CN-122010776-A - Synthesis method of dabigatran etexilate key intermediate

Abstract

The invention provides a preparation method of dabigatran etexilate key intermediate N- (4-cyanophenyl) glycine, which takes p-chlorobenzonitrile and glycine as raw materials to obtain a target compound (I) through one step, the method has the advantages of easily available raw materials, low cost, mild reaction condition and high yield, and the reaction solvent is water, so that the discharge of three wastes is obviously reduced, the method is environment-friendly and is suitable for large-scale commercial production.

Inventors

• Li Gongben
• Nie Tianjing
• SUN WEIXIANG
• Pan Chenfang

Assignees

• 北京联本医药化学技术有限公司
• 吉林佳辉化工有限公司

Dates

Publication Date

20260512

Application Date

20260205

Claims (5)

1. 1. A preparation method of dabigatran etexilate key intermediate N- (4-cyanophenyl) glycine is characterized in that p-chlorobenzonitrile and glycine are used as raw materials to obtain a compound (I) through one-step reaction, and the synthetic route is as follows: the method is characterized in that: adding glycine and water into p-chlorobenzonitrile, heating to reflux under stirring, reacting for 5-6 hours, cooling to 20-30 ℃, filtering, crystallizing and refining the filter cake by using a recrystallization solvent to obtain the compound (I).
2. 2. The preparation method according to claim 1, wherein the molar ratio of p-chlorobenzonitrile to glycine is 1:1.2-1:1.5.
3. 3. The preparation method according to claim 1, wherein the molar ratio of p-chlorobenzonitrile to water is 1:10-1:20.
4. 4. The method according to claim 1, wherein the recrystallization solvent is one of methanol, ethanol and isopropanol.
5. 5. The process according to claim 1, wherein the molar ratio of p-chlorobenzonitrile to the recrystallization solvent is 1:6 to 1:8.

Description

Synthesis method of dabigatran etexilate key intermediate Technical Field The invention belongs to the field of drug synthesis, and particularly relates to a method for synthesizing a dabigatran etexilate key intermediate. Background Dabigatran etexilate (Dabigatran etexilate) is a novel anticoagulation medicine developed by the company Boringer John in Germany, and is mainly used for preventing and treating thrombus-related diseases. The dabigatran etexilate is a prodrug, is converted into an active ingredient dabigatran in vivo after being orally taken, directly inhibits thrombin (thrombin key enzyme), blocks fibrinogen from being converted into fibrin, and reduces thrombosis. The structural formula is shown as follows: n- (4-cyanophenyl) glycine is a key intermediate for synthesizing dabigatran etexilate, and the quality and cost of the N- (4-cyanophenyl) glycine have a key effect in the synthesis of dabigatran etexilate, and the structural formula of the N- (4-cyanophenyl) glycine is shown as follows: the synthesis method of N- (4-cyanophenyl) glycine disclosed and reported at present mainly takes p-aminobenzonitrile as a raw material to react with chloroacetic acid to obtain N- (4-cyanophenyl) glycine, and the chloroacetic acid is a highly toxic product, has high use risk and is not suitable for large-scale industrial production. Disclosure of Invention In view of the defects existing in the prior art, the invention aims to provide a method for synthesizing N- (4-cyanophenyl) glycine, a key intermediate of dabigatran etexilate, which has the characteristics of simplicity in operation, mild condition, remarkable reduction in cost, environmental friendliness and the like, and is suitable for industrial production. In order to achieve the above purpose, the invention adopts the following technical scheme; A preparation method of N- (4-cyanophenyl) glycine (I) comprises the following synthetic route: the preparation method comprises the following steps: adding glycine and water into p-chlorobenzonitrile, heating to reflux under stirring, reacting for 5-6 hours, cooling to 20-30 ℃, filtering, crystallizing and refining the filter cake by using a recrystallization solvent to obtain the compound (I). In the invention, the mol ratio of the p-chlorobenzonitrile to the glycine is 1:1.2-1:1.5. In the invention, the mol ratio of the p-chlorobenzonitrile to the water is 1:10-1:20, preferably 1:15. The recrystallization solvent in the invention is one of methanol, ethanol and isopropanol, preferably methanol. In the invention, the mol ratio of the p-chlorobenzonitrile to the recrystallization solvent is 1:6-1:8. Compared with the prior art, the invention has the advantages that: the preparation method of the dabigatran etexilate key intermediate N- (4-cyanophenyl) glycine is easy to obtain raw materials, low in cost, mild in reaction condition, high in yield, free of reagents which are harmful to the environment, environment-friendly, and suitable for large-scale commercial production, and the reaction solvent is water. Detailed Description For a better understanding of the technical solution of the present invention, reference will be made to the following description of specific embodiments of the invention, which are intended to provide a better understanding of the present invention, but are not to be construed as limiting. Example 1 Glycine (70 g,1.0 mol) and water (200 g,1.0 mol) were added to p-chlorobenzonitrile (100 g,0.727 mol), heated under stirring to reflux, reacted for 5-6 hours with a large amount of solids precipitated, cooled to 20-30 ℃, filtered, and the filter cake recrystallized from methanol (163 g,5.1 mol) to give 112g of N- (4-cyanophenyl) glycine in a yield of 87.5% Example 2 Glycine (70 g,1.0 mol) and water (200 g,1.0 mol) were added to p-chlorobenzonitrile (100 g,0.727 mol), heated under stirring to reflux, reacted for 5-6 hours with a large amount of solid precipitated, cooled to 20-30 ℃, filtered, and the filter cake recrystallized from ethanol (235 g,5.1 mol) to give N- (4-cyanophenyl) glycine 107g in a yield of 81.4% Example 3 Glycine (70 g,1.0 mol) and water (200 g,1.0 mol) were added to p-chlorobenzonitrile (100 g,0.727 mol), heated under stirring to reflux, reacted for 5-6 hours with a large amount of solids precipitated, cooled to 20-30 ℃, filtered, and the filter cake recrystallized from isopropanol (306 g,5.1 mol) to give N- (4-cyanophenyl) glycine 105g in a yield of 79.8% While the invention has been described by way of examples of the invention, other embodiments which will occur to those skilled in the art are also within the intended scope of the invention, as defined and interpreted by the claims.