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Method for preparing cefotiam hexetil hydrochloride

A technology of cefotiam hydrochloride and cefotiam, which is applied in the field of preparation of cefotiam hydrochloride, can solve the problems of purification of the key intermediate cefotiam free base, poor stability of iodocarbonate, difficulty in obtaining purity of finished products, etc. , to ensure the quality and stability of the process, avoid the deterioration of intermediates, and reduce the effect of reaction steps

Inactive Publication Date: 2017-01-25
CHENGDU BRILLIANT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this process avoids the column chromatography, freeze-drying and other processes used in the original research process, the starting material iodocarbonate is poor in stability and expensive, and the process does not carry out the necessary crystallization and purification of the key intermediate cefotiam free base, and the finished product is difficult to obtain Ideal purity, quality difficult to control

Method used

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  • Method for preparing cefotiam hexetil hydrochloride
  • Method for preparing cefotiam hexetil hydrochloride
  • Method for preparing cefotiam hexetil hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] A kind of preparation method of cefotiam hydrochloride, concrete steps are as follows:

[0083] Step (1) Potassium salt formation reaction: add 0.50 kg of purified water, 0.47 kg of potassium bicarbonate, and 4.0 kg of butanone into a dry and clean reaction tank. Start stirring, raise the temperature to 20-25°C, then slowly add 1.0Kg of cefotiam hydrochloride (compound II), and keep the temperature of the material at 20-25°C after the addition, and stir for 0.5-1h. After the reaction is completed, control the temperature T≤50°C, pressure≤-0.09mMpa, and evaporate butanone under reduced pressure to obtain the potassium salt of cefotiam (compound IIa). The product in this step is not dried, and the yield is directly used in the next step according to 100% calculation.

[0084] Step (2) Esterification reaction: Add 4.5 kg of N,N-dimethylacetamide to the residue (theoretical yield 0.89 kg) of the potassium salt (compound IIa) of cefotiam in the above step (1), cool to -10 ...

Embodiment 2

[0088] A kind of preparation method of cefotiam hydrochloride, concrete steps are as follows:

[0089] Step (1) Potassium salt formation reaction: add 1.0 kg of purified water, 0.93 kg of potassium acetate, and 8.0 kg of acetone into a dry and clean reaction tank. Start stirring, raise the temperature to 25-30°C, then slowly add 1.0Kg of cefotiam hydrochloride (compound II), after the addition, keep the material temperature at 25-30°C, and stir for 0.5-1h. After the reaction is completed, the temperature is controlled at 20-25° C., the pressure is ≤-0.09 mMpa, and the acetone is evaporated under reduced pressure to obtain the potassium salt of cefotiam (compound IIa). The product in this step is not dried, and the yield is directly used in the next step according to 100% calculation.

[0090] Step (2) Esterification reaction: Add 8.9 kg of N,N-dimethylformamide to the residue (theoretical yield: 0.89 kg) of the potassium salt of cefotiam (compound IIa) in the above step (1), ...

Embodiment 3

[0094] A kind of preparation method of cefotiam hydrochloride, concrete steps are as follows:

[0095] Step (1) Potassium salt formation reaction: add 0.7 kg of purified water, 0.65 kg of potassium bicarbonate, and 6.0 kg of acetone into a dry and clean reaction tank. Start stirring, raise the temperature to 25-30°C, then slowly add 1.0Kg of cefotiam hydrochloride (compound II), after the addition, keep the material temperature at 25-30°C, and stir for 0.5-1h. After the reaction is completed, the temperature is controlled at 25-30° C., the pressure is ≤-0.09 mMpa, and the acetone is evaporated under reduced pressure to obtain the potassium salt of cefotiam (compound IIa). The product in this step is not dried, and the yield is directly used in the next step according to 100% calculation.

[0096]Step (2) Esterification reaction: Add 7.6 kg of N,N-dimethylacetamide to the residue (theoretical yield 0.89 kg) of the potassium salt (compound IIa) of cefotiam in the above step (1)...

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Abstract

The invention discloses a method for preparing cefotiam hexetil hydrochloride. The method comprises the following steps: preparing cefotiam hexetil free alkali through choride iodination and one-pot esterification method by taking stable raw materials such as cefotiam hexetil hydrochloride and chlorinated carbonate as initial materials; performing low-temperature concentration, devitrification and other processes, thereby obtaining the purified cefotiam hydrochloride free alkali; and finally, carrying out a hydrochloride formation reaction, thereby obtaining the cefotiam hexetil hydrochloride. The method has the characteristics of high reaction stability and controllability, low product impurity content, simplicity in industrialized production and the like.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of cefotiam hydrochloride. Background technique [0002] Cefotiam hydrochloride, Chinese name: (1R,S)-1-cyclohexyloxycarbonyloxyethyl-(6R,7R)-7-[2-(2-aminothiazole-4-ethyl)amido ]-3-[1-(2-Dimethylaminoethyl)-1H-tetrazole-5-thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0] Oct-2-ene-2-carboxylate dihydrochloride. Its chemical structure is as figure 1 Shown: [0003] Cefotiam hydrochloride is a second-generation cephalosporin antibiotic, which has a wide range of antibacterial effects on Gram-negative bacteria and positive bacteria, overcoming the lack of antibacterial effects of the first-generation cephalosporins on Gram-negative bacteria and the third-generation cephalosporins. Cephalosporins have a weak effect on Gram-positive bacteria, but have a significant effect. [0004] Cefotiam hydrochloride molecule contains lactam, carbonic acid ester...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/36C07D501/04
CPCC07D501/36C07D501/04
Inventor 崔阳文李英富黄浩喜黄俊杨超林平张平
Owner CHENGDU BRILLIANT PHARMA CO LTD
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