A kind of preparation method of cefcapene hydrochloride

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...

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 its inorganic salt (usually sodium salt, potassium salt), but in the process of forming inorganic salt or its free acid, it needs to be added for subsequent esterification. When inorganic bases prepare inorganic salts, the cephem carboxylic acid core structure is easily destroyed in an inorganic strong alkaline environment, resulting in low yield and poor product quality

[0013] For amino deprotection reaction, strong acids such as boron trifluoride, trifluoroacetic acid and titanium tetrachloride are often used to deaminate protecting groups. , while removing the amino protecting group, there will be a cleavage reaction of the 3- and 4-position groups of the cephalosporin nuclei, which will easily produce by-products and impurities, which will affect the quality of the product

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