[(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 -Drug Synthesis Database

【结构式】

【分子编号】32242

【品名】[(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

【CA登记号】

【分子式】C₁₈H₂₄N₂O

【分子量】284.40144

【元素组成】C 76.02% H 8.51% N 9.85% O 5.63%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(V)

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.

参考文献中间体

合成目标

【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：(V)

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.

参考文献中间体

合成目标

【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.

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)	10051	[(6aR,9R,10aR)-7-methyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinolin-9-yl]methanol; 9,10-Dyhydrosergol	18051-16-6	C₁₆H₂₀N₂O	详情	详情
(II)	36492	[(6aR,9R,10aR)-7-cyano-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinolin-9-yl]methanol		C₁₆H₁₇N₃O	详情	详情
(III)	36493	(6aR,9R,10aR)-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinolin-9-ylmethanol		C₁₅H₁₈N₂O	详情	详情
(IV)	15966	propionaldehyde	123-38-6	C₃H₆O	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3

该中间体在本合成路线中的序号：(IV)

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.

参考文献中间体

合成目标

【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.

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)	10051	[(6aR,9R,10aR)-7-methyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinolin-9-yl]methanol; 9,10-Dyhydrosergol	18051-16-6	C₁₆H₂₀N₂O	详情	详情
(II)	28758	1-iodopropane	107-08-4	C₃H₇I	详情	详情
(III)	54917	(6aR,9R,10aR)-9-(hydroxymethyl)-7-methyl-7-propyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinolin-7-ium iodide		C₁₉H₂₇IN₂O	详情	详情
(IV)	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
(V)	54918	[(6aR,9R,10aR)-7-propyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinolin-9-yl]methyl methanesulfonate		C₁₉H₂₆N₂O₃S	详情	详情

Extended Information