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A kind of preparation method of florfenicol intermediate flumethone oxazole

A technology for the production of florfenicol and florfenicol is applied in the field of preparation of florfenicol intermediates, which can solve the problems of sulfuryl fluoride toxicity, irritation, unfavorable environmental protection, and unsatisfactory effects, and achieve The effect of considerable yield, simple recycling and clear prospects for industrial production

Active Publication Date: 2021-10-08
SHANDONG GUOBANG PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, sulfuryl fluoride is toxic and irritating, and its safety is poor. The latest research shows that sulfuryl fluoride is a powerful greenhouse gas, which is not conducive to the protection of the environment.
In addition, the yield of florfenicol prepared by using sulfuryl fluoride is only moderate, and the finished product of florfenicol contains more impurities, and the effect of this method is still not satisfactory

Method used

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  • A kind of preparation method of florfenicol intermediate flumethone oxazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1: Preparation of 1-chloro-4-(difluoromethyl)benzene

[0040] Mix 97.75 g (0.5 mol) of p-chlorobenylidene dichloride and 0.7 g (0.025 mol) of antimony trichloride in an autoclave, remove the air in the autoclave under reduced pressure, suck in 90 g (4.5 mol) of hydrogen fluoride gas at room temperature, and heat up React at 120°C for 4 hours, cool to 40°C, discharge and collect the gas in the kettle, blow it clean with nitrogen (200g, 7.14mol), cool HF to liquid by cryogenic cooling, absorb the remaining gas with water, and prepare a hydrochloric acid solution. The product 1-chloro-4-(difluoromethyl)benzene was distilled off under reduced pressure from the remaining mixture in the kettle, and the fraction at 60°C-65°C / 2.4Kpa was collected, cooled and liquefied to obtain the product as a colorless liquid (78g, 0.480mol). The yield is 96.01% (calculated on the basis of p-chloro-benylidene dichloride), and the chromatographic purity is 99.80% (higher than the purit...

Embodiment 2

[0041]Embodiment two: the preparation of 1-chloro-4-(difluoromethyl)benzene

[0042] Mix 97.77g (0.5mol) of p-chlorobenylidene dichloride and 0.7g (0.025mol) of antimony trichloride in the autoclave, remove the air in the autoclave under reduced pressure, suck in 85g (4.25mol) of hydrogen fluoride gas at room temperature, and heat up React at 120°C for 4 hours, cool to 40°C, discharge and collect the gas in the kettle, blow it clean with nitrogen (200g, 7.14mol), cool HF to liquid by cryogenic cooling, absorb the remaining gas with water, and prepare a hydrochloric acid solution. The product 1-chloro-4-(difluoromethyl)benzene was distilled off under reduced pressure from the remaining mixture in the kettle, and the fraction at 60°C-65°C / 2.4Kpa was collected, cooled and liquefied to obtain the product as a colorless liquid (75.8g, 0.466mol) , Yield 93.29% (calculated on the basis of p-chloro-Benylidene dichloride), chromatographic purity 99.81%.

Embodiment 3

[0043] Example three: Preparation of 1-chloro-4-(difluoromethyl)benzene

[0044] Mix 97.75 g (0.5 mol) of p-chlorobenylidene dichloride and 0.7 g (0.025 mol) of antimony trichloride in the autoclave, remove the air in the autoclave under reduced pressure, suck in 100 g (5.0 mol) of hydrogen fluoride gas at room temperature, and heat up React at 120°C for 4 hours, cool to 40°C, discharge and collect the gas in the kettle, blow it clean with nitrogen (200g, 7.14mol), cool HF to liquid by cryogenic cooling, absorb the remaining gas with water, and prepare a hydrochloric acid solution. The product 1-chloro-4-(difluoromethyl)benzene was distilled off under reduced pressure from the remaining mixture in the kettle, and the fraction at 60°C-65°C / 2.4Kpa was collected, cooled and liquefied to obtain the product as a colorless liquid (78.05g, 0.481mol) , Yield 96.08% (calculated on the basis of p-chloro-Benylidene dichloride), chromatographic purity 99.80%.

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Abstract

The invention provides a preparation method of florfenicol intermediate flumethoxazole, the fluorination reagent adopted is 1-chloro-4-(difluoromethyl)benzene, the preparation method, adding 1-chloro-4-(difluoromethyl)benzene 4‑(Difluoromethyl)benzene, cyclamate oxazoline, and dichloromethane are heated to 80‑100°C for 1.5‑3h. This process uses 1-chloro-4-(difluoromethyl)benzene as the fluorinating reagent, which saves the complex process of preparing lshikawa reagent for fluorinating by the mixed reaction of hexafluoropropylene and diethylamine in the traditional process, compared with , the preparation of 1-chloro-4-(difluoromethyl)benzene fluorination reagent has the advantages of fast reaction speed, high conversion rate and less by-products. In addition, the present invention uses 1-chloro-4-(difluoromethyl) In the process of fluorinating the cyclic compound of the florfenicol intermediate in benzene, the main by-product is p-chlorobenzaldehyde, which can be used as a by-product after separation and purification, which improves the utilization rate of atoms.

Description

technical field [0001] The invention relates to a method for preparing a florfenicol intermediate, which belongs to the technical field of chemical synthesis. Background technique [0002] Florfenicol, also known as fluprofen and fluthiamphenicol, is a synthetic chloramphenicol spectrum antibacterial drug for veterinary medicine, and it is a monofluorinated derivative of thiamphenicol. Florfenicol has a broad antibacterial spectrum, is effective against Gram-positive bacteria, Gram-negative bacteria and mycoplasma, is rapidly absorbed orally, widely distributed, has a long half-life, high blood concentration, and long blood drug maintenance time. Applied to animal husbandry, breeding, etc. [0003] In 1995, the patent US5382673 introduced D-threo-2-(2,2-dichloro)acetamido-3-hydroxyl-3-p-(methylsulfonyl)phenyl-propionic acid ethyl ester (referred to as D ethyl ester) as the initial reactant, and the reduced product (1R, 2R)-2-amino-1-(4-(thysulfonyl)phenyl)-1,3-propanediol ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D263/10C07C17/20C07C25/13
CPCC07B2200/07C07C17/206C07D263/10C07C25/13
Inventor 邱正洲张小垒田扬孙瑞南王同龙
Owner SHANDONG GUOBANG PHARMA
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