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Practical Enantioselective Synthesis of Endothelin Antagonist S-1255 by Dynamic Resolution of 4-Methoxychromene-3-carboxylic Acid Intermediate

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journal contribution
posted on 09.10.2002, 00:00 by Toshiro Konoike, Ken-ichi Matsumura, Tadahiko Yorifuji, Shoji Shinomoto, Yutaka Ide, Takashi Ohya
A practical multikilogram-scale synthesis of enantiomerically pure S-1255 (1), a potent and orally active ETA receptor antagonist, is described. Utilizing readily available starting materials and reagents, the entire sequence of reactions starting from 2,5-dihydroxyacetophenone 8 proceeded under mild conditions to give 1 in an excellent chemical yield (8 steps, 41% overall yield) and in a high enantiopurity (98% ee). The crucial step of the synthesis is a dynamic resolution of key intermediate 16. (R)-Methoxy acid (R)-16 having 97−99% ee was obtained in 83−84% yield from racemic 16 as a crystalline (1S,2R)-(+)-norephedrine or (+)-cinchonine salt by the dynamic resolution comprising concurrent crystallization and in situ racemization. A mechanism of the dynamic resolution through a ring-opened zwitterionic intermediate is discussed. In the final synthetic step, an effective carbon−carbon bond formation between the C4 carbon and the p-anisyl group was accomplished by a conjugate addition−elimination reaction of Grignard reagent 3 to (R)-16 to give 1 having 98% ee. Owing to high efficiencies of functional group transformations, carbon−carbon bond formations, and the dynamic resolution, the synthesis required no chromatographic purification and was amenable to a multikilogram-scale preparation. Several kilograms of 1 for clinical trials were successfully prepared by this process.

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