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Synthetic method for methoxy-cephalosporin intermediate 7-MAC

A technology of methoxycephalosporin and synthesis method, applied in the direction of organic chemistry and the like, can solve the problems of difficult industrialized production and high price, and achieve the effects of simple operation, easy availability of raw materials, and recyclable solvent.

Inactive Publication Date: 2013-01-02
湖北伟德合创新材料科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The patent of Hu Zhihai's publication number CN 10225012A uses p-methylsulfur bromide instead of methylsulfur bromide to protect the amino group. Although the release problem of methyl mercaptan is solved, the synthesis of p-methylbenzenesulfide bromide The price of phenol is high and it is difficult to realize industrial production

Method used

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  • Synthetic method for methoxy-cephalosporin intermediate 7-MAC
  • Synthetic method for methoxy-cephalosporin intermediate 7-MAC
  • Synthetic method for methoxy-cephalosporin intermediate 7-MAC

Examples

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Embodiment 1

[0056] A kind of synthetic method of metoxyceph intermediate 7-MAC, it is characterized in that comprising the following steps:

[0057] 1. Synthesis of Intermediate I: Add 1000mL of acetonitrile into the reaction bottle, cool to -15~-20℃, slowly add 200mL of concentrated sulfuric acid dropwise, add 128g (1.10mol) of methylmercaptotetrazole, stir for 20min, and divide Add 200g (0.73mol) of 7-ACA in batches, dissolve, then slowly raise the temperature to 40-45°C [reaction temperature in step 1] and react for 2.0-2.5 hours. After the reaction is completed, cool to -12~-15°C, add 40mL of concentrated hydrochloric acid and 50mL of water dropwise, continue to stir for 2.0~3.0h, filter, wash with acetonitrile-acetone mixture, the volume ratio of acetonitrile and acetone is 1:1, every 300 mL each time, and washed 3 times in total. Collect the solid, add 1000 mL of acetone-water mixture, the volume ratio is 3:2, adjust the pH of the solution to 3.6-4.0 with sodium bicarbonate, filter...

Embodiment 2

[0064] The synthesis of intermediate I: increase the thiomethazolium to 152.4g (1.31mmol), and others are the same as in Example 1, and the yield of intermediate I is 92.6%.

[0065] Synthesis of Intermediate II: Add 185g (0.94mol) of benzophenone hydrazone and 180mL of dichloromethane in turn to the reaction flask, stir to dissolve, control the temperature at 25-30°C, add 320g (3.08mol) of industrial grade Electrolytic MnO 2 , Reaction 1.0~2.0h. Filter, and wash the filter residue with dichloromethane (150 mL×3 times). Collect the filtrate and washing liquid, add 180g (0.55mol) of intermediate I, 180mL of dimethyl sulfoxide, stir and raise the temperature to 35-40°C [reaction temperature in step 2] After reacting for 5-8h, lower the temperature below 30°C. Wash with 10% sodium chloride solution (1000mL×2), let stand to separate layers, evaporate the organic layer to dryness at 50-60°C, add 760mL ethyl acetate and 0.6mL triethylamine, stir at room temperature for 12-15h, coo...

Embodiment 3

[0070] Synthesis of Intermediate II: Add 185g (0.94mol) of benzophenone hydrazone and 180mL of dichloromethane in turn to the reaction flask, stir to dissolve, control the temperature at 20-25°C, add 320g (3.08mol) of industrial grade Electrolytic MnO 2 , Reaction 1.0~2.0h. Filter and wash the filter residue with dichloromethane (150mL×3). Collect the filtrate and washing liquid, add 180g (0.55mol) of intermediate I, 180mL of dimethyl sulfoxide, stir and raise the temperature to 50-60°C [reaction temperature in step 2] After reacting for 5-8h, lower the temperature below 30°C. Wash with 10% sodium chloride solution (1000mL×2), let stand to separate layers, evaporate the organic layer to dryness at 50-60°C, add 760mL ethyl acetate and 0.4mL triethylamine, stir at room temperature for 12-15h, cool to 0°C, stirred for 2.0-3.0 h, filtered, washed with ethyl acetate, and dried to obtain Intermediate II as a light red solid with a yield of 90.1% and a liquid phase purity of 98.22%...

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Abstract

The invention provides a synthetic method for methoxy-cephalosporin intermediate 7-MAC. According to the invention, 7-ACA is used as a raw material to react with 1-methyl-5-mercapto-1, 2, 3, 4-tetrazole to obtain intermediate I; the intermediate I reacts with newly-prepared diphenyldiazomethane to produce intermediate II; the intermediate II reacts with 3, 5-di-tert-butyl-4-hydroxylbenzaldehyde to produce intermediate III; and the intermediate III reacts with a compound oxidizer and methanol to produce intermediate IV, and the intermediate IV reacts with a Girard-T reagent to obtain 7-MAC, wherein overall yield is 61% to 65%, and liquid phase purity reaches 99.20%. The synthetic method provided by the invention has the advantages of easily available raw materials, advanced technology and easy industrial production and is an improved synthetic method for 7-MAC.

Description

technical field [0001] The invention belongs to the field of cephalosporin intermediates, in particular to a cephalosporin intermediate 7β-amino-7α-methoxy-3-(1-methyl-1H-tetrazole-5-thiomethyl)-3-cephem -The synthetic method of 4-diphenylmethyl carboxylate (abbreviation: 7-MAC). Background technique [0002] 7-MAC, the full chemical name is 7β-amino-7α-methoxy-3-(1-methyl-1H-tetrazole-5-thiomethyl)-3-cephem-4-carboxylic acid diphenylmethane Esters are key intermediates for the synthesis of cefmetazole, cefotetan disodium, and ceftibuzone sodium. In recent years, the demand for methoxycephalosporin intermediates has been increasing. Wang Ling et al. used 7-TMCA as a raw material to first modify the structure of the amino group at the 7β position, then add a protecting group, place a methoxyl group at the 7α position, and finally remove the protecting group on the amino group to obtain 7-MAC. Yield of 30.2%, this synthetic route, reaction conditions are easy to control, but...

Claims

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Application Information

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IPC IPC(8): C07D501/18C07D501/04
Inventor 李德江龚大春陈义兴王艳玲张义军
Owner 湖北伟德合创新材料科技有限公司
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