Method for preparing high-purity cefdinir antibiotic 7-side chain synthesis critical material

Abstract

The invention discloses a method for preparing a high-purity cefdinir antibiotic 7-side chain synthesis critical material. The method comprises the following steps of: by taking demethylated ethyl 2--2-methoxyiminoacetate and triphenylcarbinol as raw materials, taking a carbonic ester solvent as a solvent, taking a dimethyl carbonate boron trifluoride solid complex as a catalyst, preparing (Z)-2-(2-amino-4-thiazolyl)-2-benzyltrimethylimineethyl acetate; adding an inorganic alkali solution into an alcohol solvent to carry out a hydrolysis reaction, acidizing the solution by utilizing inorganic acid after the hydrolysis reaction is finished, and preparing (Z)-2-(2-amino-4-thiazolyl)-2-benzyltrimethylimineacetic acid; by taking the (Z)-2-(2-amino-4-thiazolyl)-2-benzyltrimethylimineacetic acid and DM as raw materials and a pyridines compound as a catalyst in a halogenated alkane solvent, dripping mixed solution of triethyl phosphate and triethylamine, and preparing the MEAT. The reaction process is easy to operate, and the used solvent is low in toxicity, environment-friendly, easy to recycle, high in yield, low in cost and suitable for industrialization.

Description

technical field [0001] The invention relates to the technical field of preparation of pharmaceutical intermediates, in particular to MEAT (chemical name: (Z)-thiobenzothiazole-2-(2-amino- 4-thiazolyl)-2-trityloxy imine acetate) preparation method. Background technique [0002] Cefdinir is an oral third-generation cephalosporin with a broad antibacterial spectrum. Its antibacterial effect on Staphylococcus and Streptococcus is similar to that of cefpodoxime axetil, and its antibacterial activity on Enterobacteriaceae is 2-4 times lower than that of cefixime. . Enterococcus, Pseudomonas aeruginosa and other Pseudomonas, Acinetobacter, etc. are mostly resistant to this product. [0003] At present, there are mainly 2 routes for the preparation of synthetic cefdinir: (1) 7-amino-3-vinyl cephalosporanic acid (7-AVCA) and (Z)-thiobenzothiazole-2-(2- Amino-4-thiazolyl)-2-trityloxyimine acetate (MEAT) (see chemical structure 1) is condensed, and the trityl protection is removed b...

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Problems solved by technology

[0028] The defects of this method are found through research as follows: 1. Add water to dilute the solid after the solvent is concentrated in the treatment process after the O-alkylation, and the reaction system boron trifluoride will produce a large amount of exothermic and hydrofluoric acid when it encounters water decomposition, and the intermediate O -The trityl alkylation product is subjected to heating and H+acidity to cause hydrolysis to remove the O-trityl protecting agent, and produce more unknown impurities; 2. The potassium salt (or sodium salt) of compound 2 is slightly soluble For water, acetic acid is used as an acidifying agent in the acidification process, and the PK value of the product acid is not enough, which will lead to potassium (Z)-2-(2-amino-4-thiazole)-2-triphenylmethoxyiminoacetate The salt residue is too high, which greatly affects the yield of MEAT in the next step; 3. The process of this method is more complicated than the post-treatment of alkylation, and the process uses boron trifluoride in ether (or acetonitrile, etc.) solution or boron trifluoride Gas has high requirements for transportation, and it is prone to leakage during use, which has certain safety and high requirements for equipment materials. 4. The mixed solvent of acetic acid and ethyl acetate is used as the solvent for O-trityl alkylation reaction , not suitable for industrial production for solvent recovery and separation

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