Development of Manufacturing Processes for the Carboxylic Acid Key Intermediate of Lusutrombopag: One-Pot Reaction Process of Formylation and the Horner–Wadsworth–Emmons Reaction

Abstract

We describe the development of a one-pot preparation process of (E)-3,5-dichloro-4-(3-ethoxy-2-methyl-3-oxoprop-1-en-1-yl)benzoic acid (3), which is a key carboxylic acid intermediate of lusutrombopag. This one-pot reaction process is composed of lithiation of 3,5-dichlorobenzoic acid with lithium diisopropylamide (LDA), formylation using N-formylmorpholine, followed by olefination employing the Horner−Wadsworth−Emmons reaction with triethyl 2-phosphonopropionate. This method enabled kilogram-scale manufacturing of carboxylic acid 3, a key intermediate of lusutrombopag with high purity, together with a reduced number of steps, improvement of yield, and avoidance of a cumbersome procedure for isolation of the intermediate.

Facile Synthesis and First Antifungal Exploration of Tetracyclic Meroterpenoids: (+)-Aureol, (−)-Pelorol, and Its Analogs

“…The direct introduction of formaldehyde to the aromatic ring using N -formylmorpholine and Vilsmeier–Haack conditions , did not lead to a detectable product. Interestingly, the combination of SnCl 4 and MeOCHCl 2 can successfully formylate the phenyl ring with undesired regioselectivity.…”

The First GMP Synthesis of MK-2118, a Small Molecule Agonist for Stimulator of Interferon Genes

“…Therefore, we focused our development efforts on the installation of the chiral acid side chain of MK-2118. In Scheme , we outline three potential routes that were explored: (A) a Horner–Wadsworth–Emmons − (HWE) reaction followed by asymmetric hydrogenation, (B) nucleophilic ring opening of an anhydride, and (C) a metal-mediated cross-coupling with a chiral organozinc intermediate . The original medicinal chemistry route utilized path C (Scheme ) with stoichiometric quantities of Cu.…”