Facile Synthesis of Dabigatran Etexilate Mesylatean Anticoagulant Drug Using a Novel Synthon N-Hexyl-4-nitrophenylCarbonate

摘要

Facile synthesis for Dabigatran etexilate mesylate (>1), an anticoagulant drug, is reported using a novel synthon, n-hexyl-4-nitrophenyl carbonate (>32), which substantially eliminates the formation of potential impurities >20–>27, which were generated due to the use of n-hexyl chloroformate in previously reported methods. Pinner reaction to prepare a key and critical intermediate, amidine >8, was optimized using design of experiment software to establish critical process parameters to achieve >8 in 97% yield. Nucleophilic substitution of >8 with novel synthon n-hexyl-4-nitrophenyl carbonate (>32) furnished the dabigatran base >9, which was then converted to its mesylate salt using methane sulfonic acid to provide >1 with an overall yield of 66% over three steps.