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Preparation method of sulbenicillin sodium

A technology of sulfbenicillin sodium and sodium isooctanoate, which is applied in the field of preparation of antibiotic drug sulfbenicillin sodium, can solve the problems of impurity generation and yield reduction, unfavorable control of the ratio of dextrorotary body, and increase of operation steps, etc., and the method is simple , reducing the amount of hydrolyzed impurities, and strong operability

Active Publication Date: 2018-08-07
山东四环药业股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

6-aminopenicillanic acid is easily decomposed when mixed with water under alkaline conditions, resulting in the generation of impurities and the reduction of yield
6-APA protects the household base and the deprotection group after the reaction, which increases the operation steps, and in the deprotection step, the use of strong acid will lead to product degradation and polymer production
In actual operation, about 78% / 22% sulbenicillin sodium for pharmaceutical use is generally prepared by using the different solubility of the salts corresponding to the two isomers of sulbenicillin sodium to increase the ratio of the D(-) isomer , the post-processing of the above method is complicated, the yield of the product is low, and the ratio of the left-handed body and the right-handed body is not suitable for control

Method used

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  • Preparation method of sulbenicillin sodium
  • Preparation method of sulbenicillin sodium
  • Preparation method of sulbenicillin sodium

Examples

Experimental program
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Effect test

Embodiment 1

[0059] (1) In 100ml of water, add 15.15g of L-histidine, add 20g of D,L-sulfophenylacetic acid, heat up to 45°C, stir and react for 2 hours; slowly cool down to 0°C to 10°C, stir and crystallize for 2 hour; filter, and wash the filter cake with an appropriate amount of cold ethanol to obtain 21 g of D(-)-sulfophenylacetic acid histidine salt, with a yield of 61.0%;

[0060] (2) Add D(-)-sulfophenylacetic acid histidine salt obtained in the previous step to 100ml of ethanol, adjust the temperature of the feed liquid to 20°C, add 6.5g of concentrated hydrochloric acid dropwise, stir for 2 hours, filter, and distill the filtrate under reduced pressure 12 g of D(-)-sulfophenylacetic acid was obtained with a yield of 98.4%;

[0061] (3) Mix D(-)-sulfophenylacetic acid (10.07g) with D,L-sulfophenylacetic acid (7.93g) at a mass ratio of 1.27:1 to obtain D(-)-sulfophenylacetic acid: L(+)-sulfophenylacetic acid=78%: 22%, obtain the mixture based on D(-)-sulfophenylacetic acid mixed in...

Embodiment 2

[0067] (1) In 100ml of water, add 14.2g of L-lysine and 20g of D,L-sulfophenylacetic acid, raise the temperature to 40°C, and stir for 2.5 hours. Slowly lower the temperature to 0°C-5°C, stir and crystallize for 2 hours. Filter and wash the filter cake with appropriate amount of cold ethanol. 18.7 g of D(-)-sulfophenylacetic acid lysine salt was obtained, with a yield of 55.8%;

[0068] (2) Add D(-)-sulfophenylacetic acid lysine salt obtained in the previous step to 90ml of ethanol, adjust the feed liquid temperature to 18°C, add 6.0g of concentrated hydrochloric acid dropwise, stir for 3 hours, filter, and distill the filtrate under reduced pressure 11.1 g of D(-)-sulfophenylacetic acid was obtained. Yield 99.5%;

[0069] (3) Mix D(-)-sulfophenylacetic acid (11.0g) with D,L-sulfophenylacetic acid (5.5g) in a ratio of 2:1 to obtain D(-)-sulfophenylacetic acid: L (+)-sulfophenylacetic acid=80%: 20%, obtain the mixture based on D(-)-sulfophenylacetic acid mixed in proportion...

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Abstract

The invention discloses a preparation method of sulbenicillin sodium. According to the invention, L-amino acid is firstly adopted to perform splitting on D, L-sulfonylphenylacetic acid to obtain D(-)-sulfonylphenylacetic acid, then D(-)-sulfonylphenylacetic acid is compounded with D, L-sulfonylphenylacetic acid to prepare a sulfonylphenylacetic acid mixture with D(-)-sulfonylphenylacetic acid to L(+)-sulfonylphenylacetic acid ratio being about 78%:22%, the sulfonylphenylacetic acid mixture is chlorinated and then reacts with 6-APA, and then reacts with sodium iso-octoate, to directly obtain asulbenicillin sodium mixture with the ratio of D(-)-sulbenicillin sodium to L(+)-sulbenicillin sodium being about 78%:22%. According to the invention, post-treatment process is simplified, no water isused in the step of producing sulbenicillin sodium, hydrolysis impurity level is reduced, product purity is more than 99.0%, and product mole rate is more than 90%.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of antibiotic drug sulbenicillin sodium. Background technique [0002] Sulbenicillin sodium is a broad-spectrum semi-synthetic penicillin antibiotic, which is effective against Enterobacteriaceae such as Escherichia coli, Proteus, Enterobacter, Citrobacter, Salmonella and Shigella, as well as Pseudomonas aeruginosa Bacteria, Haemophilus influenzae, Neisseria and other Gram-negative bacteria have antibacterial effect. This product also has antibacterial activity against hemolytic streptococcus, Streptococcus pneumoniae and non-penicillin-producing Staphylococcus. This product also has a certain effect on anaerobic bacteria including Peptostreptococcus and Clostridium. The mechanism of action of sulbenicillin sodium is to play a bactericidal effect by inhibiting the synthesis of bacterial cell walls. [0003] Sulbenicillin sodium, Ch...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D499/62C07D499/16
CPCC07D499/16C07D499/62
Inventor 郭建军李刚刘亚东张晓君刘慧敏徐春海
Owner 山东四环药业股份有限公司
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