Lusutrombopag

Lusutrombopag is an orally bioavailable thrombopoietin (TPO) receptor agonist developed by Shionogi for improvement of thrombocytopenia associated with chronic liver disease in patients undergoing an elective invasive procedure (e.g., liver biopsy, liver transplantation). Thrombocytopenia, which is common among patients with chronic liver disease, increases the risk of bleeding when undergoing invasive procedures, which in turn complicates therapy and increases the risk of mortality. Lusutrombopag, which was approved in Japan in September 2015, promotes platelet production by stimulating the proliferation and differentiation of human bone marrow progenitor cells into megakaryocytes via the thrombopoietic pathway. The consequent increase in platelet levels avoids postponement of invasive procedures or transfusion of platelets and administration of platelet products, the current standard of care for thrombocytopenia in these patients.

Lusutrombopag is a newly discovered thrombopoietin receptor agonist used in the treatment of patients with chronic ITP.

To date, only two synthetic routes to lusutrombopag have been reported: one in the Japanese patent literature which has been exemplified on kilogram scale and the other a closely related discovery route which has been reported in the United States patent literature. Commercial 2,6-dibromoanisole (106) was treated with isopropylmagnesium chloride to form the corresponding Grignard reagent prior to reaction with Weinreb amide 107, furnishing a ketone which underwent immediate reduction with formic acid in the presence of chiral catalyst RuCl(p-cymene)[(S,S)-Ts-DPEN] (108) and generate the desired (S)-stereogenic alcohol 109.

Unfortunately, neither the yield nor the stereoselectivity of this reduction was reported in any of the disclosures. Benzyl alcohol 109 was subjected to Williamson etherification conditions with n-hexyl bromide to furnish ether 110. The aryl bromide within 110 was then converted to the corresponding Grignard reagent, which was reacted with N-methyloxy-N-methyl-2-chloroacetamide (111), followed by subsequent treatment with thiourea in toluene/ ethanol at elevated temperatures to give aminothiazole intermediate 112 in 45% yield across the two-step sequence. Next, activation of acid 113 prior to exposure to 112 facilitated amide bond formation. Saponification of the pendant ester with sodium hydroxide furnished luxutrombopag (XIV) in 89% yield. Although acid 113 is not commercial, it could be prepared from 3,5-dichlorobenzoic acid (33) via formylation with 4-formylmorpholine, followed by a Horner-Wadsworth-Emmons reaction with triethylphosphonopropionate.