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Preparation method of cefotiam hydrochloride

A technology of cefotiam hydrochloride and base thiazole acetic acid, which is applied in the field of antibiotic drug synthesis and achieves the effects of high purity and yield, mild reaction conditions and low cost

Active Publication Date: 2015-07-01
YIYUAN XINQUAN CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is no relevant report on the N-acylation reaction of formamidothiazole acetic acid to prepare an active ester with easy storage and stable physical properties and the 7-position of the cephalosporin nucleus

Method used

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  • Preparation method of cefotiam hydrochloride
  • Preparation method of cefotiam hydrochloride
  • Preparation method of cefotiam hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Add 30mL acetone, 20mL CH 2 Cl 2 , stirred at 15°C for 10 min, added 11 g of formamidothiazole acetic acid, stirred and added 4.5 mL of triethylamine, stirred for 15 min, added 22 g of dithiodibenzothiazole at room temperature, stirred for 10 min, slowly added 20 mL of Triethyl phosphate was kept at 28°C for 1 hour, cooled to 0°C, suction filtered, washed, and dried to obtain 17.6g of active ester A, the content of which was detected by high performance liquid chromatography was 99.5%.

[0029] Add 20g ACMT and 140mL dichloromethane into a 500mL three-necked bottle, stir and add 15.2g active ester A, cool down to 8°C, add 5mL ethanol, add 20mL triethylamine dropwise, time the reaction for 3.5h after the dropwise addition, and add Add 5mL of ethanol twice, (the ADMT residual is 0.48% as detected by HPLC), add 45mL of aqueous solution (containing 0.5g of EDTA, 0.5g of sodium bisulfite) and let stand, and take the water layer. Add 8mL of concentrated hydrochloric acid to...

Embodiment 2

[0031] Add 40mL acetone, 20mL CH 2 Cl 2 , Stir at 15°C for 15 min, add 11 g of formamidothiazole acetic acid, stir and add triethylamine, stir for 15 min, add 30 g of dithiodibenzothiazole at room temperature, slowly add 25 mL of triethyl phosphite dropwise with an acid burette, Keep warm at 5°C for 3 hours, cool down to 0°C, filter with suction, wash the material, and dry to obtain 17.2g of active ester A, the content detected by high performance liquid chromatography is 99.2%.

[0032] Add 20g ACMT and 140mL dichloroethane into a 500mL three-necked bottle, stir and add 18g active ester A, cool down to 15°C, add 5mL ethanol, drop 16mL triethylamine, and react for 2 hours after the dropwise addition, adding 5mL every 30min Ethanol was added twice, (the residual ACMT detected by HPLC was 0.5%), 45mL of aqueous solution (containing 0.5g of EDTA, 0.5g of sodium hydrosulfite) was added and allowed to stand, and the water layer was taken. Add 9mL of concentrated hydrochloric acid...

Embodiment 3

[0034] Add 20mL acetone, 20mL CH 2 Cl 2 , stirred at 15°C for 10 min, added 11 g of formamidothiazole acetic acid, stirred and added 0.5 g of sodium bicarbonate, stirred for 15 min, added 20 g of dithiodibenzothiazole at room temperature, stirred for 10 min, slowly added dropwise 30 mL of sodium bicarbonate with an acid burette Triethyl phosphate was kept at 40°C for 1.5 hours, cooled to 0°C, suction filtered, washed, and dried to obtain 17.9g of active ester A, the content of which was detected by high performance liquid chromatography was 99.0%.

[0035] Add 20g ACMT and 140mL tetrahydrofuran into a 500mL three-necked bottle, stir and add 22g of active ester A, cool down to 20°C, add 5mL of ethanol, dropwise add 24mL of 15% ammonia water, and react for 4 hours after the dropwise addition, and add 5mL of ethanol every 30min for a total of Twice, (the residual ACMT detected by HPLC is 0.5%), add 45mL of aqueous solution (containing 0.5g of EDTA, 0.5g of sodium bisulfite) and ...

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Abstract

The invention belongs to the technical field of antibiotic drug synthesis, and particularly relates to a preparation method of cefotiam hydrochloride. The preparation method comprises the following steps of: adding formamido thiazole acetic acid to an organic solvent, adding base and dithio-bisbenzothiazole, stirring, then adding a catalyst, and carrying out condensation reaction, thus obtaining an active ester A, wherein the catalyst is triethyl phosphate; dissolving 7-ACMT in an alkali liquor of the organic solvent, adding the active ester A for carrying out N acylation reaction, adding a water solution after reaction is ended, getting a water layer, adding hydrochloric acid for hydrolysis, and dropwise adding a hydrophilic solvent to separate out the cefotiam hydrochloride. The preparation method has the advantages that reaction conditions are mild, strict anhydrous and anaerobic conditions are not needed, the cost is low, the synthesis process is simple, and the purity and the yield are high.

Description

technical field [0001] The invention belongs to the technical field of antibiotic drug synthesis, and in particular relates to a preparation method of cefotiam hydrochloride. Background technique [0002] Cefotiam hydrochloride is the second generation of antibiotics for injection. It was first developed by Takeda Pharmaceutical Co., Ltd. in Japan in 1981 and launched in Japan. The chemical name of cefotiam hydrochloride is (6R-trans)-7-[[(2-amino-4-thiazoleacetic acid)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-carboxylic acid di Hydrochloride, the structural formula is: [0003] [0004] The effect of cefotiam hydrochloride on Gram-positive bacteria is similar to that of cefazolin. It has strong antibacterial effect on E. , Indole-positive proteus effect. Cefotiam dihydrochloride, which is stable in clinical use for injection, has a large domestic demand for the treatment of infections cau...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/36C07D501/04C07D501/06
Inventor 李学平杜明霞周浩
Owner YIYUAN XINQUAN CHEM
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