Novel preparation technology of cefotiam hexetil hydrochloride

A cefotiam pivoxil and a preparation process technology, applied in the direction of organic chemistry and the like, can solve problems such as being unsuitable for industrialized large-scale production, poor reproducibility of product qualification, corrosion of equipment and environment, etc., achieving simple and fast post-processing and salt-forming processes, The preparation method is simple and easy to implement, and the damage to the equipment and the environment is reduced.

Inactive Publication Date: 2013-09-11
迈洋致达(北京)科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012]1) The yield is lower, making the production cost higher
[0013]2) The post-reaction treatment repeatedly adjusts the acidity and base, and the number of extractions is large, resulting in relatively high impurity content (greater than the standard specified in the Japanese Pharmacopoeia), darker chroma, and the product Poor pass reproducibility
[0014]3) Some post-processing requires column chromatography purification, which makes the production process complicated and not suitable for large-scale industrial production
[0015]4) The preparation process produces irritating acetic acid, which causes great corrosion and pollution to equipment and the environment

Method used

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  • Novel preparation technology of cefotiam hexetil hydrochloride
  • Novel preparation technology of cefotiam hexetil hydrochloride
  • Novel preparation technology of cefotiam hexetil hydrochloride

Examples

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Embodiment 1

[0052] Embodiment 1 Preparation of high-purity cefotiam axetil hydrochloride

[0053] The specific steps of the preparation method of the present embodiment cefotamate hydrochloride are as follows:

[0054] 1) Add 300mL of acetonitrile and 38.8g of anhydrous sodium iodide into a 500mL reaction flask, stir to dissolve, add 38.2g of 1-chloroethylcyclohexyl carbonate, replace with nitrogen three times, control the temperature at 55~60°C, and react in the dark for 1h. Concentrate under reduced pressure to dryness after the reaction, add 200mL ethyl acetate and 280mL water to the residue, extract, collect the organic layer, add 160mLNa 2 S 2 o 3 (5%) washing, the organic phase was collected, and the solvent was evaporated to dryness under reduced pressure to obtain 44g brownish-yellow oily matter which was 1-iodoethylcyclohexyl carbonate.

[0055] 2) Add 260mL DMF and 48g cefotiam hydrochloride into a 2000mL reaction flask, stir to dissolve at room temperature, cool down to -5~0...

Embodiment ２

[0057] Example 2 Preparation of high-purity cefotiam axetil hydrochloride

[0058] The specific steps of the preparation method of cefotamate hydrochloride in the present embodiment are as follows:

[0059] 1) Add 600mL of acetone and 78g of anhydrous sodium iodide into a 1000mL reaction flask, stir to dissolve, add 76.5g of 1-chloroethylcyclohexyl carbonate, replace with nitrogen three times, control the temperature at 55~60°C, and react in the dark for 1h. Concentrate under reduced pressure to dryness after the reaction, add 400mL ethyl acetate and 550mL water to the residue, extract, collect the organic layer, add 350mLNa 2 S 2 o 3 (5%) was washed, the organic phase was collected, and the solvent was evaporated to dryness under reduced pressure to obtain 84 g of 1-iodoethylcyclohexyl carbonate of brown oil.

[0060] 2) Add 540mL DMF and 100g cefotiam hydrochloride into a 5000mL reaction flask, stir to dissolve at room temperature, cool down to -5~0°C, add 37.2g micronize...

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Abstract

The invention provides a novel preparation technology of cefotiam hexetil hydrochloride represented by formula (I). The cefotiam hexetil hydrochloride is produced by following steps: cefotiam hydrochloride is taken as a raw material; the cefotiam hydrochloride together with an iodo-substitued substance (1-Iodoethyl cyclohexyl carbonate) are subjected to esterification reaction to obtain cefotiam hexetil in the presence of micronized carbonate; an organic solvent is added after completion of the reaction, and then insoluble alkali and salts are removed by filtration; the solution is extracted, subjected to salt forming reaction and refined, and then the cefotiam hexetil hydrochloride with high purity is obtained. The preparation technology of the invention is simple to operate. The cefotiam does not need to be pre-treated to be potassium or sodium salt and be separated. Especially extraction, crystallization and pulping are employed in the post-processing purification of the product, so that the product with high yield and purity can be obtained without purification by chromatographic columns, repeated adjustment by acid and alkali, or freeze drying. The yield of the technology is about 60%, the cost is low, and the technology is suitable for industrialized production with large scale. [0]

Description

technical field [0001] The invention belongs to the field of drug antibiotics and relates to drug synthesis technology, in particular to a new process for preparing cefotamate hydrochloride. Background technique [0002] Cefotiam hexetil (Cefotiam hexetil, formula II), chemical name: (1RS)-1-(cyclohexyloxycarbonyloxyethyl)(6R,7R)-7-[[(2-amino-4- Thiazolyl)acetyl]amino]-3-[[[1-[(2-(dimethylamino)ethyl]-1H-tetrazol-5-yl]thiomethyl]-8-oxo-5 -Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate. Cefotiam pivoxil itself is unstable, easy to degrade and isomerize, so its salt is generally used The form of acid salt. This strain was developed by Japan's Takeda (Takeda) company and was launched in Japan in 1990 under the trade name Pansporin ? T. Launched in France in 1994, the trade name is TAKETIAM ? (Takeda Corporation) and TEXODIL ? (Gassenne company), and listed in Germany at the same time, the trade name is SPIZEF ? Oral (a Takeda company), which was later launched in a num...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/36C07D501/04
Inventor 颜文革漆新国孟永刚张典鹏刘念
Owner 迈洋致达(北京)科技有限公司
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