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A kind of preparation method of cilastatin sodium intermediate

A technology of cilastatin sodium and intermediates, which is applied in the field of preparation of cilastatin sodium intermediates, can solve the problems of long reflux reaction time, long hydrolysis process time, unfavorable industrial recovery, etc., and achieve good product stability, The effect of less impurities and saving production cost

Active Publication Date: 2020-08-25
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above methods all have the possibility of long reflux reaction time and too long hydrolysis process, resulting in the possibility of new impurities, and the E-isomer impurities still have large residues, which cannot be removed in subsequent reactions, and the solvents used are mostly mixed solvents. , is not conducive to industrial recycling, and the operation is more cumbersome

Method used

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  • A kind of preparation method of cilastatin sodium intermediate
  • A kind of preparation method of cilastatin sodium intermediate
  • A kind of preparation method of cilastatin sodium intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0036] Example 1: Preparation of (Z)-7-chloro-2((2s)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid

[0037] 25.0 g (121 mmol) of ethyl 7-chloro-2-oxoheptenoate, 13.68 g (121 mmol) of (S)-2,2-dimethylcyclopropanecarboxamide, and 125 ml of toluene were added to a 500 ml flask, Stir, then add 0.5 g of concentrated sulfuric acid, heat up to reflux, continuously remove the generated water, keep warm and reflux for 5 hours. Cool down to 70°C, slowly add 50ml of concentrated hydrochloric acid, slowly pass in HCl gas until the reaction is complete, keep stirring for 2h. Stop the flow of hydrogen chloride gas, lower the temperature to -10°C, keep stirring at this temperature for 7 hours, and TLC detects that the impurity spots completely disappear. The organic phase was washed successively with saturated brine (2×100ml) and purified water (2×100ml), extracted, dried over anhydrous sodium sulfate, filtered, and the toluene was evaporated under reduced pressure at 50°C to obtain...

Embodiment 2

[0038] Example 2: Preparation of (Z)-7-bromo-2((2s)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid

[0039] 30.39g (121mmol) of ethyl 7-bromo-2-oxoheptenoate, 13.68g (121mmol) of (S)-2,2-dimethylcyclopropanecarboxamide, and 125ml of toluene were added to a 500ml flask, After stirring, 0.31 g of p-toluenesulfonic acid was added, the temperature was raised to reflux, and the generated water was continuously separated, and the temperature was kept at reflux for 6 hours. Cool down to 65°C, slowly add 75ml of concentrated hydrochloric acid, slowly inject HCl gas until the reaction is complete, and keep stirring for 1.5h. Stop the flow of hydrogen chloride gas, lower the temperature to -15°C, keep stirring at this temperature for 4 hours, and TLC detects that the impurity spots completely disappear. The organic phase was washed successively with saturated brine (2×100ml) and purified water (2×100ml), extracted, dried over anhydrous sodium sulfate, filtered, and the toluene w...

Embodiment 3

[0040] Example 3: Preparation of (Z)-7-chloro-2((2s)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid

[0041] 35.72g (121mmol) of 7-chloro-2-oxoheptenoic acid butyl ester, (S)-2, 13.68g (121mmol) of 2-dimethylcyclopropanecarboxamide, 125ml of toluene were added in a 500ml flask, After stirring, 1.79g of benzenesulfonic acid was added, the temperature was raised to reflux, and the generated water was continuously separated, and the temperature was kept at reflux for 4 hours. Cool down to 75°C, slowly add 179ml of concentrated hydrochloric acid, slowly inject HCl gas until the reaction is complete, and keep stirring for 3.5h. Stop the flow of hydrogen chloride gas, lower the temperature to -6°C, keep stirring at this temperature for 12 hours, and TLC detects that the impurity spots completely disappear. The organic phase was washed successively with saturated brine (2×100ml) and purified water (2×100ml), extracted, dried over anhydrous sodium sulfate, filtered, and the to...

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Abstract

The invention belongs to the technical field of medicines, and particularly provides a cilastatin sodium intermediate preparation method, which comprises: simply preparing a (Z)-7-X-2((2s)-2,2-dimethylcyclopropaneformamido)-2-heptenoic acid crude product through a one-pot method by using 7-X-2-oxoheptanoic acid ethyl ester and (s)-2,2-dimethylcyclopropaneformamide as raw materials sequentially under the action of a catalyst, concentrated hydrochloric acid and hydrogen chloride gas, and re-crystallizing to prepare a (Z)-7-X-2((2s)-2,2-dimethylcyclopropaneformamido)-2-heptenoic acid refined product. According to the invention, the method has advantages of short synthetic route, simple operation and high product purity, and is suitableness for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis and relates to a preparation method of a cilastatin sodium intermediate. Background technique [0002] The chemical name of cilastatin sodium is (Z)-7-[(2R)-(2-amino-2-carboxyethyl)sulfur]-[(1S)-2,2-dimethylcyclopropanecarboxamide Sodium ]-2-heptenoate is a highly effective renal dehydrodipeptidase inhibitor, which can inhibit the degradation of imipenem by renal dehydrodipeptidase when used in combination with imipenem. Its compound preparation can kill most Gram-positive and Gram-negative aerobic and anaerobic pathogenic bacteria and strains resistant to most β-lactam antibiotics. It has played an important role in the control of drug-resistant bacteria, enzyme-producing bacteria infections, and the treatment of infections in immunocompromised patients, and has been widely used clinically as a broad-spectrum antibacterial drug. [0003] Its structure is as follows: [0004] [0005]...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/63C07C231/12
CPCC07B2200/07C07B2200/09C07C231/12C07C2601/02C07C233/63
Inventor 提文利王新平
Owner LUNAN PHARMA GROUP CORPORATION
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