Convergent Synthesis of Menaquinone-7 (MK-7)

A practical synthesis of menaquinone-7 (MK-7, vitamin K-2) in the all-trans form was designed. Stereoselective synthesis of MK-7 was achieved through a 1 + 6 convergent strategy by condensation of two building blocks, menadione monoprenyl derivative (fragment 1) with hexaprenyl bromide (fragment 6, 82%). Pd-catalyzed desulfonation with LiEt3BH (78%) was followed by oxidation of the hydroquinone moiety using ammonium cerium(IV) nitrate (72%). The major challenge in our methodology was the preparation of all-trans hexaprenyl bromide by coupling of two triprenyl units derived from trans,trans-farnesol. Manufacturing on a pilot scale was accomplished through our approach. The scalable method was designed especially for a large, kilogram-scale production from easily available intermediates. Furthermore, the proposed methodology avoids many chromatographic purifications and allows for a relatively cost-effective manufacturing. Moreover, our synthesis yielded high-purity (99.9%) final product MK-7, which can be used as a dietary supplement as well as an active pharmaceutical ingredient.