CS231654B1 - Processing of alpha-l-aspartyl-l-phenylalanine-methylester hydrochloride - Google Patents

Abstract

From acidic (HCl) aqueous-methanolic solution after catalytic hydrogenolysis benzyloxycarbonyl protecting cleavage groups of mixtures of o - and - S-N-benzyloxycarbonyl-L-aspartyl-menylalanine methyl esters the desired L-aspartyl-L-phenylalanine methyl ether hydrochloride is introduced to crystallization by adding concentration-increasing substances chloride ions, preferably chloride sodium.

Description

The present invention relates to a process for the preparation of cC-L-aspartyl-L-phenylalanine methyl ester hydrochloride of formula Iysys

00H

-OH ²

Αθ - NH - CH - COOCH 2. HCl

4h ₂ (I), in which povívá as an artificial sweetener, and a mixture eth- / ON-benzyloxycarbonyl-L-aspartyl-L-fenylalaninmethylesterň formulas II and III ^ OOH _CH2

7H? -CH ₂ -O-CO-NH CO-NH-? H-COOCH-CH 2 (II),

<2>

CO - NH ₂

-O-CO-NH-CH 2 i

COOH

- _? HCH,

COOCH.

The principle of the production process is the hydrogenolithic cleavage protecting the benzyloxycarbonyl groups and the separation of the oC derivative from the resulting mixture. and A-L-aspartyl-L-phenylalamino-methyl esters. According to the prior art, the hydrogenolysis is carried out in a solution containing

Water, methanol and hydrochloric acid with hydrogen gas in the presence of palladium catalyst. The solution after reduction is added to dryness and the separation of the hydrochloride and the γ-form is effected by crystallization of the residue and a mixture of acetone and water in which β- the form remains in the mother liquor.

In a detailed study, the authors have found that the critical phase of this process is the evaporation of the solution after hydrogenation to dryness. It is the evaporation of a mixture of water, methanol and hydrochloric acid. During this evaporation, predominantly methanol is distilled and hydrogen chloride is concentrated in the solution, which in the end reaches a constant concentration of approximately 20% aqueous hydrochloric acid. ^of Omer too not improved when working under reduced pressure.

Model experiments have shown that during such evaporation, the methyl ester is partially saponified to the free acids as well as the addition of other ballasts such as L-aspartyl-L-phenylalanine dimethyl ester and a number of their unidentifiable decomposition products. These circumstances reduce the yield of the product, varying from lot to lot depending on the individual course of Evaporation and also adversely affect the quality of the isolated substance. Therefore, other possibilities of isolation of the substance from the reaction medium after hydrogenation were sought.

The present invention provides a process for the preparation of α-L-aspartyl-L-phenylalanine methyl ester hydrochloride from a mixture of X- and N-benzyloxycarbonyl-L-aspartyl-L-phenylalanine methyl esters by catalytic hydrogenolytic cleavage of the benzyloxycarbonyl group in aqueous methanol and in its presence. is characterized in that the resulting solution of the mixture of hydrochlorides of (.alpha .- and .beta.-L-aspartyl-L-phenylalanine methyl esters, optionally after distilling off the selected amount of solvents) is treated with sodium chloride as a chloride ionic substance to selectively precipitate the desired hydrochloride. (-L-aspartyl-L-phenylalanine methyl ester).

The basis of the process of the invention was a study investigating the possibility of elimination of the desired substance from the reaction medium by the addition of solvents and other substances which could be expected to promote crystallization of the desired product. In this regard, the addition of chloride ion donors has proven to be the most effective. It may be hydrochloric acid, ammonium chloride, calcium chloride and other chlorides, «alkali metal advantage, and preferably sodium chloride».

1 is a graph showing the solubility of d-L-aspartyl-L-phenylalarriethylether hydrochloride (g / 100 ml) in the system against · methanol-sodium chloride, which shows a significant decrease in solubility by addition of sodium chloride aqueous and methanolic solution of hydrochloride of C-Laspartyl-L-phenylalanine methyl ester.

Fig. 2 shows the solubility of N-aspartyl-L-alalanine methylthiyl hydrochloride in methanol-water / 1: 9 / sodium chloride, depending on the amount of sodium chloride and temperature. The X-axis shows the concentration of sodium chloride in%, and the Y-axis the amount of hydrochlorides of (L-aspartyl-L-phenylalanine methyl ester in g / 100 ml).

In all cases, the α-L-aspartyl-L-phenylalanine methyl ester hydrochloride dihydrate in the well-developed needle-like crystals which, in the range of quantitative ratios of the β-α and β-forms eligible from the prior synthesis of the β-α / β-mixtures. -N-benzyloxycarbomyl-L-aspartylphenylalanine hydrochloride not practically contaminated with β-form ·

231 854

Details of the practical application of this knowledge for the isolation of hydrochloride of α-L-aspgrtyl-D-phenylalanine methyl ester from the reaction mixture after hydrogenation can be varied within certain limits ohledem with regard to optimum process economics under given production conditions. its regeneration, and it is not very important for the result if less or more is distilled off. a greater or lesser amount of sodium chloride in the product, which is not a problem for further use of the product. the use of an organic solvent, such as acetone, for the final washing of the product, if it is preferable to dry such organic solvent under the conditions, rather than water.

The advantages of the new procedure can be summarized as follows:

1) No evaporation of the reaction solution after hydrogenation to dryness, which requires expensive equipment of foreign origin ^

2) A simple device under processing conditions (50 ° C, 5,666 Pa) is sufficient for distilling off methanol, which at the same time brings the possibility of regeneration of up to 60% methanol directly from the technological process (80> 75% methanol ·

3) Higher and regular yields are obtained against crystallization from acetone · No use of acetone and its regeneration · Expensive acetone is replaced by sodium chloride, '

4) There is no difficulty in processing too thick a crystalline slurry of the Λ-isomer resulting from the crystallization of the acetone residue. The crystal formed by the process of the invention is very filterable.

5) High purity of the product is achieved, as evidenced by electrophoresis.

Further details of the process according to the invention can be seen from the following examples:

Example 1 mβΜ

A solution of 100 g of a mixture of N-N-benzyloxycarbonyl-L-aspartyl-1-phenylalaniniaethyl esters in 600 ml of methanol and 240 ml of 15 hydrochloric acid is filtered with 1 g of activated carbon and the filter is washed with 125 ml of methanol. hydrogenolysis with a catalytic effect of 10 g of 10% palladium on carbon. Hydrogenation is carried out until the detection of carbon dioxide in the gaseous gas mixture disappears. After complete hydrogenation, the suspension was freed from the catalyst by sedimentation and filtration, and the catalyst was washed with 150 ml of methanol, which was filtered to the main. After hydrolysis, the solution is concentrated to about 15 to 20% of the original volume (170 to 220 ml) by distilling off the methanol at a temperature of up to 50 ° C and at a pressure of 5,332 to 2,666 Pa. The still warm residue, without excluding the precipitate was added 100 ml of saturated sodium chloride solution (about _2Q h - 1.19) from the solution immediately crystallized hydrochloride Ιι Λ-aspartyl · Lf enylalaninmethylesteru occasional stirring, the slurry was cooled to 6 to 10 ° C and held at this temperature for 8 hours. The crystalline precipitate is then filtered off with suction and washed on the filter with 100 ml of 10% sodium chloride solution at 10 DEG C. The wet product is dried at 50 DEG C. to constant weight. The yield of d-L-aspartyl-L-phenylalanine methyl ester dihydrate is 58 g (95.92 wt%, sodium chloride 5.2 wt%).

Example 2

The procedure is the same as in Example 1. After concentrating the solution after hydrogenolysis to 15-20% of the original volume (170-220 ml), 200 ml of saturated sodium chloride solution (h ₂ O) is added to the warm residue which must not contain precipitate. = 1.19) and crystallize Ol-L-aspartyl-L-phenylalaninraethyl ester hydrochloride. With occasional stirring, the suspension is cooled to 6-10 ° C and kept at this temperature for 8 hours. The precipitated product is filtered off with suction and washed with 100 ml of 5% sodium chloride solution at 10 ° C. The wet product is dried at 50 ° C to constant weight. The yield of α-L-aspartyl-L-phenylalanine methyl ester dihydrate is 57.2 g (97.58 wt%, sodium chloride 2.2 wt%) ·

Claims (1)

A process for the preparation of X.-L-aspartyl-L-phenylalanine methyl ester hydrochloride from a mixture of ** - and N-benzyloxycarbonyl-L-aspartyl-L-phenylalanine methyl ester by catalytic hydrogenolytic cleavage of the benzyloxycarbonyl group in aqueous methanol and in the presence of hydrochloric acid by treating the resulting solution of the mixture of β- and β-L-aspartyl-L-phenylalanine methyl esters, optionally after distilling off the selected amount of solvents, with sodium chloride as the chloride ion-forming substance to selectively precipitate the desired c (-L-aspartyl hydrochloride) -Lf enylalanine methyl ester.