阅读说明：本技术 一种制备氟苯尼考的方法 (Method for preparing florfenicol ) 是由 谢新开 黄晓飞 徐伟 于 2019-05-10 设计创作，主要内容包括：本发明公开了一种制备氟苯尼考的方法,其特征在于,以式Ⅰ化合物为原料,加入酮还原酶,在酮还原酶催化还原酮羰基的同时动态动力学拆分得到式Ⅱ化合物,再将式Ⅱ化合物的三元环进行开环氟化和可选的进行去保护、二氯乙酰化反应制得氟苯尼考。(The invention discloses a method for preparing florfenicol, which is characterized in that a compound shown in a formula I is taken as a raw material, ketoreductase is added, dynamic kinetic resolution is carried out while ketocarbonyl is catalytically reduced by the ketoreductase to obtain a compound shown in a formula II, and then, a three-membered ring of the compound shown in the formula II is subjected to ring opening fluorination, optional deprotection and dichloro acetylation to obtain the florfenicol.)

1. A method for preparing florfenicol is characterized in that a compound shown as a formula IAdding ketoreductase into raw materials, and obtaining a compound shown in a formula II through dynamic kinetic resolution while the ketoreductase catalyzes and reduces ketocarbonylIn the formula I and the formula II, R is a protective group, and then the three-membered ring of the compound in the formula II is subjected to ring opening fluorination, optional deprotection and dichloroacetylation to prepare the florfenicol.

2. The method of claim 1, wherein R is acetyl, benzyl, or-COCHCl₂。

3. The method of claim 1, wherein the step of ring-opening fluorination is accomplished by addition of triethylamine hydrofluoride.

4. The method according to claim 1, wherein a coenzyme nicotinamide adenine dinucleotide is added as a regeneration system during the enzymatic reaction.

5. The method of claim 4, wherein the regeneration of the coenzyme nicotinamide adenine dinucleotide is effected by adding glucose and glucose dehydrogenase.

6. The method of claim 4, wherein the regeneration of the coenzyme nicotinamide adenine dinucleotide is effected by addition of isopropanol and optionally alcohol dehydrogenase.

Technical Field

The invention belongs to the technical field of biological pharmacy and biochemical engineering, and particularly relates to a preparation method of florfenicol.

Background

Florfenicol is also called florfenicol, is a special broad-spectrum antibiotic for animals, and is mainly used for bacterial diseases of animals such as cattle, pigs, chickens, ducks, fishes and the like. The florfenicol has a structure similar to thiamphenicol, but the antibacterial activity is 10 times higher than that of thiamphenicol; and the antibacterial broad spectrum and adverse reaction are obviously better than thiamphenicol. Florfenicol has now become the primary antimicrobial drug for animal species. Due to the excellent drug effect, the application prospect is very wide. The synthesis of florfenicol has therefore been receiving great attention.

Florfenicol, the structural formula of which is shown below:

currently, in the industrial preparation of florfenicol, p-methylsulfonylbenzaldehyde, glycine and the like are mainly used as starting raw materials, and the (2S,3R) -p-methylsulfonylphenylserine ethyl ester (D-ethyl ester) is prepared through steps of condensation, esterification, resolution and the like. And then on the basis of taking D-ethyl ester as a raw material, preparing oxazoline by reduction and reaction with benzonitrile, carrying out fluorination, hydrolysis, dichloroacetylation and other steps under the action of an Ishikawa reagent, wherein the synthetic route is as follows:

the current florfenicol industrial production route must use a key intermediate D-ethyl ester, the steps of copper sulfate complexation preparation of amino acid copper salt, chiral resolution and the like are required for producing the D-ethyl ester, a large amount of copper sulfate wastewater is generated in the production process, 50% of raw materials are wasted in the chiral resolution process, and the method has great harm to the environment and higher cost. In addition, the process can generate a large amount of boron-salt-containing wastewater in the reduction step of the D-ethyl ester, the treatment is difficult, and the environmental burden is large. Equivalent Ishikawa reagent is required in the fluorination reaction step, and the reagent has the advantages of low fluorine atom utilization rate, high cost and high corrosion to equipment. In conclusion, the existing florfenicol production route has the defects of high production cost, serious environmental pollution and the like, so that the search for a more suitable industrial production route is valuable.

In view of this, chemists developed several asymmetric methods for the synthesis of florfenicol. Recently, it has been reported that florfenicol is synthesized by using a corresponding alcohol intermediate obtained by reducing [ aziridin-2-yl ] [4- (methylsulfonyl) phenyl ] ketone and then using the property that an aziridine three-membered ring is easy to open in an acidic environment. Such as:

chinese patent (publication No. CN102827042A) reports that aziridine-2-yl ] [4- (methylsulfonyl) phenyl ] methanol is prepared by catalytic hydrogenation with a chiral ligand-metal ruthenium catalyst, and florfenicol is prepared by ring opening of a three-membered ring. The reaction process is as follows:

the method avoids chiral resolution by using asymmetric catalytic reduction, and has high atom economy. However, the method has the disadvantages of high catalyst price, special high-pressure equipment and reactor requirement and the like, so that the method is difficult to realize industrialization.

Chinese patent (publication No. CN103936638A) reports that florfenicol is prepared from chiral [ aziridin-2-yl ] [4- (methylsulfonyl) phenyl ] ketone through steps of selective reduction, configuration inversion of alcohol, ring opening of three-membered ring, etc., and the reaction process is as follows:

the method has the advantages of high price of chiral raw materials, more reaction steps and higher production cost, so the method has low industrial value.

Chinese patent (publication No. CN 106316898A) reports that florfenicol is prepared from chiral [ aziridin-2-yl ] [4- (methylsulfonyl) phenyl ] ketone by reducing with a bulky steric reducing agent at low temperature to obtain an intermediate alcohol with a desired configuration, and then by the steps of three-membered ring opening, deprotection, dichloroacetylation and the like, the reaction process is as follows:

according to the method, chiral raw materials and a reducing agent with large steric hindrance are expensive, the reaction process needs to be carried out at low temperature, and the industrial value of the method is low due to high production cost.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a simple and feasible novel method for synthesizing florfenicol, which has the advantages of simple operation and mild conditions, greatly reduces the production cost and is suitable for large-scale industrial production.

The invention discloses a method for preparing florfenicol, which is characterized in that a compound shown as a formula IIs used as a raw material for preparing the high-purity,

adding ketoreductase, and obtaining the compound of formula II by dynamic kinetic resolution while the ketoreductase catalyzes and reduces ketocarbonylIn the formula I and the formula II, R is a protective group,

and then carrying out ring opening fluorination, optional deprotection and dichloro acetylation on the three-membered ring of the compound shown in the formula II to obtain the florfenicol.

Preferably, R is acetyl, benzyl or-COCHCl₂；

Preferably, the step of ring-opening fluorination is accomplished by adding triethylamine hydrofluoride;

preferably, in the enzyme reaction process, coenzyme nicotinamide adenine dinucleotide is added as a regeneration system;

preferably, the regeneration of coenzyme nicotinamide adenine dinucleotide is realized by adding glucose and glucose dehydrogenase;

preferably, the regeneration of the coenzyme nicotinamide adenine dinucleotide is effected by addition of isopropanol and optionally by addition of an alcohol dehydrogenase.

The reaction process of the invention is as follows:

wherein, the ketone reduction-dynamic resolution process is as follows:

preferably, when the protecting group R is COCHCl₂In the process, the reaction can be completed by only two steps, and the reaction process is as follows:

Detailed Description

The present invention will be described in further detail with reference to specific examples, but the present invention is not limited to the following examples.