AZD-4407, ZD-4407

Chemical Name: (2S,4R)-5-[4-(4-Hydroxy-2-methyltetrahydropyran-4-yl)thien-2-ylsulfanyl]-1-methyl-2,3-dihydro-1H-indol-2-one
项目整合开发状态: Discontinued
项目研究机构: AstraZeneca (Originator)
合成路线:This compound has been obtained by two similar ways:1) The sulfonation of 1-methyl-2-indolinone (I) with hot chlorosulfonic acid gives the 5-chlorosulfonyl derivative (II),which is reduced with 55% aqueous HI to yield the disulfide (III).The condensation of (III) with 2(S)-methyl-4-(3-thienyl)-4-(trimethylsilyloxy)tetrahydropyran (VII) by means of BuLi in THF affords 5-[4-(4-hydroxy-2(S)-methyltetrahydropyran-4-yl)-2-thienylsulfanyl]-1-methylindolin-2-one (VIII) as a diastereomeric mixture,from which the target isomer has been isolated by crystallization.The intermediate tetrahydropyran (VII) has been obtained by condensation of 2(S)-methyltetrahydropyran-4-one (IV) with 3-bromothiophene (V) by means of BuLi in hexane/THF to give 2(S)-methyl-4-(3-thienyl)tetrahydropyran-4-ol (VI),which is silylated with Tms-Cl and DMAP in THF to afford the target intermediate (VII).2) The reaction of intermediate (VII) with dimethyl disulfide and BuLi gives the mercaptan (IX),which is condensed with 5-bromo-1-methylindolin-2-one (X) by means of palladium tetrakis(triphenylphosphine) in hot DMSO to afford the previously described diastereomeric mixture (VIII).