CN110117291B - Synthesis method of cefotaxime acid - Google Patents

Abstract

The invention provides a synthetic method of cefotaxime acid, which comprises the following steps: (a) adding 7-aminocephalosporanic acid and benzothiazole active ester into a mixed solvent consisting of aqueous dichloromethane and a cosolvent, and uniformly stirring to obtain a mixed solution; (b) adding purified water and triethylamine into the mixed solution obtained in the step (a) for acylation reaction, wherein the reaction time is 50-80 min, and obtaining a reaction solution; (c) and extracting the reaction solution by using water, adding hydrochloric acid into the extraction solution to adjust the pH value to 2.5-3.0, crystallizing, filtering and drying to obtain cefotaxime acid. The invention provides a method for synthesizing cefotaxime acid by adding a certain amount of water into aqueous dichloromethane (the water content is 0.1-0.2%), which reduces the recovery difficulty of dichloromethane by applying the aqueous dichloromethane (the water content is 0.1-0.2%), achieves the purpose of energy saving, and simultaneously obtains the high-purity cefotaxime acid.

Description

Synthesis method of cefotaxime acid

Technical Field

The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a synthetic method of cefotaxime acid.

Background

The chemical name of cefotaxime acid is (6R, 7R) -3- [ (acetoxyl) methyl ] -7- [ (2-amino-4-thiazolyl) - (methoxyimino) acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid, which is the third generation cephalosporin, is the main raw material of cephalosporin-cefotaxime sodium for injection, and is applicable to pneumonia and other lower respiratory tract infections, urinary tract infections, meningitis, septicemia, abdominal cavity infections, pelvic cavity infections, skin soft tissues, genital tract infections, bone and joint infections and the like caused by sensitive bacteria.

At present, the synthesis method is mainly an AE active ester method, and WO9620198 reports that an AE-active ester (MEAM) is obtained by reacting bis (2-benzothiazole) Disulfide (DM) with aminothiazoly loximate, and then the AE-active ester (MEAM) is condensed with 7-ACA to obtain cefotaxime acid and obtain a byproduct 2-thio benzothiazole (M). The report uses acetone as a solvent, triethylamine is added under stirring, and after the reaction is finished, acid is added for crystallization to prepare the cefotaxime acid, which is the current method for industrially producing the cefotaxime acid.

Some improvements on the above basis have been subsequently reported, such as: CN 101560217A reports that dichloromethane or trichloromethane is used as a solvent, and after the reaction is finished, acidifying agent is directly added for acidification and then crystallization is carried out to prepare cefotaxime acid; CN101550149A reports that cefotaxime acid is prepared by taking 2-methyltetrahydrofuran as a solvent, adding an organic base, and adding acid for crystallization after the reaction is finished. CN 101613360A reports that dichloromethane is used as solvent, triethylamine is added under stirring, after the reaction is finished, water is used for extracting condensed reaction liquid, and the water extract is decolored and crystallized to prepare cefotaxime acid.

In the method using dichloromethane as a solvent, anhydrous dichloromethane is not needed for the acylation reaction of cefotaxime acid, however, in practical application, the recycled dichloromethane contains part of water, the processing difficulty of recycling dichloromethane is high, and the cost is high, so that how to research a preparation method more suitable for industrial production while ensuring the high purity of the product has important practical significance.

Disclosure of Invention

The invention aims to provide a synthetic method of cefotaxime acid, and aims to solve the problems of high difficulty and high cost in the recovery of dichloromethane in the conventional method.

The purpose of the invention is realized by the following technical scheme: a synthetic method of cefotaxime acid comprises the following steps:

(a) adding 7-aminocephalosporanic acid and benzothiazole active ester into a mixed solvent consisting of aqueous dichloromethane and a cosolvent, and uniformly stirring to obtain a mixed solution;

(b) adding purified water and triethylamine into the mixed solution obtained in the step (a) for acylation reaction, wherein the reaction time is 50-80 min, and obtaining a reaction solution;

(c) and extracting the reaction solution by using water, adding hydrochloric acid into the extraction solution to adjust the pH value to 2.5-3.0, crystallizing, filtering and drying to obtain cefotaxime acid. The synthesis reaction of cefotaxime acid is shown in figure 1.

The mass ratio of the 7-aminocephalosporanic acid to the benzothiazole active ester is 1: 1.3, and the addition amount of the purified water is 0.5-3%, preferably 2% of the mass of the 7-aminocephalosporanic acid.

The water content of the dichloromethane with water is 0.1-0.2%.

The cosolvent is an alcohol cosolvent or an amide cosolvent, and the adding amount of the cosolvent is 20-200% of the weight of 7-ACA, and is preferably 100%.

The alcohol cosolvent is methanol, ethanol or isopropanol. Ethanol and isopropanol are preferred.

The amide cosolvent is methyl formamide, methyl acetamide, N-dimethyl formamide or dimethyl acetamide. N, N-Dimethylformamide (DMF), Dimethylacetamide (DMAC) are preferred.

The invention has the following technical progress and beneficial effects:

the invention provides a method for synthesizing cefotaxime acid by adding a certain amount of water into aqueous dichloromethane (the water content is 0.1-0.2%), which reduces the recovery difficulty of dichloromethane by applying the aqueous dichloromethane (the water content is 0.1-0.2%), achieves the purpose of energy saving, and simultaneously obtains the high-purity cefotaxime acid.

According to the invention, the reaction time is shortened, the product conversion rate is improved, crystallization and filtration are carried out after HPLC detection reaction is completed, the purity of the obtained cefotaxime acid product is more than or equal to 98%, the quality is ensured within the product validity period, the yield reaches more than 98.5%, and the method is suitable for industrial popularization and application.

Drawings

FIG. 1 shows the reaction scheme for the synthesis of cefotaxime acid. Wherein 1 is cefotaxime acid, 2 is 7-ACA, and 3 is AE-active ester.

Detailed Description

Example 1

Mixing 20.0g of 7-ACA and 26.0g of AE-active ester in a mixed solvent of 100mL of aqueous dichloromethane (water content: 0.17%) and 20mL of ethanol, adding 4mL of purified water and 17mL of triethylamine, reacting for 60min, extracting an organic phase twice with water, decoloring, adjusting pH to 2.5-3.0 with hydrochloric acid, growing crystals for 1h, performing suction filtration to obtain 37g of cefotaxime acid wet powder, drying to obtain 33.38 g of cefotaxime acid, and detecting that the purity of the cefotaxime acid is 99.5% and the water content is 0.6%, wherein the water content is specifically shown in Table 1.

Comparative example 1

Mixing 20.0g of 7-ACA and 26.0g of AE-active ester in a mixed solution of 100mL of anhydrous dichloromethane (water content: 0.05%), 20mL of anhydrous ethanol and 17mL of triethylamine, reacting for 180min, extracting an organic phase with water twice, decoloring, adjusting the pH value to be 2.5-3.0 with hydrochloric acid, growing crystals for 1h, performing suction filtration to obtain 35g of cefotaxime acid wet powder, drying to obtain 31.34 g of cefotaxime acid, and detecting that the purity of the cefotaxime acid is 98.1% and the water content is 0.6%, wherein the water content is shown in Table 1.

Example 2

Mixing 20.0g of 7-ACA and 26.0 gAE-active ester in a mixed solvent consisting of 100mL of aqueous dichloromethane (water content: 0.18%) and 20mL of ethanol, adding 4mL of purified water and 17mL of triethylamine, reacting for 50min, extracting an organic phase twice with water, decoloring, adjusting the pH value to be 2.5-3.0 with hydrochloric acid, growing crystals for 1h, performing suction filtration to obtain 37g of cefotaxime acid wet powder, drying to obtain 33.66 g of cefotaxime acid, wherein the purity is 99.4% and the water content is 0.6%, and the content is shown in Table 1.

Example 3

Mixing 20.0g of 7-ACA and 26.0 gAE-active ester in a mixed solvent consisting of 100mL of aqueous dichloromethane (water content: 0.18%) and 20mL of DMF, adding 3mL of purified water and 17mL of triethylamine, reacting for 80min, extracting an organic phase twice with water, decoloring, adjusting the pH value to be 2.5-3.0 with hydrochloric acid, growing crystals for 1h, performing suction filtration to obtain 37g of cefotaxime acid wet powder, drying to obtain 33.17 g of cefotaxime acid, wherein the purity is 99.3% and the water content is 0.7%, and the specific formula is shown in Table 1.

Example 4

Mixing 20.0g of 7-ACA and 26.0 gAE-active ester in a mixed solvent consisting of 100mL of aqueous dichloromethane (water content: 0.18%) and 15mL of DMA, adding 3mL of purified water and 17mL of triethylamine, reacting for 70min, extracting an organic phase twice with water respectively, decoloring, adjusting the pH value to be 2.5-3.0 by hydrochloric acid, growing crystals for 1h, performing suction filtration to obtain 37g of cefotaxime acid wet powder, drying to obtain 33.24g of cefotaxime acid, wherein the purity is 99.0% and the water content is 0.7%, and the specific formula is shown in Table 1.

Table 1:

example 5

Examples of industrial applications:

mixing 100Kg of 7-ACA and 130Kg of AE-active ester in a mixed solvent consisting of 500L of aqueous dichloromethane (water content: 0.17%) and 75L of LDMA, adding 15L of purified water and 85L of triethylamine, reacting for 70min, extracting an organic phase with water twice, decoloring, adjusting pH to 2.5-3.0 with hydrochloric acid, growing crystals for 1h, performing suction filtration to obtain 186Kg of cefotaxime acid wet powder, and drying to obtain 116.5Kg of cefotaxime acid, wherein the purity is 99.4% and the water content is 0.6%.

Claims (1)

1. A synthetic method of cefotaxime acid is characterized by comprising the following steps:

(a) adding 7-aminocephalosporanic acid and benzothiazole active ester into a mixed solvent consisting of aqueous dichloromethane and a cosolvent, and uniformly stirring to obtain a mixed solution;

the mass ratio of the 7-aminocephalosporanic acid to the benzothiazole active ester is 1: 1.3;

the water content of the dichloromethane with water is 0.1-0.2%;

the cosolvent is an alcohol cosolvent or an amide cosolvent, the alcohol cosolvent is methanol, ethanol or isopropanol, and the amide cosolvent is methyl formamide, methyl acetamide, N-dimethyl formamide or dimethyl acetamide;

(b) adding purified water and triethylamine into the mixed solution obtained in the step (a) for acylation reaction, wherein the reaction time is 50-80 min, and obtaining a reaction solution;

the adding amount of the purified water is 0.5-3% of the mass of the 7-aminocephalosporanic acid;

(c) and extracting the reaction solution by using water, adding hydrochloric acid into the extraction solution to adjust the pH value to 2.5-3.0, crystallizing, filtering and drying to obtain cefotaxime acid.

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