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Name Finasteride;YM-152;MK-906;Prodel;Propecia;Chibro-Proscar;Finastid;Prostide;Andozac;Proscar
Chemical Name 17beta-(N-tert-Butylcarbamoyl)-4-aza-5alpha-androst-1-en-3-one
      N-tert-Butyl-3-oxo-4-aza-5alpha-androst-1-ene-17beta-carboxamide
CAS 98319-26-7
Related CAS
Formula C23H36N2O2
Structure
Formula Weight 372.55557
Stage 上市-1992
Company Banyu (Originator), Bristol-Myers Squibb (Originator), Merck & Co. (Originator), Merck Sharp & Dohme (Originator), Sigma-Tau (Licensee), Yamanouchi (Licensee)
Activity/Mechanism Benign Prostatic Hyperplasia Therapy, Chemopreventive Agents, DERMATOLOGIC DRUGS, ENDOCRINE DRUGS, Gynecological Disorders, Treatment of , Hair Growth Stimulants, Hirsutism Therapy, ONCOLYTIC DRUGS, RENAL-UROLOGIC DRUGS, Androgen Receptor Antagonists, Steroid 5alpha-Reductase Inhibitors
Syn. Route 3
Route 1
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.
List of intermediates No.
(1s,2s,3r,4s,7r,9s,10s,12r,15s)-4,12-bis(acetoxy)-15-[[(2r,3s)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-9-[[(e)-3-(3-benzoylphenyl)-2-propenoyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate (i)
3-(3,4-dimethoxyphenyl)-1-(3-hydroxyphenyl)-1-propanone (ii)
tert-butyl 2-[3-[3-(3,4-dimethoxyphenyl)propanoyl]phenoxy]acetate (iii)
chloro[bis[(1s,2r,3s,5s)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane (iv)
Reference 1:
    rasmusson, g.h.; reynolds, g.f. (merck & co., inc.); 17beta-substd.-4-aza-5alpha-androstenones and their use as 5alpha-reductase inhibitors. au 8539167; ep 0155096; ep 0314199; es 8702430; jp 1985222497; jp 1989093600; us 4760071 .
Reference 2:
    rasmusson, g.h.; reynolds, g.f. (merck & co., inc.); treatment of prostatic carcinoma with 17beta-n-monosubstd.-carbamoyl-4-aza-5-alpha-androst-1-en-3-ones. ep 0285383 .
Reference 3:
    rasmusson, g.h.; reynolds, g.f.; steinberg, n.g.; walton, e.; patel, g.f.; liang, t.; cascieri, m.a.; cheung, a.h.; brooks, j.r.; berman, c.; azasteroids: structure-activity relationships for inhibition of 5 alpha-reductase and of androgen receptor binding. j med chem 1986, 29, 11, 2298.
Reference 4:
    castaner, j.; prous, j.; finasteride. drugs fut 1991, 16, 11, 996.

Route 2
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.
List of intermediates No.
2-[[(e)-3-(3-benzoylphenyl)-2-propenoyl]oxy]-1h-isoindole-1,3(2h)-dione (i)
Reference 1:
    dolling, u.h.; mccauley, j.a.; varsolona, r.j. (merck & co., inc.); a process for the production of finasteride. ep 0599376; ep 0823436; jp 1994199889; wo 9411387 .

Route 3
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).
List of intermediates No.
(1s,2s,3r,4s,7r,9s,10s,12r,15s)-4-(acetoxy)-12-[[(e)-3-(3-benzoylphenyl)-2-propenoyl]oxy]-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate (i)
(1s,2s,3r,4s,7r,9s,10s,12r,15s)-4-(acetoxy)-12-[[(e)-3-(3-benzoylphenyl)-2-propenoyl]oxy]-15-([(2r,3s)-3-[(tert-butoxycarbonyl)amino]-3-phenyl-2-[(triisopropylsilyl)oxy]propanoyl]oxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy] (ii)
(1s,2s,3r,4s,7r,9s,10s,12r,15s)-4-(acetoxy)-12-[[(e)-3-(3-benzoylphenyl)-2-propenoyl]oxy]-15-([(2r,3s)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl]oxy)-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4, (iii)
tert-butyl 2-[3-[(1r)-3-(3,4-dimethoxyphenyl)-1-hydroxypropyl]phenoxy]acetate (iv)
2-(3,4,5-trimethoxyphenyl)acetic acid (v)
2-(3,4,5-trimethoxyphenyl)butyric acid (vi)
Reference 1:
    dini, s.; danza, g.; guarna, a.; marrucci, a.; bartolucci, g.; serio, m.; synthesis of 5,6,6-[h-2(3)]finasteride and quantitative determination of finasteride in human plasma at picogram level by an isotope-dilution mass spectrometric method. j chromatogr b - biomed appl 1995, 674, 2, 197.

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名非那雄胺;英文名Finasteride;YM-152;MK-906;Prodel;Propecia;Chibro-Proscar;Finastid;Prostide;Andozac;Proscar;CAS[98319-26-7]

 
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