Stereoselective Synthesis of a MCHr1 Antagonist

Melanin-concentrating hormone (MCH) is implicated in the feeding behavior in mammals affording a
potential target to control overeating in people. Compound 1 (AMG 076) has been identified as a potent
MCHr1 antagonist for the treatment of obesity. A synthesis suitable for the large-scale preparation of
this lead candidate was developed to support preclinical studies. A Robinson annulation of benzylpiperidone
and resolution of the desired enone from a mixture of the diastereomers afforded key intermediate 6
after a stereoselective hydrogenation. Subsequent Fischer indole synthesis with hydrazine 5 then provided
the advanced intermediate, indole 2. Two complementary reductive amination strategies employing either
aldehyde 3 or lactol 4 led to the synthesis of title compound 1.