Method for purifying intermediate of cilastatin sodium

A technology of cilastatin sodium and a purification method, which is applied in the field of drug synthesis, can solve the problems of large amount of solvent, cumbersome operation, and long operation time, and achieve the effects of cheap and easy-to-obtain reagents, simplified operation process, and reduced possibility

Active Publication Date: 2019-10-08
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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 conduci...

Method used

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  • Method for purifying intermediate of cilastatin sodium
  • Method for purifying intermediate of cilastatin sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Weigh 10.0 g of (E-Z)-7-chloro-2((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid ethyl ester crude product (HPLC purity 85%, E configuration Impurity 12%), add 10ml of acetone, stir, then add 10ml of ethanol, dropwise add 50ml of purified water, after the dropwise addition is completed, use hydrochloric acid with a mass fraction of 1% to adjust pH4, then cool down to 5°C, keep stirring for 3h, and suction filter, The obtained solid 8.4g is Z-7-chloro-2((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid ethyl ester, HPLC purity 99.5%, E configuration impurity 0.06%.

Embodiment 2

[0031] Weigh 10.0 g of (E-Z)-7-chloro-2((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid ethyl ester crude product (HPLC purity 85%, E configuration impurity 12%), add 20ml of acetone, stir, then add 10ml of isopropanol, dropwise add 50ml of purified water, after the dropwise addition, use 5% acetic acid to adjust the pH to 6, then cool down to 10°C, keep stirring for 3h, pump Filter to obtain 8.2 g of solid Z-7-chloro-2 ((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid ethyl ester, HPLC purity 99.1%, E structure Type impurity 0.09%.

Embodiment 3

[0033] Weigh 10.0 g of (E-Z)-7-chloro-2((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid ethyl ester crude product (HPLC purity 85%, E configuration impurity 12%), add 15ml of acetone, stir, then add 20ml of tert-butanol, dropwise add 80ml of purified water, adjust the pH5 with sulfuric acid with a mass fraction of 1% after the dropwise addition, then cool down to 0°C, keep stirring for 3h, pump Filter to obtain 8.5 g of solid, which is Z-7-chloro-2 ((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid ethyl ester, HPLC purity 99.0%, E structure Type impurities 0.10%.

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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...

Claims

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Application Information

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IPC IPC(8): C07C231/24C07C233/63
CPCC07B2200/07C07B2200/09C07C231/24C07C233/63
Inventor 张贵民褚延军提文利
Owner LUNAN PHARMA GROUP CORPORATION
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