Method for producing cefoxitin acid

A technology of cefoxitin and lactam, which is applied in the field of preparation of cefoxitin, can solve the problems of high operating conditions and cost requirements, difficult to store, and high operating conditions, and achieves that the reagents are easy to obtain and store, easy to separate and purify, and The effect of mild reaction conditions

Active Publication Date: 2013-02-13
ZHEJIANG XIANFENG TECH
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  • Abstract
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Problems solved by technology

The disadvantage of this line is that the line is long and the yield is low
[0007] Patent CN101613361A reported a preparation method of cefoxitin sodium. In this method, the intermediate cefoxitin acid is deacetylated 7-ACA as a raw material. By introducing thiopheneacetyl, the 3-position is carbamylated, and the 7-position is carbamylated. Oxygenation three-step reaction to obtain cefoxitin acid, the route steps are long, the yield is low, and the cost is high. At the same time, the currently used lithium methylate is used as the methylation reagent, and the operating conditions are high.
[0008] Patent CN101235045A reports a synthetic route of using cephalothin as a raw material to obtain the intermediate cefoxitin acid through carbamylation and two-step reactions of methoxylation. The methoxylation reaction in this route is also based on methanol- Lithium methoxide solution is used as a methylation reagent, and the reaction is carried out at -70°C. The methanol-lithium methoxide reagent in this step needs to be prepared and used immediately, and is not easy to store. Therefore, the operation conditions and cost requirements of this reaction are high, and it is difficult to industrialize production.

Method used

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  • Method for producing cefoxitin acid
  • Method for producing cefoxitin acid
  • Method for producing cefoxitin acid

Examples

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Effect test

Embodiment 1

[0036] Step 1: Intermediate (6R,7S)-3-carbamoyloxymethyl-7-[2-(2-thienyl)acetamido]-8-oxo-5-thia-1-aza Preparation of bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

[0037] Add 100 g of cephalothin to 500 ml of diethyl ether, add 350 ml of triethylamine and 54 g of chlorosulfonyl isocyanate, stir at -10°C for 8 hours, then add 0.75 L of 97% ethanol, stir at 25°C for 40 minutes, and concentrate the reaction solution under reduced pressure Then, it was added to ice water at 0°C and stirred for 30 minutes. After suction filtration, the filter cake was washed with ice water at 0°C and dried in vacuo to obtain 90 g of a light yellow solid (the intermediate), yield: 89.8%.

[0038] Second step: the preparation of cefoxitin

[0039] Add 85g of the intermediate obtained in the first step and 400ml of anhydrous methanol into the dry reactor, stir at 25°C for 30 minutes, then cool to -50°C, add 54.2g of powdered sodium methoxide, keep stirring for 2 hours, then add 100ml of 5% hydrochlori...

Embodiment 2

[0041] Step 1: Intermediate (6R,7S)-3-carbamoyloxymethyl-7-[2-(2-thienyl)acetamido]-8-oxo-5-thia-1-aza Preparation of bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

[0042] Add 100 g of cephalothin to 500 ml of petroleum ether, add 350 ml of triethylamine and 54 g of trimethylsilyl isocyanate, stir and react at 5°C for 12 hours, then add 0.75 L of 97% ethanol, and stir at 25°C for 40 minutes. The reaction solution was concentrated under reduced pressure, added to ice water at 0°C, and stirred for 30 minutes. After suction filtration, the filter cake was washed with ice water at 0°C and dried in vacuo to obtain 87.2 g of a light yellow solid (the intermediate), yield: 87%.

[0043] Second step: the preparation of cefoxitin

[0044] Add 85g of the intermediate obtained in the first step, 400ml of anhydrous tetrahydrofuran into the drying reactor, stir at 25°C for 30 minutes, then cool to -5°C, add 54.2g of powdered sodium methoxide, keep stirring for 2 hours, then add 100ml of 5% ...

Embodiment 3

[0046] Step 1: Intermediate (6R,7S)-3-carbamoyloxymethyl-7-[2-(2-thienyl)acetamido]-8-oxo-5-thia-1-aza Preparation of bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

[0047] Add 100 g of cephalothin to 500 ml of ethyl acetate, add 350 ml of triethylamine and 54 g of dichlorophosphorinyl isocyanate, stir and react at 0°C for 10 hours, then add 0.75 L of 97% ethanol, and stir at 25°C for 40 minutes. The reaction solution was concentrated under reduced pressure, added to ice water at 0°C, and stirred for 30 minutes. Filter with suction, and wash the filter cake with ice water at 0°C. Dry in vacuo to obtain 87.8 g of light yellow solid (ie intermediate), yield: 87.6%.

[0048] Second step: the preparation of cefoxitin

[0049] Add 85g of the intermediate obtained in the first step and 400ml of anhydrous methanol into the drying reactor, stir at 25°C for 30 minutes, then cool to -30°C, add methanol-sodium methoxide solution containing 54.2g of sodium methoxide, and keep stirring for 2 ...

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Abstract

The invention discloses a method for producing cefoxitin acid. The method comprises the following steps: (1) cephalothin is taken as a raw material to be reacted with a carbamylation reagent in organic solvent, carbamoyloxymethyl is introduced to 3-position, so that an intermediate is produced; and (2) the intermediate is reacted with a methoxylation reagent, and a methoxy group is introduced to 7-position, so that cefoxitin acid is obtained, wherein the methoxylation reagent is one of solid sodium methoxide, methanol-sodium methoxide solution or asolute methanol-beta lactam immobilized enzyme, and the beta lactam immobilized enzyme is a catalyst which consists of beta lactamase and organic or inorganic carrier. The method for producing cefoxitin acid has simple steps and less side reactions, the reagents are easily obtained and can be recycled and reused, reaction conditions are moderate, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a compound, in particular to a preparation method of cefoxitin acid. Background technique [0002] Cefoxitin acid, the chemical name is (6R,7S)-3-carbamoyloxymethyl-7-methoxy-8-oxo-7-(2-(2-thiazolyl)ethyl Amino)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. Its chemical structural formula is as follows: [0003] [0004] Cefoxitin acid is a semi-synthetic cefoxitin antibiotic developed by MercK in the United States. Its sodium salt, cefoxitin sodium, has a balanced antibacterial spectrum and is stable to β-lactamase. At present, there is a relatively serious abuse of antibiotics, which has gradually increased the resistance of antibiotics, and the resistance of bacteria has constituted a serious threat to β-lactam antibiotics. The hydrolytic ring opening under the action of β-lactamase is the main reason for the inactivation of these antibiotics. Cefoxitin, as a second-generation cephalos...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P35/00C07D501/57C07D501/04
Inventor 李凤军王焕挺熊云茂王国才王洪鑫
Owner ZHEJIANG XIANFENG TECH
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