Journal of Organic Chemistry 2005-07-22

Efficient synthesis of a GABA A alpha2,3-selective allosteric modulator via a sequential Pd-catalyzed cross-coupling approach.

Mark S Jensen, R Scott Hoerrner, Wenjie Li, Dorian P Nelson, Gary J Javadi, Peter G Dormer, Dongwei Cai, Robert D Larsen

Index: J. Org. Chem. 70(15) , 6034-6039, (2005)

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Abstract

A practical synthesis of 2-[3-(4-fluoro-3-pyridin-3-yl-phenyl)-imidazo[1,2-a]pyrimidin-7-yl]-propan-2-ol (1), an oral GABA(A) alpha(2/3)-selective agonist, is described. The five-step process, which afforded 1 in 40% overall yield, included imidazopyrimidine 2 and pyridine boronic acid 4 as key fragments. The synthesis is highlighted by consecutive Pd-catalyzed coupling steps to assemble the final free base 1 in high yield and regioselectivity. A novel method for Pd removal in the final step is also described.