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Method for preparing intermediate of cilastatin

A technology for cilastatin and intermediates, which is applied to the preparation of organic compounds, carboxylic acid amide preparation, chemical instruments and methods, etc., can solve the problem of low yield of cilastatin, and achieve simple preparation engineering, high yield, The effect of shortening the time

Inactive Publication Date: 2011-04-27
DHC CORP +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Therefore, eventually lead to low yield of cilastatin and generation of new impurities

Method used

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  • Method for preparing intermediate of cilastatin
  • Method for preparing intermediate of cilastatin

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preparation example Construction

[0019] The preparation method of cilastatin of the present invention can be generalized with [reaction formula 1].

[0020] Reaction 1

[0021]

[0022] Here, X refers to a halogen element such as fluorine or chlorine.

[0023] With reference to the first stage of the above [reaction formula 1], in (A) considered as [reaction formula 1], (E, Z)-7-halogen-2-((S)-2,2-di Add alkaline solution to methylcyclopropaneamido)-2-heptenoic acid ethyl ester.

[0024] (E, Z)-7-halo-2-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid ethyl ester can be prepared by the method described in European Patent Publication No. 48301 , In addition, although there is no record, it can also be prepared by many methods.

[0025] The base used here may be sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate or lithium hydroxide.

[0026] Add base to (A) and (B) of [Reaction Formula 1] for hydrolysis to obtain (E, Z)-7-halogen-((S)-2,2-dimethylcyclopropaneamido)-2 - an ...

reference example 1

[0044] Preparation of (E, Z)-7-chloro-2-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid ethyl ester

[0045] With reference to the method described in European Patent Publication No. 48301, 25.0 g (0.1209 mol) of 7-chloro-2-oxo-heptenoic acid ethyl ester, (S)-2,2-dimethylcyclopropaneamide 13.68 g (0.1209mol), 125ml of toluene and 0.25g of methyl sulfuric acid were put into a 500ml flask, and refluxed for 23 hours. The toluene was then evaporated to give ethyl (E,Z)-7-halo-2-((S)-2,2-dimethylcyclopropanamido)-2-heptenoate.

experiment example 1

[0047] Stage 1: Hydrolysis of (E, Z)-ethyl 7-chloro-2-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoate and preparation of (E, Z) -7-Chloro-2-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid n-propylamine salt.

[0048] At room temperature, add (E, Z)-7-chloro-2-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid ethyl ester obtained in Reference Example 1 50ml of water and 15.1g of sodium hydroxide, at the same temperature, through 24 hours of stirring, to obtain the isomer (Z)-7-chloro-2-( (S)-2,2-Dimethylcyclopropaneamido)-2-heptenoic acid sodium salt aqueous solution.

[0049] Add 150ml of toluene to (E, Z)-7-chloro-2-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid sodium salt solution, and use chloric acid aqueous solution to The pH was adjusted to 3. After separation, anhydrous magnesium sulfate was added to the organic solvent layer and then filtered. In the remaining liquid, add 8.93g of n-propylamine, after stirring for 1 hour, rotary distillation of tolu...

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Abstract

A producing method of a cilastatin intermediate is provided to obtain (Z)-7-hollow-2-((s)-2,2'-dimethylcyclopropane carboxamido)-2-heptenoic acid and its salt with high purity. A producing method of a cilastatin intermediate comprises the following steps: obtaining an (E,Z)-7-hollow-2-((s)-2,2'-dimethylcyclopropane carboxamido)-2-heptenoic acid alkali salt solution using a hydrolyzation after adding an alkali solution; extracting a first organic solvent layer from the reactant after adding a first organic solvent and acid to perform a layer separation; obtaining a mixed crystal of the (E,Z)-7-hollow-2-((s)-2,2'-dimethylcyclopropane carboxamido)-2-heptenoic acid alkali salt; and obtaining (Z)-7-hollow-2-((s)-2,2'-dimethylcyclopropane carboxamido)-2-heptenoic acid amine salt.

Description

technical field [0001] The invention relates to a method for preparing cilastatin intermediate (Z)-7-halo-2-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid or its amine salt method. Background technique [0002] Imipenem is a cyclic carbacin antibacterial agent with a broad spectrum of antibacterial activity. In the clinical use of imipenem, in order to slow down its metabolism, it is usually injected together with the sodium salt of cilastatin. [0003] The imipenem / cilastatin complex is an intramuscularly injected antimicrobial with broad action. It can be effectively used in the treatment of sepsis, neutropenia, fever, intra-abdominal, respiratory system, genital, gynecological, skin, soft tissue, bone or joint infection. Imipenem / cilastatin complexes generally have similar potency against a broad range of cephalosporins or other carbacins. [0004] The above cilastatin is prepared by cysteine ​​hydrochloride and (Z)-7-halo-2-((S)-2,2-dimethylcyclopropane which c...

Claims

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Application Information

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IPC IPC(8): C07C233/63C07C231/12C07C211/06C07C211/07C07C209/68
CPCC07C231/12C07C231/22C07C235/40
Inventor 吴锡李贤国曹明正
Owner DHC CORP
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