Design of concise, scalable route to a cholecystokinin 1 (CCK 1) receptor antagonist.
Development of efficient, scalable routes for the synthesis of (S)-3-[5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-2-m-tolyl propionic acid, a selective cholecystokinin 1 (CCK 1) receptor antagonist, is described. A key feature of the scale-up route is a concise construction of the complete pyrazole framework in a single step by reacting an aryl hydrazine with an elaborated acetylenic ketone. This route was then further refined incorporating efficient enantioselective strategies to obtain the desired S-enantiomer in high optical purity. The first strategy involved an efficient, recyclable, kinetic resolution by enzyme-catalyzed hydrolysis of the racemic ester. In the second-generation route, the requisite stereochemistry at the chiral center was generated at an early stage in the synthesis involving a remarkable diastereoselective addition of inexpensive (S)-(-)-ethyl lactate to an alkylaryl ketene. Both methods furnished optically pure (>99% ee) final drug substance as its crystalline sodium salt.
Liang
Jimmy T
JT
Department of Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.
Mani
Neelakandha S
NS
Jones
Todd K
TK
D000480:Alkynes / Q000737:chemistry; D002722:Chlorobenzenes; D015195:Drug Design; D004952:Esters / Q000737:chemistry; D006868:Hydrolysis; D007700:Kinetics; D007773:Lactates / Q000737:chemistry; D015394:Molecular Structure; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D043886:Receptor, Cholecystokinin A / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C525346:(S)-3-(5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl)-2-m-tolyl propionic acid; D000480:Alkynes; D002722:Chlorobenzenes; D004952:Esters; D007773:Lactates; D011422:Propionates; D011720:Pyrazoles; D043886:Receptor, Cholecystokinin A; C015866:ethyl lactate