title: Practical enantioselective synthesis of endothelin antagonist S-1255 by dynamic resolution of 4-methoxychromene-3-carboxylic acid intermediate.
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.
authors.affiliation: Shionogi Research Laboratories, Shionogi & Co., Ltd., 1-3, Kuise Terajima 2-chome, Amagasaki, Hyogo 660-0813, Japan. toshiro.konoike@shionogi.co.jp
authors.forename: Toshiro
authors.initials: T
authors.lastname: Konoike
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Matsumura
authors.forename: Tadahiko
authors.initials: T
authors.lastname: Yorifuji
authors.forename: Shoji
authors.initials: S
authors.lastname: Shinomoto
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Ide
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohya
mesh_terms: D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry*; D002934:Cinnamates / Q000737:chemistry*; D002942:Circular Dichroism; D065128:Endothelin Receptor Antagonists; D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry*; D013237:Stereoisomerism; D013997:Time Factors
chemical_list: C436483:2-(benzo(1,3)dioxo-5-yl)-6-isopropyl-4-(4-methoxyphenyl)-2H-chromene-3-carboxylic acid; D001578:Benzopyrans; D002934:Cinnamates; D065128:Endothelin Receptor Antagonists; C484915:N-cinnamoyl-L-proline; D011392:Proline