Preparation method of cefcapene diisopropylamine salt

A technology of diisopropylamine salt and cefcapine, which is applied in the field of cephalosporin antibiotics, can solve the problems of unfavorable industrial production, high cost, and difficulty in conforming to pharmaceutical intermediates, and achieves the effects of being convenient for large-scale production and easy to operate.

Inactive Publication Date: 2014-10-01
WEIHAI HAOTONG MEDICAL SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

CN102775425 provides a one-pot preparation method of cefcapene diisopropylamine salt, but the purity of the intermediate is not reported in the patent literature, and due to the one-pot reaction, a large amount of by-products are caused, which is difficult to meet the requirements of pharmaceutical intermediates requirements
Literature (J.-A. Jiang, et.al, Synthesis 2012, 44, 207–214) also reported the preparation method of this compound, using a large number of di Isopropylamine and methanesulfonyl chloride, although the reaction is relatively complete, the cost is higher, which is unfavorable for suitability for industrialized production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Take 29.8g (0.10mol) of raw material 1 in a reaction flask, add 250ml of dichloromethane and 10.1g (0.10mol) of triethylamine to dissolve, cool to -10°C, slowly add 13.1g (0.11mol) of thionyl chloride dropwise Reagents, after stirring for 1 hour at this temperature. Slowly add 26.7g (0.10mol) of hydrochloride of 7-HACA, 20ml of methanol and 22.8ml (20.2g, 0.2mol) of triethylamine and 1.22g (0.01mol) of 4-dimethylamino in the solution after the reaction For a solution composed of pyridine, keep the reaction solution at -10°C and continue stirring for 2 hours, filter, collect the filtrate, and adjust the pH of the filtrate to 8 with 5% sodium hydroxide solution. The aqueous layer was separated, decolorized, and then 1mol / L hydrochloric acid was added dropwise to pH=2, filtered, washed, and vacuum-dried to obtain 47.1g of intermediate product 5 with a yield of 92.1% and a content of 95.2% by HPLC normalization method.

[0023] Dissolve 25.5g (0.05mol) of the obtained inte...

Embodiment 2

[0025] Take 298g (1.0mol) of raw material 1 in a reaction flask, add 2500ml of dichloromethane and 101g (1.0mol) of triethylamine to dissolve, cool to -10°C, slowly add 131g (1.1mol) of thionyl chloride reagent dropwise, in After stirring at this temperature for 1 hour. Slowly add 267g (1.0mol) of 7-HACA hydrochloride, 200ml of methanol, 228ml (202g, 2.0mol) of triethylamine and 12.2g (0.1mol) of 4-dimethylaminopyridine to the reacted solution solution, keep the reaction solution at -10°C and continue to stir for 3 hours, filter, collect the filtrate, and adjust the pH of the filtrate to 8 with 5% sodium hydroxide solution. The aqueous layer was separated, decolorized, and then 1mol / L hydrochloric acid was added dropwise to pH=2, filtered, washed, and vacuum-dried to obtain 462g of intermediate product 5, with a yield of 90.6% and a content of 94.7% by HPLC normalization method.

[0026] Dissolve 255g (0.5mol) of the obtained intermediate product 5 in 2000ml of dichloromethan...

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Abstract

The invention relates to a preparation method of cefcapene diisopropylamine salt. The preparation method comprises the following steps: (1) obtaining acylate 3 by using cefcapene side chain acid 2 in the presence of an acylation reagent namely SOCl2 and an acid-binding agent namely triethylamine; (2) obtaining a condensation product 5 by using acylate 3 and a 7-HACA raw material 4 in the presence of triethylamine and a catalyst namely 4-dimethylaminopyridine; (3) enabling the condensation product 5 to react with chlorosulfonic acid isocyanate to obtain a 3-bit aminoacyl ester compound 6; (4) performing salt formation on the compound 6 and diisopropylamine to obtain cefcapene diisopropylamine salt 1. According to the preparation method disclosed by the invention, thionyl chloride is used as the acylation reagent, and triethylamine is used as the acid-binding agent so as to reduce the cost; 4-dimethylaminopyridine with the catalyst amount is added in the step (2) to ensure that the reaction is performed more completely and the reaction time is shortened; the preparation method is simple and convenient in whole route operation, and is convenient for large-scale production.

Description

technical field [0001] The invention relates to a preparation method of cefcapene diisopropylamine salt, a key intermediate of cefcapene proxetil, and belongs to the technical field of cephalosporin antibiotic drugs. Background technique [0002] Cefcapene pivoxil, chemical name: 7-[(Z)-2-(2-aminothiazol-4-yl)-2-pentenamido]-3-carbamoyloxymethyl-3-cephem- 4-Carboxylic acid pivaloyloxymethyl ester, CAS number 105889-45-0. Cefcapene is a new type of cephalosporin antibiotic developed by Shionogi Co., Ltd. of Japan. It was first launched in 1997 under the trade name of Flomox. It is the third generation of oral cephalosporin antibiotic. Mainly suitable for respiratory infections caused by sensitive bacteria such as pneumonia, bronchitis, pharyngitis, tonsillitis, etc.; otitis media; sinusitis; urinary tract infections such as gonorrhea, pyelonephritis, cystitis; skin and skin tissue infections; biliary tract infections, etc. . [0003] Cefcapene (Cefcapene) is an intermediat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/34C07D501/04C07C211/06C07C209/00
CPCC07D501/34C07D501/04
Inventor 姚辉涛刘凡磊
Owner WEIHAI HAOTONG MEDICAL SCI & TECH
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