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Preparation method of cefozopran hydrochloride

A compound and phenol technology, applied in the synthesis field of cefazolam hydrochloride, can solve problems such as troublesome post-processing, unfavorable for industrialized production, etc., and achieve the effect of improving the industrialization level of the process

Inactive Publication Date: 2018-09-28
HAINAN HAILING CHEMIPHARMA CORP
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Patent CN102040616 describes a synthesis method of cefozopran hydrochloride, which uses GCLE as the starting material to replace the 3-position iodine and then condenses with imidazopyridazine to obtain GIMPE, and GIMPE is deprotected by phenol and enzymatically hydrolyzed to obtain 7- ACP and 7-ACP are condensed with azole blue active ester to obtain azole blue base, and then salify with hydrochloric acid to obtain cefazolam hydrochloride. The post-processing of this method is cumbersome and unfavorable for industrialized production. The route is as follows:

Method used

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  • Preparation method of cefozopran hydrochloride
  • Preparation method of cefozopran hydrochloride
  • Preparation method of cefozopran hydrochloride

Examples

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Embodiment 1

[0031] The synthesis of embodiment 1, intermediate GIMPE (formula 3)

[0032] Add 1125g of acetone into a clean 5L reactor, add 250g of GCLE (formula 2) and 92.5g of anhydrous sodium iodide under stirring, keep the temperature at 30±2°C for 1.5 to 2 hours, and put in imidazopyridazine (formula 6 ) 104.0g, add 125g of acetone to wash the feeding port, keep the temperature at 35-45°C for 5 hours, add 1975g of isopropanol, complete the feeding in about 30 minutes, cool down at 10-15°C and stir for 30 minutes, continue to cool down to 0-15°C Stir at 5°C for 1-1.5 hours, filter, wash the filter cake with 770g isopropanol / 470g acetone, and dry under vacuum at 40±2°C overnight to obtain a yellow-green solid GIMPE (Formula 3), with a molar yield of 90.0-95.0%, and an HPLC purity greater than 90.0%, moisture less than 1.0%.

Embodiment 2

[0033] Embodiment 2, the synthesis of intermediate 7-ACP (formula 4).

[0034] In a dry and clean 5L reactor, add GIMPE (formula 3) 360g, phenol (preheated) 1.5kg, water bath temperature control inner temperature 50-55°C, stir for 11-12 hours, cool down to 35-40°C after the reaction , quickly drop a mixture of 580g of isopropyl ether and 320g of isopropanol, the addition is completed in 10 to 15 minutes, and the temperature is controlled at 35 to 40°C and stirred for 30 minutes. Control the temperature at 35-40°C and add 2325g of methyl isobutyl ketone dropwise quickly within 30 minutes, keep stirring for 1-1.5 hours after the addition, filter and wash with methyl isobutyl ketone.

[0035] Add 2.25kg of water, 72g of sodium bicarbonate and 480g of acetone into a 5L beaker. Add 30g of activated carbon to decolorize for 30 minutes, filter, wash with a mixture of 600g of purified water and 97.5g of acetone, control the temperature at 25-35°C, add 90g of immobilized penicillin ac...

Embodiment 3

[0036] Embodiment 3, the synthesis of cefzolan base crude product (formula 5).

[0037] Add 600g of methanol and 90g of 7-ACP to a 1500ml three-necked flask, add dropwise a mixture of 33g of triethylamine and 68g of methanol at 5-10°C, stir until clear after the addition, add 122g of active ester, and control the temperature at 15-10°C. React at 25°C for 8-10 hours. After the reaction, adjust the pH to 6.7-7.0 with glacial acetic acid, distill under reduced pressure in a water bath at 30-35°C until viscous, add 3360g of acetone, stir for 1-1.5 hours, filter in stages, and wash with acetone The filter cake was vacuum-dried twice at 40° C. to obtain a crude product of cefzoram base (Formula 5), ​​with a purity greater than 95% and a molar yield of 60.0-70.0%.

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Abstract

The invention discloses a synthesis method of cefozopran hydrochloride. GCLE is used as an initial raw material, GCLE and imidazo pyridazine are condensed in the presence of iodide to obtain a GIMPE intermediate,7-ACP is obtained through hydrolysis of phenol and hydrolysis of immobilized penicillin acylase, the 7-ACP and cefozopran active ester are condensed to obtain a cefozopran alkali crude product, and the crude product is recrystallized through DMF and then salified with hydrochloric acid to obtain cefozopran hydrochloride. The method is easy to operate, the conditions are easily controlled, the industrial production is facilitated, and the method has wide application prospects.

Description

technical field [0001] The present invention relates to a kind of synthetic method of cefozopram hydrochloride. Background technique [0002] Cefazolam hydrochloride is the fourth-generation cephalosporin first researched and developed by Takeda Corporation of Japan. It was first launched in Japan in 1995 under the trade name of Firstcin. The route of compound patent US4864022 is to use 7-ACP as the starting material, under the action of phosphorus pentachloride and 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxy Glycine is condensed to generate Zolan base, and then salified with hydrochloric acid to obtain Cefozopran Hydrochloride, the route is as follows: [0003] [0004] In this route, the quality of the starting material 7-ACP varies greatly, and there is no large-scale production in China. Due to the low activity of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetic acid in the condensation reaction, the reaction selectivity is poor, a large amount of impurities ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P35/00C07D519/06
CPCC07D519/06C12P35/00
Inventor 韩勇路国荣蔡亲
Owner HAINAN HAILING CHEMIPHARMA CORP
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