Synthesis method of key intermediate of dabigatran etexilate

Abstract

According to the preparation method of the key intermediate N-(4-cyanophenyl) glycine of dabigatran etexilate, p-chlorobenzonitrile and glycine serve as raw materials, a target compound (I) is obtained through one step, the raw materials are easy to obtain and low in price, reaction conditions are mild, the yield is high, water serves as a reaction solvent, emission of three wastes is remarkably reduced, and the method is environmentally friendly and more friendly, and has good industrial application prospects. The method is suitable for large-scale commercial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a method for synthesizing a key intermediate of dabigatran ester. Background Technology

[0002] Dabigatran etexilate is a novel anticoagulant drug developed by Boehringer Ingelheim in Germany, primarily used for the prevention and treatment of thrombosis-related diseases. It works by inhibiting thrombin activity, preventing excessive blood clotting. It is suitable for stroke prevention in patients with non-valvular atrial fibrillation, and for the prevention and treatment of deep vein thrombosis and pulmonary embolism. Dabigatran etexilate is a prodrug; after oral administration, it is converted into the active ingredient dabigatran in the body, directly inhibiting thrombin (a key coagulation enzyme), blocking the conversion of fibrinogen to fibrin, and reducing thrombus formation. Its structural formula is shown below:

[0003]

[0004] N-(4-cyanophenyl)glycine is a key intermediate in the synthesis of dabigatran ester. Its quality and cost play a crucial role in the synthesis of dabigatran ester. Its structural formula is shown below:

[0005]

[0006] Currently, the publicly reported methods for synthesizing N-(4-cyanophenyl)glycine mainly involve reacting p-aminobenzonitrile with chloroacetic acid to obtain N-(4-cyanophenyl)glycine. However, chloroacetic acid is a highly toxic substance, posing significant risks and is not suitable for large-scale industrial production. Summary of the Invention

[0007] In view of the shortcomings of the prior art, the purpose of this invention is to provide a method for synthesizing N-(4-cyanophenyl)glycine, a key intermediate of dabigatran ester. This method is characterized by simple operation, mild conditions, significantly reduced cost, and environmental friendliness, and is suitable for industrial production.

[0008] To achieve the above objectives, the present invention adopts the following technical solution;

[0009] A method for preparing N-(4-cyanophenyl)glycine (I), the synthetic route of which is as follows:

[0010]

[0011] The preparation method includes the following steps:

[0012] Glycine and water were added to p-chlorobenzonitrile and heated to reflux under stirring for 5-6 hours. The mixture was then cooled to 20-30°C, filtered, and the filter cake was purified by recrystallization with a recrystallization solvent to obtain compound (I).

[0013] In this invention, the molar ratio of p-chlorobenzonitrile to glycine is 1:1.2 to 1:1.5.

[0014] In this invention, the molar ratio of p-chlorobenzonitrile to water is 1:10 to 1:20, preferably 1:15.

[0015] In this invention, the recrystallization solvent is one of methanol, ethanol, and isopropanol, with methanol being preferred.

[0016] In this invention, the molar ratio of p-chlorobenzonitrile to recrystallization solvent is 1:6 to 1:8.

[0017] Compared with the prior art, the advantages of the present invention are as follows:

[0018] A method for preparing N-(4-cyanophenyl)glycine, a key intermediate of dabigatran ester, is provided. This method uses readily available and inexpensive raw materials, has mild reaction conditions, high yield, uses water as the reaction solvent, and does not use reagents that are harmful to the environment, making it more environmentally friendly and suitable for large-scale commercial production. Detailed Implementation

[0019] To better understand the technical solution of the present invention, further explanation is provided in conjunction with specific embodiments of the present invention, so that those skilled in the art can better understand the present invention, but this is not intended to be a limitation.

[0020] Example 1

[0021] Glycine (70 g, 1.0 mol) and water (200 g, 1.0 mol) were added to p-chlorobenzonitrile (100 g, 0.727 mol), and the mixture was heated to reflux with stirring for 5-6 hours. A large amount of solid precipitated out. The mixture was cooled to 20-30 °C, filtered, and the filter cake was recrystallized from methanol (163 g, 5.1 mol) to give 112 g of N-(4-cyanophenyl)glycine, with a yield of 87.5%.

[0022] Example 2

[0023] Glycine (70 g, 1.0 mol) and water (200 g, 1.0 mol) were added to p-chlorobenzonitrile (100 g, 0.727 mol), and the mixture was heated to reflux with stirring for 5-6 hours. A large amount of solid precipitated out. The mixture was cooled to 20-30 °C, filtered, and the filter cake was recrystallized from ethanol (235 g, 5.1 mol) to give 107 g of N-(4-cyanophenyl)glycine, with a yield of 81.4%.

[0024] Example 3

[0025] Glycine (70 g, 1.0 mol) and water (200 g, 1.0 mol) were added to p-chlorobenzonitrile (100 g, 0.727 mol), and the mixture was heated to reflux with stirring for 5-6 hours. A large amount of solid precipitated out. The mixture was cooled to 20-30 °C, filtered, and the filter cake was recrystallized from isopropanol (306 g, 5.1 mol) to give 105 g of N-(4-cyanophenyl)glycine, with a yield of 79.8%.

[0026] Although the present invention has been described through embodiments thereof, other embodiments that can be conceived by those skilled in the art involving variations of the present invention are also included within the scope of the present invention and are interpreted and defined by the claims of the present invention.

Claims

1. A method for preparing N-(4-cyanophenyl)glycine, a key intermediate in dabigatran ester, characterized in that: The synthetic route for compound (I) obtained from p-chlorobenzonitrile and glycine via a one-step reaction is as follows: Its features are: Glycine and water were added to p-chlorobenzonitrile and heated to reflux under stirring for 5-6 hours. The mixture was then cooled to 20-30°C, filtered, and the filter cake was purified by recrystallization with a recrystallization solvent to obtain compound (I).

2. The preparation method according to claim 1, characterized in that... The molar ratio of p-chlorobenzonitrile to glycine is 1:1.2 to 1:1.

5.

3. The preparation method according to claim 1, characterized in that... The molar ratio of p-chlorobenzonitrile to water is 1:10 to 1:

20.

4. The preparation method according to claim 1, characterized in that... The recrystallization solvent is one of methanol, ethanol, or isopropanol.

5. The preparation method according to claim 1, characterized in that... The molar ratio of p-chlorobenzonitrile to recrystallization solvent is 1:6 to 1:8.

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