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Dabigatran etexilate preparation method

A technology for dabigatran etexilate and an intermediate, which is applied in the field of preparing dabigatran etexilate, can solve the problems of difficult purification and purification of compounds, and is unfavorable for large-scale production, and achieves cheap raw materials, simple and easy-to-control operations, and reaction yields. high effect

Active Publication Date: 2014-09-10
NANTONG CHANGYOO PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The compounds in this route are difficult to refine and purify, which is not conducive to large-scale production

Method used

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  • Dabigatran etexilate preparation method
  • Dabigatran etexilate preparation method
  • Dabigatran etexilate preparation method

Examples

Experimental program
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Effect test

Embodiment 1

[0030] A method for preparing dabigatran etexilate (7), comprising the following steps:

[0031] (a) Preparation of intermediate 1: Add 40g p-aminobenzonitrile, 93.8g potassium carbonate and 150mL water to 600mL tetrahydrofuran, stir, add dropwise 200mL aqueous solution of hydroxylamine hydrochloride; after dropping, heat up to 50°C for reaction, TLC Monitor the reaction; after the reaction is completed, cool down to room temperature naturally, evaporate THF under reduced pressure, cool, filter with suction, wash the filter cake with ether, and dry to obtain 52.8 g of Intermediate 1 (1) with a purity of 98.5% and a yield of 88%. ;

[0032] (b) Preparation of Intermediate 2: In 400mL of anhydrous methanol, add 13.7g of sodium methoxide, stir to dissolve, add 30g of Intermediate 1 (1), stir, add 22.5g of diethyl carbonate dropwise, dropwise, heat up to React at 55-60°C, monitor the reaction by TLC; after the reaction is complete, concentrate under reduced pressure to remove met...

Embodiment 2

[0039] A method for preparing dabigatran etexilate (7), comprising the following steps:

[0040] (a) Preparation of intermediate 1: Add 32g p-aminobenzonitrile, 69.7g DIPEA and 100mL water to 500mL tetrahydrofuran, stir, add dropwise 100mL aqueous solution of hydroxylamine hydrochloride; after dropping, raise the temperature to 50°C for reaction, monitor by TLC Reaction: After the reaction was completed, the temperature was naturally lowered to room temperature, the tetrahydrofuran was evaporated under reduced pressure, cooled, filtered with suction, the filter cake was washed with ether, and dried to obtain 41.8 g of intermediate 1 (1) with a purity of 97.4% and a yield of 87%;

[0041](b) Preparation of Intermediate 2: Add 23g of sodium ethoxide to 500mL of absolute ethanol, stir to dissolve, add 40g of Intermediate 1 (1), stir, add 30.4g of diethyl carbonate dropwise, and heat up to 75-80°C reaction, TLC monitors the reaction; after the reaction is completed, concentrate un...

Embodiment 3

[0048] A method for preparing dabigatran etexilate (7), comprising the following steps:

[0049] (a) Preparation of intermediate 1: In 800mL of acetonitrile, add 48g of p-aminobenzonitrile, 67.2g of sodium carbonate and 200mL of water, stir, and add dropwise 200mL of hydroxylamine hydrochloride aqueous solution; after dropping, heat up to 50°C for reaction, TLC Monitor the reaction; after the reaction is completed, cool down to room temperature naturally, evaporate THF under reduced pressure, cool, filter with suction, wash the filter cake with ether, and dry to obtain 63.4 g of Intermediate 1 (1) with a purity of 97.9% and a yield of 88%. ;

[0050] (b) Preparation of Intermediate 2: In 700mL of anhydrous methanol, add 24.7g of sodium methoxide, stir to dissolve, add 54g of Intermediate 1 (1), stir, add 40.5g of diethyl carbonate dropwise, drop the temperature to React at 55-60°C, monitor the reaction by TLC; after the reaction is complete, concentrate under reduced pressure...

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Abstract

The invention discloses a dabigatran etexilate preparation method. The method comprises the following steps: preparing an intermediate 1, preparing an intermediate 2, preparing an intermediate 3, preparing an intermediate 4, preparing an intermediate 5, preparing an intermediate 6, and preparing dabigatran etexilate. The preparation method has the advantages of cheap and easily available raw materials, easy operation, easy control, high reaction yield, high product purity, and suitableness for the large-scale industrial production of dabigatran etexilate.

Description

technical field [0001] The invention belongs to the technical fields of medicinal chemistry and pharmaceutical engineering, and in particular relates to a method for preparing dabigatran etexilate. Background technique [0002] Dabigatran etexilate (trade name Pradaxa) was developed by Boehringer Ingelheim, Germany, and was first launched in Germany and the UK in April 2008. Dabigatran etexilate is a new type of synthetic direct thrombin inhibitor, which is the prodrug of dabigatran, which is a non-peptide thrombin inhibitor. Its chemical name is: 3-[[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H- Benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionate ethyl methanesulfonate, the structure is as formula (8): [0003] [0004] (8) [0005] After oral administration, dabigatran etexilate is converted into dabigatran with direct anticoagulant activity after gastrointestinal absorption. Dabigatran binds to the fibrin-specific binding s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 李泽标严军林燕峰邹林赵永星
Owner NANTONG CHANGYOO PHARMATECH CO LTD
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