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藥物詳細合成路線

Name Pergolide mesylate;LY-141-B(free base);LY-127809;Pharken;Nopar;Parkotil;Celance;Permax
Chemical Name 8beta-[(Methylthio)methyl]-6-propylergoline monomethanesulfonate;9beta-(Methylthiomethyl)-7-propyl-4,6,6abeta,7,8,9,10,10aalpha-octahydroindolo[4,3-fg]quinoline methanesulfonate
CAS 66104-23-2
Related CAS 66104-22-1 (free base)
Formula C20H30N2O3S2
Structure
Formula Weight 410.6017
Stage 上市-1989
Company Lilly (Originator), Amarin (Licensee), Draxis Health (Licensee), Elan (Licensee), Shire Pharmaceuticals (Licensee)
Activity/Mechanism Antiparkinsonian Drugs, Extrapyramidal Disorders, Treatment of, NEUROLOGIC DRUGS, Dopamine Receptor Agonists
Syn. Route 4
Route 1
a new synthesis of pergolide has been reported:the alkylation of 8,9-dihydroelymoclavine (i) with propyl iodide and na2co3 in n-methylpyrrolidone gives the quaternary compound (ii), which is mesylated with meso2cl in pyridine yielding the mesyl ester (iii). finally, (iii) is treated with sodium methylmercaptide in n-methylpyrrolidone.
List of intermediates No.
(2s,4s,5s,6s,6r,7s,11r,13s,15s,17ar,20r,20ar,20bs)-20-(tert-butyldimethylsilyloxy)-7-[4-o-[4-o-(tert-butyldimethylsilyl)-2,6-dideoxy-3-o-methyl-beta-l-mannopyranosyl]-2,6-dideoxy-3-o-methyl-beta-l-mannopyranosyloxy]-4,4-difluoro-5,6,8,19-tetramethyl-6-(1-methylpropyl)-20b-(trimethylsilyloxy)-3,4,5,6,6,7,10,11,14,15,17,17a,20a,20b-tetradecahydro-spiro[11,15-methano-2h,13h,20h-furo[4,3,2-pq][2,6]benzodioxacyclooctadecino-13,2-2h-pyran]-17-one; (2s,4s,5s,6s,6r,7s,11r,13s,15s,17ar,2 (i)
7-methyl-2h-chromen-2-one (ii)
7-(bromomethyl)-2h-chromen-2-one (iii)
Reference 1:
    misner, j.w. (eli lilly and company); one-pot process for preparing pergolide. ep 0571202 .
Reference 2:
    misner, j.w.; et al.; integration of a highly selective demethylation of a qaternized ergoline into a one-pot synthesis of pergolide. org process res dev 1997, 1, 1, 77.

Route 2
the reaction of methyl dihydro-lysergate (i) with cyanogen bromide in methylene chloride gives 6-cyano-8beta-methoxycarbonylergoline (ii), which is treated with zn dust and acetic acid - water to afford 8beta-methoxycarbonylergoline (iii). the alkylation of (iii) with propyl bromide (a) and potassium carbonate in dmf yields 6-n-propyl-8beta-methoxycarbonylergoline (iv), which is reduced with nabh4 in dioxane - methanol to 6-n-propyl-8beta-hydroxymethylergoline (v). the mesylation of (v) with mesyl chloride in pyridine gives 6-n-propyl-8beta-mesyloxymethylergoline (vi), which is finally treated with sodium methylmercaptide in dimethylacetamide and with methanesulfonic acid.
List of intermediates No.
ethyl 2-(1-piperazinyl)phenyl ether; 1-(2-ethoxyphenyl)piperazine (iii)
3-cyclopenten-1-ylmethyl 4-methylbenzenesulfonate (a)
5-chloro-6-(4-methyl-1-piperazinyl)indoline (i)
7-bromo-4-methyl-1h-indole (ii)
4-methyl-1h-indole-7-carboxylic acid (iv)
6-hydroxy-1-[(z)-3-pyridinylmethylidene]-3,4-dihydro-2-naphthalenone (v)
(5r,6s)-6-amino-5-(3-pyridinylmethyl)-5,6,7,8-tetrahydro-2-naphthalenol (vi)
Reference 1:
    kornfeld, e.c.; bach, n.j. (eli lilly and company); 6-n-propyl-8-methoxymethyl or methylmercaptomethylergolines and related compounds. at 371817b; dd 141928; ep 0003667; fr 2416891; gb 2014140; us 4166182 .
Reference 2:
    serradell, m.n.; castaner, j.; blancafort, p.; owen, r.t.; pergolide mesylate. drugs fut 1981, 6, 4, 231.

Route 3
the reaction of dihydrolysergol (i) with brcn in dmf gives the n-cyano derivative (ii), which is treated with naoh in ethylene glycol yielding the demethylated compound (iii). the reductive alkylation of (iii) with propionaldehyde (iv) and formic acid in dmf affords the propyl derivative (v), which is mesylated with mscl and pyridine giving the mesylate (vi). finally, this compound is treated with sodium methylthiolate and msoh.
List of intermediates No.
(2s,4s,5s,6s,6r,7s,11r,13s,15s,17ar,20r,20ar,20bs)-20-(tert-butyldimethylsilyloxy)-7-[4-o-[4-o-(tert-butyldimethylsilyl)-2,6-dideoxy-3-o-methyl-beta-l-mannopyranosyl]-2,6-dideoxy-3-o-methyl-beta-l-mannopyranosyloxy]-4,4-difluoro-5,6,8,19-tetramethyl-6-(1-methylpropyl)-20b-(trimethylsilyloxy)-3,4,5,6,6,7,10,11,14,15,17,17a,20a,20b-tetradecahydro-spiro[11,15-methano-2h,13h,20h-furo[4,3,2-pq][2,6]benzodioxacyclooctadecino-13,2-2h-pyran]-17-one; (2s,4s,5s,6s,6r,7s,11r,13s,15s,17ar,2 (i)
(2r)-5-[[amino(imino)methyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid (iv)
6-hydroxy-1-[(z)-3-pyridinylmethylidene]-3,4-dihydro-2-naphthalenone (v)
(5r,6s)-6-amino-5-(3-pyridinylmethyl)-5,6,7,8-tetrahydro-2-naphthalenol (vi)
(3s,10r,13s,16r,17s)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-[(1s)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthrene-16,17-diol (ii)
(2s,3r,4r,5r)-2-([(2s,3r,4r,5s)-3-(acetoxy)-2-([(3s,10r,13s,16s,17s)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-hydroxy-17-[(1s)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-16-yl]oxy)-5-[(triethylsilyl)oxy]tetrahydro-2h-pyran-4-yl]oxy)-4,5-bis[(triethylsilyl)oxy]tetrahydro-2h-pyran-3-yl 4-methoxybenzoate (iii)
Reference 1:
    misner, j.w.; et al.; integration of a highly selective demethylation of a qaternized ergoline into a one-pot synthesis of pergolide. org process res dev 1997, 1, 1, 77.

Route 4
the reaction of dihydrolysergol (i) with propyl iodide (ii) in hot sulfolane gives the quaternary salt (iii), which is treated with na2s in the same solvent, yielding the propyl derivative (iv). the reaction of (iv) with mesyl chloride and pyridine affords the corresponding mesylate (v), which is finally treated with commercial na-s-ch3 in dmf to afford the target methylsulfanyl derivative.
List of intermediates No.
(2s,4s,5s,6s,6r,7s,11r,13s,15s,17ar,20r,20ar,20bs)-20-(tert-butyldimethylsilyloxy)-7-[4-o-[4-o-(tert-butyldimethylsilyl)-2,6-dideoxy-3-o-methyl-beta-l-mannopyranosyl]-2,6-dideoxy-3-o-methyl-beta-l-mannopyranosyloxy]-4,4-difluoro-5,6,8,19-tetramethyl-6-(1-methylpropyl)-20b-(trimethylsilyloxy)-3,4,5,6,6,7,10,11,14,15,17,17a,20a,20b-tetradecahydro-spiro[11,15-methano-2h,13h,20h-furo[4,3,2-pq][2,6]benzodioxacyclooctadecino-13,2-2h-pyran]-17-one; (2s,4s,5s,6s,6r,7s,11r,13s,15s,17ar,2 (i)
3-amino-1-[2-(3-azabicyclo[3.2.2]non-3-yl)-2-oxoethyl]-5-(2-fluorophenyl)-9-methyl-1,3-dihydro-2h-1,4-benzodiazepin-2-one (ii)
6-hydroxy-1-[(z)-3-pyridinylmethylidene]-3,4-dihydro-2-naphthalenone (iv)
Reference 1:
    anastasia, l.; et al.; simple and selective one-pot replacement of the n-methyl group of tertiary amines by quaternization and demethylation with sodium sulfide or potassium thioacetate: an application to the synthesis of pergolide. j chem soc - perkins trans i 2001, 19, 2398.

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甲磺酸培高利特;英文名Pergolide mesylate;LY-141-B(free base);LY-127809;Pharken;Nopar;Parkotil;Celance;Permax;CAS[66104-23-2]

 
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