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Low-cost preparation method for cefixime

A technology of cefixime and cefixime active ester, which is applied in the field of preparation of cefixime, can solve the problems of high process environmental protection pressure, etc., and achieve the effect of short process route, low cost and stable quality

Active Publication Date: 2019-07-23
GUANGDONG LIGUO PHARMACY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The purpose of the present invention is to provide a low-cost method for preparing cefixime, which solves the problem of high environmental protection pressure in the existing process

Method used

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  • Low-cost preparation method for cefixime
  • Low-cost preparation method for cefixime
  • Low-cost preparation method for cefixime

Examples

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preparation example Construction

[0026] The present invention provides a low-cost preparation method of cefixime, including:

[0027] S1. React with D-7-ACA (hydroxymethyl-7-aminocephalosporanic acid, CAS number: 15690-38-7) and cefixime active ester (MICA active ester, CAS number: 246035-38-1) The first intermediate is obtained; specifically, the mass ratio of D-7-ACA to cefixime active ester is 1:1.7 to 3.5, that is, 1:1.7 to 1:3.5, and the mass ratio of D-7-ACA and Add tetrahydrofuran and water to the active ester of cefixime, and slowly add tetrahydrofuran and triethylamine dropwise while stirring at -10~30℃, keep at -10~30℃, and detect by HPLC until D-7-ACA The residue on the HPLC chart is less than 0.5% (area normalization method) to obtain the reaction liquid of the first intermediate, the reaction liquid of the first intermediate is extracted with an organic solvent, the organic solvent phase after extraction is recovered, and the aqueous phase Adjust the pH to 2.5-4.5 with an acid solution, and filter ...

Embodiment 1

[0038] In a 1000 ml reaction flask, add 40.0 g of D-7-ACA, 80 g of cefixime active ester, 280 ml of THF (tetrahydrofuran), and 268 ml of pure water. While stirring, control the temperature to 0-5°C, slowly add 40ml THF+28ml TEA (triethylamine) dropwise, maintain the temperature for about 1 hour and complete the addition. After the addition, maintain the temperature for 10 hours, and HPLC detects that the residual D-7-ACA is low. The reaction is complete at 0.5%. It was extracted twice with 400ml ethyl acetate, and the ethyl acetate phase was recovered after extraction. The aqueous phase was adjusted to pH 3.9-4.0 with 9% dilute hydrochloric acid to crystallize, filtered and dried to obtain about 80.2g of the first intermediate.

[0039] In a dry and anhydrous reaction flask, add 60.0g of the first intermediate, add 250ml of dichloromethane, add 20ml of DMA, stir and reduce the temperature to 0~10℃, add 32g of phosphorus pentachloride in batches, keep the temperature and stir for ...

Embodiment 2

[0042] In a 1000 ml reaction flask, add 40.0 g of D-7-ACA, 72 g of cefixime active ester, 280 ml of THF (tetrahydrofuran), and 268 ml of pure water. While stirring, control the temperature at -10~5℃, slowly add 40ml THF+28ml TEA (triethylamine) dropwise, maintain the temperature for about 1 hour and complete the addition. After the addition, maintain the temperature and react for 12 hours. HPLC detects D-7-ACA residue Less than 0.5% of the reaction is complete. It was extracted twice with 400ml ethyl acetate, and the ethyl acetate phase was recovered after extraction. The aqueous phase was adjusted to pH 3.3-3.5 with 9% dilute hydrochloric acid to crystallize, filtered and dried to obtain about 79.3g of the first intermediate.

[0043] In a dry and anhydrous reaction flask, add 60.0g of the first intermediate, add 250ml of dichloromethane, add 20ml of DMA, stir and reduce the temperature to -10~0℃, add 30g of phosphorus pentachloride in batches, maintain the temperature and stir ...

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Abstract

The invention relates to a low-cost preparation method for cefixime. The low-cost preparation method comprises the following steps: enabling D-7-ACA and cefixime active ester to react to obtain a first intermediate; enabling the first intermediate and phosphorus pentachloride to react to obtain the reaction liquid of a second intermediate; enabling the reaction liquid of the second intermediate, sodium iodide, triphenylphosphine and formaldehyde to react to obtain a third intermediate; hydrolyzing the third intermediate by alkali liquor, adding acid after hydrolysis to regulate pH (Potential of Hydrogen), and carrying out crystallization to obtain the cefixime. According to the low-cost preparation method for the cefixime, the D-7-ACA is adopted as a starting material, and the molecular weight of the D-7-ACA is about half smaller than the molecular weight of GCLE (7-phenylacetamide-3-chloromethyl cephalosporanic acid p-methoxyl benzyl ester), so that the effective mole number of the D-7-ACA which is taken as the starting material is two times or above higher than the effective mole number of the GCLE, obviously, the cost is low, the quality is stable, and in addition, a process route is short.

Description

Technical field [0001] The invention relates to the technical field of medicines, in particular to a low-cost preparation method of cefixime. Background technique [0002] Cefixime is a third-generation cephalosporin antibiotic developed by Fujisawa, Japan for oral use. It is suitable for the treatment of respiratory, urinary and biliary infections caused by sensitive bacteria. Cefixime is highly stable to the β-lactamase produced by gram-negative bacilli. Its antibacterial effect on gram-negative bacilli is stronger than that of the first and second generation cephalosporins, and its antibacterial effect on gram-positive cocci is not as good as that of the first and second generation cephalosporins. The second generation cephalosporin. [0003] my country introduced domestic cefixime raw materials as early as around 2000. At that time, the common process was based on GCLE (7-phenylacetamido-3-chloromethylcephalosporanic acid p-methoxybenzyl ester, the molecular formula is C 24 H ...

Claims

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Application Information

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IPC IPC(8): C07D501/22C07D501/04
CPCC07D501/22C07D501/04
Inventor 曾良兵杜穿邓德福曾建江刘荣威罗文津
Owner GUANGDONG LIGUO PHARMACY
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