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药物详细合成路线

Name Cabergoline;CG-101;FCE-21336;Cabaseril;Sogilen;Cabaser;Dostinex
Chemical Name 1-[(6-Allylergolin-8beta-yl)carbonyl]-1-[3-(dimethylamino)propyl]-3-ethylurea
      (6aR,9R,10aR)-7-Allyl-N-[3-(dimethylamino)propyl]-N-(N-ethylcarbamoyl)-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide
CAS 81409-90-7
Related CAS
Formula C26H37N5O2
Structure
Formula Weight 451.61709
Stage 上市-1993
Company Pfizer (Originator), National Institute on Drug Abuse (Not Determined), Paladin (Marketer), Kissei (Licensee)
Activity/Mechanism Antiparkinsonian Drugs, ENDOCRINE DRUGS, Extrapyramidal Disorders, Treatment of, NEUROLOGIC DRUGS, Pituitary Disorder Therapy, Treatment of Acromegaly, Treatment of Cocaine Dependency, Treatment of Growth Hormone Secretion Disorders, Treatment of Hyperprolactinemia, TREATMENT OF POISONING, DRUG ABUSE & DEPENDENCY, Treatment of Substance Dependency, Dopamine D2 Agonists, Prolactin Secretion Inhibitors
Syn. Route 3
Route 1
the synthesis of tritiated cabergoline by two similar routes has been described:1) the acylation of 6-nor-dihydrolysergic acid methyl ester (i) with propargyl bromide yields the corresponding 6-propargyl derivative (ii), which is hydrogenated with tritium gas over pd/c in the presence of quinoline to give the ditritiated 6-allyl derivative (iii). this compound is treated with 3-(dimethylamino)propylamine at 120 c, yielding the amide (iv), which is finally treated with ethyl isocyanate.2) the reaction of the propargyl derivative (ii) with 3-(dimethylamino)propylamine as before gives the amide (v). the reaction of (v) with ethyl isocyanate gives compound (vi), which is then hydrogenated with tritium as before.
List of intermediates No.
1-(2-chloroethyl)azepane
ethyl 2-(1-piperazinyl)phenyl ether; 1-(2-ethoxyphenyl)piperazine (i)
ethyl 3-cyclohexylpropanoate (ii)
4-([[amino(imino)methyl]amino]methyl)cyclohexanecarboxylic acid (iv)
benzyl salicylate (v)
benzyl 2-([[4-([[amino(imino)methyl]amino]methyl)cyclohexyl]carbonyl]oxy)benzoate (vi)
(r,r)-cyclohexane-1,2-diamine dichloro platinum complex (iii)
methyl 2-butyl-4-oxo-3,4-dihydro-6-quinazolinecarboxylate
Reference 1:
    mantegani, s.; brambilla, e.; ermoli, a.; fontana, e.; angiuli, p.; vicario, g.p.; syntheses of tritium and carbon-14 labelled n-(3-dimethyl aminopropyl)-n-(ethylaminocarbonyl)-6-(2-propenyl)ergoline-8beta-carboxamide (cabergoline), a potent long lasting prolactin lowering agent. j label compd radiopharm 1991, 29, 5, 519.

Route 2
the synthesis of [14c]-cabergoline has also been described:the reaction of 6-allylergoline-8beta-carboxylic acid methyl ester (i) with hydrazine in refluxing methanol gives the hydrazide (ii), which by reaction with nano2-hcl in water is converted to the amine (iii). the reaction of (iii) again with nano2-hcl in water, followed by reaction with sncl2, affords the chloro derivative (iv), which is condensed with [14c]-cnk in refluxing ethanol-water yielding the nitrile (v). hydrolysis of (v) with naoh in refluxing ethanol affords the acid (vi), which is finally condensed with n-ethyl-n-[3-(dimethylamino)propyl]carbodiimide in dmf.
List of intermediates No.
(r,r)-cyclohexane-1,2-diamine dichloro platinum complex (i)
6-nitro-2,3-dihydro-1h-inden-5-yl phenyl ether; 5-nitro-6-phenoxyindane (ii)
n,n-dimethyl-n-[(5-nitro-6-phenoxy-2,3-dihydro-1h-inden-1-ylidene)methyl]amine; n,n-dimethyl(5-nitro-6-phenoxy-2,3-dihydro-1h-inden-1-ylidene)methanamine (iii)
5-nitro-6-phenoxy-1-indanone (iv)
5-amino-6-phenoxy-1-indanone (v)
6-phenoxy-2,3-dihydro-1h-inden-5-ylamine; 6-phenoxy-5-indanamine (vi)
2-butyl-6-(1-hydroxy-1-methylethyl)-4(3h)-quinazolinone (vi)
Reference 1:
    mantegani, s.; brambilla, e.; ermoli, a.; fontana, e.; angiuli, p.; vicario, g.p.; syntheses of tritium and carbon-14 labelled n-(3-dimethyl aminopropyl)-n-(ethylaminocarbonyl)-6-(2-propenyl)ergoline-8beta-carboxamide (cabergoline), a potent long lasting prolactin lowering agent. j label compd radiopharm 1991, 29, 5, 519.

Route 3
this compound can be obtained by two differents ways:1) by condensation of 6-allyl-n-[3-(dimethylamino)propyl]ergolin-8-beta-caboxamide (i) with ethyl isocyanate (ii) in refluxing toluene.2) by condensation of 6-allylergolin-8-beta-carboxylic acid (iii) with n-ethyl-n-[3-(dimethylamino)propyl]carbodiimide (iv) in refluxing thf.
List of intermediates No.
4-([[amino(imino)methyl]amino]methyl)cyclohexanecarboxylic acid (i)
methyl (z)-7-[(2r,4r,5s)-4-(hydroxymethyl)-2-methyl-1,3-dioxan-5-yl]-5-heptenoate (iv)
methyl 2-butyl-4-oxo-3,4-dihydro-6-quinazolinecarboxylate (ii)
2-butyl-6-(1-hydroxy-1-methylethyl)-4(3h)-quinazolinone (iii)
Reference 1:
    temperilli, a.; bernardi, l.; brambilla, e. (pharmacia corp.); regiospecific process for the preparation of ergoline derivatives. be 0894060; jp 58038282 .
Reference 2:
    salvati, p.; et al. (pharmacia & upjohn spa); composés dérivés de lergoline, procédé pour les préparer et leur usage comme médicaments. de 3112861; fr 2479829 .
Reference 3:
    serradell, m.n.; azccheo, t.; castaner, j.; castaner, r.m.; giudici, d.; cabergoline. drugs fut 1987, 12, 9, 842.

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卡麦角林;英文名Cabergoline;CG-101;FCE-21336;Cabaseril;Sogilen;Cabaser;Dostinex;CAS[81409-90-7]

 
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