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Method for preparing p-nitrobenzyl-7-phenoxyacetamido-3-exomethylenecepham-4-carboxylate-1-beta-oxide

A technology of phenoxyacetamide and exomethylene cephalosporin, which is applied in the field of preparing p-nitrobenzyl in the Ming Dynasty, can solve the problems of solvent waste environment, long reaction time, low yield, etc., achieve good effect and improve Reaction conversion rate and yield, effect of high yield

Inactive Publication Date: 2010-05-19
吉林省石油化工设计研究院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

British patent GB2,003,475 uses p-nitrobenzyl bromide as protecting group and penicillin V sulfoxide acid in the presence of triethylamine, reacts in acetone solution at room temperature for 24 hours to prepare penicillin V sulfoxide p-nitrobenzyl ester, there is a reaction Disadvantages such as long time and low efficiency
U.S. Patent No. 4,115,643 uses p-nitrobromobenzyl as a protecting group and penicillin V sulfoxide acid in the presence of triethylamine, reacts in dimethylformamide solution at room temperature for 4 hours, and uses ice water for post-treatment precipitation. Ethyl acetate and dichloromethane mixed solvent recrystallization method prepares penicillin V sulfoxide p-nitrobenzyl ester, and this method yield is lower, and dimethylformamide and water are difficult to separate and obtain anhydrous dimethylformamide, cause Solvent waste and environmental pollution

Method used

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  • Method for preparing p-nitrobenzyl-7-phenoxyacetamido-3-exomethylenecepham-4-carboxylate-1-beta-oxide
  • Method for preparing p-nitrobenzyl-7-phenoxyacetamido-3-exomethylenecepham-4-carboxylate-1-beta-oxide
  • Method for preparing p-nitrobenzyl-7-phenoxyacetamido-3-exomethylenecepham-4-carboxylate-1-beta-oxide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] In a 500ml four-necked bottle, add 50.6ml of peracetic acid with a concentration of 18%, lower the temperature to 0-5°C, dissolve 38.8g of penicillin V potassium salt in 250ml of distilled water, gradually add it dropwise to the four-necked bottle within 2 hours, and keep the temperature 0-5°C, continue to react for 3 hours, raise the temperature to 35°C, add 32ml of 10% sulfuric acid solution, measure the pH value to 1.5, cool down to 0°C, keep it for 0.5 hours, filter, and wash the filter mass with distilled water three times until neutral , vacuum-dried at 50°C to constant weight to obtain 36.2g of penicillin V sulfoxide acid, with a molar yield of 99%, a melting point of 151-152°C, and a purity of 98.7% by liquid chromatography analysis.

[0017] Carboxyl protection reaction: 7.5g of penicillin V sulfoxide acid was added to a 500ml four-necked flask, and 60ml of acetone, 2.88ml of triethylamine, and 4.86g of p-nitrobenzyl bromide were added to the four-necked flask i...

Embodiment 2

[0021] In a 500ml four-necked bottle, add 114ml of peracetic acid with a concentration of 8%, cool down to 0-5°C, dissolve 38.8g of penicillin V potassium salt in 250ml of distilled water, gradually drop into the four-necked bottle within 2 hours, and keep the temperature at 0-5°C, continue to react for 3 hours, raise the temperature to 35°C, add 32ml of sulfuric acid solution with a concentration of 10%, measure the pH value as 1.5, cool down to 0°C, keep for 0.5 hours, filter, wash the filter mass with distilled water three times until neutral, Vacuum drying at 50°C to constant weight yielded 34.6g of penicillin V sulfoxide acid with a molar yield of 94.5%, a melting point of 151-152°C, and a purity of 98.5% by liquid chromatography analysis.

[0022] Carboxyl protection reaction: 7.5g of penicillin V sulfoxide acid was added to a 500ml four-necked flask, and 60ml of acetone, 3.42ml of triethylamine, and 5.31g of p-nitrobenzyl bromide were successively added to the four-necke...

Embodiment 3

[0026] In a 500ml four-necked bottle, add 65.1ml of peracetic acid with a concentration of 14%, lower the temperature to 0-5°C, dissolve 38.8g of penicillin V potassium salt in 250ml of distilled water, gradually add it dropwise to the four-necked bottle within 2 hours, and keep the temperature 0-5°C, continue to react for 3 hours, raise the temperature to 35°C, add 35ml of 10% sulfuric acid solution, measure the pH value to 1.5, cool down to 0°C, keep it for 0.5 hours, filter, and wash the filter mass with distilled water three times until neutral , vacuum-dried at 50°C to constant weight to obtain 35.4g of penicillin V sulfoxide acid, with a molar yield of 96.7%, a melting point of 151-152°C, and a purity of 98.7% by liquid chromatography analysis.

[0027] Carboxyl protection reaction: 7.5g of penicillin V sulfoxide acid was added to a 500ml four-necked flask, and 60ml of acetone, 3.1ml of triethylamine, and 4.6g of p-nitrobenzyl bromide were successively added to the four-n...

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Abstract

The invention pertains to a novel preparation method of p-nitrobenzyl-7-phenoxy-ace-tamide-3-exomethylenecepham-4-carboxylate-1-Beta-oxide. Penicillin V potassium salt and peracetic acid react to obtain penicillin V sulfoxide by reverse titration; the penicillin V sulfoxide and p-monobromo-methylbenzeneare nitrate are treated with reflux reaction under the action of triethylamine in acetone solution to prepare penicillin V sulfoxide p-nitrobenzyl ester group; the penicillin V sulfoxide p-nitrobenzyl ester group under the action of N-chlorosuccinimide and calcium oxide opens five ring and closes hexatomic ring again under the action of stannic chloride and then reacts with methanol to prepare the p-nitrobenzyl-7-phenoxy-ace-tamide-3-exomethylenecepham-4-carboxylate- 1-Beta-oxide. The preparation method has the advantages of short preparation and reaction time and production cycles, low cost of raw materials, less dosage and high yield.

Description

[0001] Technical field: the invention belongs to the method for preparing p-nitrobenzyl-7-phenoxyacetamide-3-exomethylene cephalosporin-4-carboxylate-1-β-oxide Background technique [0002] p-nitrobenzyl-7-phenoxyacetamide-3-exomethylene cephalosporin-4-carboxylate-1-β-oxide is an intermediate for the preparation of antibiotic cefaclor, which is the first Second-generation cephalosporin antibiotics, widely used in Europe and the United States. [0003] Due to the use of different raw materials and different process conditions, the yield level of the reaction varies greatly. Chinese Journal of Antibiotic Industry, 1999,6,463-464 discloses the preparation of p-nitrobenzyl-7-phenoxyacetamide-3-exomethylene cephalosporin-4-carboxylate-1-beta-oxide Method, use p-nitrochlorobenzyl as protective group, reflux reaction with penicillin V sulfoxide in the presence of triethylamine in acetone solution, and use potassium iodide to promote the reaction, the reaction yield is low, caused b...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/22
Inventor 张会良翟守志袁辉环魏巍杨文库田蕾李英君
Owner 吉林省石油化工设计研究院
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