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A kind of preparation method of key intermediate of cilastatin sodium

A technology of cilastatin sodium and intermediates, applied in the field of organic chemical synthesis, can solve the problems of difficult removal of impurities, low conversion rate, easy generation of impurities, etc., and achieve the effect of simple operation

Active Publication Date: 2022-08-05
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0024] The invention provides a preparation method of a key intermediate of cilastatin sodium, which solves the technical problems of low conversion rate, easy generation of impurities and difficult removal of impurities in the heating isomerization process existing in the prior art, and makes the final product The yield and purity of cilastatin sodium are significantly improved

Method used

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

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Effect test

Embodiment 1

[0038] Step (1), in a reaction device equipped with a water separator, 50g (0.24mol) of 7-chloro-2-oxoheptanoic acid ethyl ester, (S)-2, 2-dimethylcyclopropanecarboxamide 27.16 g (0.24 mol) and 0.9 g of p-toluenesulfonic acid were added to 240 mL of toluene, and the mixture was kept under reflux for 10 h. After the reaction, the reaction solution was cooled to room temperature. The HPLC purity was 89.5%, and the E-configuration impurity was 10%.

[0039] Step (2), the reaction solution obtained in the previous step is placed in a 30°C incubator, and irradiated with ultraviolet light under a 20W ultraviolet lamp (the emission wavelength is 280 nm, and the control light intensity is 450 μW cm -2 ), after irradiating for 60 min, the reaction solution was washed twice with water, the organic layer was dried over anhydrous sodium sulfate, filtered, and the toluene was evaporated to obtain (Z) 7-chloro-2((S)-2,2-dimethyl ring Propanecarboxamido)-2-heptenoic acid ethyl ester, molar y...

Embodiment 2

[0041] Step (1), in a reaction device equipped with a water separator, 50g (0.24mol) of 7-chloro-2-oxoheptanoic acid ethyl ester, (S)-2, 2-dimethylcyclopropanecarboxamide 27.16 g (0.24 mol) and 0.9 g of p-toluenesulfonic acid were added to 240 mL of benzene, and the mixture was kept under reflux for 13 h. After the reaction, the reaction solution was cooled to room temperature. The HPLC purity was 87.3%, and the E-configuration impurity was 12%.

[0042] Step (2), the reaction solution obtained in the previous step was placed in a 30°C incubator, and irradiated with ultraviolet light under a 20W ultraviolet lamp (the emission wavelength was 300 nm, and the control light intensity was 450 μW cm -2 ), after irradiating for 60 min, the reaction solution was washed twice with water, the organic layer was dried over anhydrous sodium sulfate, filtered, and the benzene was evaporated to obtain (Z) 7-chloro-2((S)-2,2-dimethyl ring Propanecarboxamido)-2-heptenoic acid ethyl ester, mola...

Embodiment 3

[0044] Step (1), in a reaction device equipped with a water separator, 50g (0.24mol) of 7-chloro-2-oxoheptanoic acid ethyl ester, (S)-2, 2-dimethylcyclopropanecarboxamide 41.74 g (0.36 mol) and 0.9 g of p-toluenesulfonic acid were added to 240 mL of xylene, and the mixture was kept under reflux for 10 h. After the reaction was completed, the reaction solution was cooled to room temperature. The HPLC purity was 88.0%, and the E-configuration impurity was 9%.

[0045] Step (2), the reaction solution obtained in the previous step was placed in a 40°C incubator, and irradiated with ultraviolet light under a 20W ultraviolet lamp (the emission wavelength was 250 nm, and the control light intensity was 450 μW cm -2 ), after irradiating for 60 min, the reaction solution was washed twice with water, the organic layer was dried over anhydrous sodium sulfate, filtered, and the xylene was evaporated to obtain (Z) 7-chloro-2((S)-2,2-dimethylene) Cyclopropanecarboxamido)-2-heptenoic acid et...

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Abstract

The invention belongs to the field of organic chemical synthesis and provides a method for preparing a key intermediate of cilastatin sodium, the method comprising: using 7-halo-2-ethyl oxoheptanoate and (S)-2, 2- Dimethylcyclopropanecarboxamide is a raw material, and through condensation reaction, Z / E type 7-halogen-2((S)-2,2-dimethylcyclopropanecarboxamide group)-2-heptenoic acid ethyl ester is obtained The reaction solution is placed under an ultraviolet lamp to irradiate to obtain a high-purity Z-type cilastatin sodium key intermediate. The invention reduces the generation of impurities, improves the efficiency of the isomerization process, simplifies the preparation process, and effectively improves the yield and purity of the key intermediate of cilastatin sodium.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis, and in particular relates to a preparation method of a key intermediate of cilastatin sodium. Background technique [0002] Cilastatin Sodium Chemical Name: (Z)-7-[(2R)-(2-amino-2-carboxyethyl)thio]-2-[(1S)-2,2-dimethylcyclopropanemethane Amido]-2-heptenoate sodium, the molecular formula is: C 16 H 25 N 2 O 5 SNa, its chemical structure is shown in formula (I): [0003] [0004] Cilastatin is a high-efficiency specific inhibitor of renal dehydrodipeptidase developed by Merck in the United States. It has no bactericidal effect by itself, but it is used in combination with the carbapenem antibiotic imipenem. Inhibit the decomposition of imipenem by renal dehydrodipeptidase to enhance the concentration of imipenem, thereby enhancing its efficacy. The combination of cilastatin sodium and imipenem in a ratio of 1:1 can kill most gram-positive and gram-negative aerobic and anaerobic p...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/63C07C231/12C07C231/18
CPCC07C231/12C07C231/18C07C2601/02C07B2200/07C07C233/63
Inventor 王海波提文利
Owner LUNAN PHARMA GROUP CORPORATION
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