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Synthesis method for aspoxicillin

A technology of amoxicillin and amoxicillin, applied in the field of drug synthesis, can solve the problems of poor repeatability, unstable synthesis process, unsuitable for industrial production, etc., and achieve the effects of less impurities, convenient post-processing, and shortened reaction period

Inactive Publication Date: 2016-08-17
JIANGXI FUSHINE PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Aiming at the problem that the existing apoxicillin synthesis process is unstable, poor in repeatability and not suitable for industrial production, the present invention provides a process with simple operation, no need to use toxic reagents such as 2-nitrobenzenethiochloride, and high yield , high product purity, few impurities, apoxicillin synthesis method suitable for industrial production

Method used

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  • Synthesis method for aspoxicillin
  • Synthesis method for aspoxicillin
  • Synthesis method for aspoxicillin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Add 80 g of amoxicillin trihydrate, 700 g of isopropanol, and 300 g of toluene into a 2000 ml bottle, stir, heat up and reflux to separate water for 0.5 hours. Cool down rapidly under the protection of nitrogen, filter, wash the filter cake with a small amount of anhydrous isopropanol, and vacuum-dry at 45°C to obtain anhydrous amoxicillin.

[0035] Take 20 g of the above-prepared anhydrous amoxicillin, 120 g of anhydrous DCM, and 2.25 eq (calculated based on the amount of anhydrous amoxicillin) of TEA, cool down to -20 ° C, and dropwise add TMSCl (2.2 eq, calculated based on the amount of anhydrous amoxicillin) (calculated based on the amount of moxicillin) (<-15°C), after the dropwise addition, the temperature was raised to 0-10°C and kept for 1 hour to obtain solution A.

[0036] Combine Deng potassium salt (1.5eq of amoxicillin), dichloromethane and catalytic amount of N-methylmorpholine (0.05eq of amoxicillin), stir and cool down to -20°C, and add chlorine dropwise...

Embodiment 2

[0039] Add 80 g of amoxicillin trihydrate, 700 g of isopropanol, and 300 g of toluene into a 2000 ml bottle, stir, heat up and reflux to separate water for 0.5 hours. Cool down rapidly under the protection of nitrogen, filter, wash the filter cake with a small amount of anhydrous isopropanol, and vacuum-dry at 45°C to obtain anhydrous amoxicillin.

[0040] Take 20 g of anhydrous amoxicillin prepared above, 120 g of anhydrous DCM, and 2.5 eq (calculated based on the amount of anhydrous amoxicillin) of TEA, cool down to -20 ° C, dropwise add TMSCl (2.5 eq, calculated as anhydrous amoxicillin) (calculated based on the amount of moxicillin) (<-15°C), after the dropwise addition, the temperature was raised to 0-10°C and kept for 1 hour to obtain solution A.

[0041] Combine Deng potassium salt (1.5eq of amoxicillin), acetonitrile and catalytic amount of N-methylmorpholine (0.05eq of amoxicillin), stir and cool down to -20°C, and add chloroformic acid dropwise under temperature cont...

Embodiment 3

[0044] Add 80g of amoxicillin trihydrate, 700g of n-butanol, and 300g of toluene into a 2000ml bottle, stir, heat up and reflux to separate water for 0.5 hours. Cool down rapidly under the protection of nitrogen, filter, wash the filter cake with a small amount of anhydrous isopropanol, and vacuum-dry at 55°C to obtain anhydrous amoxicillin.

[0045] Take 20 g of anhydrous amoxicillin prepared above, 120 g of anhydrous DCM, and 2.25 eq (calculated based on the amount of anhydrous amoxicillin) of TEA, cool down to -30 ° C, dropwise add TMSCl (2.2 eq, calculated as anhydrous amoxicillin) (calculated based on the amount of moxicillin) (<-15°C), after the dropwise addition, the temperature was raised to 0-10°C and kept for 1 hour to obtain solution A.

[0046] Combine Deng potassium salt (1.5eq of amoxicillin), acetonitrile and catalytic amount of N-methylmorpholine (0.08eq of amoxicillin), stir and cool down to -20°C, and add chloroformic acid dropwise under temperature control -...

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Abstract

The invention discloses a synthesis method for aspoxicillin. The method comprises the following steps: (1) dissolving anhydrous amoxicillin and triethylamine in dichloromethane, adding trimethylchlorosilane drop by drop at a temperature of -10 DEG C or below and carrying out a reaction as temperature is maintained at -15 to 10 DEG C so as to obtain a solution A; (2) reacting potassium (R)-[(3-ethoxy-1-methyl-3-oxoprop-1-enyl)amino]phenylacetate, chloroformate and N-methylmorpholine in dichloromethane at a temperature of -10 DEG C or below so as to obtain a solution B; and (3) adding the solution B into the solution A drop by drop at a temperature of -10 DEG C or below and carrying out after-treatment after completion of the reaction so as to obtain the aspoxicillin product. The method has creativity; in the whole reaction process, after-treatment is not needed, and the solution A can be directly reacted with the solution B; so the method has the characteristics of simple operation, convenient after-treatment, shortened reaction period, low impurity content, high yield and the like and is suitable for mass production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a method for synthesizing apoxicillin. Background technique [0002] Apoxicillin, chemical name: (2S,5R,6R)-6-[(2R)-2-[(2R)-2-amino-3-(N-methylcarbamoyl)propionamide]-2- (p-Hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3,2,0]-heptane-2-carboxylic acid tris Hydrate, English name: Aspoxicillin Foreign trade name: Doyle Chinese pinyin name: APu Xi Lin, its structure is as follows: [0003] [0004] Compound (I). [0005] Apoxicillin is the world's first amino acid semi-synthetic penicillin drug for injection developed by Tanabe Pharmaceutical Company of Japan. It was first listed in Japan in 1987. Clinically, it can be used to treat sepsis, infective endocarditis, secondary infections of trauma, burns, surgical wounds, pharyngitis, tonsillitis, acute bronchitis, pneumonia, lung abscess, secondary infections of chronic respiratory diseases, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D499/68C07D499/04
CPCC07D499/68C07D499/04
Inventor 谢永居郑裕义余明远王玉娟龚杰周忠波余翔胡涛杨玉平刘霞
Owner JIANGXI FUSHINE PHARMA CO LTD
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