A kind of purification method of cilastatin sodium intermediate

Abstract

The invention belongs to the field of drug synthesis, and particularly discloses a method for purifying an intermediate of cilastatin sodium. The method includes adding (E-Z)-7-halo-2 ((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid ethyl ester into acetone, stirring, and adding a certain amount of organic alcohol; then dropping purified water, adjusting pH to 4-6 with acid after dropping, cooling to 0-10 DEG C, keeping the temperature and stirring for 3-4 hours; and filtering to obtain a solid, namely Z-7-halo-2 ((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid ethyl ester.Through the technical scheme, the HPLC purity of the product Z-7-halo-2 ((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid ethyl ester reaches more than 99.0%, and the impurity of the E configuration is reduced to less than 0.1%.

Description

technical field [0001] The invention belongs to the field of medicine synthesis, and in particular relates to a purification method of a cilastatin sodium intermediate. Background technique [0002] Cilastatin sodium (Z)-7-[(2R)-(2-amino-2-sulfoylethyl)sulfur]-[(1s)-2,2-dimethylcyclopropanecarboxamido]-2 -Sodium heptenoate, which is combined with imipenem as a broad-spectrum β-lactam antibiotic, can kill most Gram-positive and Gram-negative aerobic and anaerobic pathogens and most β-lactams class of antimicrobial resistant strains. It has played an important role in the control of drug-resistant bacteria, enzyme-producing bacteria infections, and the treatment of infections in immunodeficiency patients, and is one of the anti-severe infection drugs with high clinical evaluation. The structure looks like this: [0003] [0004] At present, there are many reports about the synthesis of cilastatin sodium, mostly by synthesizing ethyl 7-chloro-2-oxoheptanoate, and then usi...

AI Technical Summary

Problems solved by technology

Stir for 3-6 hours under the same conditions, then wash with toluene and water, use a mixed reagent (n-hexane / diisopropyl ether volume ratio of 1 / 3) at low temperature, slowly cool to 0-5°C, filter and wash with n-heptane Washing, this process consumes a lot of solvent, takes a long time, and the steps are cumbersome, which is not conducive to industrial production

[0012] In summary, most of the above-mentioned methods are to hydrolyze the ester into an acid, and achieve the purpose of purification by refining the acid or its corresponding salt, but there is a possibility that the hydrolysis process takes too long and new impurities are produced, and the operation more cumbersome

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