ORGN 19 |
| We will describe our efforts to develop a scaleable synthesis of a pyrazole-based CCK1 receptor antagonist (1). The key synthetic challenges in the synthesis of 1 involved the need for a regioselective pyrazole formation and control of the absolute stereochemistry for a racemization prone benzylic, lone stereogenic center via asymmetric alkylation. Our initial plan involved controlling the regiochemistry for the pyrazole ring closure of the substituted phenyl hydrazine by utilizing an acetylenic ketone 3. Attempted synthesis of acetylenic ketone 3 via a conventional Weinreb amide approach, however, resulted in enaminoketone (4) as the major product in a single geometrical isomeric form. More intriguingly, enaminoketone 4 was found to be a sequentially armed intermediate suitable for a regioselective pyrazole (5) formation. A highly stereoselective, asymmetric alkylation of the pyrazole iodide (5; X=I) was accomplished using Evan's oxazolidinone-based chiral auxiliary. However, removal of the chiral auxiliary on a large scale required safety precautions as it involved the use of hydrogen peroxide. The scale-up conditions for each step of the synthesis including oxidative cleavage of the Evan's chiral auxiliary will be presented along with the precautions needed to handle H2O2. R1, R2, R3, R* and X are defined as in WO 2005/005393
|
|
Combinatorial, Parallel, and Process Chemistry
8:00 AM-11:40 AM, Sunday, August 19, 2007 BCEC -- 253 A/B/C, Oral
Division of Organic Chemistry |
