KR910005748B1 - Purity and crystallisation of l-phenyl alanine methylester hydrochloric acid salt - Google Patents

Abstract

Crystallization of L-phenylalanine metylester hydrochlorate comprises (a) removing methanol by heating L-phenylalanine methylester hydrochlorate-methanol solm (A) at 65 deg.C or more, (b) inserting the same amt. of toluene to the methanol-distilled reaction residual soln., and then removing the residual methanol by heating the mixt. at 75 deg.C more, and (c) agitating and cooling the reaction soln. to 10 deg.C or less. The soln. (A) is prepd. by reacting L-phenylalamine with an excess amt. of methanol in the presence of a catalyst.

Description

Crystallization of L-phenylalanine Methyl Ester Hydrochloride

The present invention relates to a method for crystallizing L-phenylalanine methyl ester hydrochloride prepared by esterification of L-phenylalanine using toluene. L-phenylalanine methyl ester hydrochloride, which is a raw material of L-aspartyl-L-phenylalanine methyl ester, which is an artificial sweetener, is generally prepared in an organic solvent (especially methanol) and converted into an aqueous solution, and then used in the next step or used as an organic solvent or an organic solvent. It has been prepared in the state dissolved in a mixed solution of water (US Patent No. 4521514). In addition, a method of concentrating a reaction solvent to obtain crystals or using a method of precipitating crystals using an organic solvent such as acetone or ether was used.

The conventionally used concentration crystallization method is difficult to obtain crystals with high yield because it cannot be completely crystallized due to the solubility of the target compound in the reaction solvent, and the crystal form is also very bad, which causes difficulty in recovery and lowers the yield. . In order to eliminate this cause, methanol has been removed, and a method of crystallization by another organic solvent has been selected, and acetone or ether has been used. However, in the case of acetone or ether, the methanol remaining in the reaction solution tends to remain and is not completely precipitated as crystals or the crystal form is poor, so that the yield is difficult because of poor recovery.

It is an object of the present invention to reduce the yield by reducing the amount of organic solvent required to precipitate crystals using toluene, which is relatively higher in vision than methanol as a reaction solvent, and minimizing residual methanol to improve the yield of crystals. To complete.

The present inventors heat the L-phenylalanine methyl ester hydrochloride-methanol solution formed by esterifying L-phenylalanine with an excess of methanol mixture under a thionyl chloride catalyst to first remove methanol and remove residual methanol. To this end, the reaction balance was cooled to 50 ° C, and the same amount of toluene as the methanol input was divided into three portions, and the difference between the amount of methanol first mixed with L-phenylalanine and the amount of methanol first distilled off (the amount of methanol present in the reaction balance). And distilled methanol and toluene mixture, distilled the other half again, and distilled again. After adding the final part, the mixture was slowly stirred and slowly cooled to below 10 ° C. 90% or more of L-phenylalanine methyl Crystals of ester hydrochloride precipitated in a relatively good form. When explaining the present invention as an embodiment as follows.

Example 1

L-phenylalanine methyl ester hydrochloride-methanol solution (concentration = 32.2%, yield: 98.7%) prepared by esterifying L-phenylalanine with excess methanol under a catalyst was heated and distilled at 65 ° C. or higher to first remove methanol. . The same amount of toluene was slowly injected into the reaction mixture, in which methanol was distilled off, and then heated to 75 ° C or higher to distill off residual methanol, and stirred slowly, and the temperature of the reaction solution was lowered to 10 ° C or lower, thereby reducing L-phenylalanine methyl ester hydrochloride. A crystal was precipitated. The crystals were vacuum filtered, washed with cold toluene and then vacuum dried. The dried L-phenylalanine methyl ester hydrochloride crystals showed a yield of 98.5% at 321.3 g, and HPLC analysis showed a purity of 91.4% to obtain a total yield of 90%.

Example 2

Methanol was distilled by heating 400 ml of L-phenylalanine methyl ester hydrochloride-methanol solution (concentration = 32.2%, yield: 98.7%) produced by esterifying L-phenylalanine with excess methanol under a catalyst for a short time at 65 ° C or higher. .

The same amount of toluene was slowly added to the reaction mixture, in which methanol was distilled, and then heated to a temperature of 75 ° C. or higher for a short time to distill off the residual methanol, and stirred slowly. Good crystals of methyl ester hydrochloride were precipitated. The crystals were vacuum filtered, washed with cold toluene, and vacuum dried at about 45 ° C.

The dried L-phenylalanine methyl ester hydrochloride crystal had a weight yield of 99.2%, which was 129.5 g, and showed HPLC purity of 93.7%, yielding a total production yield of 93.0%.

Example 3

L-phenylalanine methyl ester hydrochloride-methanol solution 2L (concentration = 32.2%, yield: 98.7%) prepared by esterifying L-phenylalanine with excess methanol under a catalyst was distilled off methanol at 65 ° C or higher. The same amount of toluene was slowly injected into the reaction mixture, in which methanol was distilled off, and then heated to 75 ° C. or higher to distill off residual methanol, stirred slowly, and the temperature was lowered to 10 ° C. or lower. .

The crystals were vacuum filtered, washed with cold toluene and then vacuum dried. The dried L-phenylalanine methyl ester hydrochloride crystals showed a yield of 98.7% at 633.6 g, and HPLC analysis showed a purity of 91.5%, yielding a total production yield of 90.3%.

Claims (1)

L-phenylalanine methyl ester salt-methanol solution prepared by esterifying L-phenylalanine with excess methanol under a catalyst was heated to 65 ° C. or higher to first remove methanol and to remove residual methanol to 50 ° C. After cooling, the same amount of toluene as the amount of methanol is divided into three parts, and the amount of difference between methanol mixed with L-phenylalanine and the first distilled methanol (the amount of methanol present in the reaction balance) is added to the mixture. It is distilled by heating with distillation, and the other half is added again and distilled again, and after adding a final part, it is stirred slowly, and it cools slowly below 10 degreeC, and precipitates the crystal | crystallization of L-phenylalanine methyl ester hydrochloride.