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Original development quality ceftazidime and medicine preparation thereof

A technology of ceftazidime and ceftazidime side chain acid, which is applied in the field of ceftazidime and its pharmaceutical preparations, can solve the problems of low yield, difficult to handle, high production cost, etc., and achieve the effects of reducing production cost, reducing waste residue, and improving product quality

Active Publication Date: 2016-06-08
广东金城金素制药有限公司 +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this method is that dichloromethane is used as the solvent, the solubility of the product is too large, the yield is low, the price of triphenylphosphine is expensive, and the production cost is high
[0008] Therefore, for the existing synthetic route of ceftazime, in the process of preparing ceftazidime side chain acid active ester and ceftazidime hydrochloride, the condensing agent triphenylphosphine that uses has high toxicity, and cost is high, and reaction by-product triphenoxyphos and DM cannot be effectively recovered, and the amount of waste water and residue is large and difficult to handle, which is not conducive to industrial production

Method used

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  • Original development quality ceftazidime and medicine preparation thereof

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preparation example Construction

[0031] The preparation process flow chart of ceftazidime provided by the invention is as follows figure 1 As shown, in a mixed solvent of toluene and acetonitrile, add ceftazidime side chain acid and dibenzothiazole disulfide, then add aniline, 2-picoline, and then dropwise add triethyl phosphite to establish the preparation of ceftazidime side chain After the reaction is completed, the temperature of the active ester reaction system is cooled down and filtered with suction to obtain the crude product of the active ester of ceftazidime side chain acid; the crude product is refined to obtain the active ester of ceftazidime side chain acid, and the first mother liquor is recovered; in methanol and dichloromethane In the mixed solvent, add ceftazidime side chain acid active ester and 7-APCA, add triethylamine dropwise while stirring, after the reaction is completed, cool down and crystallize, suction filter to obtain ceftazidime tert-butyl ester, and the second mother liquor is rec...

Embodiment 1

[0035] Controlling around 20°C, add 30g of ceftazidime side chain acid and 30g of DM30g to a mixture of 100ml of toluene and 50ml of acetonitrile, add 8.0g of aniline, 0.4g of 2-methylpyridine, and then dropwise add 4.5g of triethyl phosphite. After the reaction is completed, the temperature is lowered, and the crude product is obtained by post-treatment, and the active ester of ceftazidime side chain acid is obtained after purification, with a yield of 95.1% and a purity of 99%. Among them, the crude first mother liquor was recovered and concentrated to obtain 25 g of concentrated waste residue, numbered 1.

[0036] Control 0~10℃, add 31.2g of ceftazidime side chain acid active ester and 25g of 7-APCA into 25ml methanol and 100ml dichloromethane mixed solvent, add 12.5ml triethylamine dropwise, after the insulation reaction is completed, filter to obtain ceftazidime tert-butyl ester , The yield is 86.5%, and the purity is 97.5%. The second mother liquor of the crude product was...

Embodiment 2

[0039] Controlling around 20°C, add 30g of ceftazidime side chain acid and 30g of DM30g to a mixture of 100ml of toluene and 50ml of acetonitrile, add 8.0g of aniline, 0.4g of 2-methylpyridine, and then dropwise add 6.0g of triethyl phosphite. After the reaction is completed, the temperature is lowered, and the crude product is obtained by post-treatment, and the active ester of ceftazidime side chain acid is obtained after purification, with a yield of 95.5% and a purity of 99%. Among them, the crude first mother liquor was recovered and concentrated to obtain 25 g of concentrated waste residue, numbered 1.

[0040] Control 0~10℃, add 31.2g of ceftazidime side chain acid active ester and 25g of 7-APCA into 25ml methanol and 100ml dichloromethane mixed solvent, add 12.5ml triethylamine dropwise, after the insulation reaction is completed, filter to obtain ceftazidime tert-butyl ester The yield is 87.1%, and the purity is 97.9%. The second mother liquor of the crude product was r...

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Abstract

The invention discloses original development quality ceftazidime and a medicine preparation thereof. The third-generation cephalosporin antibiotics active ester midbody key technology and industrialization obtains the second prize of National Scientific and Technological Progress Award. The cephalosporin antibiotics active ester belongs to a key factor for influencing the internal quality of the cephalosporin. A preparation method comprises the following steps that (a) mixed solvents are added into ceftazidime side chain acid, dibenzothiazyl disulfide, aniline and 2-picoline; triethyl phosphate is dripped for reaction; (b) a coarse product is refined to obtain ceftazidime side chain acid active ester, and the first mother liquid is recovered; (c) the material is added into a mixed solvent for neutralizing 7-APCA; triethylamine is dripped; the temperature reduction is performed for crystal separation and filtering to obtain ceftazidime tert-butyl ester; the second mother liquid is recovered; (d) the ceftazidime tert-butyl ester is subjected to hydrolysis and purification, and then, the ceftazidime is obtained. The original development quality ceftazidime has the advantages that high-toxicity triphenylphosphine is not used; waste liquid and waste slag can be sufficiently recovered and reutilized; the method is safe; the cost is low; the yield is high; the industrial production is facilitated.

Description

Technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a ceftazidime and its pharmaceutical preparations. Background technique [0002] Ceftazidime is an antibiotic with outstanding curative effect against Pseudomonas aeruginosa. It is one of the important third-generation semi-synthetic cephalosporin antibiotics. It has the characteristics of strong bactericidal power and broad antibacterial spectrum. It is widely used in clinical practice and is currently on the market. One of the latest cephalosporin drugs on the market. [0003] At present, the synthesis method of ceftazidime mainly uses ceftazidime side chain acid as raw material, and reacts with dibenzothiazole disulfide (DM) under the catalysis of organic bases to generate ceftazidime side chain acid active ester; and then with 7-amino-3 -(1-pyridylmethyl)cephalosporin (7-APCA) undergoes a series of reactions to produce ceftazidime. [0004] Jincheng Pharmaceutical’s "Key Technolog...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/46C07D501/04A61K31/546A61K9/14A61P31/04
CPCA61K9/0019A61K9/14A61K31/546C07D501/04C07D501/46
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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