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A kind of dabigatran etexilate intermediate and its preparation method and application

A technology of dabigatran etexilate and reaction is applied in the new intermediate of dabigatran etexilate and its preparation, and prepares the field of dabigatran etexilate, which can solve the problems such as complex operation and environmental pollution, and achieve simple purification method, The effect of high yield and simple preparation method

Active Publication Date: 2017-02-22
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Using this new intermediate to synthesize dabigatran etexilate overcomes the shortcomings of other existing processes such as complicated operation and environmental pollution

Method used

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  • A kind of dabigatran etexilate intermediate and its preparation method and application
  • A kind of dabigatran etexilate intermediate and its preparation method and application
  • A kind of dabigatran etexilate intermediate and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Example 1: Preparation of 3-(2-chloroacetamido)-4-(methylamino)-benzoic acid

[0070]

[0071]Add 6 g of 3-amino-4-methylaminobenzoic acid and 6.3 g of chloroacetic anhydride into 30 ml of tetrahydrofuran solution, and stir at room temperature for 3 hours. Filter and concentrate the filtrate under reduced pressure. The concentrated solution was added with 15 ml of tetrahydrofuran, stirred for 30 minutes, and then filtered. Two batches of filter cakes were combined and dried to obtain 6 grams of 3-(2-chloroacetamido)-4-(methylamino)-benzoic acid with a yield of 69%.

[0072] 1 H NMR (400MHz, DMSO-d 6 , ppm) δ12.20 (br s, 1H), 9.42 (s, 1H), 7.69 (dd, 1H, J = 8.4Hz and J' = 1.6Hz), 7.63 (d, J = 1.6Hz, 1H), 6.61 ( d, J = 8.4 Hz, 1H), 4.28 (s, 2H), 5.94 (brs, 1H), 2.27 (d, J = 8.8 Hz, 3H).

Embodiment 2

[0073] Example 2: Preparation of 2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid

[0074]

[0075] Put 6 g of 3-(2-chloroacetamido)-4-(methylamino)-benzoic acid into the reaction flask, add 60 ml of methanol, drop 2 drops of concentrated hydrochloric acid, and react under reflux at 70°C for 3 hours. After the reaction, the reaction solution was cooled to 0° C. and filtered to obtain 4 grams of 2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid with a yield of 72.7%.

Embodiment 3

[0076] Example 3: Preparation of 2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid

[0077]

[0078] Put 6 grams of 3-amino-4-methylaminobenzoic acid and 6.3 grams of chloroacetic anhydride into the reaction flask, and add 60 milliliters of ethyl acetate. 2 drops of concentrated hydrochloric acid were added dropwise, and the mixture was refluxed at 80°C for 2 hours. After the reaction was completed, the reaction solution was cooled to 0°C and filtered. 5.1 g of 2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid was obtained with a yield of 62.9%.

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Abstract

The invention discloses a novel dabigatran etexilate intermediate shown in a formula 4 as shown in the specification and a preparation method of the novel dabigatran etexilate intermediate. The method is simple to operate, moderate in reaction condition, low in production cost, high in yield, and very suitable for industrialized preparation. The invention further relates to the application of the intermediate compound shown in the formula 4 in preparation for dabigatran etexilate.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a new intermediate of dabigatran etexilate and a preparation method thereof, and the use of the intermediate in preparing dabigatran etexilate. Background technique [0002] Dabigatran etexilate (Dabigatran Etexilate) is a novel oral anticoagulant drug developed by Boehringer Ingelheim, Germany, and its chemical formula is as shown in formula 6: [0003] [0004] Boehringer Ingelheim reported a synthetic method of dabigatran etexilate in patent WO9837075, and its synthetic route is as follows: [0005] [0006] The total yield of this synthetic route is low, and it is difficult to separate the final product and the intermediate, and a large amount of hydrogen chloride gas needs to be used when synthesizing the benzamidine intermediate, which seriously corrodes the equipment and causes environmental pollution. [0007] In response to the shortcomings of the abo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D235/10C07D235/12C07D401/12
CPCC07D235/10C07D235/12C07D401/12
Inventor 梅以成叶其壮
Owner ZHEJIANG HISUN PHARMA CO LTD