Practical enantioselective synthesis of endothelin antagonist S-1255 by dynamic resolution of 4-methoxychromene-3-carboxylic acid intermediate |
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Authors: | Konoike Toshiro Matsumura Ken-Ichi Yorifuji Tadahiko Shinomoto Shoji Ide Yutaka Ohya Takashi |
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Institution: | Shionogi Research Laboratories, Shionogi & Co., Ltd., 1-3, Kuise Terajima 2-chome, Amagasaki, Hyogo 660-0813, Japan. toshiro.konoike@shionogi.co.jp |
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Abstract: | A practical multikilogram-scale synthesis of enantiomerically pure S-1255 (1), a potent and orally active ET(A) 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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