ChemicalBook CAS DataBase List Dabigatran etexilate

Dabigatran etexilate synthesis

7synthesis methods

Product Name:Dabigatran etexilate
CAS Number:211915-06-9
Molecular formula:C34H41N7O5
Molecular Weight:627.73

The chemical synthesis of dabigatran etexilate starts with the acylation of ethyl 3-(2-pyridylamino)propionate with 4-(methylamino)-3-nitrobenzoyl chloride to produce the corresponding amide. Subsequent reduction of the nitro group by catalytic hydrogenation, and cyclization of the resultant phenylenediamine with N-(4-cyanophenyl)glycine leads to a benzimidazole intermediate. The cyano group is then transformed into an amidine by employing the Pinner reaction. Finally, acylation of the amidino group with hexyl chloroformate gives rise to dabigatran etexilate.

N-[[2-[[[4-(Aminoiminomethyl)phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]arbonyl]-N-2-pyridinyl-beta-alanine ethyl ester 4-methylbenzenesulfonate

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6092-54-2 Synthesis

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Yield:211915-06-9 16.4 g

Reaction Conditions:

Stage #1:1-methyl-2-[N-(4-amidino-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid N-(2-pyridyl)-N-2-(ethoxycarbonylethyl)-amide p-toluenesulfonic acid salt with potassium carbonate in water;acetonitrile at 27; for 0.5 h;
Stage #2:n-hexyl chloroformate in water;acetonitrile at 12 - 20; for 2 h;

Steps:

2 Reference Example-2: Preparation of Dabigatran etexilate free base
Reference Example-2: Preparation of Dabigatran etexilate free base To a stirred suspension of p-TSA salt of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]- benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide(20g) in acetonitrile (80 mL), at 27°C, was charged a solution of potassium carbonate (24.7 g) in DM water (50 mL).The reaction mass was stirred for 30 min, and then cooled to 12-15°C. n-Hexyl chloroformate (4.9g) was added and stirred for 30 min. The temperature of the reaction mass was raised 17°C and stirred for 30 min. Second lot of n-hexylchloroformate (1.49 g) was charged and the reaction mass stirred for another hour at 16-20°C, when analytical HPLC revealed completion of the reaction. DM water (50mL) was added and the reaction mass slurred for 15 min at 30°C. The precipitate was filtered, washed with water, dried under vacuum, at 50°C, to afford Dabigatran Etexilate as off-white solid material ( 16.4g, >96% hplc pure).

References:

LAURUS LABS PRIVATE LIMITED;VELAYUDHAN, Subha Nair;BOLLU, Ravindra Babu;BARIK, Prasanth Kumar;INDUKURI, Venkata Sunil Kumar;GORANTLA, Seeta Rama Anjaneyulu WO2015/33353, 2015, A2 Location in patent:Page/Page column 13; 14

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