Preparation method for cefcapene pivoxil hydrochloride

A technology of cefcapene hydrochloride and carboxylic acid, applied in the direction of organic chemistry, etc., can solve the problems of cefcapene carboxylic acid core structure damage, easy production of by-products and impurities, affecting yield and quality, etc., to avoid ring opening Effect of destruction, reduction of dissolution time, improvement of yield and purity

Active Publication Date: 2015-12-09
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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  • Abstract
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AI Technical Summary

Problems solved by technology

[0011] There are relatively few manufacturers of 7-DACA in China and the quality is unstable. 7-DACA is easy to form internal salts, so it has poor solubility in organic solvents and is difficult to participate in chemical reactions. At the same time, 7-DACA is unstable to alkali and heat. , when the pH is greater than 9 or the temperature exceeds 40°C, it will decompose, and the hydroxyl group of the 3-position hydroxymethyl group will dehydrate with the 4-position carboxyl group to form a lactone, and even a series of side effects such as the migration of the 3-4-position double bond of the main ring will occur. reaction, thereby affecting its yield and quality
[0012] In the published literature, the intermediate of cefcapene acid mostly exists in the form of free acid or...

Method used

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  • Preparation method for cefcapene pivoxil hydrochloride
  • Preparation method for cefcapene pivoxil hydrochloride
  • Preparation method for cefcapene pivoxil hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0041] Embodiment 1: the synthesis of 7-amino-3-hydroxymethyl cephalosporanic acid (7-DACA, compound 6)

[0042] Weigh 27.2g (0.1mol) of 7-ACA, add 50mL methanol and 50mL water, add 3.0g tetra-n-butylammonium chloride and stir to dissolve at -5-5°C, and add 2mol / L hydrogen dropwise at this temperature Sodium oxide solution 105mL, after dripping, keep the temperature and continue to stir for 0.5-1 hour, then add 30% hydrochloric acid to adjust the pH to neutral, precipitate a solid, suction filter, wash with absolute ethanol, dry to obtain 20.7g of off-white solid, and collect The yield was 90.1%, the HPLC purity analysis was 97.35% (area normalization method), and the lactone impurity was 0.33%.

Embodiment 2

[0043] Embodiment 2: the synthesis of 7-amino-3-hydroxymethyl cephalosporanic acid (7-DACA, compound 6)

[0044] Weigh 27.2g (0.1mol) of 7-ACA, add 50mL methanol and 50mL water, add 1.5g tetra-n-butylammonium chloride and stir to dissolve at -5-5°C, and add 2mol / L hydrogen dropwise at this temperature Sodium oxide solution 105mL, after dripping, keep the temperature and continue to stir for 0.5-1 hour, then add 30% hydrochloric acid to adjust the pH to neutral, precipitate a solid, suction filter, wash with absolute ethanol, dry to obtain 19.6g of off-white solid, and collect The yield was 85.2%, the HPLC purity analysis was 95.58% (area normalization method), and the lactone impurity was 0.56%.

Embodiment 3

[0045] Embodiment 3: the synthesis of 7-amino-3-hydroxymethyl cephalosporanic acid (7-DACA, compound 6)

[0046] Weigh 27.2g (0.1mol) of 7-ACA, add 50mL of methanol and 50mL of water, add 1.5g of benzyltrimethylammonium chloride and stir to dissolve at -5-5°C, and add 2mol / L of Sodium hydroxide solution 105mL, after dropping, keep the temperature and continue to stir for 0.5-1 hour, then add 30% hydrochloric acid to adjust the pH to neutral, a solid is precipitated, suction filtered, washed with absolute ethanol, and dried to obtain 18.6g of off-white solid, Yield 80.5%, HPLC purity analysis 93.8% (area normalization method), lactone impurity 0.88%.

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Abstract

The invention belongs to the technical field of antibiotic synthesis, and relates to a preparation method for cefcapene pivoxil hydrochloride. The preparation method comprises the following steps: (1) reacting 7-ACA with sodium hydroxide in a solution with quaternary ammonium salt under the temperature of (-5 DEG C)-5 DEG C to generate 7-DACA; (2) adding (cefcapene pivoxil side chain acid, compound 5) into the solution containing 7-DACA, diisopropylamine and phenyltriethylammonium chloride under the temperature of 0-10 DEG C to react with a methylsufonyl chloride reaction solution under the temperature of (-15 DEG C)-0 DEG C to obtain a compound (4); reacting the compound 4 and chlorosulfonyl isocyanate to obtain a compound (3); further reacting the compound (3) with iodomethyl pivalate to obtain a compound (2); removing the protection base of the compound (2) in a hydrochloric acid methanol solution to obtain the cefcapene pivoxil hydrochloride (compound 1).

Description

technical field [0001] The invention belongs to the technical field of antibiotic synthesis, and relates to a preparation method of cefcapene hydrochloride. Background technique [0002] Cefcapene pivoxil is a new type of cephalosporin antibiotic developed by Shionogi Co., Ltd. in Japan. It was first listed under the trade name of Flomox in 1997. It is the third generation of oral cephalosporin antibiotic. + The antibacterial activity of bacteria is the same as that of cefotiam and cefaclor; the activity against Streptococcus pneumoniae is better than that of Cefaclor and equivalent to that of Cefditoren; the activity against Streptococcus pneumoniae resistant to penicillin (including moderate drug resistance) very strong. to G - Among the bacteria, Citrobacter freundii, Enterobacter cloacae, Providencia rettii, Branhamella catarrhalis, and Serratia marcescens were stronger than cefditoren and cefotiam. The activity against Proteus, Haemophilus influenzae, Morganella morg...

Claims

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Application Information

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IPC IPC(8): C07D501/34C07D501/06
CPCC07D501/06C07D501/34
Inventor 王金星侯孝龙徐勤艳
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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