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Dabigatran etexilate mesylate preparation method

A technology of dabigatran etexilate mesylate and ethyl propionate, which is applied in the field of drug synthesis, can solve the problems of many impurities, pollute the environment, and long reaction time, and achieve high purity and yield, easy-to-obtain reaction raw materials, The effect of improving the reaction yield

Inactive Publication Date: 2019-06-04
辽宁博美医药科技有限公司
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AI Technical Summary

Problems solved by technology

[0011] In the process of preparing intermediate (5) in this route, Pinner is used to form an amidine reaction. There are mainly three synthetic methods: the first method needs to feed dry hydrogen chloride gas and ammonia gas, which have high toxicity, strong corrosion and irritation. It pollutes the environment and needs to be purified by column chromatography, which is troublesome for post-processing; the second method uses hydroxylamine hydrochloride to be reduced by ammonium formate and palladium carbon, and the cost of metal palladium catalyst is relatively high; the third method is to react with hydrogen chloride gas and ammonium carbonate successively , the reaction time is long, the reaction is insufficient and there are many impurities, and column chromatography purification is also required
There are certain shortcomings in all three synthesis conditions, which are not conducive to industrial production

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] (1) Closed loop reaction

[0039] Add 120ml of ethyl acetate, 28g of ethyl 3-[(3-amino-4-methylaminobenzoyl)(pyridin-2-yl)amino]propionate and 14.5g of chloroacetic anhydride to the reactor at room temperature. , Stir and heat to 65°C for 2 hours, then cool to 40°C, add 15g of potassium carbonate, and keep at 40°C for 4 hours. After filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was cooled to 0°C with 150ml methyl tert-butyl ether to crystallize to obtain N-[[2-(chloromethyl)-1-methyl-1H-benzimidazole-5 -Yl]carbonyl]-N-2-pyridyl-β-alanine ethyl ester 29.5 g, yield 90%, product HPLC purity 98.0%. 1 H-NMR(CDCl 3 )δ1.1(t,3H, -CH 3 ),δ2.7(t,2H,-CH 2 -),δ2.8(s,3H,-NCH 3 ),δ4.1(m,2H,-NCH 2 -),δ4.2(s,2H,-CH 2 -),δ4.4(t,2H,-CH 2 Cl),δ6.5(m,1H,Ar-H),δ6.8(m,1H,Py-H),δ7.2(m,2H,Ar-H),δ7.4(m,1H, Py-H), δ8.0 (m, 1H, Py-H), δ8.5 (m, 1H, Py-H).

[0040] (2) Condensation reaction

[0041] Add 1.5 g of sodium iodide, 6.6 g of potassium carbonate, a...

Embodiment 2

[0047] (1) Closed loop reaction

[0048] Add 120ml of ethyl acetate, 28g of ethyl 3-[(3-amino-4-methylaminobenzoyl)(pyridin-2-yl)amino]propionate and 14.5g of chloroacetic anhydride to the reactor at room temperature. , Stir and heat to 65°C for 2 hours, add 15g potassium carbonate to the reaction solution after cooling slightly, and keep at 65°C for 2 hours. After filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was cooled to 0°C with 150ml methyl tert-butyl ether to crystallize to obtain N-[[2-(chloromethyl)-1-methyl-1H-benzimidazole-5 -Yl]carbonyl]-N-2-pyridyl-β-alanine ethyl ester 29.8 g, yield 91%, product HPLC purity 98.0%.

[0049] (2) Condensation reaction

[0050] At room temperature, 1.5 g of sodium iodide, 8.0 g of sodium bicarbonate, and 0.75 g of tetrabutylammonium chloride were sequentially added to the reactor at room temperature, and then 50 ml of water and 65 ml of butyl acetate were added and stirred. After the solid is c...

Embodiment 3

[0056] (1) Closed loop reaction

[0057] Add 120ml of ethyl acetate, 28g of ethyl 3-[(3-amino-4-methylaminobenzoyl)(pyridin-2-yl)amino]propionate and 14.5g of chloroacetic anhydride to the reactor at room temperature. , Stir and heat to 65°C for 2 hours. After cooling slightly, add 12g of sodium carbonate and raise the temperature to 78°C for 1 hour. After filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was cooled to 0°C with 150ml methyl tert-butyl ether to crystallize to obtain N-[[2-(chloromethyl)-1-methyl-1H-benzimidazole-5 -Yl]carbonyl]-N-2-pyridyl-β-alanine ethyl ester 29.1 g, yield 89%, product HPLC purity 98.1%.

[0058] (2) Condensation reaction

[0059] At room temperature, 1.5 g of sodium iodide, 6.6 g of potassium carbonate, and 0.75 g of tetrabutylammonium bromide were sequentially added to the reactor at room temperature, and then 50 ml of water and 65 ml of ethyl acetate were added and stirred. After the solid is completely...

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Abstract

The invention belongs to the field of pharmaceutical synthesis, and provides a dabigatran etexilate mesylate preparation method, which comprises: carrying out a ring closure reaction on 3-[(3-amino-4-methylaminobenzoyl)(pyridine-2-yl)amino] ethyl propionate and chloroacetic anhydride to generate N-[[2-(chloromethyl)-1-methyl-1H-benzimidazole-5-yl]carbonyl]-N-2-pyridyl-beta-alanine ethyl ester, carrying out a condensation reaction on the N-[[2-(chloromethyl)-1-methyl-1H-benzimidazole-5-yl]carbonyl]-N-2-pyridyl-beta-alanine ethyl ester and 4-aminobenzamidine dihydrochloride to obtain 3-({2-[(4-amidino-phenylimino)-methylene]-1-methylene-1H-benzimidazole-5-carbonyl}-pyridine-2-imine)-ethyl propionate, carrying out ester forming on the 3-({2-[(4-amidino-phenylimino)-methylene]-1-methylene-1H-benzimidazole-5-carbonyl}-pyridine-2-imine)-ethyl propionate and hexyl chloroformate to obtain dabigatran etexilate, and carrying out salt forming on the dabigatran etexilate and methanesulfonic acid to obtain dabigatran etexilate mesylate. According to the present invention, the route of the method has characteristics of high yield, mild condition and convenient intermediate purification, and meets the requirements of industrial production.

Description

Technical field [0001] The invention belongs to the field of drug synthesis, and specifically relates to a preparation method of dabigatran etexilate mesylate. Background technique [0002] Dabigatran Etexilate Mesylate, developed by Boehringer Ingelheim, Germany, was first listed in Germany and the United Kingdom in April 2008 under the trade name Pradaxa. Dabigatran etexilate mesylate is the first new class of oral anticoagulant drug to be marketed in 50 years after warfarin. It can directly act on the fibrin-specific binding site of thrombin to block the formation of thrombus. As a new type of synthetic oral anticoagulant, it has good clinical treatment and high safety. It is easy to use, quick onset and has little interaction with food and drugs. It has low bleeding risk and does not require timely detection of coagulation indicators. Due to its various advantages, its clinical application prospects are optimistic. The listing of dabigatran etexilate mesylate is a major adv...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
Inventor 周小明姜琳王倩刘勇潘大林姜超
Owner 辽宁博美医药科技有限公司
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