The reaction of (I) with acetonitrile in sulfuric acid provides the amide (II), which after hydrolysis in 12N HCl/methanol yields the 4-amino derivative (III). Acylation of (III) with isobutyryl chloride followed by reduction with borane-methylsulfide complex gives the racemate (V), MK-927 (2). The resolution of MK-927 is accomplished through the di-p-toluoyl-D-tartaric acid salt.
A new synthesis of MK-417 has been published: The reaction of thiophene (I) with butyllithium and sulfur in THF yields thiophene-2-thiol lithium salt (II) which, without isolation, is condensed with potassium 3-bromopropionate (III) in water - THF giving 3-(2-thienylthio)propanoic acid (IV). The cyclization of (IV) with trifluoroacetic anhydride in hot toluene affords 5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-one (V), which is oxidized with H2O2 and sodium tungstate in ethyl acetate - toluene to give the corresponding 7,7-dioxide (VI). The stereocontrolled reduction of (VI) with borane - methylsulfide and (S)-1-methyl-3,3-diphenyltetrahydropyrrolo[1,2-c][1,3,2]oxaazaborole as catalyst in THF yields (R)-(+)-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-ol 7,7-dioxide (VII), which is converted to the corresponding sodium salt (VIII) with sodium acetylide in THF. This salt (VIII), without isolation, is treated with p-toluenesulfonyl chloride to afford the corresponding tosylate (IX) which, also without isolation, is condensed with isobutylamine (X) to give (S)-(-)-4-(2-methylpropylamino)-5,6-dihydro-4H-thieno[2,3-b]thiopyran 7,7-dioxide (XI). The reaction of (XI), first with oleum and then with thionyl chloride, yields the corresponding 2-sulfonyl chloride (XII), which is finally treated with aqueous ammonium hydroxide.