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【结 构 式】 
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【药物名称】Cabergoline, CG-101, FCE-21336, Cabaseril, Sogilen, Cabaser, Dostinex 【化学名称】1-[(6-Allylergolin-8beta-yl)carbonyl]-1-[3-(dimethylamino)propyl]-3-ethylurea 【CA登记号】81409-90-7 【 分 子 式 】C26H37N5O2 【 分 子 量 】451.61709 |
【开发单位】Pfizer (Originator), National Institute on Drug Abuse (Not Determined), Paladin (Marketer), Kissei (Licensee) 【药理作用】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 |
合成路线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.
| 【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. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11176 | 3-Bromopropyne; 3-Bromo-1-propyne | 106-96-7 | C3H3Br | 详情 | 详情 | |
| 28738 | ethyl isocyanate | 109-90-0 | C3H5NO | 详情 | 详情 | |
| (I) | 11273 | 8beta-Methoxycarbonylergoline; Methyl (6aR,9R,10aR)-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate | C16H18N2O2 | 详情 | 详情 | |
| (II) | 11274 | methyl (6aR,9R,10aR)-7-(2-propynyl)-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate | C19H20N2O2 | 详情 | 详情 | |
| (III) | 11279 | methyl (6aR,9R,10aR)-7-allyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate | C19H22N2O2 | 详情 | 详情 | |
| (III) | 63076 | methyl (6aR,9R,10aR)-7-allyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate | C19H22N2O2 | 详情 | 详情 | |
| (IV) | 11276 | (6aR,9R,10aR)-7-allyl-N-[3-(Dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide | C23H32N4O | 详情 | 详情 | |
| (IV) | 63077 | (6aR,9R,10aR)-7-allyl-N-[3-(dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide | C23H32N4O | 详情 | 详情 | |
| (V) | 11277 | (6aR,9R,10aR)-N-[3-(Dimethylamino)propyl]-7-(2-propynyl)-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide | C23H30N4O | 详情 | 详情 | |
| (VI) | 11278 | N-[[(6aR,9R,10aR)-7-(2-Propynyl)-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinolin-9-yl]carbonyl]-N-[3-(dimethylamino)propyl]-N'-ethylurea | C26H35N5O2 | 详情 | 详情 |
合成路线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.
| 【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. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 11279 | methyl (6aR,9R,10aR)-7-allyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate | C19H22N2O2 | 详情 | 详情 | |
| (II) | 11280 | (6aR,9R,10aR)-7-Allyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carbohydrazide | C18H22N4O | 详情 | 详情 | |
| (III) | 11281 | (6aR,9R,10aR)-7-Allyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinolin-9-amine; (6aR,9R,10aR)-7-Allyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinolin-9-ylamine | C17H21N3 | 详情 | 详情 | |
| (IV) | 11282 | (6aR,9R,10aR)-7-Allyl-9-chloro-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline | C17H19ClN2 | 详情 | 详情 | |
| (V) | 11283 | (6aR,9R,10aR)-7-Allyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carbonitrile | C18H19N3 | 详情 | 详情 | |
| (V) | 63078 | (6aR,9R,10aR)-7-allyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carbonitrile | C18H19N3 | 详情 | 详情 | |
| (VI) | 11284 | (6aR,9R,10aR)-7-Allyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylic acid | C18H20N2O2 | 详情 | 详情 | |
| (VI) | 28739 | (6aR,9R,10aR)-7-allyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylic acid | C18H20N2O2 | 详情 | 详情 |
合成路线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.
| 【1】 Temperilli, A.; Bernardi, L.; Brambilla, E. (Pharmacia Corp.); Regiospecific process for the preparation of ergoline derivatives. BE 0894060; JP 58038282 . |
| 【2】 Salvati, P.; et al. (Pharmacia & Upjohn SpA); Composés dérivés de l'ergoline, procédé pour les préparer et leur usage comme médicaments. DE 3112861; FR 2479829 . |
| 【3】 Serradell, M.N.; Azccheo, T.; Castaner, J.; Castaner, R.M.; Giudici, D.; Cabergoline. Drugs Fut 1987, 12, 9, 842. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 11276 | (6aR,9R,10aR)-7-allyl-N-[3-(Dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide | C23H32N4O | 详情 | 详情 | |
| (II) | 28738 | ethyl isocyanate | 109-90-0 | C3H5NO | 详情 | 详情 |
| (III) | 28739 | (6aR,9R,10aR)-7-allyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylic acid | C18H20N2O2 | 详情 | 详情 | |
| (IV) | 24945 | N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide | 25952-53-8 | C8H17N3 | 详情 | 详情 |