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Sulbenicillin sodium preparation method

A technology of sodium sulbenicillin and sodium isooctanoate, applied in the direction of organic chemistry, can solve the problems of low conversion rate of mixed anhydrides, low yield of sulbenicillin, poor solubility, etc., and achieve shortened production cycle, easy availability and low cost low effect

Active Publication Date: 2013-09-25
REYOUNG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Disadvantages of this route: cumbersome, low conversion rate of mixed anhydride, poor solubility of 6-APA in mixed anhydride reaction liquid, forming solid-liquid two-phase reaction, resulting in low yield and poor quality of sulbenicillin produced
Therefore, the currently marketed sulbenicillin sodium for injection is sterile freeze-dried powder

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0043] (1) Add 126kg of dichloromethane to a 200L reactor, add 10kg (46.3mol) of α-sulfophenylacetic acid under rapid stirring, then add 9.37kg (92.6mol) of diisopropylamine, stir until the solution is clear, and cool down To -10°C, add 4.49kg (48.7mol) ethyl chloroformate at a uniform rate, and keep it at -10°C for 1.5h to prepare solution a, which is stored at -15°C for later use.

[0044] (2) Add 10kg (46.3mol) 6-APA (6-aminopenicillanic acid) and 101kg dichloromethane to a clean 1000L reaction kettle, stir well, cool down to 0°C, and slowly add diisopropyl Base amine 9.37kg (92.6mol), after the dropwise addition, keep the temperature at -5 ~ 5 ° C and stir to completely dissolve 6-APA, and obtain solution b.

[0045] (3) Heat preservation at -15°C and slowly add solution b to solution a. After the dropwise addition, continue to heat at -15°C for 2 hours, and the reaction ends. Add 40kg of n-butanol to the reaction solution, then slowly add cold 17% hydrochloric acid solutio...

Embodiment 2

[0049] (1) Add 126kg of dichloromethane to a 200L reactor, add 10kg (46.3mol) of α-sulfophenylacetic acid under rapid stirring, and then add 8.0kg (69.5mol) of tetramethylguanidine, and stir until the solution is clear and cooled to -10°C, add 6.65kg (48.7mol) butyl chloroformate at a constant rate, keep it at -10°C for 2 hours, and then prepare solution a, store it at -15°C for later use.

[0050] (2) Add 10kg (46.3mol) 6-APA (6-aminopenicillanic acid) and 101kg dichloromethane to a 1000L reactor, stir well, cool down to 0°C, and slowly add tetramethylguanidine dropwise 5.86kg (50.9mol), after the tetramethylguanidine is added dropwise, keep the temperature at -5~5°C and stir to dissolve the 6-APA, and store it at low temperature for later use.

[0051] (3) Keep warm at -15°C, slowly add solution b to solution a, after the dropwise addition, keep warm at -15°C for 2 hours, and the reaction ends. Add 40kg of n-butanol to the reaction solution, then slowly add cold 17% hydroch...

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Abstract

The invention discloses a sulbenicillin sodium preparation method, and belongs to the technical field of medicine. According to the preparation method, alpha-sulfophenylacetic acid reacts with chloroformate to produce a mixed anhydride, 6-APA and an organic alkali are subjected to salt formation, and then dissolved in an organic solvent, the obtained material is subjected to a condensation reaction in the mixed anhydride solution, acidification liquid separation is performed after completing the reaction, the organic phase is retained, and sodium2-ethylhexanoate is added to the organic phase to carry out salt formation to obtain the sulbenicillin sodium, wherein the sulbenicillin sodium is further subjected to sterile crystallization through a system comprising water, ethanol and acetone to obtain sulbenicillin sodium for injection. The preparation method has characteristics of low cost, good quality and easy operation, and is suitable for industrialization.

Description

technical field [0001] The invention relates to a preparation method of sulbenicillin sodium, which belongs to the technical field of medicine. Background technique [0002] Sulbenicillin Sodium is a semi-synthetic penicillin developed and synthesized by Takeda Corporation of Japan. Takeda licensed it under the trade name Lilacillin in August 1972, and began selling injections in January 1973. It is mainly used clinically for infections caused by sensitive bacteria such as Pseudomonas aeruginosa, Proteus, and Escherichia coli. [0003] 1. Technical background of synthesis method [0004] The relevant synthetic method of sulbenicillin sodium reported in literature both at home and abroad is mainly with acid chloride method and mixed acid anhydride method at present. [0005] 1) Acid chloride method (the typical reaction equation is shown in route 1) [0006] [0007] US3660379 (1972) report: Dissolve 6-APA with sodium carbonate aqueous solution, α-sulfophenylacetyl chl...

Claims

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Application Information

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IPC IPC(8): C07D499/62C07D499/16C07D499/18
Inventor 李刚张颖朱玉正孙玉芳
Owner REYOUNG PHARMA
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