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A kind of preparation method of cefotiam hydrochloride

A technology of cefotiam hydrochloride and 7-ACA, applied in the field of pharmaceutical antibiotics, can solve the problems of insufficient product recovery, high labor intensity, long processing cycle, etc., and achieve stable and controllable product quality, reduced labor intensity, and operation. easy effect

Active Publication Date: 2016-09-14
ZHEJIANG ZHEBANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This operation has the problems of high labor intensity, long processing cycle, and insufficient recovery of products in the mother liquor

Method used

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  • A kind of preparation method of cefotiam hydrochloride
  • A kind of preparation method of cefotiam hydrochloride
  • A kind of preparation method of cefotiam hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] In a 500 ml clean and dry four-necked reaction flask, add 100 ml of acetonitrile, 25 g (0.092 mol) of 7-ACA, and 17.5 g (0.101 mol) of DMMT, stir and suspend, cool down to 0-5 °C in a cold bath, and drop in trifluoride 120 g of boron acetonitrile complex (mass concentration 19%, 0.209 mol) was dropped, and the temperature of the water bath was raised to 25-30° C. for 2 hours. After the reaction, 50 ml of purified water was added dropwise, and the pH of triethylamine was adjusted to 7.5 to obtain clarification. Transparent reaction solution, continue to cool down to -15°C, add 23.5 grams (0.110mol) of ATC.HCl in batches, keep the temperature for 1 hour, add 60 ml of dichloromethane and 40 grams of refined hydrochloric acid after the reaction, stir for 10 minutes and then let it stand Layering, the temperature of the layered water layer was raised to 15-20°C, 600 milliliters of acetone was added, stirred at 15-25°C for 2.5 hours, filtered, washed with acetone, and vacuum-d...

Embodiment 2

[0036]In a 500 ml clean and dry four-necked reaction flask, add 120 ml of acetonitrile, 25 g (0.092 mol) of 7-ACA, and 18.5 g (0.107 mol) of DMMT, stir and suspend, cool down to 0-5 °C in a cold bath, and drop in trifluoride 130 grams of boroacetonitrile complex (mass concentration 19%, 0.226mol) was dropped, and the water bath was heated to 25-30°C for 2 hours of reaction. After the reaction, 50 ml of purified water was added dropwise, and 10% sodium carbonate aqueous solution was adjusted to pH=8.2. To obtain a clear and transparent reaction solution, continue to cool down to -20°C, add 24.5 grams (0.115 mol) of ATC.HCl in batches, keep the temperature for 1 hour, add 60 ml of dichloromethane and 45 grams of refined hydrochloric acid after the reaction, and stir for 10 minutes Leave to stand for stratification, heat up the layered water layer to 15-20°C, add 650 milliliters of acetone, stir at 15-25°C for 2 hours, filter, wash with acetone, and dry in vacuo to obtain 47.5 gra...

Embodiment 3

[0038] Into a 500 ml clean and dry four-necked reaction flask, add 120 ml of acetonitrile, 25 g (0.092 mol) of 7-ACA, 18.0 g (0.104 mol) of DMMT, stir and suspend, cool down to 0-5 °C in a cold bath, and drop in trifluoride 110 g of boronacetonitrile complex (mass concentration 19%, 0.191 mol) is dropped, and the temperature of the water bath is raised to 25-30° C. for 2 hours. After the reaction is completed, 50 ml of purified water is added dropwise, and the pH of 10% potassium bicarbonate aqueous solution is adjusted to 8.5 , to obtain a clear and transparent reaction solution, continue to cool down to -23 ° C, add ATC.HCl 24.5 grams (0.115mol) in batches, keep the temperature for 1 hour, add 60 ml of dichloromethane and 45 grams of refined hydrochloric acid after the reaction, and stir for 10 minutes After standing still for stratification, the layered water layer was heated to 15-20°C, 630 ml of ethanol was added, stirred at 15-25°C for 3 hours, filtered, washed with ethan...

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Abstract

The invention discloses a method for preparing cefotiam hydrochloride. The method comprises the following steps: carrying out a condensation reaction by using 7-ACA and DMMT as raw materials, a boron trifluoride acetonitrile complex as a catalyst and acetonitrile as a reaction solvent to prepare a 7-ACMT reaction liquid; carrying out a 'one-pot' acylation on the reaction liquid with ATC.HCl after treatment of direct water addition and alkali regulation without separating and purifying 7-ACMT; extracting and separating organic impurities from the acylation reaction liquid by acidification and organic solvent, and adding hydrophilic solvent to separate high-purity cefotiam hydrochloride. According to the method, two reactions are carried out in one step, the equipment using efficiency and labor efficiency can be improved, the labor intensity is reduced, the product yield is improved on the premise of guaranteeing the product quality, and the production cost is reduced; all impurity separating operations are carried out after the acylation reaction, product loss caused by intermediate separating operation can be reduced, and the product purity can be guaranteed.

Description

technical field [0001] The invention belongs to the field of drug antibiotics, in particular to a preparation method of cefotiam hydrochloride. Background technique [0002] Cefotiam hydrochloride is the second generation of antibiotics for injection. Its hydrochloride and buffer sodium carbonate mixed preparation are used clinically. The structural formula is: [0003] [0004] The effect of cefotiam hydrochloride on Gram-positive bacteria is similar to that of cefazolin. It has good antibacterial effect on E. , Indole-positive proteus also has antibacterial effect. [0005] In the prior art, in the process of preparing cefotiam hydrochloride, 7-ACA (7-aminocephalosporanic acid) is used as raw material, and 2 intermediates ATC. HCl and 7-ACMT, and then carry out acylation reaction on the two to obtain cefotiam hydrochloride. [0006] [0007] Publication No. CN 101045733B and patent documents CN 101648961 all adopt similar processes. In the process of preparing 7-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/36C07D501/06
CPCC07D501/06C07D501/36
Inventor 胡宇超俞迪虎刘正文
Owner ZHEJIANG ZHEBANG PHARMA
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