阅读说明：本技术 一种氟苯尼考中间体的制备方法 (Preparation method of florfenicol intermediate ) 是由 袁庆 郑剑锋 康先禄 叶海波 于 2020-03-18 设计创作，主要内容包括：本发明属于药物合成技术领域。本发明公开了一种氟苯尼考中间体的制备方法,由环合物经过氟化反应和提纯后制得氟苯尼考中间体,其中氟化反应中采用以二氯甲烷为溶剂,在二甲胺中通入四氟乙烯气体制得的氟化试剂进行。本发明中采用了不同于现有技术中Ishikawa试剂的氟化试剂,避免了采用成本较高的六氟丙烯合成Ishikawa试剂,同时制备工艺的工艺条件更加温和,制备工艺更加简便；能够较大程度的降低氟苯尼考中间体及后续制备氟苯尼考的生产成本,具有广阔的市场前景。(The invention belongs to the technical field of drug synthesis. The invention discloses a preparation method of a florfenicol intermediate, which is characterized in that a cyclic compound is subjected to fluorination reaction and purification to prepare the florfenicol intermediate, wherein the fluorination reaction is carried out by adopting a fluorination reagent prepared by taking dichloromethane as a solvent and introducing tetrafluoroethylene gas into dimethylamine. The method adopts a fluorination reagent different from the Ishikawa reagent in the prior art, avoids the synthesis of the Ishikawa reagent by adopting hexafluoropropylene with higher cost, and simultaneously has the advantages of milder process conditions and simpler and more convenient preparation process; the production cost of the florfenicol intermediate and the subsequent preparation of the florfenicol can be greatly reduced, and the method has wide market prospect.)

1. A preparation method of a florfenicol intermediate is characterized by comprising the following steps:

the cyclic compound is subjected to fluorination reaction and purification to prepare a florfenicol intermediate;

the cyclic compound is

，

The florfenicol intermediate is

。

2. The preparation method of the florfenicol intermediate according to claim 1, characterized in that:

the fluorination reaction takes dichloromethane as a solvent and takes a cyclic compound and a fluorination reagent as reaction raw materials.

3. The preparation method of the florfenicol intermediate according to claim 1, characterized in that:

in the fluorination reaction, the weight ratio of the cyclic compound to the fluorination reagent is 1: 2.5-2.8.

4. The preparation method of the florfenicol intermediate according to claim 1, characterized in that:

the temperature of the fluorination reaction is 75-85 ℃, and the reaction time is 1-4 hours.

5. The process for preparing a florfenicol intermediate according to any one of claims 1 or 4, wherein:

the temperature of the fluorination reaction was 85 ℃ and the reaction time was 2 hours.

6. The preparation method of the florfenicol intermediate according to claim 1, characterized in that:

the fluorinating agent is prepared by introducing tetrafluoroethylene gas into dimethylamine by taking dichloromethane as a solvent.

7. The method for preparing a florfenicol intermediate according to claim 6, wherein:

in the preparation process of the fluorinating reagent, dimethylamine is cooled to-5 ℃ and below.

8. The method for preparing a florfenicol intermediate according to claim 6, wherein:

in the preparation process of the fluorination reagent, the weight ratio of tetrafluoroethylene to dimethylamine is 1.5-2.5: 1.

9. a process for the preparation of a florfenicol intermediate according to any one of claims 1-8, characterized in that:

specifically, adding the cyclic compound and dichloromethane into a reaction kettle, adding a fluorination reagent into the reaction kettle, sealing the reaction kettle, heating, keeping the temperature and the pressure for reaction, and cooling after the reaction to obtain a fluorination reaction product.

10. A process for the preparation of a florfenicol intermediate according to any one of claims 1 or 2, characterized in that:

and the water washing process specifically comprises the steps of washing the fluorination reaction product with water, extracting and layering, recovering dichloromethane, adding methanol, heating to dissolve the product, adding carbon for decolorization and filtration, freezing the filtrate, and performing suction filtration to obtain the florfenicol intermediate.

Technical Field

The invention relates to the technical field of drug synthesis, in particular to a preparation method of a florfenicol intermediate.

Background

Florfenicol is also called florfenicol and florfenicol, is a chemically synthesized broad-spectrum antibacterial drug specially used in animal health-care markets, has a structure similar to that of thiamphenicol, has two chiral centers and four corresponding isomers, has the bactericidal capacity 10 times that of thiamphenicol, is safe and efficient, and is particularly suitable for aplastic anemia caused by chloramphenicol antibiotics. Currently approved for marketing in more than 20 countries of the world.

Florfenicol has more synthesis process routes, most of the synthesis processes are that D-threo-methylsulfonylphenyl serine ethyl ester is reduced by potassium borohydride and cyclized by dichloroacetonitrile according to the introduction of a patent US5382673, and a cyclic compound oxazoline (also called (4R,5R) -2- (1, 1-dichloromethyl) -4-hydroxymethyl-5- (4-methylsulfonylphenyl) -4, 5-oxazoline) is obtained through reaction. The cyclic oxazoline is fluorinated by Ishikawa reagent and then hydrolyzed to prepare the florfenicol. But the preparation process is more complicated, firstly dichloromethane and diethylamine are added into a reaction kettle uniformly, then hexafluoropropylene is slowly introduced below 10 ℃, the mixture is stirred for 18 hours at room temperature to obtain a fluorination reagent, and secondly the oxazoline of the cyclic compound and the lshikawa reagent can be fluorinated for 2 hours at about 100 ℃ to recover the solvent; adding the product into aqueous solution of sodium acetate and isopropanol, refluxing for 4 hr, hydrolyzing, recovering solvent, concentrating, crystallizing, centrifuging, and refining to obtain the final product. For example, chinese patent publication No. CN103304505A discloses a method for preparing a florfenicol intermediate in 2013, 9/18, in the technical scheme of the patent, a cyclic oxazoline is also used as an initial reactant, an Ishikawa reagent prepared from dichloromethane, diethylamine and hexafluoropropylene is also used in the process for a fluorination reaction, and after the fluorination reaction is completed, dichloromethane is recovered after an alkali solution is washed, and then florfenicol is prepared. Although the process effectively changes the color and the impurity content of florfenicol and has the yield of 95 percent, the process of preparing the Ishikawa reagent by using high-price hexafluoropropylene and then carrying out the fluorination reaction is not changed, the process still has higher cost and severer process conditions, and the process is not satisfactory.

Disclosure of Invention

In order to solve the problems, the invention provides a preparation method for preparing florfenicol intermediate fluoro-product by taking a cyclic compound as an initial reactant without adopting Ishikawa reagent for fluorination, which has higher yield and greatly reduces the production cost.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

a preparation method of a florfenicol intermediate is characterized by comprising the following steps:

the cyclic compound is subjected to fluorination reaction and purification to prepare a florfenicol intermediate;

the cyclic compound is

The florfenicol intermediate is

The preparation method comprises the steps of carrying out fluorination reaction on a dried product of a (4R,5R) -2- (1, 1-dichloromethyl) -4-hydroxymethyl-5- (4-methylsulfonyl phenyl) -4, 5-oxazoline cyclic compound (hereinafter referred to as the cyclic compound), and washing and purifying the product to obtain the florfenicol intermediate.

Preferably, the fluorination reaction uses methylene chloride as a solvent, and a cyclic compound and a fluorination reagent as reaction raw materials.

Preferably, in the fluorination reaction, the weight ratio of the cyclic compound to the fluorinating agent is 1: 2.5-2.8.

Preferably, the fluorination reaction is carried out at a temperature of 75 to 85 ℃ for a reaction time of 1 to 4 hours.

Preferably, the fluorination reaction is carried out at a temperature of 85 ℃ for a reaction time of 2 hours.

Preferably, the fluorinating agent is prepared by introducing tetrafluoroethylene gas into dimethylamine using methylene chloride as a solvent.

Preferably, dimethylamine is cooled to-5 ℃ or below during the preparation of the fluorinating agent.

Preferably, the weight ratio of tetrafluoroethylene to dimethylamine in the preparation of the fluorinating agent is 1.5-2.5: 1.

compared with the traditional Ishikawa reagent, the novel fluorination reagent adopted in the invention has the advantages of mild operation conditions, low cost and the like.

Preferably, the fluorination reaction is specifically that the cyclic compound and dichloromethane are added into a reaction kettle, then the fluorination reagent is added into the reaction kettle, the reaction kettle is closed, the temperature is raised, the temperature and pressure are kept for reaction, and the temperature is reduced after the reaction to prepare the fluorination reaction product.

Preferably, the water washing process specifically comprises the steps of washing the fluorination reaction product with water, extracting and layering, recovering dichloromethane, adding methanol, heating to dissolve, adding carbon, decolorizing, filtering, freezing the filtrate, and performing suction filtration to obtain the florfenicol intermediate.

The reaction scheme in the invention is as follows:

preparation of fluorinating reagents

Fluorination of cyclic compounds

The key process of the invention is two steps,

preparing a fluorination reagent by taking tetrafluoroethylene and dimethylamine as raw materials and dichloromethane as a solvent at a low temperature of (-5 ℃);

and the second step is fluorination reaction, namely, the cyclic compound and a fluorination reagent are subjected to heat preservation and pressure maintaining reaction in a dichloromethane solution, and the fluorination reaction product is purified by washing, dichloromethane recovery and the like to obtain a fluoro compound, namely, a solid of the florfenicol intermediate.

And the purification process after the second step of fluorination reaction comprises the steps of firstly, washing and extracting the fluorination reaction product, recovering dichloromethane, then adopting methanol to remove color through activated carbon adsorption, and then cooling to 0 +/-2 ℃ for suction filtration to obtain a fluoro-product, namely the florfenicol intermediate.

Therefore, the invention has the following beneficial effects: the method adopts a fluorination reagent different from the Ishikawa reagent in the prior art, avoids the synthesis of the Ishikawa reagent by adopting hexafluoropropylene with higher cost, and simultaneously has the advantages of milder process conditions and simpler and more convenient preparation process; the production cost of the florfenicol intermediate and the subsequent preparation of the florfenicol can be greatly reduced, and the method has wide market prospect.

Drawings

FIG. 1 is a report on the HP L C HPLC assay of the product florfenicol intermediate of example 1;

FIG. 2 is a HP L C HPLC assay report of the product florfenicol intermediate of example 2;

FIG. 3 is a HP L C HPLC assay report of the product florfenicol intermediate of example 3;

FIG. 4 is a HP L C HPLC assay report of the product florfenicol intermediate of example 4;

FIG. 5 is a HP L C HPLC assay report of the product florfenicol intermediate of example 5;

figure 6 is a HP L C hplc assay report of the product florfenicol intermediate of example 6.

Detailed Description

The technical solution of the present invention will be further described with reference to the following embodiments.

It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.