Green preparation method of N-substituted-L-pyroglutamate

Abstract

The invention provides a green preparation method of N-substituted-L-pyroglutamate. The method comprises the steps as follows: L-glutamic acid diester hydrochloride (III) is prepared from L-glutamic acid (II) as a starting material in the presence of an acidic reagent by an esterification reaction; then, L-glutamic acid diester hydrochloride (III) is subjected to N-substituted protective reactionwith an N-substituent protective reagent with a one-pot method in the presence of a base and a solvent, an N-substituted protective group is introduced, heating is performed for dealcoholization cyclization in molecules, and N-substituted-L-pyroglutamate as shown in the formula (I) is obtained. The method has the advantages of cheap and easily available raw materials, classic reaction types, shortprocess route, simple and convenient operation, small waste water amount, green and environment-friendly production process, high reaction yield and low product cost. 5R-benzyloxyaminopiperidine-2S-carboxylate, 5R-benzyloxyaminopiperidine-2S-formate ethanedioate and avibactam can be prepared from N-substituted-L-pyroglutamate as shown in the formula (I).

Description

technical field [0001] The invention relates to a green preparation method of N-substituted-L-pyroglutamate, which belongs to the field of pharmaceutical biochemical industry. Background technique [0002] N-substituted-L-pyroglutamic acid ester (I) is an important chemical and pharmaceutical intermediate. In the field of medicine, N-substituted-L-pyroglutamic acid ester can be used to prepare a new type of ultra-broad-spectrum β-endo The amidase inhibitor avibactam, patents CN103649051A, CN105294690A, and US20140275001 all use N-substituted-L-pyroglutamate (I) to prepare avibactam. The structural formulas of N-substituted-L-pyroglutamate (I) and avibactam are as follows: [0003] [0004] The existing N-substituted-L-pyroglutamic acid ester (I) preparation method is to use pyroglutamic acid as raw material, react with benzyl chloride, organic base, 1,2-dichloroethane (CN105732454A method) or react with bromine Benzyl, organic base, and acetone react (CN105130870A metho...

AI Technical Summary

Problems solved by technology

[0007] The above methods all use highly irritating benzyl bromide or benzyl chloride as raw material, the reaction time is long, the production efficiency is low, and the amount of waste water is large; the price of pyroglutamic acid is higher in addition, and pyroglutamic acid needs to be produced by glutamic acid high temperature (150 -160°C) melt preparation, inconvenient operation, cumbersome post-processing, multiple decolorization is required, a large amount of waste water is generated in the decolorization process, and the yield is only 75%; and the preparation process of the above method requires three operation steps, and the process route is long, which is not conducive to green production

Images