Several novel approaches have been investigated for the synthesis of the LTD4/E4 antagonist LY290154. Significant improvements to the discovery route were first made by using an indoline nucleophile instead of an indolyl anion in the key substitution step. An alternative approach, introducing the 7-chloroquinoline moiety in the latest stages of the synthesis was then demonstrated. Interestingly, the pivotal intermediate of this latter route was also obtained in a one-pot process following a Katritzky methodology. Finally, an asymmetric synthesis offering significant advantages over the enantioselective route reported by McKillop was demonstrated.

K u m a d a C o u p l i n g o f a n A c e t a l d e h y d e S y n t h o n w i t h 2 -B r o m o b e n z o a t e s

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The stereospecific synthesis of the PPAR alpha/gamma agonist 1 was accomplished via ethylation of the optically pure trihydroxy derivative 6, itself derived via an enzymatic resolution. The ethylation can be accomplished without epimerization only under strict control of the reaction conditions and the choice of base (sodium tert-amylate), temperature (-30 degrees C), order of addition, and solvent (DMF). The key diastereospecific SN2 reaction of the phenol 4 with S-2-chloropropionic acid is best achieved via the sodium phenoxide of 4 derived from Na0 as the reagent of choice. The structure elucidation and key purification protocols to achieve pharmaceutical purity will also be described.

Thiadiazole derivatives R 0300The Ring Opening of 3,4-Dichloro-1,2,5-thiadiazole with Metal Amides. A New Synthesis of 3,4-Disubstituted-1,2,5-thiadiazoles. -The ring-opened products (III) can be further treated with various nucleophiles. Reaction of the resulting products with a second nucleophile results in recyclization to 3,4-disubstituted 1,2,5-thiadiazoles. -(MERSCHAERT*, A.; BOQUEL, P.; GORISSEN, H.; VAN HOECK, J.-P.; BORGHESE, A.; ANTOINE, L.; MANCUSO, V.; MOCKEL, A.; VANMARSENILLE, M.; Tetrahedron Lett. 47 (2006) 47, 8285-8288; Lilly Res. Lab., Chem. Proc. R&D, Lilly Dev. Cent. S. A., B-1348 Mont St. Guibert, Belg.; Eng.) -Mais 09-134