Background and overview of the synthesis method of dabigatran etexilate intermediate 1
Dabigatran etexilate intermediate 1 can be used to synthesize dabigatran etexilate. Dabigatran etexilate was developed by the German company Boehringer Ingelheim and was first launched in Germany and the United Kingdom in April 2008. Dabigatran etexilate is a new synthetic direct thrombin inhibitor, a prodrug of Dabigatran, and a non-peptide thrombin inhibitor. Its chemical name is: 3-[[2-[[[4-[[[hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzo Imidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester methanesulfonate.
Synthetic method of dabigatran etexilate intermediate 1
1) Add 50g of 4-methylamino-3-nitrobenzoic acid, 300mL of methylene chloride, and 3mL of DMF into a 1000mL reaction bottle. After stirring and heating to 40°C, add 90g of thionyl chloride dropwise for 0.5h. After the addition is completed, keep the reflux reaction at 40°C for 5 hours, and concentrate to dryness under reduced pressure to obtain a yellow solid;
2) Add 500 mL of methylene chloride to the product obtained in step 1), stir until the solid is basically dissolved, add 38.5g of triethylamine, heat to 40°C, and add N-2-pyridyl-alanine ethyl dropwise 45g of ester was added dropwise for 0.5h, and the reflux reaction was maintained at 40°C for 5h; after the reaction solution dropped to room temperature, it was washed with 600mL of saturated sodium bicarbonate solution and 600mL of water, and the organic layer obtained by extraction was dried with anhydrous sodium sulfate and filtered. Concentrate the filtrate to dryness to obtain an oily substance, add 500 mL of absolute ethanol to dissolve, stir and cool down to crystallize, freeze at -7°C overnight, filter with suction the next day, and vacuum dry at 50°C for 2 hours to obtain 64.4g of yellow solid, with a purity of 99.22% as measured by HPLC;
3) Add 100mL water to a 250mL reaction bottle, adjust the pH to 3 with glacial acetic acid, add 4.48g of iron powder, heat to 70°C under mechanical stirring, stir for 0.5h, and dropwise add 7.45g of the product obtained in step 2) 112.5 mL of warm ethanol solution was added dropwise within 20 minutes, and the reaction was maintained at 70°C for 0.5 h; after the reaction was completed, the pH value was adjusted to 8 with saturated sodium carbonate solution, hot filtered, extracted with 100 mL × 2 methylene chloride, and 2 boric acid Wash the combined methylene chloride layer with 00 mL of water, dry over anhydrous sodium sulfate, and concentrate under negative pressure to obtain an oil. Add 10 mL of ethyl acetate and heat to dissolve completely. Stir and cool down to crystallize. Freeze overnight in the refrigerator. Filter the next day and freeze acetic acid. Wash with ethyl ester and dry in a vacuum oven at 40°C to obtain 4.9 g of hydroxytetrahydrofuran, a light yellow solid of dabigatran etexilate intermediate 1, whose purity is 99.02% as measured by HPLC.
References
[1][Chinese invention] CN201410310415.9 A method for preparing dabigatran etexilate intermediate
