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Method for preparing 7-phenylacetylamino-3-methylcephalosporanic acid

A technology of methyl cephalosporanic acid and phenylacetamido is applied in the field of preparation of cephalosporanic acid, which can solve the problems of discharging a large amount of waste water, low CEFG purity, and complicated steps, and achieve the effects of avoiding waste water discharge, simplifying the process and improving the purity.

Active Publication Date: 2010-10-13
NORTH CHINA PHARMA COMPANY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The problem that this method exists is, the CEFG crystallization process step is numerous and diverse, needs to discharge a large amount of waste water, and because contain a large amount of organic matters such as high polymer, toluene, butyl acetate, xylene, pyridine, picoline, silicon ether in the crystallization mother liquor , silanol, pigment, so the purity of CEFG is low
At present, there are few reports on how to improve the purity of CEFG, simplify the production process of CEFG, reduce its process cost, and avoid environmental pollution.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] a. Penicillin G sulfoxide is dissolved in an organic solution, and an esterification agent is added to carry out an esterification reaction;

[0022] Add 100g of penicillin G sulfoxide, 1300ml of toluene, and 120g of N,N-bistrimethylsilylurea (esterification agent) into a 2000ml three-neck flask with a reflux condenser, raise the temperature to 50±2°C, and perform the esterification reaction for 1 hr;

[0023] b. Add 23g of catalyst pyridine hydrobromide to the above esterification reaction solution, raise the temperature and reflux for 2 hours, cool down to 80°C, add 100ml of water, stir for 10min, cool down to 45-50°C, add ammonia solution to adjust pH=7.5-7.6 , to obtain rearrangement ring expansion reaction solution;

[0024] c. The above-mentioned rearrangement and ring expansion reaction solution was left to stand for phase separation to obtain an aqueous phase solution and an organic phase solution of ammonium 7-phenylacetamido-3-methylcephalosporanate respective...

Embodiment 2

[0033] Add 100g of penicillin G sulfoxide, 1300ml of butyl acetate, and 120g of N,N-bistrimethylsilylurea (esterification agent) into a 2000ml three-neck flask with a reflux condenser, heat up to 50±2°C, and the esterification reaction 1hr, add 23g of pyridinium hydrobromide (catalyst), heat up and reflux for 2hr, cool down to 80°C, add 100ml of water, stir for 10min, cool down to 45-50°C, add sodium hydroxide solution to adjust pH=7.5-7.6, let stand Separate the phases to obtain an aqueous solution of sodium 7-phenylacetamido-3-methylcephalosporanate, which is divided into three equal parts: A, B, and C.

[0034] Part A solution: at 40-50°C, adjust the pH to 2.3 with 20% sulfuric acid, lower to 30°C, filter, wash with appropriate amount of water, drain, and dry to obtain 28g of crystalline CEFG.

[0035] Sampling measurement: 425nm absorbance value: 0.90

[0036] Purity (HPLC): 98.4%

[0037] Solvent residue: 0.27%

[0038] Part B solution 1000ml: Add 2...

Embodiment 3

[0047] Add 100g of penicillin G sulfoxide, 1300ml of xylene, 120g of N,N-bistrimethylsilylurea into a 2000ml three-neck flask with a reflux condenser, raise the temperature to 50±2°C, perform esterification reaction for 1hr, add dimethyl Pyridine hydrobromide 24g, heat up and reflux for 2hr, cool down to 80°C, add 100ml of water, stir for 10min, cool down to 45-50°C, add ammonia solution to adjust pH=7.5-7.6, stand still and separate phases to get 7-phenylacetyl Aqueous solution of ammonium amino-3-methylcespranate, divided into four equal portions.

[0048] Part A solution 300ml: adjust pH=2.3 with 20% sulfuric acid at 40-50°C, lower to 30°C, filter, wash with appropriate amount of water, drain, and dry to obtain 21g of crystalline CEFG.

[0049] Sampling measurement: 425nm absorbance value: 0.92

[0050] Purity (HPLC): 98.3%

[0051] Solvent residue: 0.21%

[0052] Part B solution 300ml: Add 300ml of xylene solution containing 0.2% tetraheptylammonium ...

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PUM

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Abstract

The invention discloses a method for preparing 7-phenylacetylamino-3-methylcephalosporanic acid. The method comprises the following steps of: a, dissolving penicillin G sulfoxide into organic solution, and adding an esterifying agent into the solution to perform esterification reaction; b, adding a catalyst into the solution to perform rearrangement ring-enlarging reaction, hydrolysis and alkali dissolution; c, standing the rearrangement ring-enlarging reaction solution and splitting phases; d, adding an organic solvent containing quaternary ammonium salt cationic surfactant into brine solution, stirring the solution uniformly, standing the solution and splitting the phases; and e, after the aqueous phase is subjected to degassing treatment, directly performing a cracking process to obtain the 7-phenylacetylamino-3-methylcephalosporanic acid, and returning the organic solution to the process d for recycle. The method greatly improves the purity of CEFG, and effectively avoids a process for crystallizing the CEFG in the traditional process so as to simplify the process for preparing the CEFG, reduce the production and manufacture costs, avoid wastewater discharge and reduce environmental pollution at the same time.

Description

Technical field: [0001] The invention relates to a preparation method of cephalosporanic acid, in particular to a preparation method of 7-phenylacetamido-3-methylcephalosporanic acid. Background technique [0002] 7-phenylacetamido-3-methylcephalosporanic acid (CEFG for short) is an important semi-synthetic intermediate of cephalosporin antibiotics, such as cephalexin, cefadroxil, cephradine, ceftazidime, etc. synthesized by the body. The traditional synthetic method of CEFG is to be raw material with penicillin G sulfoxide, under the effect of catalyst, add organic solvent (such as toluene, butyl acetate, xylene) to carry out esterification, rearrangement ring expansion, hydrolysis, alkaline hydrolysis, by This produces an aqueous solution containing the CEFG salt. Since the CEFG brine solution in this process contains a large amount of organic impurities that are difficult to remove, it is necessary to acidify and crystallize the CEFG before entering the subsequent synth...

Claims

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Application Information

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IPC IPC(8): C07D501/22C07D501/12
Inventor 温同礼王京米振瑞孙孟生刘云坡王明波梁雪智张致一杨梦德马金玉郑宝丽高俊艳于辉段志刚徐扣山白永祥
Owner NORTH CHINA PHARMA COMPANY
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