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Cefepime dihydrochloride preparation method suitable for industrial production

A technology for cefepime hydrochloride and cephalosporin, which is applied in the field of preparation of cefepime hydrochloride, can solve the problems of inability to realize industrialized production, high production equipment requirements, and high solvent recovery pressure, and achieves reduction of production cost and environmental protection expenditure, production Low cost and small product loss

Active Publication Date: 2016-08-17
QILU ANTIBIOTICS PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

First of all, because the crystallization process requires a certain sound field effect, the method has high requirements for production equipment. Secondly, a mixture of three organic solvents is used for crystallization, and the solvent recovery pressure is relatively high. In short, there is still a need for this method to be used in large-scale industrial production. areas for further improvement;
[0009] (3) Patent CN103665003A discloses a method for refining high-purity cefepime dihydrochloride monohydrate, but its starting material is cefepime inner salt, because it is not easy to obtain solids, so it has not yet been commercialized production and sales, so this patented method cannot realize industrialized production

Method used

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  • Cefepime dihydrochloride preparation method suitable for industrial production
  • Cefepime dihydrochloride preparation method suitable for industrial production
  • Cefepime dihydrochloride preparation method suitable for industrial production

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1: the preparation of cefepime hydrochloride crude product

[0036] Put 150L of dichloromethane into the reaction bottle, cool down to 0-5°C, add 20kg (67mol) of 7-MPCA, 25kg (71mol) of MAEM, add 1.5L of 6% sulfurous acid solution, keep the temperature not higher than 5°C, slowly Add 11.2L (80mol) of triethylamine, keep warm at 0-5°C after addition, and react until the residue of 7-MPCA is less than 0.5% (HPLC);

[0037] Put 90L of purified water into the reaction bottle, and separate layers; then use 15L of water to back-extract dichloromethane, combine the water layers, add 1kg of activated carbon, decolorize for 1 hour, filter, wash the filter cake with 10L of water, combine the filtrates, and keep the temperature at 15-25 ℃, add 300L of acetone, 0.05kg of seed crystals, grow the crystals for 2 hours until a large amount of precipitation occurs, then use it for 90-120min, add 390L of acetone, cool down to 0-5℃ and stir for 1 hour. Filtration, washing with...

Embodiment 2

[0038] Embodiment 2: Preparation of crude product of cefepime hydrochloride

[0039] Put 150L of dichloromethane into the reaction bottle, cool down to 0-5°C, add 20kg (67mol) of 7-MPCA, 27kg (77mol) of MAEM, add 0.75L of 6% sulfurous acid solution, keep the temperature not higher than 5°C, slowly Add 10.3L (74mol) of triethylamine, keep warm at 0-5°C after the addition, and react until the residual 7-MPCA is less than 0.5% (HPLC);

[0040] Put 90L of purified water into the reaction bottle, and separate layers; then use 15L of water to back-extract dichloromethane, combine the water layers, add 1kg of activated carbon, decolorize for 1 hour, filter, wash the filter cake with 10L of water, combine the filtrates, and keep the temperature at 15-25 ℃, add 320L of isopropanol, 0.05kg of seed crystals, grow the crystals for 2 hours until a large amount of precipitation occurs, then use it for 90-120min, add 400L of isopropanol, cool down to 0-5℃ and stir for 1 hour. Filtration, wa...

Embodiment 3

[0041] Embodiment 3: Preparation of crude product of cefepime hydrochloride

[0042] Put 150L of dichloromethane into the reaction bottle, cool down to 0-5°C, add 20kg (67mol) of 7-MPCA, 26kg (74mol) of MAEM, add 1L of 6% sulfurous acid solution, keep the temperature not higher than 5°C, and add slowly Diisopropylamine 11.3L (80mol), keep warm at 0-5°C after addition, and react until the residual 7-MPCA is less than 0.5% (HPLC);

[0043]Put 90L of purified water into the reaction bottle, and separate layers; then use 15L of water to back-extract dichloromethane, combine the water layers, add 1kg of activated carbon, decolorize for 1 hour, filter, wash the filter cake with 10L of water, combine the filtrates, and keep the temperature at 15-25 ℃, add 360L of ethanol, 0.05kg of seed crystals, grow crystals for 2 hours until a large amount of precipitation occurs, then use for 90-120min, add 420L of ethanol, cool down to 0-5℃ and stir for 1 hour. Filtration, washing with ethanol,...

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Abstract

The invention relates to the technical field of chemical medicine synthesizing, in particular to a cefepime dihydrochloride preparation method suitable for industrial production. The preparation method is characterized in that crude cefepime dihydrochloride is obtained by the acylation reaction of a compound I (7-MPCA) and a compound II (MAEM) and acidizing crystallization, and refining is performed to obtain the high-purify cefepime dihydrochloride. The preparation method has the advantages that a single solvent is used, and recycling and reusing are facilitated; the refining process is performed in an anhydrous system, product degradation under the strong acid condition during the refining process is reduced, and corrosion to production equipment is avoided; the acylation reaction and the refining are simple to operate, extremely high product conversion rate is achieved, production cost is low, and the method is suitable for industrial production of high-quality cefepime dihydrochloride.

Description

(1) Technical field [0001] The invention relates to the technical field of chemical drug synthesis, in particular to a preparation method of cefepime hydrochloride suitable for industrial production. (2) Background technology [0002] Cefepime (BMY-28142, CFPM) is the fourth-generation injectable cephalosporin antibiotic developed by Bristol-Myers Squibb. It was first launched in Sweden in 1993, followed by France and Italy. , Japan, Canada and other countries, listed in the United States in 1996, and entered the Chinese market in 1998. [0003] Compared with the third-generation cephalosporin antibiotics, cefepime has a wider antibacterial spectrum, stronger antibacterial activity, and is more stable to β-lactamase produced by bacteria. Cefepime has good activity against Gram-negative bacteria, especially Pseudomonas aeruginosa, and also has good antibacterial activity against Gram-positive bacteria. Intra-abdominal infection, and empiric treatment of patients with sepsis...

Claims

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Application Information

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IPC IPC(8): C07D501/46
CPCC07D501/46
Inventor 王欣付景龙赵振华侯传山王立汤沸李凤侠王晓艳
Owner QILU ANTIBIOTICS PHARMA
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