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Method for preparing cefoxitin acid as antibacterial medicament

A technology for cefoxitin and antibacterial drugs, applied in the field of preparation of antibacterial drug cefoxitin, can solve the problems of requiring precious metal catalysts, high cost, difficult to obtain, etc. The effect of small particle size of synthetic powder

Active Publication Date: 2013-04-03
YIYUAN XINQUAN CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this type of reaction has disadvantages such as cumbersome process and the need for noble metal catalysts, so it has not met the needs of industrialized mass production.
[0007] 2) Using 7-ACA or its derivatives as raw materials, through amino conversion, bromination, azidation, hydrogenation reduction, deprotection, etc., the method has many steps and high cost, and there are environmental and safety hazards
[0008] 3) Using 7-MAC as a raw material, first modify the C7 amino side chain of 7-MAC, and then modify the side chain on the C3 position. Although the synthesis steps of this type of method are relatively simplified, 7-MAC is expensive and difficult to obtain, so has never been applied to industrialization

Method used

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  • Method for preparing cefoxitin acid as antibacterial medicament
  • Method for preparing cefoxitin acid as antibacterial medicament
  • Method for preparing cefoxitin acid as antibacterial medicament

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] A preparation method of antibacterial drug cefoxitin, comprising the steps of:

[0046] Preparation of deacetyl 7-aminocephalosporanic acid

[0047] Add 60g of 7-ACA into the reaction vessel, disperse in 350mL of water, add 25% sodium hydroxide solution, adjust the pH of the solution to 8.1, control the temperature at 5°C for hydrolysis reaction, continue to stir for 45min after dissolving, and add ethyl acetate 125mL, stirred for 15min, then added dropwise 1.2mol / L dilute hydrochloric acid to adjust the pH to 2.7, precipitated crystals, and dried to obtain 49.9g of deacetylated 7-aminocephalosporanic acid, with a yield of 98.34%;

[0048] Preparation of compound Ⅱ

[0049] Add 49.9g of compound I into a mixture of 360mL of dichloromethane and 30mL of methanol, cool down to -23°C, and stir for 20min. Add 2.082g of methanesulfonic acid, cool to -55°C, add 77.15g of NBS in batches, add 292.55g of sodium methoxide, stir thoroughly for 3h, take samples every 0.5h by high-...

Embodiment 2

[0055] A preparation method of antibacterial drug cefoxitin, comprising the steps of:

[0056] Preparation of deacetyl 7-aminocephalosporanic acid

[0057] Add 60g of 7-ACA to the reaction vessel, disperse it in 350mL of water, add 20% sodium hydroxide solution, adjust the pH of the solution to 8.2, control the temperature at 2°C for hydrolysis reaction, continue to stir for 60min after dissolving, Add 125 mL of ethyl acetate, stir for 15 min, then add 1.2 mol / L dilute hydrochloric acid dropwise to adjust the pH=3, crystals are precipitated, and dried to obtain 50.1 g of deacetyl 7-aminocephalosporanic acid with a yield of 98.73%.

[0058] Preparation of compound Ⅱ

[0059] Add 50.01g of compound I into a mixture of 300mL of dichloromethane and 36mL of methanol, cool down to -25°C, and stir for 20min. Add 2.091g of methanesulfonic acid, cool to -60°C, add 39.01g of NBS in batches, add 352.2g of sodium methoxide, stir thoroughly for 6h, take samples every 0.5h by high perform...

Embodiment 3

[0065] A preparation method of antibacterial drug cefoxitin, comprising the steps of:

[0066] Preparation of deacetyl 7-aminocephalosporanic acid

[0067] Add 60g of 7-ACA to the reaction vessel, disperse it in 350mL of water, add 30% sodium hydroxide solution, adjust the pH of the solution to 8.4, control the temperature at 4°C for hydrolysis reaction, continue to stir for 30min after dissolving, add Ethyl acetate 125mL, stirred for 15min, then dilute hydrochloric acid (1.2mol / L) was added dropwise to adjust the pH=3.4, crystals were precipitated, and dried to obtain 50.3g of deacetylated 7-aminocephalosporanic acid, with a yield of 99.12%;

[0068] Preparation of compound Ⅱ

[0069] Add 50.3g of compound I into a mixture of 360mL of dichloromethane and 36mL of methanol, cool down to -20°C, and stir for 20min. Add 2.099g of methanesulfonic acid, cool to -55°C, add 59.22g of NBS in batches, add 294.84 (401.45) g of sodium methoxide, stir well for 4 hours, and take samples e...

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Abstract

The invention discloses a method for preparing cefoxitin acid as an antibacterial medicament, comprising the following steps: (1) dissolving 7-aminocephalosporanic acid as a raw material into an alkaline solution, stirring after the alkaline solution becomes clear, adding ethyl acetate, adjusting the pH value, and separating out a crystal to obtain a compound I; (2) carrying out a reaction on the compound I, NBS (N-bromosuccinimide) and sodium methoxide, and introducing a methoxyl to the site 7 of the compound 1 to obtain a mixed solution containing a compound II; (3) carrying out a reaction on the compound II and a 2-thienyl acetylation reagent, introducing thienyl acetyl, and separating out a crystal to obtain a compound III; and (4) enabling the compound III to act with an ammonia methoxyl acylation reagent, and introducing a carbamoyl-methoxyl to the site 3 of the compound III to obtain the cefoxitin acid. The method is simple in preparation process and low in cost, is easy to implement, is suitable for large-scale production, adopts the low-cost raw materials which are easy to purchase and improves the yield of the cefoxitin acid significantly.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a preparation method of an antibacterial drug cefoxitin acid. Background technique [0002] The chemical name of cefoxitin acid is: (6R, 7S)-3-(hydroxymethyl)-7-methoxy-8-oxo-7-[2-(2-thienyl)acetamido]-5 -Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; belongs to the second-generation cephalosporin antibiotics, and its structural formula is: [0003] [0004] The drug intermediate was developed by Merck Company of the United States. Because cefoxitin contains 7α-methoxyl structural characteristics, it has high resistance to β-lactamase produced by bacteria, so cefoxitin that is stable to β-lactamase has great market potential. [0005] The route of synthetic cefoxitin mainly contains at present: [0006] 1) Using cephamycin C as a raw material, first modify the amino group on its carboxylic acid side chain, and then modify its four-membered ring. However, this type of reaction h...

Claims

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Application Information

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IPC IPC(8): C07D501/57C07D501/04
Inventor 钱先华张立明田廷璀
Owner YIYUAN XINQUAN CHEM
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