合成路线1

Synthesis of 5,6,6-trideuterated finasteride: The reaction of 3-oxo-4-aza-5-androstene-17beta-carboxylic acid (I) with D2O and CH3CO2D gives the monodeuterated compound (II), which, without isolation is hydrogenated with D2 over PtO2 to yield 5,6,6-(D)3-3-oxo-4-aza-5alpha-androstane-17beta-carboxylic acid (III). The dehydrogenation of (III) with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and bis(trimethylsilyl)trifluoroacetamide (BSTFA) affords 5,6,6-(D)3-3-oxo-4-aza-5alpha-androst-1-ene-17beta-carboxylic acid (IV), which is esterified with 2,2'-dithiopyridine (V) and triphenylphosphine in toluene to give the corresponding thioester (VI). Finally, this compound is treated with tert-butylamine (VII) in THF).

合成路线2

2) The oxidation of 3-oxo-4-androstene-17beta-carboxylic acid (I) with KMnO4/NaIO4/Na2CO3 in refluxing tert-butanol/water affords the seco-steroid (VIII), which is cyclized with NH3 in ethylene glycol at 180 C, giving the 5-unsaturated steroid (IX). The hydrogenation of (IX) with H2 over PtO2 in acetic acid yields the saturated azasteroid (X), which is esterified with 2,2-dimethoxypropane/HCl in methanol to afford the corresponding methyl ester (XI). The dehydrogenation of (XI) with phenylseleninic anhydride in refluxing chlorobenzene gives the 1-unsaturated azasteroid (XII), which is hydrolyzed with KOH in refluxing methanol/water to yield the corresponding unsaturated free acid (XIII). The esterification of (XIII) with 2,2'-dipyridyl disulfide (XIV) by means of triphenylphosphine in toluene affords the 2-pyridyl thioester (XV), which is finally amidated with 2,5-bis(trifluoromethyl)aniline (III) by means of silver trifluomethanesulfonate in dichloromethane. 3) The previously obtained unsaturated free acid (XIII) can also be treated with SOCl2 in pyridine to give the corresponding acyl chloride (XVI), which is then condensed directly with 2,5-bis(trifluoromethyl)aniline (III) in pyridine.

合成路线3