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Name 4-MA
Chemical Name N,N-Diethyl-4-methyl-3-oxo-4-aza-5alpha-androstane-17beta-carboxamide
CAS 73671-86-0
Related CAS
Formula C24H40N2O2
Structure
Formula Weight 388.5986
Stage 未确定
Company
Activity/Mechanism  
Syn. Route 2
Route 1
the reaction of pregnenolone (i) with i2 and pyridine at 90 c gives (3beta-hydroxypregn-5-en-20-one-21-yl)pyridinium iodide (ii), which by treatment with sodium methoxide in refluxing methanol is converted into methyl 5-androsten-3beta-ol-17beta-carboxylate (iii). the meerwein-poundorf oxidation of (iii) with cyclohexanone (a) and aluminum isopropoxide in refluxing toluene yields methyl 4-androsten-3-one-17beta-carboxylate (iv), which is hydrolyzed with koh in refluxing methanol - water to the corresponding free acid (3-oxo-4-etienic acid) (v). the reaction of (v) with oxalyl chloride (b) and diethylamine in refluxing toluene affords 17beta-(n,n-diethylcarbamoyl)-4-androstene-3-one (vi), which is oxidized with o3 or with naio4 and kmno4 giving 17beta-(n,n-diethylcarbamoyl)-5-oxo-3,5-secoandrostan-3-oic acid (vii). the cyclization of (vii) with methylamine ethylene glycol at 180 c in a pressure vessel affords 17beta-(n,n-diethylcarbamoyl)-4-methyl-4-aza-5-androsten-3-one (viii), which is finally reduced with h2 over pt in acetic acid.the cyclization of the acid (vii) with nh3 in ethanol at 180 c in a pressure vessel gives 17beta-(n,n-diethylcarbamoyl)-4-aza-5-androsten-3-one (ix), which is reduced with h2 over pt in acetic acid yielding 17beta-(n,n-diethylcarbamoyl)-4-aza-5alpha-androstan-3-one (x). finally, this compound is methylated with ch3i by means of nah in toluene.
List of intermediates No.
(2r,3s)-1,1,1-trifluoro-4-methyl-3-nitro-2-pentanol (a)
3,5-dimethylisonicotinaldehyde (v)
(2s)-2-(acetamido)-3-methyl-3-sulfanylbutyric acid (iv)
1-(1,5-diisopropyl-1h-pyrazol-3-yl)-2-propen-1-one (b)
(7r,8r,9s,13s,14s,17s)-3-hydroxy-7-(9-hydroxynonyl)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6h-cyclopenta[a]phenanthren-17-yl acetate (i)
(7r,8r,9s,13s,14s,17s)-17-(acetoxy)-7-(9-hydroxynonyl)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6h-cyclopenta[a]phenanthren-3-yl benzoate (ii)
(7r,8r,9s,13s,14s,17s)-17-(acetoxy)-13-methyl-7-[9-[(methylsulfonyl)oxy]nonyl]-7,8,9,11,12,13,14,15,16,17-decahydro-6h-cyclopenta[a]phenanthren-3-yl benzoate (iii)
4,4,5,5,5-pentafluoropentylhydrosulfide; 4,4,5,5,5-pentafluoro-1-pentanethiol (vi)
(7r,8r,9s,13s,14s,17s)-17-(acetoxy)-13-methyl-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfanyl]nonyl]-7,8,9,11,12,13,14,15,16,17-decahydro-6h-cyclopenta[a]phenanthren-3-yl benzoate (vii)
(7r,8r,9s,13s,14s,17s)-13-methyl-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfanyl]nonyl]-7,8,9,11,12,13,14,15,16,17-decahydro-6h-cyclopenta[a]phenanthrene-3,17-diol (viii)
(4s,4as,5ar,12as)-9-[(2-bromoacetyl)amino]-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide (ix)
2-(tert-butylamino)acetyl chloride (x)
Reference 1:
    hillier, k.; blancafort, p.; serradell, m.n.; castaner, j.; 4-ma. drugs fut 1983, 8, 4, 323.
Reference 2:
    jobson, r.b.; johnston, d.b.r.; rasmusson, g.h.; reinhold, d.f.; utne, t. (merck & co., inc.); preparation of 4-aza-17-substituted-5 alpha -androstan-3-ones useful as 5 alpha -reductase inhibitors. us 4220775 .

Route 2
the oxidation of 3-oxo-4-etienic acid (v) with naio4 and kmno4 in tert-butanol - water gives 5-oxo-3,5-secoandrostane-3,17beta-dioic acid (xi), which is cyclized with methylamine in ethanol at 180 c in a pressure vessel yielding 17beta-carboxy-4-methyl-4-aza-5-androsten-3-one (xii). the hydrogenation of (xii) with h2 over pt in acetic acid affords 17beta-carboxy-4-methyl-4-azaandrostan-3-one (xiii), which is finally treated with oxalyl chloride (b) and diethylamine in toluene-thf.the amidation of (xiii) with oxalyl chloride (b) and nh3 in toluene-thf gives 17beta-carboxamide-4-methyl-4-azaandrostanone (xiv), which is alkylated with ethyl bromide and nah in toluene.the amidation of (xiii) with ethylamine and oxalyl chloride (b) in toluene-thf gives 17beta-(n-ethylcarbamoyl)-4-methyl-4-azaandrostan-3-one (xv), which is finally alkylated with ethyl bromide and nah in toluene.
List of intermediates No.
3,5-dimethyl-4-nitro-1-pyridiniumolate (xiii)
3,5-dimethylisonicotinaldehyde (v)
2-formylphenethyl benzoate (xi)
1-(1,5-diisopropyl-1h-pyrazol-3-yl)-2-propen-1-one (b)
(s)-(+)-2-amino-1-butanol; l-(+)-2-amino-1-butanol; (s)-2-amino-1-butanol (xii)
(2r)-2-ethyl-1-[(4-methylphenyl)sulfonyl]aziridine (xiv)
3-chlorothiophene; 3-thienyl chloride (xv)
Reference 1:
    hillier, k.; blancafort, p.; serradell, m.n.; castaner, j.; 4-ma. drugs fut 1983, 8, 4, 323.
Reference 2:
    jobson, r.b.; johnston, d.b.r.; rasmusson, g.h.; reinhold, d.f.; utne, t. (merck & co., inc.); preparation of 4-aza-17-substituted-5 alpha -androstan-3-ones useful as 5 alpha -reductase inhibitors. us 4220775 .

 
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