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Preparation method of cilastatin sodium

A technology of cilastatin sodium and sodium hydroxide, applied in the field of preparing cilastatin sodium, can solve the problems of reducing the yield and purity of the product, being lengthy, and the operation of the purification method is cumbersome, so as to improve the chromaticity and purity, avoid the cumulative effect

Inactive Publication Date: 2010-08-04
ZHEJIANG UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

And, because carry out in the base exchange process of cationic exchange resin, the heat that acid-base reaction releases can cause a small amount of cilastatin to decompose and reduce the yield and the purity of product
In addition, the purification method of this method is cumbersome and lengthy, and is not suitable for large-scale industrial preparation

Method used

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  • Preparation method of cilastatin sodium
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  • Preparation method of cilastatin sodium

Examples

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Embodiment 1

[0027] The preparation of (Z)-7-halo-2((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid sodium crystals comprises the following steps:

[0028] 1. 100g 7-chloro-2-oxoheptanoic acid ethyl ester, 53g (S)-2,2-dimethylcyclopropanecarboxamide and 1.3g p-toluenesulfonic acid were refluxed in 600ml toluene at 130°C for 10 Hour. After the reaction was completed, the toluene was concentrated and recovered. Add 300ml of sodium hydroxide solution (10%) to the concentrate, monitor the reaction process by HPLC, and react at 30-45°C for 8 hours. 100 ml of toluene was added to the reaction solution obtained by hydrolysis each time, and the reaction solution was washed repeatedly three times. The organic phase was discarded, acidified by adding concentrated hydrochloric acid, and the pH of the aqueous phase was adjusted to 3.5. The liquid layer was extracted three times with 280ml of toluene, the aqueous phase was discarded, and the organic phase was dried over anhydrous sodium su...

Embodiment 2

[0031] After obtaining the hydrolysis reaction liquid by the method described in Step 1 of Example 1, add 150 ml of dichloromethane each time, wash the hydrolyzate repeatedly 3 times, discard the organic phase, and add concentrated sulfuric acid to adjust the pH of the aqueous phase to 3.5. The material-liquid layer was extracted three times with 800 ml of ethyl acetate, and the aqueous phase was discarded. The organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. Add 500ml of acetonitrile to the concentrate, fully stir to dissolve, and filter to remove insoluble impurities. Slowly add 30% potassium hydroxide solution to the above filtrate until the pH of the solution is 7.0, stop adding the potassium hydroxide solution dropwise, continue stirring for 1.0 hour, and concentrate the reaction solution under reduced pressure after the pH is stable. The concentrated solution was crystallized at low temperature, and a large amount of ...

Embodiment 3

[0033] 1.50g (Z)-7-chloro-2((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid sodium solid was dissolved in 350ml10% sodium hydroxide solution, until all After dissolving, 28 g of L-cysteine ​​hydrochloride was added, and the reaction was incubated at 55° C. for 8 hours. The condensation reaction solution was cooled to room temperature, acidified with 3N hydrochloric acid, and the pH of the solution was adjusted to 3.0. Add 150ml of petroleum ether to wash the acidified solution, discard the organic layer, and concentrate the solution volume under reduced pressure to 1 / 2 of the original volume. The obtained solution was loaded onto an AP400 macroporous resin adsorption column, and washed with distilled water until the conductivity of the effluent was less than 10 μs / cm.

[0034] 2. Slowly elute the above-mentioned macroporous adsorption resin with 0.3N sodium hydroxide solution (440ml), and collect the obtained cilastatin sodium solution. Add 1.3 g of activated carbo...

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Abstract

The invention discloses a preparation method of cilastatin sodium, comprising the following steps of: taking 7-chloro-oxo-ethyl oenanthate and (S)-(+)-2, 2-dimethyl cyclopropane formamide as raw materials, and carrying out condensation reaction and basic hydrolysis to obtain (Z)-7-chloro-2((S)-2, 2-dimethyl cyclopropane formamido)-2-heptenoic acid; then, adding alkaline compound for reaction, and separating and purifying to obtain (Z)-7-chloro-2((S)-2, 2-dimethyl cyclopropane formamido)-2-heptenoic acid metal salt crystal; leading the metal salt crystal and cysteine hydrochloride for condensation reaction, acidizing the reaction liquid by hydrochloric acid, washing by organic solvent and concentrating, then loading sample into macroporous absorption resin for purifying, directly using sodium hydroxide solution for elution, and obtaining cilastatin sodium solid after the treatment of eluent. The preparation method simplifies the preparation technique, and effectively improves the chrominance, the purity and the yield of the cilastatin sodium.

Description

(1) Technical field [0001] The invention relates to a new method for preparing cilastatin sodium. (2) Background technology [0002] The chemical name of cilastatin sodium is (Z)-7-[(2R)-(2-amino-2-carboxyethyl)sulfur]-[(1S)-2,2-dimethylcyclopropanecarboxamide ]-2-sodium heptenoate is a highly efficient specific inhibitor of renal dehydrodipeptidase, and its chemical structure is shown in formula (VI). Cilastatin sodium can block the metabolism of carbapenem antibiotic imipenem in human kidney epithelial cells, reduce the nephrotoxicity of the drug, thereby increasing the concentration of unaltered imipenem in the urinary tract and enhancing the curative effect . The combination of cilastatin sodium and imipenem at a ratio of 1:1 has played an important role in the control of drug-resistant bacteria, enzyme-producing bacteria infections and the treatment of infections in patients with immunodeficiency. It is a highly clinically evaluated anti-severe infection. One of the ...

Claims

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Application Information

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IPC IPC(8): C07C323/59C07C319/14
Inventor 郑裕国白骅郑仁朝杨志清杨仲毅沈寅初
Owner ZHEJIANG UNIV OF TECH
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