Total Synthesis of Dabigatran Revisited; Synthesis of Amidine‐Tosylated Dabigatran

• Published in: ChemistrySelect (Weinheim) 2019-12, Vol.4 (47), p.13802-13805
• Main Authors: Jopp, Stefan, Molenda, Ricardo, Seiler, Elisabeth R. D., Maitz, Manfred F., Villinger, Alexander, Ehlers, Peter, Langer, Peter
• Format: Article
• Language: English
• Subjects: anticoagulant; dabigatran; selective tosylation; thrombin; total synthesis
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.201903881

The total synthesis of a new dabigatran derivative featuring a tosyl protecting group at the amidine group of dabigatran was explored. During the course of this work, different new synthetic pathways towards dabigatran intermediates are investigated and known concepts revisited. In this context, it was found that, in our hands, a published synthesis did not work as reported. Part of the synthetic strategy presented herein is an amidine‐selective tosylation of 4‐aminobenzamidine. Furthermore, two new dabigatran derivatives exhibit thrombin inhibition activity. In the work presented herein a new derivative of the anticoagulant dabigatran, bearing a tosyl group at the amidine function, was prepared. The desired final product was achieved after a 7 step synthesis in overall good yields. A main part of the strategy was the selective tosylation of 4‐aminobenzamidine, which was proven via NMR and crystal structure. The final product and its precursor were tested for their inhibition activity for FIIa (thrombin). In the context of this work the authors found that a published procedure for the synthesis of dabigatran did not proceed as reported and thus presented a new approach.