Enantioselective synthesis of Janus kinase inhibitor INCB018424 via an organocatalytic aza-Michael reaction.
An enantioselective synthesis of INCB018424 via organocatalytic asymmetric aza-Michael addition of pyrazoles (16 or 20) to (E)-3-cyclopentylacrylaldehyde (23) using diarylprolinol silyl ether as the catalyst was developed. Michael adducts (R)-24 and (R)-27 were isolated in good yield and high ee and were readily converted to INCB018424.
Lin
Qiyan
Q
Incyte Corporation, Experimental Station, Route 141 and Henry Clay Road, Wilmington, Delaware 19880, USA. qlin@incyte.com
Meloni
David
D
Pan
Yongchun
Y
Xia
Michael
M
Rodgers
James
J
Shepard
Stacey
S
Li
Mei
M
Galya
Laurine
L
Metcalf
Brian
B
Yue
Tai-Yuen
TY
Liu
Pingli
P
Zhou
Jiacheng
J
D001565:Benzoates / Q000737:chemistry; D002384:Catalysis; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D009570:Nitriles; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines; D013237:Stereoisomerism
D001565:Benzoates; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib; D053612:Janus Kinases