9, 301-323 (1926). These conclusions have been confirmed by Wolfrom et al. (ML Wolfrom, RU Lemieux, SM Olin: J. Am. Chem. Soc. 71, 2 870-2). 873 (1949)), which prepared chiral purely acetyl-L-alanine without yielding a yield of 122-123 ° C, [α] π ²³ = -62 ° (c = 3; water) by demanding purification of the product with tt 112 ^DEG -128 ^DEG C., [ _.alpha. ] _D = -36 DEG (c = 2; water), also obtained by acetylation with acetic anhydride, on the basis of the finding that the racemate is less soluble in ethyl acetate than the optically pure isomer.

The tendency to racemize N-acetyl-amino acids including N-acetyl-La-alanine in the presence of 0.1-2.0% free-acetic anhydride is so significant that it has been used to totally racemize acetylamino acids at elevated temperature within 93 minutes with 93% yield. (M. Karrenbauer, A. Kleemann: Ger. Offen. DE No. 3,435,095 (1986); Ref. Chem. Abstr. 105,227,290e (1986).)

Attempts to acetylate by heating in acetic acid resulted in 44% to 61% ^. % yield of acetylderivative with total loss of optical activity (EA Bell .: J. Chem. Soc. 1958, 2,423-2,425).

Successful preparation of chirally čistého- acetyl-L-alanine starting from L-alanine, which under Schotten-Baumann-yl, the reaction gives three-fold excess of acetyl chloride with a product of mp 126 ° C, [a] D = -65.6 ° ^Z0 (water , 5.5 mg / ml) (H. Krebs, W. Schumacher: Chem. Ber. 99, 1341-1346 (1966)) or from L-alanine acetylated with lsetene in an aqueous alkaline medium (G. Franzmann, HL Huelsmann: Ger. Offen 2 741 081 (1979); Ref. Chem. Abstr. 91, 103 22-9z (1979)).

A number of other approaches to obtain acetyl L-alanine of varying chiral purity, such as e.g. resolution of the racemic mixture using 1-amphetamine (JM Gillingham: US No. 3,028,395 (1962); Ref. Chem. Abstr. 57, 16,742-d / 1962), utilizing asymmetric ion-exchange sorbents (SV Rogozhin, VA Davankov, VV Korshak , V. Vesa, AL Belchich: Izv. Acad, Nauk, USSR Ser. Khim., 1971 (3), 502-508, Ref. Chem., 75, 21, 557a (1971), or the formation of acetyl-L-alanine in a mixture of other glucose substances by Candida troicalis OH23 (M. Okuhara, T. Harada: Biochem. Biophys. Acta 244, 16-18 (1971)) has no practical significance for industrial use.

Some of the above processes for the preparation of acetyl-L-alanine result in more or less partial racemization, others are technically or industrially demanding. An exception is technically simple acetylation with acetyl chloride, but the disadvantage of this is the necessity of using a considerable excess of economically and physically disadvantageous acetyl chloride.

The aforementioned drawbacks are eliminated by the process for the preparation of chiral highly pure N-acetyl-L-α-alanine or N-acetyl-D-α-alanine of the formula by acetylating L- or-D-α-alanine with acetic anhydride in an aqueous alkaline medium according to the invention. The process is characterized in that the acetylation is carried out in an aqueous solution containing a stoichiometric amount of an inorganic base, for example sodium hydroxide, based on the free carboxyl groups, preferably at a concentration of 3.5 to 4.5 M, with acetic anhydride added in the of an excess of 1.1 to 1.5 moles simultaneously with an aqueous solution of an inorganic base, for example sodium hydroxide, preferably at a concentration of 3.5 to 4.5 M, maintaining the temperature of the reaction mixture at -10 to - 25 ° C and the pH 9.0 to 11.5, after which the reaction mixture is acidified with a mineral acid such as sulfuric acid and the reaction product is isolated by extraction with an organic, water-miscible solvent such as ethyl acetate, evaporation of the solvent and crystallization of the residue.

To carry out the process according to the invention, a solution of the starting material in an equimolar amount of 4 to 6 M sodium hydroxide solution, having a pH value of 9.0 to 11.5, is reacted at a temperature of from -10 to -25 ° C with from 1.1 to with a 1.5 molar excess of acetic anhydride added sequentially while adding the sodium hydroxide solution at the indicated concentration at such a rate that the initially set reaction conditions were maintained.

In the described arrangement, the acetic anhydride preferably reacts with the electron pair of the nitrogen of the amino group, and racemization on the chiral α-carbon of the amino group occurs only minimally.

Upon completion of the acetylation, the reaction mixture is acidified with a mineral acid, preferably sulfuric acid, while cooling to 0 ° C, and the desired product is taken up in a water-miscible organic solvent, for example ethyl acetate. The combined extracts were concentrated in vacuo and the residue was crystallized easily from ethyl acetate / petroleum ether. The product is obtained in high chemical and optical purity, with a high yield of 85-88% of theory, mp 125-126 ° C and [α] D ²⁰ = -64.5 + 0.5 ° (c = 1; water).

The process according to the invention is time-consuming, economically advantageous and economically advantageous and achieves surprisingly good results, with less hygiene requirements when handling the acetylating agent.

Further details of the process according to the invention are given in the following exemplary embodiment, which only illustrates but does not limit it.

Claims (1)

A method for producing chirally highly pure N-acetyl-L-α-alanine or N-acetyl-D-α-alanine of the formula H3C—CH—COOH NH H3C—co by acetylation of L- or Da-alanine with acetic anhydride in an aqueous alkaline medium, characterized in that the acetylation is carried out in an aqueous solution containing stoichiometric 89.1 g of L-alanine suspended in 50 ml of water is mixed with 250 ml of 4 M sodium hydroxide solution at a temperature of 1 to 5 °C under vigorous stirring. The reaction mixture is cooled to -15 to -20 °C and 153 g of acetic anhydride and 375 ml of 4 M aqueous sodium hydroxide solution are simultaneously added dropwise to the reaction mixture under vigorous stirring at such a rate that the temperature is maintained within the set limits and in such a ratio that the pH is maintained in the range of 9.5 to 11.5. After completion of the reaction, the reaction mixture is acidified with sulfuric acid and shaken gradually with ethyl acetate until acetyl-L-alanine is detectable in the ethyl acetate layer. The combined ethyl acetate fractions are dried and concentrated in vacuo at a temperature of up to 45 °C, the remaining yellowish oil is dissolved in boiling 600 ml of ethyl acetate and, after hot filtration, crystallized with petroleum ether. Yield 116 g (88% of theory) of colorless crystals, mp 125-126 °C, [α] _D ²⁰ ₌ -64.8° (c = 1; water). The same procedure is used to produce N-acetyl-D-α-alanine. a certain amount of an inorganic base, for example sodium hydroxide, based on free carboxyl groups, with acetic anhydride, added in an excess of 1.1 to 1.5 moles simultaneously with an aqueous solution of an inorganic base, for example sodium hydroxide, while maintaining the temperature of the reaction mixture at -TO to -25 °C and the pH value at 9.0 to 11.5, after which the reaction mixture is acidified with a mineral acid after completion of the reaction, and the reaction product is isolated by extraction with an organic solvent that is partially miscible with water, evaporation of the solvent and crystallization of the residue.