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
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Problems solved by technology

Therefore, eventually lead to low yield of

Method used

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

Examples

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Example Embodiment

[0019] The preparation method of cilastatin of the present invention can be summarized by [Reaction Formula 1].

[0020] Reaction formula 1

[0021]

[0022] Here, X means halogen elements such as fluorine and chlorine.

[0023] With reference to the first stage of the above [Reaction Formula 1], the (E, Z)-7-halo-2-((S)-2, 2-two (A), (B) of [Reaction Formula 1] Methyl cyclopropane amido)-2-heptenoic acid ethyl ester is added with an alkaline solution.

[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 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 alkali to (A) and (B) of [Reaction Formula 1] to hydrolyze to obtain (E,Z)-7-halo-((S)-2,2-dimethylcyclopropaneamido)-2 -An aqueous solution of the...

Example Embodiment

[0043] 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, 7-chloro-2-oxo-heptenoic acid ethyl ester 25.0g (0.1209mol), (S)-2,2-dimethylcyclopropane amide group 13.68g (0.1209 mol), 125 ml of toluene and 0.25 g of methyl sulfuric acid were put into a 500 ml flask and refluxed for 23 hours. Then the toluene was evaporated to obtain ethyl (E,Z)-7-halo-2-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoate.

Example Embodiment

[0046] Experimental example 1

[0047] Stage 1: Hydrolysis and preparation of ethyl (E, Z)-7-chloro-2-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoate (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 were stirred for 24 hours at the same temperature to obtain the isomer (Z)-7-chloro-2-( (E) form containing 10-13% (S)-2,2-Dimethylcyclopropaneamido)-2-heptenoate sodium salt aqueous solution.

[0049] Add 150ml of toluene to (E,Z)-7-chloro-2-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoate sodium salt aqueous solution, and use chloric acid aqueous solution to Adjust the pH to 3. After the layers were separated, anhydrous magnesium sulfate was added to the organic solvent layer and then filtered. In the remaining liquid, add 8.93g of n-propylamine, st...

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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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