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.
Andersen
Denise
D
Chemistry Process Research and Development, Amgen Inc., Thousand Oaks, California 19320, USA. danders555@yahoo.com
Storz
Thomas
T
Liu
Pingli
P
Wang
Xin
X
Li
Leping
L
Fan
Pingchen
P
Chen
Xiaoqi
X
Allgeier
Alan
A
Burgos
Alain
A
Tedrow
Jason
J
Baum
Jean
J
Chen
Ying
Y
Crockett
Rich
R
Huang
Liang
L
Syed
Rashid
R
Larsen
Robert D
RD
Martinelli
Mike
M
D001557:Benzenesulfonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry; D015394:Molecular Structure; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism
C526481:AMG 076; D001557:Benzenesulfonates; D003509:Cyclohexanecarboxylic Acids; D007546:Isoquinolines; C103263:MCHR1 protein, human; D017481:Receptors, Somatostatin