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Process method for preparing methoxycephems intermediate 7-MAC (7-methoxycephalosporin)

A technology of methoxycephalosporin and process method, which is applied in the field of preparation of methoxycephalosporin intermediate 7-MAC, which can solve the problems of difficult precise control, fluctuation of content and light transmittance, many changing factors, etc.

Inactive Publication Date: 2011-11-23
江苏力达宁化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when this methoxylation method moves from the laboratory to the industrialization, there are many factors that change, and it is difficult to control accurately, which often leads to large fluctuations in the content and light transmittance.

Method used

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  • Process method for preparing methoxycephems intermediate 7-MAC (7-methoxycephalosporin)
  • Process method for preparing methoxycephems intermediate 7-MAC (7-methoxycephalosporin)
  • Process method for preparing methoxycephems intermediate 7-MAC (7-methoxycephalosporin)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] (1) Synthesis of formula II7-TMAC: In a 1000ml four-necked reaction flask, add 27.2 grams of 7-ACA, 12 grams of 1-methyl-5-mercaptotetrazolium, and 140 grams of acetonitrile, stir well, and place at 30°C to 40°C, add 10 grams of boron trifluoride ether and 25 grams of methanesulfonic acid dropwise, continue the heat preservation reaction at 30-40°C for 1 hour after the drop, cool the reaction solution to 0°C to 5°C after the reaction, add 600°C of purified water dropwise After adding water, add dropwise 30% liquid caustic soda to adjust the pH value to 4.0, control the temperature below 10°C, and stir for 2 hours to crystallize. Then filter, and the filter cake is beaten and washed with water once more. Vacuum-dried at 40°C until the moisture content was less than 0.5%, to obtain 30.6 g of the product.

[0035] (2) Synthesis of formula III intermediate:

[0036] A. Preparation of sulfur bromide reagents:

[0037] ①In a 250ml four-necked bottle, add 8.1 grams of dimet...

Embodiment 2

[0056] (1) The synthesis of 7-TMCA is the same as in Example 1.

[0057] (2) Synthesis of formula III intermediate:

[0058] A. The preparation of methyl sulfur bromide is the same as in Example 1.

[0059] B. The preparation of diphenyldiazomethane is the same as the method in Example 1 1.

[0060] C. Synthesis of the intermediate of formula III: 1000ml four-necked reaction flask with reflux condenser, put 25.5 grams of 7-TMCA into it, stir 180 grams of methylene chloride for 10 minutes, add 32 grams of hexamethyldisilamine (HMDS for short) dropwise , After dropping, react at 25°C for 2 hours, cool to 10°C and add 5 grams of propylene oxide, then add dropwise the methyl sulfur bromide solution obtained in step A, and react at 35°C for 2 hours after dropping. Then add the diphenyldiazomethane solution obtained by the manganese dioxide method in Step B, and react at 35° C. for 3 hours. Add 200 g of water, stir and separate the layers. The organic layer is concentrated under ...

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Abstract

The invention discloses a process method for preparing a methoxycephems intermediate 7-MAC (7-methoxycephalosporin), belonging to the technical field of chemical engineering. The process method provided by the invention comprises the following steps of: condensing 7-ACA (7-amino Cephalosporanic Acid) and 1-methyl-5-sulfydryl tetrazole under the catalysis of boron trifluoride-methanesulfonic acid to prepare 7-TMCA (7-amino-3-[(1-methyltetrazol-5-yl)thiomethyl]cephem-4-carboxylic Acid); then protecting carboxyl of the 7-TMCA with BSA (Bovine Serum Albumin) or HMDS (Hexamethyl Disilazane), and subjecting the protected 7-TMCA and methyl sulfur bromide to imidization; then subjecting a product and diphenyldiazomethane to an esterification; then reacting the obtained intermediate with methanol to obtain the methoxycephems intermediate 7-MAC under the catalysis of aluminum trichloride-sodium bicarbonate-triphenyl phosphorus. The catalysts of all steps are optimally screened. Side reactions and the generation of impurities are tracked and analyzed so that a method for avoiding the side reactions is found. The process method provided by the invention is an improved industrial synthesis method of the 7-MAC.

Description

technical field [0001] The invention relates to the technical field of chemical industry, in particular to a process for preparing methoxycephalosporin intermediate 7-MAC. Background technique [0002] Metoxycephalosporin refers to a cephalosporin with a trans-methoxy group on the 7th carbon of the β-lactam ring of the cephalosporin nucleus. This type of antibiotic has strong resistance to β-lactamase. It has a strong bactericidal effect on the bacteria that produce this enzyme. Representatives of this class of antibiotics are cefmetazole, cefminox, cefotetan and cefbuperazone. 7-MAC provides a common mother core for these drugs. [0003] The structure of 7-MAC is as follows: [0004] [0005] There are mainly two kinds of preparation methods of 7-MAC, one is to synthesize from methoxamycin C as a raw material, and the other is to synthesize from 3-acetoxymethyl-5-sulfur-7-amino-8-oxygen-1 -Azabicyclooct-2-ene-2-carboxylic acid (abbreviated as 7-ACA) was synthesized a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/18C07D501/04
Inventor 胡治海
Owner 江苏力达宁化工有限公司
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