Preparation method of dabigatran etexilate intermediate

A technology of dabigatran etexilate and intermediates, applied in the field of preparation of dabigatran etexilate intermediates, can solve the problems of slow reaction rate, low yield, difficult purification, etc., and achieve easy operation, high reaction rate and high product quality. The effect of high purity

Active Publication Date: 2014-09-10
SHANGHAI INST OF PHARMA IND +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] The technical problem solved by the present invention is to provide a kind of preparation method of dabigatran etexilate intermediate in order to overc...

Method used

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  • Preparation method of dabigatran etexilate intermediate
  • Preparation method of dabigatran etexilate intermediate
  • Preparation method of dabigatran etexilate intermediate

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Experimental program
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Embodiment 1

[0029] Compound 1 (21.2g, 56.12mmol) and dimethyl sulfoxide (77.0ml) were added to the reaction kettle, the temperature was raised to 70°C, 27.0%-32.0% methylamine in ethanol solution (21.0ml) was slowly added dropwise, and stirred for 30min. Ethyl acetate (39.0ml) was added to the reaction solution, washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain compound 2 (20.6g, yield 98.56%). mp86~88℃; 1H-NMR (DMSO-d 6 , 400MHz) δ: 1.11(t, 3H), 2.66(t, 2H), 2.91(t, 3H), 3.96(q, 2H), 4.18(t, 2H), 6.83(d, 1H), 7.08(d , 1H), 7.21 (m, 1H), 7.32 (dd, 1H), 7.69 (m, 1H), 7.93 (d, 1H), 8.36 (d, 1H), 8.43 (dd, 1H). HPLC purity 98.3%.

Embodiment 2

[0031] Add compound 1 (5.0g, 13.24mmol) and N,N-dimethylformamide (18.0ml) into the reaction kettle, raise the temperature to 70°C, and slowly add 27.0%-32.0% methylamine in ethanol solution (5.0ml) dropwise , stirred for 30min. Ethyl acetate (10.0ml) was added to the reaction solution, washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain compound 2 (4.8g, yield 97.36%). mp86~88℃; 1H-NMR (DMSO-d 6 , 400MHz) δ: 1.11(t, 3H), 2.66(t, 2H), 2.91(t, 3H), 3.96(q, 2H), 4.18(t, 2H), 6.83(d, 1H), 7.08(d , 1H), 7.21 (m, 1H), 7.32 (dd, 1H), 7.69 (m, 1H), 7.93 (d, 1H), 8.36 (d, 1H), 8.43 (dd, 1H). HPLC purity 98.9%.

Embodiment 3

[0033] Add compound 1 (5.0g, 13.24mmol) and N,N-dimethylacetamide (18.0ml) into the reaction kettle, raise the temperature to 70°C, and slowly add 27.0%-32.0% methylamine in ethanol solution (5.0ml) dropwise , stirred for 30min. Ethyl acetate (10.0ml) was added to the reaction solution, washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain compound 2 (4.9g, yield 99.39%). mp86~88℃; 1H-NMR (DMSO-d 6 , 400MHz) δ: 1.11(t, 3H), 2.66(t, 2H), 2.91(t, 3H), 3.96(q, 2H), 4.18(t, 2H), 6.83(d, 1H), 7.08(d , 1H), 7.21 (m, 1H), 7.32 (dd, 1H), 7.69 (m, 1H), 7.93 (d, 1H), 8.36 (d, 1H), 8.43 (dd, 1H). HPLC purity 98.0%.

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Abstract

The invention discloses a preparation method of a dabigatran etexilate intermediate. The preparation method of the dabigatran etexilate intermediate 2 comprises that in an aprotic organic solvent, a compound 1 and a C1-C3 alkyl alcohol solution of methylamine undergo a reaction to produce the dabigatran etexilate intermediate, wherein X represents chlorine, bromine or iodine. The preparation method of the dabigatran etexilate intermediate has simple processes, can be operated easily, has a high reaction rate and a high yield, can be purified easily and can produce the product having high purity.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of a dabigatran etexilate intermediate. 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, the chemical structural formula is shown in formula 1-1. [0003] [0004] 1-1 Dabigatran etexilate [0005] Dabigatran etexilate is a new type of oral anticoagulant drug developed and marketed by Boehringer Ingelheim (Boehringer Ingelheim) in Germany, which belongs to non-peptide thrombin inhibitors. The drug was first launched in Germany and the UK in April 2008, and was approved by the FDA in 2010. The drug has the advantages of oral administration, no need for clinical testing, and few drug interactions. [0006] About the synthesis of dabigatran etexil...

Claims

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Application Information

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IPC IPC(8): C07D213/75
CPCC07D213/75
Inventor 郭雅俊单汉滨朱雪焱袁哲东俞雄江华
Owner SHANGHAI INST OF PHARMA IND
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