Preparation method for dabigatran etexilate intermediate and intermediate compound

A technology of dabigatran etexilate and compounds, applied in the field of drug synthesis, can solve the problems of high preparation difficulty, many side reactions, and difficult purification, and achieve the effects of simple preparation method, easy purification, and easy operation

Active Publication Date: 2014-07-16
SHANGHAI INST OF PHARMA IND CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The technical problem solved by the present invention is to provide a kind of dabigatran etexilate in order to overcome the high difficulty of preparation of the existing dabigatran etexilate intermediate, side reactions are more, not only the yield is low and difficult to purify The preparation method of intermediate and intermediate compound

Method used

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  • Preparation method for dabigatran etexilate intermediate and intermediate compound
  • Preparation method for dabigatran etexilate intermediate and intermediate compound
  • Preparation method for dabigatran etexilate intermediate and intermediate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Synthesis of 3-nitro-4-chlorobenzoyl chloride (compound 2)

[0056]

[0057] Add 3-nitro-4-chlorobenzoic acid (10.0g, 49.6mmol), N,N-dimethylformamide (0.3ml, 3.6mmol) and toluene (50ml) into the reaction kettle, heat to 70°C, add Thionyl chloride (4.3ml, 59.5mmol), continue to heat and reflux for 30min, distill off thionyl chloride and solvent under reduced pressure to obtain a light yellow oil (compound 2), add dichloromethane (60ml) to dissolve, and directly use Next reaction.

Embodiment 2

[0059] Synthesis of ethyl 3-[(3-nitro-4-chlorobenzoyl)(pyridin-2-yl)amino]propanoate (compound 3)

[0060]

[0061] Add ethyl 3-(pyridin-2-yl-amino)propionate (9.6g, 49.6mmol), triethylamine (13.8ml, 99.2mmol) and dichloromethane (20ml) into the reaction kettle, dropwise add the The dichloromethane solution of the obtained compound 2. After the addition, stir at room temperature for 1h. The reaction solution was washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness, and the remaining solid was purified by column chromatography to obtain compound 3 (16.3 g, yield 87.0%). mp63~65℃; ESI-MS(m / z): 378[M+H] + , 400[M+Na] + ; 1 H-NMR (DMSO-d 6 , 400MHz) δ: 1.19 (t, 3H), 2.70 (t, 2H), 3.95 (q, 2H), 4.20 (t, 2H), 7.22 (d, 2H), 7.25 (t, 1H), 7.44 (dd , 1H), 7.66 (d, 1H), 7.75 (m, 1H), 7.92 (d, 1H), 8.35 (dd, 1H). HPLC purity 98.5%.

Embodiment 3

[0063] Synthesis of ethyl 3-[(4-methylamino-3-nitrobenzoyl)(pyridin-2-yl)amino]propanoate (compound 4)

[0064]

[0065] Compound 3 (16.3g, 47.15mmol) and ethanol (60.0ml) were added to the reaction kettle, the temperature was raised to 40°C, 27.0%-32.0% methylamine in ethanol solution (16.3ml) was slowly added dropwise, and stirred for 2h. The reaction solution was evaporated to dryness, and the remaining solid was purified by column chromatography to obtain compound 4 (13.6 g, yield 84.6%). mp86~88℃; 1 H-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 97.9%.

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Abstract

The invention discloses a preparation method for a dabigatran etexilate intermediate and an intermediate compound. The preparation method of the dabigatran etexilate intermediate 4 comprises the following step: in a protic organic solvent, reacting a compound 3 with a C1-C3 alkanol solution of methylamine. In the formula of the compound 3, X is chlorine, bromine or iodine. The invention also discloses the intermediate compound 3 and a preparation method of the intermediate compound 3. The preparation method for the dabigatran etexilate intermediate is simple and easy to operate, the yield is high, the product is easy to purity, and the preparation method is suitable for industrial production. The formula of the preparation method for the dabigatran etexilate intermediate is shown in the specification.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of a dabigatran etexilate intermediate and an intermediate compound. 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 s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/75
CPCC07D213/75
Inventor 郭雅俊单汉滨朱雪焱袁哲东俞雄
Owner SHANGHAI INST OF PHARMA IND CO LTD
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