阅读说明：本技术 一种制备瑞格列奈中间体的新方法 (Novel method for preparing repaglinide intermediate ) 是由 王建 叶刚 陈波 朱向宏 黄鹿 甘自强 于 2020-07-21 设计创作，主要内容包括：本发明公开了一种制备瑞格列奈中间体的新工艺,以邻氟苯腈为起始原料,经格式、缩合、还原反应得到目标产物瑞格胺消旋体。本发明提供了一种收率高、适宜工业化大生产、经济环保的新合成工艺,该目标产物可进一步用于缩合制备治疗糖尿病的药物瑞格列奈。(The invention discloses a novel process for preparing a repaglinide intermediate, which takes o-fluorobenzonitrile as an initial raw material and obtains a target product regamine racemate through format, condensation and reduction reactions. The invention provides a new synthesis process which is high in yield, suitable for industrial mass production, economical and environment-friendly, and the target product can be further used for preparing repaglinide for treating diabetes through condensation.)

1. Method for preparing repaglinide intermediate regenamine shown in formula (I)

The method is characterized by comprising the following steps:

(1) carrying out Grignard reaction on o-fluorobenzonitrile and isobutyl magnesium halide shown in a formula (II) to generate imine compounds shown in a formula (III):

(2) the imine compound shown in the formula (III) and piperidine are subjected to condensation reaction to generate an imine compound shown in the formula (IV):

(3) imine compounds of formula (IV) undergo a reduction reaction in the presence of a reducing agent to produce Ruigosamine of formula (I):

2. the production method according to claim 1,

in the step (3), the reducing agent includes one or two or more of potassium borohydride, sodium borohydride, lithium borohydride and sodium cyanoborohydride.

3. The production method according to claim 2, wherein in the step (1), X is a chlorine atom or a bromine atom.

4. The process according to claim 1, wherein the molar ratio of the o-fluorobenzonitrile to the format reagent of formula (II) in step (1) is 1:1.8 to 3.

5. The preparation method of claim 1, wherein in the step (2), the reaction temperature is 40-100 ℃, the reaction time is 3-6h, and the molar ratio of the formula (III) to the piperidine is 1: 1.8-2.5.

6. The preparation method according to claim 4, wherein in the step (1), the reaction temperature is 30-70 ℃, the reaction time is 3-10h, the reaction solvent is toluene and 2-methyltetrahydrofuran, and the volume ratio of toluene to 2-methyltetrahydrofuran is 1: 3.

7. The preparation method according to claim 5, wherein in the step (3), the molar ratio of the compound of formula (IV) to the potassium borohydride is 1: 1.1-2.0, the reaction solvent is dichloromethane, the reaction temperature is 0-35 ℃, and the reaction time is 2-6 h.

Technical Field

The invention belongs to the field of drug synthesis, and relates to a preparation method of a repaglinide intermediate for treating diabetes.

Background

Repaglinide (shown in a structural formula V), has a chemical name of S (+) -2-ethoxy-4- [ N- {1- (2-piperidyl phenyl) -3-methyl-1-butyl } aminocarbonyl methyl ] benzoic acid, has a trade name of noh long, is an oral non-sulfonylurea insulin release promoter for treating type II diabetes, belongs to one of methylbenzylamine benzoic acids, has the characteristics of quick absorption and short action time, has good safety, has a synergistic effect with biguanide medicines, can be independently administered, and can be jointly administered with other hypoglycemic medicines to increase the curative effect.

The regoramide (formula I) is a key intermediate for synthesizing repaglinide, so that the development of a safe, efficient and cheap synthesis process has important economic benefits. Through research in the literature, the synthesis of regoramine mainly has the following routes:

the university of Jilin bulletin (2000.4.83) reports that the raceme of the regoramine is prepared by 4 steps of reaction by using o-fluorobenzaldehyde as a raw material. The route has the defects of longer route, lower total yield and the like.

Process Chemistry (2006.60.9) reported that Raynamide racemate was obtained from o-chlorobenzonitrile as a starting material by 3-step reaction. The first step of the route is high-temperature reaction (220 ℃), so that the method has high danger and cannot be used for industrial production.

Shenyang university of pharmacy (2012.29.6) reports that the raceme of regoramide is prepared by 5 steps of reaction by using o-fluorobenzaldehyde as a raw material. The route has the defects of long route and low total yield.

The Ruigyamine racemate prepared by 5 steps of reaction by using o-fluorobenzaldehyde as a raw material is reported by Chinese medical industry journal (2008.39.10). The route has the defects of longer route, fussy post-treatment and low total yield.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides a synthetic process of repaglinide intermediate regenamine, which is simple and convenient to operate, safe, reliable, high in yield, suitable for industrial mass production and has great social, economic and environmental benefits.

In order to solve the technical problems, the invention adopts the following technical scheme:

the invention discloses a new synthesis process of a repaglinide intermediate, which takes o-fluorobenzonitrile as an initial raw material and obtains a target product regamine racemate through format, condensation and reduction reactions. The invention provides a new synthesis process which is high in yield, suitable for industrial mass production, economical and environment-friendly, and the target product can be further used for preparing repaglinide for treating diabetes through condensation.

The method comprises the following steps in sequence:

(1) reacting o-fluorobenzonitrile with an isobutyl magnesium halide Grignard reagent shown in a formula (II) to generate an imine compound shown in a formula (III):

(2) the imine compound of the formula (III) and piperidine are subjected to condensation reaction at a certain temperature to generate the imine compound of the formula (IV):

(3) imine compounds of formula (IV) undergo a reduction reaction in the presence of a reducing agent to produce Ruigosamine of formula (I):

further, in the step (3), the reducing agent includes one or two or more of potassium borohydride, sodium borohydride, lithium borohydride and sodium cyanoborohydride.

Further, in the step (1), X is a chlorine atom or a bromine atom.

Further, in the step (1), the molar ratio of the o-fluorobenzonitrile to the compound shown in the formula (II) is 1: 1.8-3.

Further, in the step (1), the reaction temperature is 30-70 ℃, the reaction time is 3-10h, the reaction solvent is toluene and 2-methyltetrahydrofuran, and the volume ratio of the reaction solvent is 1: 3.

Further, in the step (2), the reaction temperature is 40-100 ℃, the reaction time is 3-6h, and the molar ratio of the formula (III) to the piperidine is 1: 1.8-2.5.

Further, in the step (3), the molar ratio of the formula (IV) to the potassium borohydride is 1: 1.1-2.0, the reaction solvent is dichloromethane, the reaction temperature is 0-35 ℃, and the reaction time is 2-6 h.

In summary, the invention has the following advantages:

(1) the invention creatively provides a new repaglinide intermediate synthesis process. The process shortens the synthetic route, has the advantages of simple operation, easy industrialization, high yield and the like, and the synthetic route is not reported in documents and has obvious innovation.

(2) The route of the invention is different from the route reported in the literature to the greatest extent that the Grignard reaction precedes the condensation reaction, which helps to improve the reaction yield and facilitate subsequent operation.

(3) The invention achieves the aim of the invention, overcomes the defects in the prior art, and provides the repaglinide intermediate synthesis process which is simple to operate, high in yield, suitable for industrial mass production and great in social, economic and environment-friendly benefits.

Detailed Description

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

The first step is as follows: grignard reaction