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  • Design of concise, scalable route to a cholecystokinin 1 (CCK 1) receptor antagonist.

Design of concise, scalable route to a cholecystokinin 1 (CCK 1) receptor antagonist.

The Journal of organic chemistry (2007-09-25)
Jimmy T Liang, Neelakandha S Mani, Todd K Jones
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Ethyl lactate, ≥98%, FCC, FG
Sigma-Aldrich
(−)-Ethyl L-lactate, 98%
Sigma-Aldrich
Ethyl lactate, natural, ≥98%, FCC, FG