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Method for preparing cefamandole nafate derivative through enzymatic method

A technology for the preparation of cefamandole sodium and enzymatic method, which is applied in the field of pharmaceutical and chemical technology synthesis, can solve the problems of cumbersome operation, low yield and high cost, and achieve the effect of high purity

Pending Publication Date: 2019-09-17
苏州盛达药业有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the prior art, liquid mass methods are usually used to determine the structure of the above derivatives or to purify them by chromatographic separation, but the existing methods are cumbersome to operate, low in yield and high in cost

Method used

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  • Method for preparing cefamandole nafate derivative through enzymatic method

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Cefamandole Sodium Free Acid:

[0030] Add 200ml of purified water into a 500ml four-necked bottle, control the temperature at 18°C ​​to 22°C, add 20g of cefamandole sodium, stir to dissolve, add 15g of penicillin acylase (Fleige Biotechnology Co., Ltd.), and use 3mol / L NH 3 ·H 2 O control the pH value to 6.0-7.5, carry out the hydrolysis reaction, the pH value is stable after about 1 hour of reaction, and continue the reaction for 30 minutes. Filtered with 50ml H 2 O washing enzyme. The water phase was transferred into a 1000ml four-necked flask, and 250ml of ethyl acetate was added. Adjust the pH value to 1.8-2.2 with 2N HCl solution, stir and separate layers. The organic phase was successively washed with 100ml H 2 o. Wash with 100ml 15% NaCl. Add 10 g of anhydrous magnesium sulfate and 1 g of AC (activated carbon) to the organic phase for dehydration and decolorization for 1 h, and filter. Add dropwise the lye solution formed by dissolving 6g of sodium is...

Embodiment 2

[0032] Add 180ml of purified water into a 500ml four-necked bottle, control the temperature at 20°C to 25°C, add 20g of cefamandole sodium, stir to dissolve, add 10g of penicillin acylase (Fleige Biotechnology Co., Ltd.), and use 5 %NaHCO 3 The pH value of the solution is controlled to be 5.5-7.0, and the hydrolysis reaction is carried out. After about 1 hour of reaction, the pH value is stable, and the reaction is continued for 30 minutes. Filtered with 50ml H 2 O washing enzyme. The water phase was transferred into a 1000ml four-necked flask, and 250ml of ethyl acetate was added. Adjust the pH value to 1.8-2.2 with 2N HCl solution, stir and separate layers. The organic phase was successively washed with 100ml H 2 O. Wash with 100ml 15% NaCl. Add 10 g of anhydrous magnesium sulfate and 1 g of AC to the organic phase for dehydration and decolorization for 1 h, and filter. Add dropwise 3.5g of sodium acetate dissolved in 50ml of methanol to the organic phase to form a lye...

Embodiment 3

[0034] 3-Methyl Cefamandole Sodium:

[0035] 3-Methyl Free Acid Mendoic Acid:

[0036] Add 250ml of purified water into a 500ml four-necked bottle, control the temperature at 15°C to 20°C, add 25g of 3-methylcefamandoxamate sodium, stir to dissolve, add 10g of penicillin acylase (Fleige Biotechnology Co., Ltd.) , with 3mol / LNH 3 ·H 2 O controls the pH value to be 6.5-7.5, and carries out the hydrolysis reaction. After about 1.5 hours of reaction, the pH value is stable, and the reaction is continued for 30 minutes. Filter with 50mlH 2 O washing. The water phase was transferred into a clean 500ml four-necked bottle, and the temperature was controlled at 15°C to 20°C. Use 2N HCl solution to adjust the pH value to 2.0-2.3, and a solid precipitates out, cool down to 5°C-10°C, grow crystals for 1 hour, filter, and wash with water. After drying in vacuo, 20.5 g of 3-methyl free acid mentolic acid was obtained with a yield of 94% and a purity of 98.2%.

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Abstract

The invention relates to a method for preparing a cefamandole nafate derivative through an enzymatic method. A penicillin acylase is adopted for carrying out a hydrolysis reaction on a compound 1, the pH in the hydrolysis reaction is controlled to be 5-8.5, the temperature in the hydrolysis reaction is controlled to be 5-25 DEG C, and after the reaction is finished, acidification is conducted to obtain the cefamandole nafate derivative 1, wherein the structural formula of the compound 1 is shown in the description, the structural formula of the cefamandole nafate derivative 1 is shown in the description, and R1 is an akyl group with the carbon number of 1-3, or R2 and R3 are independently alkyl groups with the carbon number of 1-3. By means of the preparing method, the cefamandole nafate derivative with high yield can be obtained, help is provided for pharmaceutical research relevant to cefamandole nafate, and meanwhile, a new idea is provided for the synthesis of new compounds with cephalosporin structures.

Description

technical field [0001] The invention belongs to the technical synthesis field of medicine and chemical industry, and in particular relates to a method for enzymatically preparing cefamandole sodium derivatives. Background technique [0002] Cefamandole sodium is a second-generation injectable cephalosporin antibiotic developed by Eli Lilly Company of the United States. The product has a wider antibacterial spectrum than cefazolin, has enhanced antibacterial power, and is relatively stable against β-lactamase. The product was launched in 1983. Cefamandole sodium due to its own product characteristics: a series of cefamandole sodium derivatives will be obtained during the synthesis process or during the product placement process, such as: Wait. In the prior art, liquid-mass methods are usually used to determine the structure of the above-mentioned derivatives or to purify them by chromatographic separation, but the existing methods are cumbersome to operate, low in yield ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P35/00
CPCC12P35/00
Inventor 周自金王磊黄军豪罗新祖陈锋
Owner 苏州盛达药业有限公司