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Antibacterial drugs cefoxitin preparation process

A technology for cefoxitin and cephalosporanic acid, applied in the field of compound preparation, can solve problems such as high production cost and low yield, and achieve the effects of saving cost, improving reaction yield and solving the problem of excessively low reaction yield

Active Publication Date: 2007-08-01
SHANDONG SALUBRIS PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The actual production has very strict requirements on the reaction conditions, and the production cost is high
[0008] Orchid Company (Deshpande et al., WO 2004083217) omits the protection and deprotection of carboxyl groups, directly uses sodium methylate or lithium methylate as strong base, and uses NCS or tert-butyl hypochlorite as reagents at -90°C. The 7-position of sodium introduces a methoxy group, and one step obtains II, but the yield is low

Method used

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  • Antibacterial drugs cefoxitin preparation process
  • Antibacterial drugs cefoxitin preparation process
  • Antibacterial drugs cefoxitin preparation process

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Step 1: Synthesis of 7α-methoxy-7β-[2-(2-thienyl)acetamido]-cephalosporanic acid (II)

[0039] Mix 30.2 g of 7α-methoxy-7β-amino-cephalosporanic acid (7-MAC) with 300 mL of water and cool to 0°C. Sodium bicarbonate was added portionwise with stirring until pH=7. A mixed solution of 24 g of thiopheneacetyl chloride and 30 mL of acetone was added dropwise within 1 hour, and saturated aqueous sodium carbonate solution was added dropwise at the same time to control the system to maintain pH=7-8. The reaction temperature is controlled between -5°C and 5°C. The reaction was monitored by high performance liquid chromatography until the starting material was consumed completely. After the reaction was completed, 900 mL of dichloromethane was added, and the pH was adjusted to 1-2 with 5% hydrochloric acid. Warm up to room temperature and separate the phases. The aqueous phase was extracted with appropriate amount of dichloromethane. The dichloromethane phases were combined ...

Embodiment 2

[0041] The first step: Synthesis of triethylamine salt of 7α-methoxy-7β-[2-(2-thienyl)acetamido]-cephalosporanic acid (II) 7α-methoxy-7β-amino-cephem Mix 30.2g of acid (7-MAC) with 300mL of water and cool to 0°C. Sodium bicarbonate was added portionwise with stirring until pH=7. A mixed solution of 24 g of thiopheneacetyl chloride and 30 mL of acetone was added dropwise within 1 hour, and saturated aqueous sodium carbonate solution was added dropwise at the same time to control the system to maintain pH=7-8. The reaction temperature is controlled between -5°C and 5°C. The reaction was monitored by high performance liquid chromatography until the starting material was consumed completely. After the reaction was completed, 900 mL of dichloromethane was added, and the pH was adjusted to 1-2 with 5% hydrochloric acid. Warm up to room temperature and separate the phases. The aqueous phase was extracted with appropriate amount of dichloromethane. The dichloromethane phases were...

Embodiment 3

[0043] Synthesis of Dibenzylamine Salt of 7α-Methoxy-7β-[2-(2-thienyl)acetamido]-cephalosporanic acid (II)

[0044] Mix 30.2 g of 7α-methoxy-7β-amino-cephalosporanic acid (7-MAC) with 300 mL of water and cool to 0°C. Sodium bicarbonate was added portionwise with stirring until pH=7. A mixed solution of 24 g of thiopheneacetyl chloride and 30 mL of acetone was added dropwise within 1 hour, and saturated aqueous sodium carbonate solution was added dropwise at the same time to control the system to maintain pH=7-8. The reaction temperature is controlled between -5°C and 5°C. The reaction was monitored by high performance liquid chromatography until the starting material was consumed completely. After the reaction was completed, 900 mL of dichloromethane was added, and the pH was adjusted to 1-2 with 5% hydrochloric acid. Warm up to room temperature and separate the phases. The aqueous phase was extracted with appropriate amount of dichloromethane. The dichloromethane phases ...

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Abstract

The invention provides a method for preparing cefoxitin (I). It comprises taking 7 alpha- methoxy- 7 beta- aminocephalosporanic acid (7- MAC) as raw material, carrying out 2- thiofuran acetylation reaction, hydrolytic reaction, carbamylation reaction and getting cefoxitin (I). The invention greatly increases the prductivity for cefoxitin and its sodium salt and reduces production cost.

Description

technical field [0001] The invention relates to a preparation method of a compound, in particular to a preparation method of a cephalosporin. Background technique [0002] Cefoxitin (Cefoxitin,), the chemical name is (6R, 7S)-3-carbamoyloxymethyl-7-methoxy-8-oxo-7-[2-(2-thienyl)acetamido ]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is a semi-synthetic cephamycin antibiotic developed by Merck Company of the United States. Its chemical structural formula (I) is as follows: [0003] [0004] Clinically, the sodium salt of cefoxitin is used to make injections for the treatment of bacterial infections. The drug was first approved for marketing by Japan's Daiichi Pharmaceutical Development Company in August 1979 under the trade name Cenomycin. The antibacterial effect of cefoxitin is similar to that of the second-generation cephalosporins, but because its structure contains a 7α-methoxy group, it greatly reduces the hydrolytic damage of β-lactamase in bacteria, an...

Claims

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Application Information

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IPC IPC(8): C07D501/34
Inventor 谭端明张黎辉叶澄海
Owner SHANDONG SALUBRIS PHARMA
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