Lusutrombopag Chemische Eigenschaften,Einsatz,Produktion Methoden
Beschreibung
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.
Synthese
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.
Lusutrombopag Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
