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Preparation method of cilastatin sodium key intermediate

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

Active Publication Date: 2020-06-16
LUNAN PHARMA GROUP CORPORATION
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  • 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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  • Preparation method of cilastatin sodium key intermediate
  • Preparation method of cilastatin sodium key intermediate
  • Preparation method of cilastatin sodium key intermediate

Examples

Experimental program
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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 27.16g (0.24mol) and 0.9g of p-toluenesulfonic acid were added to 240mL of toluene, kept at reflux for 10h, and the reaction solution was cooled to room temperature after the reaction. The HPLC purity was 89.5%, and the E-configuration impurity was 10%.

[0039] In 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 280nm, and the control light intensity is 450μW·cm -2 ), after irradiating for 60min, the reaction solution was washed twice with water, the organic layer was dried over anhydrous sodium sulfate, filtered, and toluene was evaporated to obtain (Z) 7-chloro-2((S)-2,2-dimethylcyclo Propanecarboxamido)-2-heptenoic acid ethyl ester, molar yield 99.5%, HPLC purity 99.8%,...

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 27.16g (0.24mol) and 0.9g of p-toluenesulfonic acid were added to 240mL of benzene, kept at reflux for 13h, and the reaction solution was cooled to room temperature after the reaction. The HPLC purity was 87.3%, and the E-configuration impurity was 12%.

[0042] In 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 300nm, and the control light intensity is 450μW·cm -2 ), after irradiating for 60min, the reaction solution was washed twice with water, the organic layer was dried over anhydrous sodium sulfate, filtered, and benzene was evaporated to obtain (Z) 7-chloro-2((S)-2,2-dimethylcyclo Propane carboxamido)-2-heptenoic acid ethyl ester, molar yield 98.5%, HPLC purity 99.6%...

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 41.74g (0.36mol) and 0.9g of p-toluenesulfonic acid were added to 240mL of xylene, kept at reflux for 10h, and the reaction solution was cooled to room temperature after the reaction. The HPLC purity was 88.0%, and the E-configuration impurity was 9%.

[0045] In step (2), the reaction solution obtained in the previous step is placed in a 40°C incubator, and irradiated with ultraviolet light under a 20W ultraviolet lamp (the emission wavelength is 250nm, and the light intensity is controlled to be 450μW·cm -2 ), after irradiating for 60min, the reaction solution was washed twice with water, the organic layer was dried over anhydrous sodium sulfate, filtered, and xylene was evaporated to obtain (Z) 7-chloro-2((S)-2,2-dimethyl Cyclopropanecarboxamido)-2-heptenoic acid ethyl ester, molar yield 98.2%, HPLC purity ...

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Abstract

The invention belongs to the field of organic chemical synthesis, and provides a method for preparing a cilastatin sodium key intermediate. The method comprises the following steps: by taking 7-halogen-2-oxoethyl heptanoate and (S)-2,2-dimethylcyclopropanecarboxamide as raw materials, carrying out a condensation reaction to obtain a reaction solution of Z / E type 7-halogen-2((S)-2,2-dimethylcyclopropanecarboxamide)-2-ethyl heptenoate, and irradiating the reaction solution under an ultraviolet lamp to obtain the high-purity Z type cilastatin sodium key intermediate. According to the method, thegeneration of impurities is reduced, the efficiency of the isomerization process is improved, the preparation process is simplified, and the yield and the purity of the cilastatin sodium key intermediate are effectively improved.

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)sulfur]-2-[(1S)-2,2-dimethylcyclopropane Sodium amido]-2-heptenoate, 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 of the United States. It has no bactericidal effect by itself, but it can be used in combination with the carbapenem antibiotic imipenem to pass Inhibit the decomposition of imipenem by renal dehydrodipeptidase to enhance the concentration of imipenem, thereby enhancing its efficacy. The compound preparation of cilastatin sodium and imipenem at a ratio of 1:1 can kill most Gram-positive and Gram-negative aerobic ...

Claims

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Application Information

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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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