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Synthesis method of cefotiam hydrochloride

A technology of cefotiam hydrochloride and a synthesis method, applied in the field of drug synthesis, can solve the problems of low yield, difficult operation, difficult content assurance, etc., and achieve the effects of shortening the reaction time, speeding up the reaction rate, and increasing the purity of the product

Active Publication Date: 2019-03-26
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD +2
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  • Application Information

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Problems solved by technology

The patent with the publication number CN101096373A discloses a method that first reacts formylamino-thiazolyl-4-acetic acid and thionyl chloride to prepare formylamino-thiazolyl-4-acetyl chloride, and then condenses it with 7-ACMT. method, the production process of this method is not easy to control, and the crude product obtained needs to be refined many times to meet the corresponding quality requirements
The patent with the publication number CN101648961A discloses a reaction of aminothiazole acetic acid hydrochloride (ATA·HCl) with an acylating agent to prepare acid chloride hydrochloride (ATC·HCl), and further synthesis to obtain cefotiam hydrochloride The method of salt, for the first time adopts liquid chlorinating agent to prepare cefotiam hydrochloride, this method is more suitable for industrialization, the disadvantage is that the reaction temperature is relatively low, and the synthesis reaction time of acid chloride is longer
The patent of CN102850381A also adopts this method, the yields of ATC·HCl and cefotiam hydrochloride are not high, the reaction time is also long, and the maximum impurity of the final product reaches 0.28%
However, it is necessary to prepare unstable acid chlorides in advance, which brings difficulties to the operation. In addition, the one-pot method contains intermediate reaction liquid and crystallization mother liquid. Even if the purity of the product is qualified, the content is difficult to guarantee, and the controllability of product quality is low.

Method used

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  • Synthesis method of cefotiam hydrochloride
  • Synthesis method of cefotiam hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] (1) Add 60mL of dimethyl carbonate and 7.06g of citric acid to a 500mL three-necked flask, add 6.36g of DMMT while stirring, add 10.00g of 7-ACA, and slowly add boron trifluoride-dimethyl carbonate complex 34.82 g, control the temperature at 20-30°C, and monitor the reaction by HPLC after 1h. Add 1.28g of sodium dithionite, stir for 10min, transfer to water, add 80mL of isopropanol, slowly add concentrated ammonia water dropwise to adjust the pH to 3.0, and control the dropping time After 30-60 minutes, cool down to 0-10°C to crystallize for 1 hour. Suction filtration yielded 18.82 g of 7-ACMT wet product, with a purity of 99.4% by HPLC and a maximum of 0.08% impurity.

[0033] (2) Add 150mL of dichloromethane to a 500mL three-necked flask, add 20.00g of aminothiazole acetic acid hydrochloride, cool down to -5~5°C, add 31.62g of phosphorus oxychloride, and slowly add N,N-diisopropyl Add 13.32 g of ethylamine, raise the temperature to 10-20° C. after adding, add 2.00 g ...

Embodiment 2

[0036] (1) Add 60mL of dimethyl carbonate and 9.86g of 2-hydroxysuccinic acid into a 500mL three-necked flask, add 6.36g of DMMT while stirring, add 10.00g of 7-ACA, and slowly add boron trifluoride-dimethyl carbonate complex Compound 40.62g, temperature control 20~30℃, react after 1h, HPLC monitors the reaction is over, add sodium dithionite 2.56g, stir for 10min and transfer to water, add isopropanol 80mL, slowly add concentrated ammonia water to adjust the pH to 4.5, control The dropping time is 30-60 minutes, and the temperature is lowered to 0-10°C for 1 hour of crystallization. Suction filtration yielded 18.65 g of 7-ACMT wet product, with a purity of 98.9% by HPLC and a maximum of 0.09% impurity.

[0037] (2) Add 150mL of dichloromethane to a 500mL three-necked flask, add 20.00g of aminothiazole acetic acid hydrochloride, cool down to -5~5°C, add 31.62g of phosphorus oxychloride, and slowly add N,N-dimethyl 7.53g of formamide, after the addition, the temperature was ra...

Embodiment 3

[0040] (1) Add 60mL of dimethyl carbonate and 6.62g of acetic acid into a 500mL three-necked flask, add 6.36g of DMMT while stirring, add 10.00g of 7-ACA, and slowly add 46.42g of boron trifluoride-dimethyl carbonate complex, Control the temperature at 20-30°C and react. After 1 hour, HPLC monitors that the reaction is over. Add 0.64g of sodium dithionite, stir for 10 minutes, transfer to water, add 80mL of isopropanol, slowly add concentrated ammonia water to adjust the pH to 4.0, and control the dropping time for 30~ After 60 minutes, the temperature was lowered to 0-10°C for 1 hour of crystallization. Suction filtration yielded 18.82 g of 7-ACMT wet product, with a purity of 99.4% by HPLC and a maximum of 0.08% impurity.

[0041] (2) Add 150mL of dichloromethane to a 500mL three-necked flask, add 20.00g of aminothiazole acetic acid hydrochloride, cool down to -5~5°C, add 31.62g of phosphorus oxychloride, and slowly add N,N-dimethyl 8.97 g of acetamide was added. After the ...

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Abstract

The invention belongs to the technical field of medicines and discloses a synthesis method of cefotiam hydrochloride. The synthesis method comprises the steps: carrying out a condensation reaction ina mixed solvent by taking 7-aminocephalosporanic acid and 1-[2-(dimethylamino)ethyl]-1H-tetrazole-5-thiol as raw materials and a high-concentration boron trifluoride and dimethyl carbonate complexingcompound as a catalyst to prepare a three-position intermediate; and then, reacting the three-position intermediate with (2-aminothiazole-4-yl)acetyl chloride to obtain cefotiam hydrochloride. The method provided by the invention is stable and soft in reaction and few in byproducts, and the yield and purity of the produced cefotiam hydrochloride are relatively ideal.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a method for synthesizing cefotiam hydrochloride Background technique [0002] Cefotiam hydrochloride is a second-generation semi-synthetic cephalosporin developed by Takeda Corporation of Japan and first listed in Japan in 1981. Existing literature is all with 7-aminocephalosporanic acid (7-ACA) as raw material, its 3 and 1-(2-dimethylaminoethyl)-5-mercaptotetrazole (DMMT) in sodium bicarbonate or 3-[[[(N,N)-dimethyl-aminoethyl-tetrazol-1-yl]sulfur]methyl can be obtained by condensation of dichlorophosphoric acid, trichloroacetic acid, boron trifluoride, etc. ]-8-Oxo-5-thia-1H azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (7-ACMT). This method technology is very mature, but the total yield and purity of the product are not ideal. The patent with the publication number CN06967091A discloses a method for preparing 7-ACTM by using methanesulfonic acid instead of boron trifluoride as...

Claims

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Application Information

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IPC IPC(8): C07D501/36C07D501/06
CPCC07D501/06C07D501/36
Inventor 单良张冬冬薛莲
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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