A highly efficient synthesis of sitagliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM), has been developed. The key dehydrositagliptin intermediate 9 is prepared in three steps in one pot and directly isolated in 82% yield and >99.6 wt % purity. Highly enantioselective hydrogenation of dehydrositagliptin 9, with as low as 0.15 mol % of Rh(I)/(t)Bu JOSIPHOS, affords sitagliptin, which is finally isolated as its phosphate salt with nearly perfect optical and chemical purity. This environmentally friendly, 'green' synthesis significantly reduces the total waste generated per kilogram of sitagliptin produced in comparison with the first-generation route and completely eliminates aqueous waste streams. The efficiency of this cost-effective process, which has been implemented on manufacturing scale, results in up to 65% overall isolated yield.
A direct asymmetric hydrogenation of unprotected enamino esters and amides is described. Catalyzed by Rh complexes with Josiphos-type chiral ligands, this method gives beta-amino esters and amides in high yield and high ee (93-97% ee). No acyl protection/deprotection is required.
A new synthesis of sitagliptin (MK-0431), a DPP-IV inhibitor
and potential new treatment for type II diabetes, suitable for
the preparation of multi-kilogram quantities is presented. The
triazolopyrazine fragment of sitagliptin was prepared in 26%
yield over four chemical steps using a synthetic strategy similar
to the medicinal chemistry synthesis. Key process developments
were made in the first step of this sequence, the addition of
hydrazine to chloropyrazine, to ensure its safe operation on a
large scale. The beta-amino acid fragment of sitagliptin was
prepared by asymmetric reduction of the corresponding beta-ketoester followed by a two-step elaboration to an N-benzyloxy
beta-lactam. Hydrolysis of the lactam followed by direct
coupling to the triazolopiperazine afforded sitagliptin after
cleavage of the N-benzyloxy group and salt formation. The
overall yield was 52% over eight steps.
Molnupiravir (MK-4482,
EIDD-2801) is a promising orally bioavailable
drug candidate for the treatment of COVID-19. Herein, we describe
a supply-centered and chromatography-free synthesis of molnupiravir
from cytidine, consisting of two steps: a selective enzymatic acylation
followed by transamination to yield the final drug product. Both steps
have been successfully performed on a decagram scale: the first step
at 200 g and the second step at 80 g. Overall, molnupiravir has been
obtained in a 41% overall isolated yield compared to a maximum 17%
isolated yield in the patented route. This route provides many advantages
to the initial route described in the patent literature and would
decrease the cost of this pharmaceutical should it prove safe and
efficacious in ongoing clinical trials.
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