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藥物詳細合成路線

Name Oxazacort;Azacort;Deflazacort;MDL-458;L-5458;DL-458IT;Calcort;Dezacor;Deflan;Flantadin
Chemical Name 11beta,21-Dihydroxy-2-methyl-5-betaH-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione 21-acetate
CAS 14484-47-0
Related CAS
Formula C25H31NO6
Structure
Formula Weight 441.52892
Stage 上市-1985
Company Aventis Pharma (Originator), Lepetit (Originator), Guidotti (Licensee), Shire Laboratories (Licensee)
Activity/Mechanism Allergic Skin Disorders, Treatment for, Antiallergy/Antiasthmatic Drugs, Antiarthritic Drugs, Asthma Therapy, DERMATOLOGIC DRUGS, RESPIRATORY DRUGS, Rheumatoid Arthritis, Treatment of, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Corticosteroids
Syn. Route 2
Route 1
the cyclization of 17alpha-azido-3beta,16alpha-acetoxy-5alpha-pregnane-11,20-dione (i) by hydrogenation with h2 over pt in methanol, followed by a treatment with 10% hcl gives 3beta-hydroxy-5alpha-pregnane-11,20-dione-[17alpha,16alpha-d]-2-methyloxazoline (ii), which is converted into the semicarbazone (iii) by treatment with semicarbazide hydrochloride (a) and pyridine in refluxing methanol. the reduction of one ketonic group of (iii) with nabh4 in refluxing ethanol yields the dihydroxy-semicarbazone (iv), which is hydrolyzed with 10% hcl in refluxing methanol to afford the ketodiol (v). the oxidation of (v) with cyclohexanone and aluminum isopropoxide in refluxing toluene gives 11beta-hydroxy-5alpha-pregnane-3,20-dione-[17alpha,16alpha-d]-2-methyloxazoline (vi). the dehydrogenation of (vi) by treatment with br2 in dioxane-acetic acid, followed by treatment with li2co3 in dmf at 140 c yields the corresponding 1,4-diene derivative (vii). finally, the reaction of (vii) with i2 by means of azobisisobutyronitrile in ch2cl2 affords the corresponding 21-iodo compound, which is then acetylated with triethylammonium acetate in refluxing acetone.
List of intermediates No.
ethyl (e)-3-(2-furyl)-2-propenoate (a)
2-(aminomethyl)[1,1-biphenyl]-3-carboxylic acid (i)
2-[[((2s)-2-[[(9h-fluoren-9-ylmethoxy)carbonyl]amino]-3-methylbutanoyl)amino]methyl][1,1-biphenyl]-3-carboxylic acid (ii)
2-([[(2s)-2-amino-3-methylbutanoyl]amino]methyl)[1,1-biphenyl]-3-carboxylic acid (iii)
2-[(4s,7s)-7-amino-4-isopropyl-3,6,13-trioxo-15-phenyl-14-oxa-2,5,12-triazapentadec-1-yl][1,1-biphenyl]-3-carboxylic acid (iv)
n-alpha-fmoc--n-epsilon-z-l-lysine; fmoc-nepsilon-z-l-lysine; n-epsilon-z-n-alpha-fmoc-l-lysine; (2s)-6-[[(benzyloxy)carbonyl]amino]-2-[[(9h-fluoren-9-ylmethoxy)carbonyl]amino]hexanoic acid (v)
2-((4s,7s)-7-[[(2r)-2-amino-3-(1h-indol-3-yl)propanoyl]amino]-4-isopropyl-3,6,13-trioxo-15-phenyl-14-oxa-2,5,12-triazapentadec-1-yl)[1,1-biphenyl]-3-carboxylic acid (vi)
2-((4s,7s)-7-[[(2r)-2-[((2r)-2-amino-3-[4-[(2,6-dichlorobenzyl)oxy]phenyl]propanoyl)amino]-3-(1h-indol-3-yl)propanoyl]amino]-4-isopropyl-3,6,13-trioxo-15-phenyl-14-oxa-2,5,12-triazapentadec-1-yl)[1,1-biphenyl]-3-carboxylic acid (vii)
benzyl 4-[(11s,14s,17r,20s)-20-[4-[(2,6-dichlorobenzyl)oxy]benzyl]-17-(1h-indol-3-ylmethyl)-11-isopropyl-10,13,16,19,22-pentaoxo-9,12,15,18,21-pentaazatricyclo[21.3.1.0(2,7)]heptacosa-1(27),2,4,6,23,25-hexaen-14-yl]butylcarbamate (viii)
Reference 1:
    nathansohn, g.; et al.; steroids possessing nitrogen atoms. iii. synthesis of new highly active corticoids [17alpha,16alpha-d]-ozazolino steroids. j med chem 1967, 10, 5, 799.
Reference 2:
    castaner, j.; de angelis, l.; aclacinomycin a. drugs fut 1978, 3, 3, 171.

Route 2
the monoacetylation of (v) with acetic anhydride and pyridine at 100 c gives the 3-acetoxy-11-hydroxy compound (ix), which is dehydrated by treatment with methanesulfonyl chloride and then with sodium acetate yielding 3beta-acetoxy-5alpha-pregn-9(11)-ene-20-one-[17alpha,16alpha-d]-2-methyloxazoline (x). the hydrolysis of (x) with koh in refluxing methanol affords the corresponding hydroxy compound (xi), which is acetoxylated by treatment with i2 and azbn as before giving the iodo derivative (xii), and then with triethylammonium acetate also as before, yielding 3beta-hydroxy-21-acetoxy-5alpha-pregn-9(11)-ene-20-one-[17alpha,16alpha-d]-2-methyloxazoline (xiii). the oxidation of (xiii) with cro3 in acetone yields the 3,20-diketone (xiv), which by treatment with br2 and li2co3 as before is dehydrogenated affording the 1,4,9(11)-pregnatriene (xv). finally, the reaction of (xv) with n-bromoacetamide in thf yields 9alpha-bromo-11beta-hydroxy-21-acetoxy-5alpha-pregna-1,4-dieno-3,20-dione-[17alpha,16alpha-d]-2-methyloxazoline (xvi), which is then debrominated by reaction with chromous acetate and butanethiol in dmso.
List of intermediates No.
n-alpha-fmoc--n-epsilon-z-l-lysine; fmoc-nepsilon-z-l-lysine; n-epsilon-z-n-alpha-fmoc-l-lysine; (2s)-6-[[(benzyloxy)carbonyl]amino]-2-[[(9h-fluoren-9-ylmethoxy)carbonyl]amino]hexanoic acid (v)
(2r)-2-[[(9h-fluoren-9-ylmethoxy)carbonyl]amino]-3-[5-[(z)-1-propenyl]-4-vinyl-1h-pyrrol-3-yl]propionic acid (ix)
(2r)-3-[4-[(2,6-dichlorobenzyl)oxy]phenyl]-2-[[(9h-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid (x)
tert-butyl 3-(4-morpholinyl)propylcarbamate (xi)
4-[3-[(tert-butoxycarbonyl)amino]propyl]-4-methylmorpholin-4-ium iodide (xii)
4-(3-aminopropyl)-4-methylmorpholin-4-ium iodide (xiii)
2,6-dimethyl-4h-pyran-4-one (xiv)
2,6-dimethyl-4h-pyran-4-thione (xv)
4-[3-[2,6-dimethyl-4-thioxo-1(4h)-pyridinyl]propyl]-4-methylmorpholin-4-ium iodide (xvi)
Reference 1:
    nathansohn, g.; et al.; steroids possessing nitrogen atoms. iv. further studies on the synthesis of [17-alpha,16alpha-d]ozazolino corticoids. steroids 1969, 13, 383.
Reference 2:
    castaner, j.; de angelis, l.; aclacinomycin a. drugs fut 1978, 3, 3, 171.

來源:藥化網

作者:藥化小編

摘要:本文合成路線介紹的是藥物中文名地夫可特;英文名Oxazacort;Azacort;Deflazacort;MDL-458;L-5458;DL-458IT;Calcort;Dezacor;Deflan;Flantadin;CAS[14484-47-0]

 
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