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Dabigatran etexilate intermediate, preparation method for same and method for preparing dabigatran etexilate

A technology of dabigatran etexilate and intermediates, applied in the field of dabigatran etexilate intermediates and its preparation, can solve the problems of low yield of intermediates, low purity of intermediates, high price of dehydrating agent, etc., and achieve product yield The effect of high yield and purity, simplified preparation process and good market prospect

Inactive Publication Date: 2012-08-15
NANJING UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The main problem that above-mentioned two kinds of routes exist is: these routes all contain benzimidazole cyclization step, and this step usually will adopt dehydrating agent, and dehydrating agent is expensive and is unfavorable for reducing cost; Simultaneously, the intermediate yield obtained after cyclization Lower, and use dehydrating agent can introduce a large amount of impurity again, cause intermediate purity to be very low, and finally cause the purity of product dabigatran etexilate to be also very low

Method used

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  • Dabigatran etexilate intermediate, preparation method for same and method for preparing dabigatran etexilate
  • Dabigatran etexilate intermediate, preparation method for same and method for preparing dabigatran etexilate
  • Dabigatran etexilate intermediate, preparation method for same and method for preparing dabigatran etexilate

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preparation example Construction

[0062] The present invention also provides a preparation method of the above-mentioned dabigatran etexilate intermediate, comprising the following steps:

[0063] The compound of formula (1) is acylated with the compound of formula (A) to obtain the aforementioned dabigatran etexilate intermediate (that is, the compound of formula (2));

[0064]

[0065] In formula (A), X is selected from chlorine, bromine, iodine, R is selected from hydroxyl, chlorine, -O-CH 2 CH 3 ,

[0066] Preferably, the specific process of the reaction between the compound of formula (1) and the compound of formula (A) is as follows: first drop the ethyl acetate solution of the compound of formula (A) into the tetrahydrofuran solution of the compound of formula (1) to obtain a reaction solution, and then react The liquid was reacted at a temperature of 25°C-50°C for at least 10 hours, then the reaction liquid was cooled and suction filtered, and the obtained solid was the aforementioned dabigatran e...

Embodiment 1

[0098] Example 1 Preparation of N-(3-bromoacetamido-4-methylamino)benzoyl-N-(2-pyridyl)-3-aminopropionic acid ethyl ester (i.e. X is a bromine formula (2) compound)

[0099] Put 130g of the compound of formula (1) and 4000ml of tetrahydrofuran into the reaction flask, stir evenly, then slowly dropwise add ethyl acetate solution (200ml) containing 109g of bromoacetic anhydride to the flask at 25°C, and then heat to 50°C to react for at least 10 Hour. Cooling and suction filtration; the filter cake was washed with tetrahydrofuran (2×100ml), and dried to obtain N-(3-bromoacetamido-4-methylamino)benzoyl-N-(2-pyridyl)-3-aminopropyl Acetate ethyl ester 166g, yield is 95.8%, HPLC purity is 98.5%, 1 H-NMR picture as figure 1 shown, 13 C-NMR picture as figure 2 shown. 1 H-NMR (CDCl 3 )δ: 1.1(t, 3H), 2.7(t, 2H), 2.7(s, 3H), 4.0(m, 2H), 4.0(s, 2H), 4.3(t, 2H), 6.4(m, 1H ), 6.7 (m, 1H), 7.0 (m, 2H), 7.2 (m, 1H), 7.9 (m, 1H), 8.4 (m, 1H). 13 C-NMR (CDCl 3 )δ: 14.0, 28.6, 30.0, 33...

Embodiment 2

[0104] Embodiment 2 prepares formula (6) compound by N-(3-bromoacetamido-4-methylamino)benzoyl-N-(2-pyridyl)-3-aminopropionic acid ethyl ester

[0105] 46.2g N-(3-bromoacetamido-4-methylamino)benzoyl-N-(2-pyridyl)-3-alanine ethyl ester, 600ml dimethylformamide (DMF), 17.6g Put p-aminobenzonitrile, 5.2g potassium iodide, and 13.8g potassium carbonate into the reaction bottle, react at 40°C for 10 hours, then slowly heat to 80°C for 2 hours; then cool to room temperature, add 2500ml of water to precipitate for 0.5 hours (during this process Stir in middle), suction filtration; Filter cake is washed with water (2 * 100ml), recrystallizes from ethyl acetate (960ml) after drying, obtains 41g formula (6) compound after drying again, i.e. 3-[[[2-[[ (4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester, yield 85% , optical purity ≥ 97%, 1 H-NMR picture as image 3 shown. 1 H-NMR (DMSO) δ: 1.1(t, 3H), 2.7(t, 2H), 3.9(s, 3...

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Abstract

The invention relates to a dabigatran etexilate intermediate, a preparation method for the same and a method for preparing dabigatran etexilate, which belong to the technical field of pharmaceutical chemistry and pharmaceutical engineering. The dabigatran etexilate intermediate is represented as a structural formula (2), so that a preparation process for the dabigatran etexilate is simplified, yield and purity of the dabigatran etexilate are high, reaction temperature is low, expensive dehydrating agent is not needed, and good market prospect is provided.

Description

technical field [0001] The invention relates to a dabigatran etexilate intermediate and a preparation method thereof, and a method for preparing dabigatran etexilate by using the intermediate, belonging to the technical fields of medicinal chemistry and pharmaceutical engineering. Background technique [0002] Dabigatran etexilate, English name: Dabigatran etexilate, chemical name: 3-[[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]toluene ]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester, chemical structural formula: [0003] [0004] It is a new type of oral anticoagulant drug developed by Boethringer Ingelhein, Germany, which belongs to non-peptide thrombin inhibitor. [0005] The drug was first marketed in Germany and the UK in April 2008 and was approved by the US FDA in 2010. The drug has the advantages of oral administration, strong efficacy, no need for special drug monitoring, and few drug interactions. It is ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/75C07D401/12
Inventor 徐浩申国辉周长岭
Owner NANJING UNIV OF TECH
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