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Cefmenoxime hydrochloride compound containing 1/2 of water and pharmaceutical composition preparation thereof

A technology of cefmenoxime hydrochloride and its compound, which is applied in the field of preparation of 1/2 water cefmenoxime hydrochloride compound and its pharmaceutical composition, and can solve problems such as poor crystal form, complex process, and difficult recovery of solvents

Inactive Publication Date: 2019-01-04
陈立平
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the past, the synthesis process of cefmenoxime hydrochloride was long and complex, and the conversion rate of the organic solvent used was low. The solvent was not easy to recover, and other separation methods such as adsorption were required. Instead of using a single recrystallization method, the obtained crystal form was not good. , not easy to separate and dry
[0005] The present invention is dedicated to solving the problems of too long synthetic route and complex process, improving the conversion rate of the product, and preparing a single crystal form of cefmenoxime hydrochloride compound. The process route is simple, the synthesis yield is high, and the production cost is reduced. The method for preparing crystals is suitable for industrial production

Method used

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  • Cefmenoxime hydrochloride compound containing 1/2 of water and pharmaceutical composition preparation thereof
  • Cefmenoxime hydrochloride compound containing 1/2 of water and pharmaceutical composition preparation thereof
  • Cefmenoxime hydrochloride compound containing 1/2 of water and pharmaceutical composition preparation thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1: Preparation of 1 / 2 water cefmenoxime hydrochloride compound

[0029] making process

[0030](1) In reactor 1, add 7 aminocephalosporanic acid (7ACA) (136g, 0.5mol) and 5-mercapto-1-methyl-1H-tetrazolium (MMT) (70g, 0.6mol) in 600ml three Under the catalysis of boron fluoride ether, react in 1500ml acetonitrile for 2h, control the temperature at 45°C;

[0031] (2) After the above reaction is completed, adjust the pH to 3.6 with concentrated ammonia to precipitate crystals, filter with suction, wash the filter cake with water, and dry in vacuo to obtain off-white solid I;

[0032] (3) Add the above solid I (82g, 0.25mol) into Reactor 2, then add dichloromethane (900ml) and 2-(2aminothiazol-4 base)(cis)-2-methoxyimine Acetylthiobenzothiazole active ester (MEAM) (105 g, 0.3 mol) was added in batches with triethylamine (75 ml) with stirring to adjust the pH of the solution to 7.0, and reacted at room temperature for 4 h. After the reaction, add water to extr...

Embodiment 2

[0037] Embodiment 2: Preparation of 1 / 2 water cefmenoxime hydrochloride compound

[0038] making process

[0039] (1) Add 7 aminocephalosporanic acid (7ACA) (272g, 1mol) and 5-mercapto-1-methyl-1H-tetrazolium (MMT) (139g, 1.2mol) in 600ml trifluoro React in 3000ml of acetonitrile under the catalysis of boron ether for 2.5h, and control the temperature at 50°C;

[0040] (2) After the above reaction is completed, adjust the pH to 3.5 with concentrated ammonia to precipitate crystals, filter with suction, wash the filter cake with water, and dry in vacuo to obtain off-white solid I;

[0041] (3) Add the above solid I (164g, 0.5mol) into Reactor 2, then add dichloromethane (1800ml) and 2-(2aminothiazol-4 base)(cis)-2-methoxyimine Acetylthiobenzothiazole active ester (MEAM) (210 g, 0.6 mol) was added in batches with triethylamine (150 ml) with stirring to adjust the pH of the solution to 7.1, and reacted at room temperature for 5 h. After the reaction, add water to extract, comb...

Embodiment 3

[0046] Embodiment 3: Preparation of 1 / 2 water cefmenoxime hydrochloride compound

[0047] making process

[0048] (1) Add 7 aminocephalosporanic acid (7ACA) (540g, 2mol) and 5-mercapto-1-methyl-1H-tetrazolium (MMT) (280g, 2.4mol) in 1200ml trifluoro React in 6000ml of acetonitrile under the catalysis of boron ether for 3h, and control the temperature at 50°C;

[0049] (2) After the above reaction is completed, adjust the pH to 3.4 with concentrated ammonia to precipitate crystals, filter with suction, wash the filter cake with water, and dry in vacuo to obtain off-white solid I;

[0050] (3) Add the above solid I (320g, 1mol) into Reactor 2, then add dichloromethane (3600ml) and 2-(2-aminothiazol-4 base) (cis)-2-methoxyimine acetyl Thiobenzothiazole active ester (MEAM) (420 g, 1.2 mol) was added in batches with triethylamine (300 ml) with stirring to adjust the pH of the solution to 7.2, and reacted at room temperature for 6 h. After the reaction, add water to extract, comb...

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Abstract

The invention discloses a cefmenoxime hydrochloride compound containing 1 / 2 of water and a pharmaceutical composition preparation thereof. Each mole of cefmenoxime hydrochloride contains 1 / 2 mole of water. 7-amino-cephalosporanic acid (7ACA) is taken as a starting material, firstly reacts with 5-sulfydryl-1-methyl-1H-tetrazole (MMT) to generate 3-(1-methyl-1-tetrazole-5H) methyl sulfide-7-amino-cephalosporanic acid (7ACT) at C-3 position, then reacts with MAEM to synthesize cefmenoxime at C-7 position, and then reacts with hydrochloric acid to form salt, so that the cefmenoxime hydrochloride compound containing 1 / 2 of water is obtained. The operation is simple, the reactants are obtained easily, the reaction conditions are mild, and the yield is high. The cefmenoxime hydrochloride compoundcontaining 1 / 2 of water has low hygroscopicity, low impurity content, good mobility, good thermodynamic stability and wider application prospects.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical industry, in particular to a 1 / 2 water cefmenoxime hydrochloride compound and its pharmaceutical composition preparation. Background technique [0002] Cefmenoxime (cefmenoxime) is the third-generation cephalosporin developed by Japan's Takeda in the 1970s. It was launched in Japan in 1983, and then in the United States, South Korea and other countries. With its broad-spectrum antibacterial activity and anti-β-endo Amidase has high stability and is widely used in the treatment of various infectious diseases caused by sensitive bacteria. [0003] Cefmenoxime is a cell wall synthesis inhibitor, which achieves bactericidal effect by inhibiting the biosynthesis of bacterial cell walls. This product is effective against both Gram-positive and Gram-negative bacteria. Among Gram-positive bacteria, the antibacterial effect on Streptococcus pyogenes and Pneumococcus is also strong. It also...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/36C07D501/06A61K31/546A61P31/04
CPCC07B2200/13C07D501/06C07D501/36
Inventor 陈立平
Owner 陈立平
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