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Preparation method of cefquinome sulfate intermediate 7-aminocefquinome

A technology of aminocefaquineme and cefquinoxime sulfate, which is applied in the field of preparation of cefquinoxime sulfate intermediate 7-aminocefaquineme, can solve the problems of slow material reaction, reduced solvent amount, low production efficiency, etc., and achieves reduction The effects of stirring the dead zone, increasing the reaction speed, and increasing the yield

Pending Publication Date: 2021-12-17
CHONGQING MEDICAL & PHARMA COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Existing reaction kettles generally use arc-shaped bottoms. During the reaction, even if the stirring is extended, the materials at the bottom of the kettle cannot be stirred, resulting in the ammonia gas at the bottom of the kettle cannot be discharged smoothly, and the reaction of the materials is slow, resulting in silanization. The reaction takes more than ten hours even if dichloromethane is used as the solution
It takes about 3-4 days for a batch of materials to be finished, and the production efficiency is low
[0009] For this reason, we thought of blowing nitrogen into the reaction solution to take out the ammonia gas as much as possible, but due to the low boiling point of the solvent, the nitrogen gas also took away most of the solvent, resulting in a large reduction in the amount of solvent after the reaction, or even drying up

Method used

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  • Preparation method of cefquinome sulfate intermediate 7-aminocefquinome

Examples

Experimental program
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Effect test

Embodiment 1

[0024] The alkylation reaction kettle includes a reaction kettle body 1, which is a flat-bottomed kettle, and a jacket 2 is provided outside, through which condensed water or a heating medium can be passed through to heat the inside of the kettle. There is a stirring 3 inside, and the stirring 3 extends to the bottom of the alkylation reaction kettle, and the top cover is provided with a feeding port (including a solid material feeding port and a liquid material feeding port, wherein a feeding tube is arranged on the liquid material feeding port), and the alkylation A condensation pipe 4 is inserted on the top cover of the chemical reaction kettle, and a jacket is provided outside the condensation pipe 4 for passing condensed water. The top outlet of the condensation pipe 4 is connected to an ammonia recovery pipe, and the ammonia gas recovery pipe is connected to the ammonia adsorption recovery device 5. Water is contained in the ammonia adsorption device 5 for absorbing the g...

Embodiment 2

[0029] Clean the alkylation reactor, dry it, and cool it for use.

[0030] In a 500L alkylation reactor, add 85kg of dichloromethane, 19.5KG of hexamethyldisilazane, stir, add 25KG of 7-ACA plus 0.22KG of trimethylchlorosilane, stir, and raise the temperature to 53-57°C. The reaction was refluxed for 2 hours.

[0031] After the reaction is complete, lower the temperature to 3-7°C, add 25KG N,N-diethylaniline, and stir evenly. Add 28.5 kg of iodotrimethylsilane to the reaction kettle, and stir for 30 minutes. Steam was introduced to raise the temperature to 15-20°C, and the reaction was stirred for 2.5 hours. After the reaction is complete, lower the temperature to 3-7°C, add 4.5KG tetrahydrofuran, and stir for 20 minutes

[0032] 26KG 5,6,7,8-tetrahydroquinoline and 46.5KG N,N-dimethylacetamide were added, and the reaction was stirred for 6 hours.

[0033] After the reaction is complete, add 150KG dichloromethane, stir evenly, cool down to 3-7°C with chilled water, stir, o...

Embodiment 3

[0036] Clean the alkylation reactor, dry it, and cool it for use.

[0037] In a 500L alkylation reactor, add 85kg of dichloromethane, 19.5KG of hexamethyldisilazane, stir, add 25KG of 7-ACA plus 0.22KG of trimethylchlorosilane, stir, and raise the temperature to 53-57°C. The reaction was refluxed for 4 hours.

[0038] After the reaction is complete, lower the temperature to 3-7°C, add 25KG N,N-diethylaniline, and stir evenly. Add 28.5 kg of iodotrimethylsilane to the reaction kettle, and stir for 30 minutes. Steam was introduced to raise the temperature to 15-20°C, and the reaction was stirred for 2.5 hours. After the reaction is complete, lower the temperature to 3-7°C, add 4.5KG tetrahydrofuran, and stir for 20 minutes

[0039] 26KG 5,6,7,8-tetrahydroquinoline and 46.5KG N,N-dimethylacetamide were added, and the reaction was stirred for 6 hours.

[0040] After the reaction is complete, add 150KG dichloromethane, stir evenly, pour chilled water to cool down to 3-7°C, stir...

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Abstract

The invention discloses a preparation method of a cefquinome sulfate intermediate 7-aminocefquinome, wherein the preparation method comprises a step of carrying out silanization reaction in dichloromethane by taking 7-aminocephalosporanic acid as an initial raw material and hexamethyldisilazane as a silanization reagent: adding dichloromethane into an alkylation reaction kettle; the preparation method is characterized in that the alkylation reaction kettle is a flat-bottom kettle, a stirrer is arranged in the alkylation reaction kettle and extends to the kettle bottom of the alkylation reaction kettle, a condensation pipe is inserted into a top cover of the alkylation reaction kettle, and an outlet in the top end of the condenser pipe is connected with an ammonia recovery pipe; then hexamethyldisilazane is added into the alkylation reaction kettle and stirred, 7-aminocephalosporanic acid and trimethylchlorosilane are added, stirring and heating reflux reaction are carried out, in the reflux process, dichloromethane returns to the alkylation reaction kettle through the condensation pipe, and ammonia gas is recycled through an ammonia gas recycling pipe. The reaction efficiency is improved, and the reaction time is shortened.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of cefquinome sulfate intermediate 7-aminocefaquineme. Background technique [0002] Cefquinome sulfate, chemical name: (6R-7R)-7-[(2-amino-4-thiazolyl)-(methoxyimino)acetamido]-3-[(5,6,7,8- Tetrahydroquinolyl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]octane-2-ene-2-formic acid sulfate, structural formula: [0003] [0004] It is the fourth-generation cephalosporin antibiotic developed in the 1980s. It has a broad antibacterial spectrum and strong bactericidal effect. It has strong antibacterial activity both in vitro and in vivo. It has a strong killing effect on Staphylococcus aureus, Streptococcus, Pseudomonas aeruginosa, and Enterobacteriaceae. It also has a good killing effect on many methicillin-resistant staphylococci and enterobacteriaceae. With low toxicity, low residue and high safety, it is currently one of the first-selected drugs for preventi...

Claims

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Application Information

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IPC IPC(8): C07D501/04C07D501/12C07D501/18
CPCC07D501/04C07D501/12C07D501/18
Inventor 何东贤郭胜超谭文龙邵倩
Owner CHONGQING MEDICAL & PHARMA COLLEGE
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