A Facile and Scaleable Synthesis of ABT-239, A Benzofuranoid H₃ Antagonist

Abstract

A facile and scaleable synthesis of a potent and selective histamine H3 receptor antagonist, ABT-239 (1), was developed starting from commercially available 4‘-hydroxy-biphenyl-4-carbonitrile (2). The synthesis comprised four chemical steps and a salt formation step with an overall yield of 40%. A highly selective monoiodination of a phenol was developed and used to prepare iodophenol (3b) in near quantitative yield using NIS in AcOH in the presence of a small amount of H2SO4. A Pd-catalyzed cross coupling reaction of the iodophenols (3b) with butyn-3-ol (4a) provided benzofuran (5) in one step in >80% yield, en route to 1. The new process required no chromatographic purification throughout the synthesis and was successfully demonstrated on scale-up to prepare 1.7 kg of the target ABT-239 (1).

Histamine H3 Antagonists as Wake-Promoting and Pro-Cognitive Agents

“…ABT-239 also showed efficacy in several behavioral models including a social recognition memory model, a 5-trail inhibitory avoidance acquisition model, a 2-choice water maze, a PPI of startle and N40 gating [82,83]. Even with these extensive, promising preclinical studies and the publication of a scalable synthesis [84], the development of ABT-239 was halted in phase I, presumably due to cardiovascular liabilities because of QT c prolongation (hERG K i =195 nM) [85,86]. Additional SAR studies examined the substitution on the phenyl ring [87] as well as heterocyclic replacement of the phenyl ring to After exploring the conformationally restricted aminoethyl benzofuran analogs, researchers at Abbott also investigated using a combination of the amino ethyl group and other similarly spaced core replacements [89] such as 36-38.…”

Development of a Multikilogram Scale Synthesis of a TRPV1 Antagonist

“…The preparation of the penultimate compound 14 involved S N Ar displacement of the chlorine atom of intermediate 11 with ( R )-2-methylpyrrolidine 13 (Scheme ). At the time, compound 13 was not commercially available in sufficient quantities and was prepared by a four-step sequence we have previously disclosed . Reaction of piperazine 7 with 1.5 equiv of the tartrate salt of 13 was successfully accomplished at 95 °C in DMAc in the presence of 4 equiv of K 2 CO 3 for 18 h. The optimal reaction temperature was found to be +95 °C; however, this temperature was at the boiling point of the free base of pyrrolidine 13 and required an excess of pyrrolidine 13 to achieve complete conversion .…”

Selective Synthesis of Unnatural α‐, β‐ and γ‐Amino Esters

“…The difficulty of separating the product diastereomers of 2h, (S,S)-2h and (R,S)-2h, and the importance of 2-methylpyrrolidine, an advanced intermediate for the synthesis of histamine H 3 receptor antagonist ABT-239 used in the treatment of Alzheimer disease, [23] encouraged us to further convert it into the substituted pyrrolidine 4h. The synthesis (Scheme 3) relies on commercially available starting materials and inexpensive reagents to provide the methylbenzyl protected pyrrolidine.…”