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Synthesis method of high-purity 7-amino-3-propylene-1-yl-3-cephem-4-carboxylic acid

A technology of aminocephalosporanic acid and synthesis method, which is applied in the field of chemical synthesis, can solve problems such as harsh operating conditions, poor product purity, and difficult recycling of waste liquid, and achieve the effects of easy recycling, less reagents, safe and environmentally friendly recycling

Active Publication Date: 2015-08-19
QILU ANTIBIOTICS PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Both route (1) and route (2) require a large amount of organic solvents, the waste liquid is difficult to recycle, and the pollution is large; the route (1) is complicated to operate and the yield is low, and the route (2) requires anhydrous reaction with harsh operating conditions and the purity of the product obtained Poor, only 95%

Method used

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  • Synthesis method of high-purity 7-amino-3-propylene-1-yl-3-cephem-4-carboxylic acid
  • Synthesis method of high-purity 7-amino-3-propylene-1-yl-3-cephem-4-carboxylic acid
  • Synthesis method of high-purity 7-amino-3-propylene-1-yl-3-cephem-4-carboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] (1) Preparation of formula (I) compound:

[0038] Water 100mL, cool down to 0-10°C, add 20g of deacetyl-7-aminocephalosporanic acid under stirring, add dropwise 10% sodium bicarbonate solution, stir until clear, add 4.5g of sodium bromide, 0.9g of 2, To 2,6,6-tetramethylpiperidine nitrogen oxide (TEMPO), 66 ml of 10.2% sodium hypochlorite solution was added dropwise, reacted for 2 hours, and 9% hydrochloric acid solution was added to adjust the pH to 3.2 to obtain 18.4 g of the product;

[0039] (2) Preparation of 7-amino-3-propene-1-yl-3-cephem-4-carboxylic acid

[0040] Put 15g of the compound of formula (I) into 60mL of dichloromethane, add 16.6mL of hexamethyldisilazane under stirring, reflux for 8 hours, cool down to 0-5°C, add 27.1g of ethyltriphenylphosphine bromide, After reacting for 2 hours, 180 mL of methanol was added for crystallization to obtain 14.4 g of the product. The total molar yield is 84.5%, the purity is 99.6%, and the trans isomer accounts for ...

Embodiment 2

[0042] (1) Preparation of formula (I) compound:

[0043] Water 80mL, cool down to 0-10°C, add 20g of deacetyl-7-aminocephalosporanic acid under stirring, add dropwise 5% sodium hydroxide solution, stir until clear, add 2g of potassium bromide, 0.5g 2,2 , 6,6-tetramethylpiperidine nitrogen oxide (TEMPO), 69 mL of 10.2% sodium hypochlorite solution was added dropwise, reacted for 3 hours, and 40% sulfuric acid solution was added to adjust the pH to 3.5 to obtain 18.2 g of the product;

[0044] (2) Preparation of 7-amino-3-propene-1-yl-3-cephem-4-carboxylic acid

[0045] Put 15g of the compound of formula (I) into 80mL of dichloromethane, add 32mL of N,O-bistrimethylsilylacetamide under stirring, react at room temperature for 3 hours, cool down to 0-5°C, add 27.3g of ethyltriphenyl Phosphine bromide was reacted for 3 hours, and 200 mL of ethanol was added for crystallization to obtain 14.6 g of the product. The total molar yield is 84.8%, the purity is 99.7%, and the trans isomer...

Embodiment 3

[0047] (1) Preparation of formula (I) compound:

[0048] Water 120mL, cool down to 0-10°C, add 20g of deacetyl-7-aminocephalosporanic acid under stirring, add dropwise 8% sodium carbonate solution, stir until clear, add 1g of sodium bromide, 0.7g2,2,6 , 6-tetramethylpiperidine nitrogen oxide (TEMPO), 80mL of calcium hypochlorite solution with a mass fraction of 8% was added dropwise, and after reacting for 2.5 hours, a phosphoric acid solution with a mass fraction of 85% was added to adjust the pH to 3.5 to obtain 18g of the product;

[0049] (2) Preparation of 7-amino-3-propen-1-yl-3-cephem-4-carboxylic acid

[0050] Put 15g of the compound of formula (I) into 100mL of dichloromethane, add 25mL of trimethylchlorosilane under stirring, reflux for 7 hours, cool down to 0-5°C, add 27.5g of ethyltriphenylphosphine bromide, and react for 3 hours , 150 mL of isopropanol was added for crystallization to obtain 14.2 g of the product. The total molar yield is 81.6%, the purity is 99...

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Abstract

The invention relates to a synthesis method of high-purity 7-amino-3-propylene-1-yl-3-cephem-4-carboxylic acid. The method takes deacetylated-7-aminocephalosporanic acid (D-7-ACA) as a starting raw material, and the starting raw material is reacted with ethyltriphenyl phosphonium bromide through oxidization to generate the 7-amino-3-propylene-1-yl-3-cephem-4-carboxylic acid. The synthesis method has a simple process, low cost and high product yield; the purity is more than 99% and the synthesis method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, in particular to a method for synthesizing high-purity 7-amino-3-propen-1-yl-3-cephem-4-carboxylic acid. Background technique [0002] Cefprozil (Cefprozil) is a second-generation novel cephalosporin antibiotic developed by Bristol-Myers Squibb and approved by the FDA in December 1992. Cefprozil is the first oral cephalosporin antibiotic approved by the FDA for the treatment of children. Due to its good safety, cefprozil has been increasing its market share in recent years. 7-amino-3-propen-1-yl-3-cephem-4-carboxylic acid is the most critical intermediate in the preparation of cefprozil, which has always restricted the production and cost of cefprozil. [0003] Combining domestic and foreign literature and patent reports, there are two starting materials for the synthesis of 7-amino-3-propen-1-yl-3-cephem-4-carboxylic acid, 7-phenylacetamido-3-chloroform Base-4-cephalosporanic acid ...

Claims

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Application Information

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IPC IPC(8): C07D501/18C07D501/04
CPCC07D501/04C07D501/18
Inventor 李凤侠王勇进王欣付景龙范美菊史韶华张亮林军杨丽媛
Owner QILU ANTIBIOTICS PHARMA
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