Preparation method of cilastatin sodium

A technology of cilastatin sodium and dimethylcyclopropanecarboxamide, applied in the field of pharmaceutical synthesis, can solve the problems of low conversion rate, difficult to remove impurities, easy generation of impurities and the like, achieves improved yield and purity, and reduced solvent content , the effect of simplifying the purification process

Active Publication Date: 2012-10-03
SHANDONG NEWTIME PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] The invention provides a preparation method 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. The pH value of the reaction solution, and the reaction solution is pretreated, effectively solves the problems in the prior art, and simultaneously has the effect of simplifying the purification process of the macroporous adsorption resin, so that the yield of the final product cilastatin sodium and Purity is significantly improved, the invention is easy to operate and suitable for industrial production

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  • Preparation method of cilastatin sodium

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Embodiment 1

[0024] The preparation of embodiment 1 cilastatin sodium

[0025] Step (1) 25g ethyl 7-chlorooxyheptanoate, 13.68g(s)-2,2-dimethylcyclopropanecarboxamide and 0.14g p-toluenesulfonic acid were dissolved in toluene solution, and the temperature was refluxed at 110°C After the condensation was completed, the reaction mixture was washed with dilute hydrochloric acid and a saturated aqueous solution of sodium bisulfite, and then concentrated to recover toluene. The viscous was hydrolyzed in 20ml of ethanol and 25ml of 50% sodium hydroxide aqueous solution for 12h, then adjusted to pH 3.0-4.0 with concentrated hydrochloric acid, extracted three times with 30ml of ethyl acetate, and concentrated to obtain 31.2g of viscous.

[0026] Step (2) Add 20 g of cysteine ​​hydrochloride and 120 ml of 2N sodium hydroxide solution to the viscous material in the previous step, and stir and react at room temperature for 12 hours under nitrogen protection;

[0027] Step (3) Use hydrochloric acid t...

Embodiment 2

[0029] The preparation of embodiment 2 cilastatin sodium

[0030] Step (1) using dean-stark trap, 20g ethyl 7-bromooxyheptanoate, 12g(s)-2,2-dimethylcyclopropanecarboxamide and 0.2g p-toluenesulfonic acid were dissolved in toluene solution 120 Under the condition of reflux and water separation for 24 hours, after the condensation was completed, the reaction mixture was washed with dilute hydrochloric acid and a saturated aqueous solution of sodium bisulfite, and then concentrated to recover toluene. The viscous was hydrolyzed in 15ml of ethanol and 50ml of 30% sodium carbonate aqueous solution for 8 hours, adjusted to pH 3.0-4.0 with concentrated hydrochloric acid, extracted twice with 25ml of ethyl acetate, and concentrated to obtain 22.8g of viscous.

[0031] Step (2) Stir and dissolve the sticky substance in the previous step, 15g of cysteine ​​hydrochloride in 100ml of water and 20ml of ethanol, add dropwise 20ml of 50% sodium hydroxide solution, and stir at room temperatu...

Embodiment 3

[0035] Step (1) 15g ethyl 7-chlorooxyheptanoate, 8.2g(s)-2,2-dimethylcyclopropanecarboxamide and 0.25g p-toluenesulfonic acid were dissolved in xylene solution at a temperature of 130°C Reflux for water separation reaction. After the condensation is completed, the reaction mixture is washed with dilute hydrochloric acid and saturated aqueous sodium bisulfite solution, and then concentrated to recover xylene. The viscous was hydrolyzed in 15ml of ethanol and 15ml of 50% sodium hydroxide solution, adjusted to pH 3-4 with 2N hydrochloric acid solution, extracted twice with 20ml of ethyl acetate, and concentrated to obtain 19.8g of viscous.

[0036] Step (2) Add 12g of cysteine ​​hydrochloride and 80ml of 2N sodium hydroxide solution to the sticky substance in the previous step, and stir at room temperature for 13h;

[0037] Step (3) Use hydrochloric acid to adjust the pH of the solution to 2.0, wash 3 times with 50ml of petroleum ether, heat up to 90°C, and then keep warm for 1h;...

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Abstract

The invention belongs to the field of pharmaceutical synthesis, and provides a preparation method of cilastatin sodium, and the method comprises the following steps: performing condensation, alkaline hydrolysis, and thioetherification of raw materials of 7-oxyhalogen alkyl heptylate and (s)-2,2-dimethylcyclopropane methanamide, adjusting the pH value of the thioetherified solution, washing by a nonpolar solvent, performing isomerization, purification by a neutral macroporous adsorption resin, and salt formation so as to obtain the cilastatin sodium solid. The invention reduces the generation of impurities, improves the isomerization efficiency, simplifies the preparation process, and effectively improves the yield and purity of cilastatin sodium.

Description

technical field [0001] The invention belongs to the field of medicine synthesis, and in particular relates to a preparation method of cilastatin sodium. Background technique [0002] Cilastain Sodium Salt, chemical name: (z)-7-[(2R)-(2-amino-2-carboxyethyl)sulfur][(1S)-2,2-dimethyl Cyclopropanecarboxamido]-2-sodium heptenoate, its chemical structural formula is as follows: [0003] [0004] Cilastatin sodium can inhibit the degradation of β-lactam antibiotics such as imipenem by renal dehydrodipeptidase, increase the concentration of imipenem in the urinary tract, improve the activity of imipenem, and reduce the Renal toxicity, enhanced efficacy. At present, the combination of imipenem / cilastatin sodium has been widely used clinically as a broad-spectrum antibacterial drug. [0005] At present, the synthetic methods reported in the literature about cilastatin sodium are similar, all of which are first reacted with (s)-2,2-dimethylcyclopropanecarboxamide by the halide o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C323/59C07C319/20C07C319/28
Inventor 赵志全提文利王新平
Owner SHANDONG NEWTIME PHARMA
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