Synthesis of D,L-norvaline

Abstract

The invention discloses a method for synthesizing D, L-norvaline with n-pentanoic acid as a main initial raw material, orderly comprising the following steps: 1) bromo reaction: n-pentanoic acid is reacted with liquid bromine to form alpha-bromo n-pentanoic acid; 2) ammonolysis: the obtained alpha-bromo n-pentanoic acid is firstly neutralized by strong aqua ammonia under the protection of nitrogen and under ice bath cooling, and then is ammonolyzed for 0.5 to 12 hours at a temperature between 40 and 90 DEG C by using ammonia water or ammonia gas as an ammonolysis reagent and hexamethylenetetramine as a catalyst; then the obtained suspension is filtered, and the filtering cake is washed by methanol or ethanol and dried to form the D, L-norvaline; and 3) ion exchange to separate and recycle: the obtained filtrate in the step of ammonolysis and cation exchange resin are subjected to ion exchange, and materials on the resin are eluted with weak aqua ammonia, decolored, dewatered, washed by methanol or ethanol and dried to form the D, L-norvaline. The D, L-norvaline obtained in step 2) and step 3) is combined, and the ammonolysis yield is over 95 percent. The method for synthesizing the D, L-norvaline has advantages of simple process, few reaction steps, high yield, low cost, short production period and the like. The obtained D, L-norvaline can be further subjected to chemical resolution or enzymatic resolution to form chiral norvaline.

Description

technical field [0001] The invention relates to a method for synthesizing organic compounds, and in particular provides a method for synthesizing D, L-norvaline with n-valeric acid. Background technique [0002] D, L-norvaline, as an unnatural amino acid, plays an important role in drug synthesis, especially norvaline with a single optical activity. L-norvaline is the key intermediate of the synthetic drug Perindopril; D-norvaline can be used as a D-source to synthesize some macrolides with D-such as Pamamycin-607 and alkaloids ( R)-Epilachnene. Chiral norvaline can be obtained by splitting racemic D, L-norvaline, or by direct synthesis, and there are few related reports. Japanese patent JP7553587 is produced by fermentation, and the yield is about 3.79g / L, which is far lower than the yield of amino acids produced by general fermentation, and it is difficult to meet the needs of industrial production. Chinese patent CN1651400 discloses the technology of synthesizing L-nor...

AI Technical Summary

Problems solved by technology

Japanese patent JP7553587 is produced by fermentation, and the yield is about 3.79g / L, which is far lower than the yield of amino acids produced by general fermentation, and it is difficult to meet the needs of industrial production.

Chinese patent CN1651400 discloses the technology of synthesizing L-norvaline with n-butyraldehyde and acetone cyanohydrin as raw materials. The method uses highly toxic acetone cyanohydrin as the reaction raw material, and acetone cyanohydrin is not easy to obtain and the price is high , has its limitations

Chinese patent CN101007772 has carried out certain improvement to it, adopts sodium cyanide to replace acetone cyanohydrin as reaction raw material, has reduced raw material cost, but has the same shortcoming that sodium cyanide is also highly toxic chemical raw material, and simultaneously reaction steps is many, and total yield not tall

In Chinese patent CN1962613, Chen Xinzhi disclosed the technology of using n-valeric acid as the starting material for acyl chloride, bromination, ammoniation, resolution, recrystallization, and hydrolysis to synthesize L-norvaline, and at the same time disclosed in Chinese patent CN101007774 The technology for synthesizing D-norvaline with the same process route, the above two patents avoid the use of highly toxic raw materials and reduce production costs, but there are still problems such as many reaction steps and low overall yield

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