Practical and scalable synthesis of a selective CCK1 receptor antagonist.
We describe a practical and scalable route to compound (Z)-1, a selective CCK1 receptor antagonist. Notable features of this concise route are (1) a regioselective construction of the pyrazole core through the reaction of an aryl hydrazine and an elaborated acetylenic ketone, (2) a Tf2O/pyridine mediated Z-selective dehydration of an α-hydroxyester, and (3) a stereoselective hydrolysis. The sequence is high-yielding and amenable for large-scale synthesis.
Johnson & Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, California 92121, United States.
Christopher M
CM
Mapes
Neelakandha S
NS
Mani
Xiaohu
X
Deng
Chennagiri R
CR
Pandit
Kelly J
KJ
McClure
Marna C W
MC
Pippel
Clark A
CA
Sehon
Laurent
L
Gomez
Shirin
S
Shinde
J Guy
JG
Breitenbucher
Todd K
TK
Jones
D002722:Chlorobenzenes / Q000138:chemical synthesis* / Q000737:chemistry; D004149:Dioxoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006834:Hydrazines / Q000737:chemistry*; D006868:Hydrolysis; D007659:Ketones / Q000737:chemistry; D015394:Molecular Structure; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism
C525346:(S)-3-(5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl)-2-m-tolyl propionic acid; C000589596:5-benzo(1,3)dioxol-5-yl-1-(2,5-dichloro-phenyl)-1H-pyrazole-3-carbaldehyde; D002722:Chlorobenzenes; D004149:Dioxoles; D006834:Hydrazines; D007659:Ketones; D011422:Propionates; D011720:Pyrazoles; D043562:Receptors, G-Protein-Coupled; C029424:hydrazine; C031280:pyrazole