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Original quality cefuroxime acid and drug preparation thereof

A technology of cefuroxime acid and cefuroxime sodium, applied in drug delivery, medical preparations containing active ingredients, antibacterial drugs, etc. Increased fat solubility, less impurities, and high yield

Active Publication Date: 2016-03-30
广东金城金素制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The common process of cefuroxime acid is to use 7-aminocephalosporanic acid as the starting material, and carry out N-acylation reaction with furoacetyl chloride at the 7-position; among them, there is an isomer (E)-2-formazan in the furan ammonium salt product Oxyimino-2-(furan-2-yl) ammonium acetate, although the content of the trans isomer in the furan ammonium salt product can be less than 0.1%, furan ammonium salt and thionyl chloride, phosphorus pentachloride, When strong acidic reagents such as oxalyl chloride, phosgene, and p-toluenesulfonyl chloride carry out acyl chloride reaction, this will inevitably make the content of (E)-2-methoxyimino-2-(furan-2-yl)acetyl chloride increase, and then increase the content of trans isomers in cefuroxime acid, affecting product purity; patents such as CN101613359, CN102134252A, and CN101928292A are such methods

Method used

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  • Original quality cefuroxime acid and drug preparation thereof

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preparation example Construction

[0019] A kind of preparation method of original research quality cefuroxime acid, the synthetic route is as follows:

[0020]

Embodiment 1

[0022] Preparation of Intermediate 1

[0023] In a 500ml three-necked reaction flask, add 18.6 grams of furan ammonium salt, 36.5 grams of dibenzothiazole disulfide, 5 ml of aniline, 200 ml of dichloromethane, and 100 ml of acetonitrile, stir evenly, then add 10.2 g of triethylamine, stir and heat up to 30~ 35°C, put 19.9 grams of triethyl phosphite into the dropping funnel, drop it within 1.0-2.0 hours, continue the heat preservation reaction for 1.0 hours, when the remaining ammonium furan salt is less than 1% as detected by HPLC, cool down to 0-5°C and analyze After crystallization for 1.0 hour, 29.7 g of intermediate 1 was obtained by suction filtration and drying, with a yield of 93.4% and a purity of 99.4% by HPLC.

[0024] Preparation of Intermediate 2

[0025] Add 27.2g of 7-ACA into a 500ml three-necked bottle, then add 100ml of purified water and 150ml of ethanol, stir evenly, cool down to below -20°C, use 10% aqueous sodium hydroxide solution to adjust the pH to 11...

Embodiment 2

[0031] The preparation of intermediate 1, with embodiment 1

[0032] The preparation of intermediate 2, with embodiment 1

[0033] Preparation of Cefuroxime Acid

[0034] In a 1000ml three-necked reaction flask, add 150ml tetrahydrofuran, add 29.7g of intermediate 1 and 21.0g of intermediate 2 in turn, and stir at room temperature for 2.0 hours; after the completion of the reaction of intermediate 2 by HPLC, cool the reaction solution to below -30°C , add 32.3 g of chlorosulfonyl isocyanate (n=2.5) dropwise, and after insulated and stirred for 1.0 hour, add 200 ml of purified water dropwise, and naturally heat up to 0-5° C. to obtain a cefuroxime acid reaction solution;

[0035] Refining Treatment of Cefuroxime Acid

[0036] Add 350ml of dichloromethane to the cefuroxime acid reaction solution, stir and separate at 0-5°C, wash the organic phase with 100ml of 1.0mol / L hydrochloric acid aqueous solution and 100ml of saturated saline twice, wash the organic phase with 10 400ml...

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Abstract

The invention discloses original quality cefuroxime acid and a drug preparation thereof. A preparation method of original quality cefuroxime acid comprises the following steps: (1), adding SMIA, dibenzothiazyl disulfide, phenylamine, dichloromethane, acetonitrile and triethylamine into a reaction bottle, stirring and increasing the temperature, dropwise adding triethyl phosphate, carrying out thermal reaction, cooling for crystallization, carrying out suction filtration, and drying to obtain an intermediate 1; (2), after hydrolyzing, crystallizing 7-ACA, filtering, and drying to obtain an intermediate 2; (3), in a tetrahydrofuran solvent, enabling the intermediate 1 and the intermediate 2 to be subjected to N-acylation reaction, after reaction, dropwise adding chlorosulfonyl isocyanate, and hydrolyzing to obtain cefuroxime acid reaction liquid; (4), purifying the cefuroxime acid reaction liquid to obtain cefuroxime acid products. The preparation method can effectively reduce the content of isomers and solve the residue problem of an accelerator M, is easy to operate, reliable in quality, and suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an original quality cefuroxime acid and its pharmaceutical preparation. Background technique [0002] Cefuroxime is a second-generation cephalosporin with broad-spectrum antibacterial effect and high stability to the hydrolytic enzymes produced by bacteria that destroy the drug effect, thus ensuring excellent antibacterial activity. Excellent curative effect on infections caused by germs. Cefuroxime sodium was first developed and listed by Glaxo (Glaxo) in the UK in 1975. The original product name developed by Glaxo was Xilixin, and the product name developed and listed by Eli Lilly (Lifule, Chinnut) Ingots), the raw material of cefuroxime sodium produced by ACSDobfar S.P.A complied with the audit of the original development standard, after which the corresponding preparation company realized sub-package production. Adverse reactions rarely occur in clinical application, and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/34C07D501/06A61K31/546A61K9/19A61P31/04
CPCA61K9/0019A61K9/19A61K31/546C07D501/06C07D501/34
Inventor 傅苗青赵叶青孙滨许蕾朱旭伟马庆双周白水王雷
Owner 广东金城金素制药有限公司
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