【结 构 式】 |
【分子编号】11273 【品名】8beta-Methoxycarbonylergoline; Methyl (6aR,9R,10aR)-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate 【CA登记号】 |
【 分 子 式 】C16H18N2O2 【 分 子 量 】270.3312 【元素组成】C 71.09% H 6.71% N 10.36% O 11.84% |
合成路线1
该中间体在本合成路线中的序号:(III)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.
【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 . |
【2】 Serradell, M.N.; Castaner, J.; Blancafort, P.; Owen, R.T.; Pergolide mesylate. Drugs Fut 1981, 6, 4, 231. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(A) | 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 |
(I) | 32239 | Methyl dihydro-lysergate; Methyl (6aR,9R,10aR)-7-methyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate | C17H20N2O2 | 详情 | 详情 | |
(II) | 32240 | 6-Cyano-8beta-methoxycarbonylergoline; Methyl (6aR,9R,10aR)-7-cyano-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate | C17H17N3O2 | 详情 | 详情 | |
(III) | 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 | |
(IV) | 32241 | 6-n-Propyl-8beta-methoxycarbonylergoline; Methyl (6aR,9R,10aR)-7-propyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate | C19H24N2O2 | 详情 | 详情 | |
(V) | 32242 | [(6aR,9R,10aR)-7-propyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinolin-9-yl]methanol; 6-n-Propyl-8beta-hydroxymethylergoline | C18H24N2O | 详情 | 详情 | |
(VI) | 32243 | 6-n-Propyl-8beta-mesyloxymethylergoline; (6aR,9R,10aR)-9-([[Methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-7-propyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline | C21H30N2OS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(I)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 |