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Method for synthesizing cilastatin sodium

A technology of cilastatin sodium and a synthesis method, which is applied in the field of drug synthesis, can solve the problems of complicated post-processing process of cilastatin sodium, requires large solvent, pollutes the environment, etc., and achieves easy control of operation process and high optical purity. , the effect of high yield

Inactive Publication Date: 2010-10-06
ZHEJIANG NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this method, the post-treatment process of cilastatin sodium is relatively complicated, requires a large amount of solvent, has high cost and pollutes the environment

Method used

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  • Method for synthesizing cilastatin sodium
  • Method for synthesizing cilastatin sodium
  • Method for synthesizing cilastatin sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] The preparation of embodiment 1 (Z)-7-chloro-2-((1S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid ethyl ester

[0043] Dissolve 1.1g (S)-2,2-dimethylcyclopropanecarboxamide, 2g ethyl 7-chloro-2-oxoheptanoate and 0.01g p-toluenesulfonic acid in 50mL toluene, heat to reflux, and separate water, the reaction was completed, toluene was evaporated, washed with water, washed with saturated brine, dried, and spin-dried to obtain a crude product, which was purified to obtain a light yellow oil (Z)-7-chloro-2-((1S)-2, 2-Dimethylcyclopropanecarboxamido)-2-heptenoic acid ethyl ester, yield 67%.

Embodiment 2

[0044] The preparation of embodiment 2 cilastatin dialkyl ester

[0045] Add 0.5 g of (Z)-7-chloro-2-((1S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid prepared in Example 1 in a 100 mL round bottom flask Ethyl ester (1.66mmol), 0.25gNaI (1.66mmol) and 45mL acetone, heated to reflux for 12h, after the reaction, filtered, and the filtrate was spin-dried to obtain (Z)-7-iodo-2-((S)-2,2 -Dimethylcyclopropanecarboxamido)-2-ethyl heptenoate, directly used in the next step reaction.

[0046] Under a nitrogen atmosphere, add 0.22 g of the above-mentioned (Z)-7-iodo-2-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid ethyl ester (0.56mmol) and 0.1g (0.56mmol) cysteine ​​methyl ester hydrochloride, 0.36g K 3 PO 4 (1.7mmol) and 40mL tetrahydrofuran (THF), react in ultrasonic for 15min, place the reaction device in an oil bath heated to 80°C for reflux for 12h, after the reaction, cool to room temperature, evaporate the solvent under reduced pressure, and It was dis...

Embodiment 3～4

[0050] The preparation of embodiment 3~4 cilastatin dialkyl ester

[0051] In addition to CsCO 3 or K 2 HPO 4 Replace K 3 Except for PO4, other operations were the same as in Example 2 to prepare cilastatin dialkyl ester.

[0052] Investigate the impact of different bases on the cilastatin dialkyl ester yield under the same conditions in Table 1:

[0053] The kind of table 1 alkali is on the impact of cilastatin dialkyl ester productive rate

[0054]

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Abstract

The invention discloses a method for synthesizing cilastatin sodium, comprising the following steps: preparing (Z)-7-iodine-2-((S)-2, 2-dimethyl cyclopropane formamido)-2-heptenoic acid alkyl ester by reaction of (Z)-7-chlorine-2-((S)-2, 2-dimethyl cyclopropane formamido)-2-heptenoic acid alkyl ester and sodium iodide; enabling (Z)-7-iodine-2-((S)-2, 2-dimethyl cyclopropane formamido)-2-heptenoic acid alkyl ester, cysteine alkyl ester hydrochloride, alkali and a solvent to react to obtain cilastatin dialkyl ester; and enabling the cilastatin dialkyl ester and sodium hydroxide to react to obtain cilastatin sodium. The alkali used in the method can be one of or more of K2HPO4, CsCO3 and K3PO4, thereby avoiding the usage of strong alkali and an anhydrous reaction system and realizing mild reaction and easy operation. The method has the advantages of good economical efficiency, mild reaction conditions, high yield, little three wastes (waste gas, waste water and industrial residue) and no pollution and can be used for industrialization production. The product can be separated easily and has high purity.

Description

technical field [0001] The invention belongs to the field of medicine synthesis, in particular to a synthesis method of cilastatin sodium. Background technique [0002] Cilastatin Sodium, also known as (Z)-7-[(2R)-2-amino-2-carboxyethyl]thio-2-[[(1S)-2,2-dimethylcyclopropanyl ]amino]hept-2-enoate sodium, cilastatin; molecular formula: C 16 h 25 N 2 o 5 SNa, the molecular weight is: 380.44, and the structural formula is as follows: [0003] [0004] At present, the synthesis of cilastatin sodium mostly uses cilastatin and sodium salt as raw materials. The compound drug of cilastatin and imipenem - Taineng, is a widely used carbapenem antibacterial drug in clinical practice (Thienanycin: development of imipenem-cilastatin; Frederick, M.K.; JAnitimicrob Agents Chemother 1983, 12, Suppl .D, 1.). Cilastatin itself does not have a bactericidal effect, but it can inhibit the decomposition of imipenem by dehydrodipeptidase in the kidney, thereby increasing the activity of ...

Claims

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Application Information

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IPC IPC(8): C07C323/59C07C319/20C07C319/14
Inventor 李新生欧阳罗陈瑞业徐东成
Owner ZHEJIANG NORMAL UNIVERSITY
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