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Green synthetic method for cefotaxime acid

A green synthesis technology of cefotaxime acid, applied in organic chemistry, antibacterial drugs, etc., can solve the problems of damage to the central nervous system and respiratory system, strong skin and mucous membrane irritation, low recovery rate of dichloromethane, etc., and achieve production The effect of low cost, good product quality and easy operation

Inactive Publication Date: 2009-10-07
ZHEJIANG UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The recovery rate of dichloromethane is low, it accumulates in groundwater, and has certain toxicity. It is highly irritating to the skin and mucous membranes, and damages the central nervous system and respiratory system; both tetrahydrofuran and acetone are easily miscible with water and difficult to recover. Applied, resulting in higher cost

Method used

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  • Green synthetic method for cefotaxime acid
  • Green synthetic method for cefotaxime acid
  • Green synthetic method for cefotaxime acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] The amount ratio of feeding material is 7-ACA: AE-active ester: organic base=1: 1.0: 0.4; Described organic base is triethylamine, and the consumption of 2-methyltetrahydrofuran is 4 times of 7-ACA feeding quality, The consumption of water is 0.6 times of 7-ACA feeding quality.

[0040] Control the temperature at 23±2°C (t), add 7-ACA (250.0g, 0.918mol) and AE-active ester (321.7g, 0.918mol) in a mixed solvent consisting of 2-MeTHF (1000g) and water (150g) , and triethylamine (37.1 g, 0.367 mol) was added simultaneously, and the reaction was stirred for 2 hours (T). The pH of the reaction solution was adjusted to 2.5±0.3 with 6 mol / L dilute hydrochloric acid, and a white solid was precipitated, filtered and dried to obtain 407.7 g of cefotaxime acid with a yield of 97.5% and a purity of 98.9% by HPLC. The filtrate was distilled under normal pressure to reclaim 1096g of the azeotropic liquid of 2-methyltetrahydrofuran and water (containing 2-MeTHF 980g), and the by-prod...

Embodiment 2

[0042]The molar ratio of the feed material is 7-ACA:AE-active ester:organic base=1:1.3:0.05; the organic base is pyridine. The specific addition is 250.0g (0.918mol) 7-ACA, 418.1gMEAM (1.193mol), 3.6g (0.046mol) pyridine, the consumption of 2-methyltetrahydrofuran is 1750g, and the consumption of water is 37.5g; It is 2mol / L, and the initial pH of crystallization is 2.85; t=20±2°C, T=2 hours.

[0043] Other operations are the same as in Example 1. 409.3 g of cefotaxime acid was obtained with a yield of 97.9% and a purity of 98.7% by HPLC. Recover 1770 g of azeotropic liquid of 2-methyltetrahydrofuran and water (containing 1743 g of 2-MeTHF), and 146.2 g of by-product 2-mercaptobenzothiazole.

Embodiment 3

[0045] The molar ratio of the feed material is 7-ACA:AE-active ester:organic base=1:1.8:0.5; the organic base is N-methylpyrrole. The specific addition amount is 250.0g (0.918mol) 7-ACA, 579.1g (1.652mol) MEAM, 37.7g (0.459mol) N-methylpyrrole, the amount of 2-methyltetrahydrofuran is 750g, and the amount of water is 250g; The concentration of the hydrochloric acid is 1mol / L, the initial pH of crystallization is 1.5; t=18±2°C, T=2.5 hours.

[0046] Other operations are the same as in Example 1. 411.0 g of cefotaxime acid was obtained with a yield of 98.3% and a purity of 98.5% by HPLC. Recover 818 g of azeotropic liquid of 2-methyltetrahydrofuran and water (containing 736 g of 2-MeTHF), and 145.1 g of by-product 2-mercaptobenzothiazole.

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Abstract

The invention discloses a green synthetic method for cefotaxime acid showed in formula (I), which comprises the following steps: adding 2-methyl tetrahydrofuran, water, 7-Aminocephalosporanic acid showed in formula (II), AE-active ester showed in formula (III) and organic base into a reaction vessel; reacting at the temperature of 0-40 degrees for 1-2 hours; adjusting system pH value to 1-3 by diluted hydrochloric acid after the reaction; precipitating solid, filtering to obtain filter cake and filtrate; and drying the filter cake to obtain cefotaxime acid. the organic base is organic amine or pyridine compound; the ratio of the 7-Aminocephalosporanic acid, the AE-active ester and the organic base is 1.0:1.0-1.8:0.01-1.5. The invention prepares cefotaxime acid in 2-methyl tetrahydrofuran which is a green solvent, avoids the using of poisonous harmful solvent such as dichloromethane; has the advantages of mild condition, good product quality, high yield and low production cost; achieves higher industrial value and potential social economic benefit.

Description

(1) Technical field [0001] The invention relates to a green synthesis method of cefotaxime acid, in particular to an environmentally friendly process for preparing cefotaxime acid by using green solvent 2-methyltetrahydrofuran (2-MeTHF) instead of toxic and harmful solvents such as dichloromethane, belonging to the pharmaceutical chemical industry field. (2) Background technology [0002] Cefotaxime sodium is a third-generation cephalosporin antibiotic widely used clinically, and cefotaxime acid is the main raw material of cefotaxime sodium. With the increasingly fierce market competition, the quality requirements for cefotaxime sodium are more stringent. In order to increase the yield of cefotaxime sodium and improve the color grade of the product, it is undoubtedly imperative to develop a new synthesis process for cefotaxime acid. [0003] At present, the synthesis of cefotaxime acid mainly adopts active ester method, such as: phosphorous active ester method, triazone act...

Claims

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Application Information

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IPC IPC(8): C07D501/34C07D501/06A61P31/04
Inventor 钟为慧洪玲娟汤有坚郑叶敏苏为科方善综
Owner ZHEJIANG UNIV OF TECH
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