Method for preparing 7-phenylacetylamino-3-hydroxyl-3-cyclo-4-p-nitrobenzyl cephalosporin carboxylate

A technology of phenylacetamido and nitrobenzyl ester, applied in directions such as organic chemistry, can solve the problems of production restriction of various cephalosporins, easy environmental pollution, serious environmental pollution, etc., and achieves shortened reaction time, low cost, Simple to use effects

Inactive Publication Date: 2017-08-18
SHAXING CHEM TAIZHOU CITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But the technology of my country's production 7-amino-3-chloro-3-cephalosporin-4-carboxylic acid is still immature at present, and the preparation cost of each intermediate is higher, and yield is low, pollutes serious simultaneously, makes the production of multiple cephalosporins Production is constrained
[0003] In the preparation method described in the patent whose application publication number is CN103694257A, the raw materials used are highly toxic, seriously pollute the environment, and the price is high, so that the cost is also high
[0004] In the preparation method described in the patent whose application publication number is CN103387584A, the raw materials used are highly toxic, the environment is seriously polluted, and the price is high, so that the cost is also high
[0005] In the patent application No. US4064343, the raw materials used are highly toxic, the yield is low, and the cost is high
[0006] Although the patent application No. US4079181 also adopts a one-pot method to synthesize 7-phenylacetamido-3-hydroxyl-3-cephalosporin-4-carboxylic acid p-nitrobenzyl ester from thiazoline enol ester , but its yield is low, and the raw materials used are easy to cause pollution to the environment

Method used

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  • Method for preparing 7-phenylacetylamino-3-hydroxyl-3-cyclo-4-p-nitrobenzyl cephalosporin carboxylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Preparation of p-nitrobenzyl 7-phenylacetamido-3-hydroxy-3-cephalosporin-4-carboxylate.

[0029] Add 150mL of dichloromethane (as an organic solvent) and 22.7g of thiazoline enol ester to a 500mL four-neck flask, cool down to -5°C, add 10.5g of p-toluenesulfonyl chloride, add 10.6g of sodium carbonate, keep warm for 2h, TLC Monitor, add 4.8g of morpholine dropwise, finish dropping in 10 minutes, stir for 30min, monitor by TLC, then add 4.8gBr2 dropwise, finish dropping in 10 minutes, start adding 3.4g of 30% hydrogen peroxide dropwise after 15min, finish dropping in 20 minutes, TLC Monitor, use 8% sulfuric acid aqueous solution to adjust pH=0.8~1.0, add catalyst tetrabutylammonium bromide (TBABr) 1.2g, heat up to 30 ℃ and react for 3 hours, TLC monitors, add water 32mL, fully stir for 10 minutes, divide liquid, the organic phase was adjusted to pH=7 with 2% sodium bicarbonate, and the above organic phase was washed twice with 100 mL of water, and all the above water pha...

Embodiment 2

[0031] Preparation of p-nitrobenzyl 7-phenylacetamido-3-hydroxy-3-cephalosporin-4-carboxylate.

[0032] Add 150mL of dichloromethane and 22.7g of thiazoline enol ester to a 500mL four-neck flask, cool down to -5°C, add 10.5g of p-toluenesulfonyl chloride, add 10g of sodium carbonate, keep warm for 2h, monitor by TLC, and then dropwise add molybdenum 4.8g of morphine, dropped in 10 minutes, stirred for 30min, monitored by TLC, then added dropwise 4.8gBr2, added dropwise in 10 minutes, after 15min, started to add 3.4g of 30% hydrogen peroxide, dropped in 20 minutes, monitored by TLC, with 8% Sulfuric acid aqueous solution to adjust pH=0.8~1.0, add 1.2g of catalyst tetrabutylammonium bromide (TBABr), heat up to 30°C and react for 3 hours, monitor by TLC, add 32mL of water, fully stir for 10 minutes, separate liquid, use for organic phase Adjust the pH to 7 with 2% sodium bicarbonate, wash the above organic phase twice with 100 mL of water, combine all the above water phases, extr...

Embodiment 3

[0034] Preparation of p-nitrobenzyl 7-phenylacetamido-3-hydroxy-3-cephalosporin-4-carboxylate.

[0035] Add 150mL of dichloromethane and 22.7g of thiazoline enol ester to a 500mL four-neck flask, cool down to -5°C, add 10.5g of p-toluenesulfonyl chloride, add 10.6g of sodium carbonate, keep warm for 2h, monitor by TLC, and then add dropwise Morpholine 6.5g, dripped in 10 minutes, stirred for 30min, monitored by TLC, then added dropwise 4.8gBr2, added dropwise in 10 minutes, after 15min, began to drop 3.4g of 30% hydrogen peroxide, dripped in 20 minutes, monitored by TLC, used 8 % sulfuric acid aqueous solution to adjust the pH=0.8~1.0, add catalyst tetrabutylammonium bromide (TBABr) 1.2g, heat up to 30°C and react for 3 hours, monitor by TLC, add water 32mL, fully stir for 10 minutes, separate liquid, organic phase Use 2% sodium bicarbonate to adjust pH=7, wash the above organic phase with 100mL water twice, combine all the above water phases, extract the combined water phase ...

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Abstract

The invention belongs to the field of preparation methods for compounds and particularly relates to a method for preparing 7-phenylacetylamino-3-hydroxyl-3-cyclo-4-p-nitrobenzyl cephalosporin carboxylate. The 7-phenylacetylamino-3-hydroxyl-3-cyclo-4-p-nitrobenzyl cephalosporin carboxylate is prepared from thiazoline enol ester, which serves as a raw material, by a one-pot method through acylation, ene-amination, bromization and cyclization. According to the method, through one-pot method continuous reactions, the operation is simple, the total reaction time is shortened, and the energy consumption is greatly lowered; and the reaction process is carried out at normal temperature or under the condition of being close to room temperature, the reaction conditions are mild, the reaction time is relatively short, the raw materials used are readily available, the cost is low, the pollution is light, the total yield reaches 82.5% or more, the purity can reach 98.0% or more, and the quality of the product is relatively good, so that the method is applicable to industrial production.

Description

technical field [0001] The invention belongs to the field of compound preparation methods, and in particular relates to a preparation method of 7-phenylacetamido-3-hydroxyl-3-cephalosporin-4-carboxylic acid p-nitrobenzyl ester. Background technique [0002] 7-Amino-3-chloro-3-cephalosporin-4-carboxylic acid is the key mother nucleus for the preparation of antibiotic cefaclor, referred to as 7-ACCA, and 7-phenylacetamido-3-hydroxyl-3-cephalosporin-4- Carboxylic acid p-nitrobenzyl ester is a key intermediate for the preparation of 7-amino-3-chloro-3-ceph-4-carboxylic acid. But the technology of my country's production 7-amino-3-chloro-3-cephalosporin-4-carboxylic acid is still immature at present, and the preparation cost of each intermediate is higher, and yield is low, pollutes serious simultaneously, makes the production of multiple cephalosporins Production is constrained. [0003] In the preparation method described in the patent whose application publication number is C...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/59C07D501/10
CPCC07D501/59C07D501/10
Inventor 王文秀吴金跃
Owner SHAXING CHEM TAIZHOU CITY
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