The oxidative cleavage of N-tert-butyl-3-oxo-5alpha-androst-4-ene-17beta-carboxamide (I) with NaIO4 and KMnO4 in tert butanol - aqueous Na2CO3 gives the seco-ketoacid (II), which is cyclized with liquid ammonia in ethylene glycol at 180 C to afford the DELTA5-azasteroid (III). Hydrogenation of (III) with H2 over PtO2 in acetic acid yields the corresponding saturated aza-steroid (IV), which is finally dehydrogenated with benzeneseleninic anhydride in refluxing chlorobenzene or with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) and bis(trimethylsilyl)trifluoroacetamide (BSTFA) in refluxing dioxane.

L-654066 has been obtained by three related ways: 1) Reaction of methyl (5alpha)-3-oxo-4-azaandrostene-17beta-carboxylate (I) with potassium hydroxide, followed by treatment with pyridyl disulfide, gives S-(2-pyridyl) (5alpha)-3-oxo-4-azaandrostene-17beta-thiocarboxylate (II). Compound (II) is reacted with isobutylmagnesium chloride (III) in THF to give (5alpha)-23-methyl-4-aza-21-norcholane-3,20-dione (IV), which is finally dehydrogenated using benzeneseleninic anhydride in chlorobenzene. 2) Compound (I) is converted to its dehydro analogue methyl (5alpha)-3-oxo-4-azaandrost-1-ene-17beta-carboxylate (V) with benzeneselenic anhydride, followed by reaction with isobutylmagnesium bromide (VI) in THF in the presence of hexamethyldisilazane. 3) Reaction of (5alpha)-3-oxo-4-azaandrost-1-ene-17beta-carboxylic acid (VII) with carbonyldiimidazole in THF gives 1-[[(5alpha,17beta)-3-oxo-4-azaandrost-1-en-17-yl]carbonyl]-1H-imidazole (VII), which is treated with isobutylmagnesium chloride (III) in THF in the presence of ferric chloride.

The oxidative cleavage of N-tert-butyl-3-oxo-5alpha-androst-4-ene-17beta-carboxamide (I) with NaIO4 and KMnO4 in tert butanol - aqueous Na2CO3 gives the seco-ketoacid (II), which is cyclized with liquid ammonia in ethylene glycol at 180 C to afford the DELTA5-azasteroid (III). Hydrogenation of (III) with H2 over PtO2 in acetic acid yields the corresponding saturated aza-steroid (IV), which is finally dehydrogenated with benzeneseleninic anhydride in refluxing chlorobenzene or with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) and bis(trimethylsilyl)trifluoroacetamide (BSTFA) in refluxing dioxane.

A new method for the synthesis of finasteride is described: Finasteride is obtained by reaction of 3-oxo-4-aza-5alpha-androst-1-ene-17beta-carboxylic acid methyl ester (I) with tert-butylamine by means of ethylmagnesium bromide in refluxing THF.

The oxidative cleavage of N-tert-butyl-3-oxo-5alpha-androst-4-ene-17beta-carboxamide (I) with NaIO4 and KMnO4 in tert butanol - aqueous Na2CO3 gives the seco-ketoacid (II), which is cyclized with liquid ammonia in ethylene glycol at 180 C to afford the DELTA5-azasteroid (III). Hydrogenation of (III) with H2 over PtO2 in acetic acid yields the corresponding saturated aza-steroid (IV), which is finally dehydrogenated with benzeneseleninic anhydride in refluxing chlorobenzene or with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) and bis(trimethylsilyl)trifluoroacetamide (BSTFA) in refluxing dioxane.

L-654066 has been obtained by three related ways: 1) Reaction of methyl (5alpha)-3-oxo-4-azaandrostene-17beta-carboxylate (I) with potassium hydroxide, followed by treatment with pyridyl disulfide, gives S-(2-pyridyl) (5alpha)-3-oxo-4-azaandrostene-17beta-thiocarboxylate (II). Compound (II) is reacted with isobutylmagnesium chloride (III) in THF to give (5alpha)-23-methyl-4-aza-21-norcholane-3,20-dione (IV), which is finally dehydrogenated using benzeneseleninic anhydride in chlorobenzene. 2) Compound (I) is converted to its dehydro analogue methyl (5alpha)-3-oxo-4-azaandrost-1-ene-17beta-carboxylate (V) with benzeneselenic anhydride, followed by reaction with isobutylmagnesium bromide (VI) in THF in the presence of hexamethyldisilazane. 3) Reaction of (5alpha)-3-oxo-4-azaandrost-1-ene-17beta-carboxylic acid (VII) with carbonyldiimidazole in THF gives 1-[[(5alpha,17beta)-3-oxo-4-azaandrost-1-en-17-yl]carbonyl]-1H-imidazole (VII), which is treated with isobutylmagnesium chloride (III) in THF in the presence of ferric chloride.

1) The reaction of 3-oxo-4-androstene-17beta-carboxylic acid (I) with SOCl2/pyridine in THF gives the acyl chloride (II), which is condensed with 2,5-bis(trifluoromethyl)aniline (III) by means of pyridine in refluxing THF, yielding amide (IV). The oxidation of (IV) with KMnO4/NaIO4/Na2CO3 in refluxing tert-butanol/water affords the seco-steroid (V), which is cyclized with NH3 in ethylene glycol at 180 C to give the 5-unsaturated azasteroid (VI). The hydrogenation of (VI) with H2 over PtO2 in acetic acid yields the saturated azasteroid (VII), which is finally dehydrogenated by means of 2,3-dichloro-5,6-dicyanobenzoquinone (DCQ)/bis(trimethylsilyl)trifluoroacetamide in dioxane.

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.

The oxidative cleavage of N-tert-butyl-3-oxo-5alpha-androst-4-ene-17beta-carboxamide (I) with NaIO4 and KMnO4 in tert butanol - aqueous Na2CO3 gives the seco-ketoacid (II), which is cyclized with liquid ammonia in ethylene glycol at 180 C to afford the DELTA5-azasteroid (III). Hydrogenation of (III) with H2 over PtO2 in acetic acid yields the corresponding saturated aza-steroid (IV), which is finally dehydrogenated with benzeneseleninic anhydride in refluxing chlorobenzene or with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) and bis(trimethylsilyl)trifluoroacetamide (BSTFA) in refluxing dioxane.

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).