|
【结 构 式】 
|
【分子编号】26455 【品名】5-(benzyloxy)-2,2,4,6,7-pentamethyl-3-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-2,3-dihydro-1-benzofuran 【CA登记号】 |
【 分 子 式 】C24H32O3S 【 分 子 量 】400.58228 【元素组成】C 71.96% H 8.05% O 11.98% S 8% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The cyclization of 2,5-dimethoxy-1,3,4-trimethylbenzene (I) with 2-bromo-2-methylpropionyl bromide (II) by means of FeCl3 and NaOH in methanol/water gives 5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-3-one (III), which is treated with benzyl bromide (IV) and K2CO3 to yield the benzyl ether (V). The reaction of (V) with methylmagnesium bromide, followed by dehydration of the intermediate carbinol affords the methylene derivative (VI), which is hydroxylated with borane / dimethylsulfide and NaOH/H2O2 to furnish the hydroxymethyl compound (VII). The reaction of (VII) with MsCl and TEA gives the mesylate (VIII), which is finally condensed with 1-methylpiperazine (IX) by means of K2CO3 and debenzylated by hydrogenation with H2 over Pd/C in ethanol/HOAc to afford the target compound as a racemic mixture.
| 【1】 Petty, M.A.; Marciniak, G.; Design and biological evaluation of new antioxidants for use in cerebrovascular disorders. Drugs Fut 1996, 21, 10, 1037. |
| 【2】 Ayers, T.A.; Schnettler, R.A.; Marciniak, G.; Krysan, D.J. (Hoechst Marion Roussel Inc.); Novel process for preparing derivatives of 2,2,4,6,7-pentaalkyl-2,2-dihydrobenzofuranols. EP 0813530 . |
| 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) | 41220 | 1,4-dimethoxy-2,3,5-trimethylbenzene; 4-methoxy-2,3,5-trimethylphenyl methyl ether | C11H16O2 | 详情 | 详情 | |
| (II) | 19367 | 2-bromo-2-methylpropanoyl bromide | 20769-85-1 | C4H6Br2O | 详情 | 详情 |
| (III) | 41221 | 5-hydroxy-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one | C13H16O3 | 详情 | 详情 | |
| (IV) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (V) | 41222 | 5-(benzyloxy)-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one | C20H22O3 | 详情 | 详情 | |
| (VI) | 41223 | 5-(benzyloxy)-2,2,4,6,7-pentamethyl-3-methylene-2,3-dihydro-1-benzofuran; benzyl 2,2,4,6,7-pentamethyl-3-methylene-2,3-dihydro-1-benzofuran-5-yl ether | C21H24O2 | 详情 | 详情 | |
| (VII) | 30773 | [5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methanol | C21H26O3 | 详情 | 详情 | |
| (VIII) | 26455 | 5-(benzyloxy)-2,2,4,6,7-pentamethyl-3-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-2,3-dihydro-1-benzofuran | C24H32O3S | 详情 | 详情 | |
| (IX) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 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 condensation of 5-(benzyloxy)-2,2,4,6,7-pentamethyl-3,4-dihydrobenzofuran-3-ylmethyl methanesulfonate (I) with 2-(methylamino)ethanol (II) by heating at 120 C gives the tertiary amine (III), which is treated with SOCl2 in benzene yielding the chloroethylamino compound (IV). The condensation of (IV) with 4-nitrophenol (V) by means of K2CO3 in hot DMF affords the 4-nitrophenoxy compound (VI), which is reduced with H2 over Pd/C in ethyl acetate to the corresponding 4-aminophenoxy compound (VII). The condensation of (VII) with ethyl acrylate (VIII) by means of NaNO2 and HBr in methanol/water gives the 2-bromopropionic ester (IX), which is cyclized with thiourea (X) by means of NaOAc in refluxing ethanol yielding the thiazolidinedione (XI). Finally, this compound is debenzylated with HCl in hot acetic acid.
| 【1】 Casturi, S.R.; Lohray, V.B.; Kallam, A.R.; Pingali, H.; Ramanujam, R.; Alla, S.R. (Dr. Reddy's Research Foundation); Cpds. having antidiabetic, hypolipidemic, antihypertensive properties, process for their preparation and pharmaceutical compsns. containing them. US 5925656 . |
| 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) | 26455 | 5-(benzyloxy)-2,2,4,6,7-pentamethyl-3-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-2,3-dihydro-1-benzofuran | C24H32O3S | 详情 | 详情 | |
| (II) | 13324 | 2-Methylaminoethanol; 2-(Methylamino)-1-ethanol | 109-83-1 | C3H9NO | 详情 | 详情 |
| (III) | 26456 | 2-[[[5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methyl](methyl)amino]-1-ethanol | C24H33NO3 | 详情 | 详情 | |
| (IV) | 26457 | N-[[5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methyl]-2-chloro-N-methyl-1-ethanamine | C24H32ClNO2 | 详情 | 详情 | |
| (V) | 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 |
| (VI) | 26458 | N-[[5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methyl]-N-methyl-2-(4-nitrophenoxy)-1-ethanamine | C30H36N2O5 | 详情 | 详情 | |
| (VII) | 26459 | 4-[2-[[[5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methyl](methyl)amino]ethoxy]aniline | C30H38N2O3 | 详情 | 详情 | |
| (VIII) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (IX) | 26460 | ethyl 3-(4-[2-[[[5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methyl](methyl)amino]ethoxy]phenyl)-2-bromopropanoate | C35H44BrNO5 | 详情 | 详情 | |
| (X) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (XI) | 26461 | 5-(4-[2-[[[5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methyl](methyl)amino]ethoxy]benzyl)-1,3-thiazolidine-2,4-dione | C34H40N2O5S | 详情 | 详情 |