Improved method for preparing amoxicillin by enzymic method

A technology for amoxicillin and enzymatic preparation, applied in the field of amoxicillin preparation, can solve the problems of poor fluidity, high toxicity to operators, low bulk density and the like

Active Publication Date: 2012-09-12
UNITED LAB INNER MONGOLIA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Relatively speaking, the chemical synthesis method has a long synthetic route (for example, mixed anhydride, condensation, hydrolysis, crystallization, filtration, washing, drying, etc. after mixing p-hydroxyphenylglycine potassium salt and pivaloyl chloride), and the production process uses a lot of solvents, such as: pivaloyl chloride, pyridine, triethylamine, dichloromethane and other highly toxic substances, not only are highly toxic to operators, but also cause great pollution to the environment; moreover, amoxicillin synthesized by chemical methods has crystal Defects of small size, poor fluidity, low bulk density, and difficult packaging

Method used

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  • Improved method for preparing amoxicillin by enzymic method
  • Improved method for preparing amoxicillin by enzymic method
  • Improved method for preparing amoxicillin by enzymic method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] Material preparation:

[0092] 6-APA 12g; D-p-hydroxyphenylglycine methyl ester hydrochloride 15.6g; penicillin G acylase 2.2KU / L; 3mol / l ammonia 8ml; acetone 60ml (90% concentration); 6mol / l hydrochloric acid 11ml; 6mol / l ammonia water: 9.5ml; purified water 500ml.

[0093] Preparation Process:

[0094] Add 240ml of purified water into a 1000ml beaker, add 12g of 6-APA while stirring, then add dropwise 3mol / l ammonia water to adjust the pH to 7.5, keep the temperature at 15°C, 6-APA is completely dissolved, and the amount of 3mol / l ammonia water is 5ml; add to the beaker Add D-p-hydroxyphenylglycine methyl ester hydrochloride; then add penicillin G acylase to start the reaction; keep the reaction system at a constant temperature of 22°C, add ammonia water to control the pH=6.25, and use 3ml of 3mol / l ammonia water; after 1 hour of reaction , taking samples at regular intervals and measuring the 6-APA conversion rate (mg / ml) by HPLC: 23.17 in the first hour; 18.11 in ...

Embodiment 2

[0096] Material preparation:

[0097] 6-APA 12g; D-p-hydroxyphenylglycine methyl ester hydrochloride 16.8g; penicillin G acylase 2.2KU / L; 3mol / l ammonia 9ml; acetone 60ml (98% concentration); 6mol / l hydrochloric acid 12ml; 6mol / l ammonia water 10ml; purified water: 500ml

[0098] Preparation Process:

[0099] 240ml of purified water was added to a 1000ml beaker, and 12g of 6-APA was added while stirring. Add 3 mol / l ammonia water dropwise, when T=15°C and pH=7.5, 6-APA is completely dissolved, and the dosage of 3 mol / l ammonia water is 5ml. Add D-p-hydroxyphenylglycine methyl ester hydrochloride to the beaker. Add synthetase and start the reaction. Keep the reaction system at a constant temperature of 22°C, add ammonia water to control the pH=6.25, and use 4ml of 3mol / l ammonia water. After reacting for 1 hour, sample 6-APA at regular intervals to measure the conversion rate (mg / ml): 1st hour: 22.89; 2nd hour: 17.55; 3rd hour: 8.68; 4th hour: 6.71; 5th hour: 4.33; stop t...

Embodiment 3

[0102] Material preparation:

[0103] 6-APA 12g; D-hydroxyphenylglycine methyl ester hydrochloride 19.2g; penicillin G acylase 2.2KU / L; 3mol / l ammonia 10.5ml; methanol 60ml (85% concentration); 6mol / L hydrochloric acid 12.5 ml; 6mol / L ammonia water 11ml; purified water 500ml.

[0104] Preparation Process:

[0105] Add 240ml of purified water into a 1000ml beaker, then add 12g of 6-APA, and stir at the same time; add dropwise 3mol / l ammonia water, when T=15°C, pH=7.5, 6-APA is completely dissolved, and the dosage of 3mol / l ammonia water is 6ml; Add D-p-hydroxyphenylglycine methyl ester hydrochloride into the beaker; add synthetase to start the reaction; keep the reaction system at a constant temperature of 22°C, add ammonia water to control the pH=6.25, and use 4.5ml of 3mol / l ammonia water; - APA conversion rate (mg / ml): 23.01 in the 1st hour; 17.61 in the 2nd hour; 8.54 in the 3rd hour; 6.83 in the 4th hour; 4.35 in the 5th hour; stop the reaction; Crude.

[0106] In a 50...

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Abstract

The invention relates to the field of pharmacy, and provides an improved method for preparing amoxicillin by an enzymic method, and a product obtained by the improved method for preparing amoxicillin by the enzymic method. The method comprises the following steps of: 1) dissolving 6-aminopenicillanic acid (6-APA) at the temperature of between 10 and 20 DEG C by using water or/and aqueous solution of ammonia which has the pH value of 7.0 to 8.0, and adding D-p-Hydroxyphenylglycine methyl ester hydrochlorid and penicillin G acyltransferase; 2) adjusting the pH value of a solution obtained in the step 1) to be 6.0 to 6.5, and reacting at the temperature of between 21 and 30 DEG C until the content of 6-APA is less than 5mg/ml to obtain a solution of an amoxicillin product; and 3) separating the penicillin G acyltransferase from the solution of the amoxicillin product, adjusting by using hydrochloric acid until the solution of the amoxicillin product is clarified, adding the aqueous solution of ammonia, adjusting the pH value to be 5.5 to 6.5, and crystallizing at the temperature of between 0 and 5 DEG C to obtain amoxicillin. By the improved method for preparing amoxicillin by the enzymic method, the quality of the amoxicillin product is greatly improved, and the medication safety of the amoxicillin product is further improved.

Description

technical field [0001] The invention relates to a method for preparing amoxicillin, in particular to an improved method for preparing amoxicillin by enzymatic method. Background technique [0002] Amoxicillin, the chemical name is (2S,5R,6R)-3,3-dimethyl-6-[(R)-(-)-2-amino-2-(4-hydroxynitro)acetamido] -7-oxo-4-thia-1-azabicyclo[3,2,0]heptane-2-carboxylic acid trihydrate, which is a commonly used penicillin-like broad-spectrum β-lactam antibiotic. [0003] Amoxicillin has strong bactericidal effect and strong ability to penetrate cell walls, and is one of the most widely used oral penicillins at present. The preparation of amoxicillin includes chemical synthesis method and enzymatic preparation method. The invention patent applications with application numbers CN00100579.0, CN02100123.5, CN200410043624.8 and CN201110162540.6 disclose the chemical synthesis method of amoxicillin. Relatively speaking, the chemical synthesis method has a long synthetic route (for example, mixe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P37/04
Inventor 刘红池
Owner UNITED LAB INNER MONGOLIA CO LTD
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