【结 构 式】 |
【药物名称】L-644122 【化学名称】(+)-4-[3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl]benzoic acid 【CA登记号】84040-56-2 【 分 子 式 】C21H29NO4S 【 分 子 量 】391.53358 |
【开发单位】Merck & Co. (Originator), Merck Sharp & Dohme (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Vasodilators |
合成路线1
The condensation of ethyl 4-methylbenzoate (I) with 2-(2-bromoethyl)-1,3-dioxolane (II) by means of lithium diisopropylamide gives ethyl 4-[3-(1,3-dioxolan-2-yl)propyl]benzoate (III), which is hydrolyzed to ethyl 4-(3-formylpropyl)benzoate (IV). The condensation of (IV) with 1-(2-aminoethyl) cyclohexanol (V) affords the corresponding imine (VI), which is cyclized with methyl thioglycolate (VII) yielding ethyl 4-[3-[3-[2-[1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl]benzoate (VIII) . The hydrolysis of (VIII) with KOH gives L-644122 as a racemic mixture (IX), which is methylated with MeI and K2CO3 to the corresponding methyl ester (X). Esterification of (X) with (-)-camphanic acid (XI) by means of dicyclohexylcarbodumide in methylene chloride affords the diastereomeric mixture of esters (XII), which is separated into its components by fractionated crystallization in ethyl acetate hexane. Finally, the (+)-diastereomer (XIII) is hydrolyzed with KOH in refluxing toluene containing diclohexyl-18-crown-6.
【1】 Mohan, P.; Smith, E.C.R.; Cushman, M.; Synthesis an dbiological activity of structural analogues of the anticancer benzopheanthridine alkaloid nitidine chloride. J Med Chem 1983, 26, 3, 342-348. |
【2】 Blaine, E.H. (Merck & Co., Inc.; Merck Sharp & Dohme Ltd.); Anti-inflammatory composition. US 4379792 . |
【3】 Bock, M.G.; di Pardo, R.M. (Merck & Co., Inc.); Intermediates for the resolution of some interphenylene-9-thia-11-oxo-12-azaprostanoic. AT 235482; AT 378189B; GB 2100733; US 4390703 . |
【4】 Serradell, M.N.; Castaner, J.; L-644122. Drugs Fut 1986, 11, 5, 372. |
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) | 28807 | ethyl 4-methylbenzoate | 94-08-6 | C10H12O2 | 详情 | 详情 |
(II) | 15724 | 2-(2-bromoethyl)-1,3-dioxolane | 18742-02-4 | C5H9BrO2 | 详情 | 详情 |
(III) | 28808 | ethyl 4-[3-(1,3-dioxolan-2-yl)propyl]benzoate | C15H20O4 | 详情 | 详情 | |
(IV) | 28809 | ethyl 4-(4-oxobutyl)benzoate | C13H16O3 | 详情 | 详情 | |
(V) | 28810 | 1-(2-aminoethyl)cyclohexanol | C8H17NO | 详情 | 详情 | |
(VI) | 28811 | ethyl 4-(4-[[2-(1-hydroxycyclohexyl)ethyl]imino]butyl)benzoate | C21H31NO3 | 详情 | 详情 | |
(VII) | 18838 | methyl 2-sulfanylacetate | 2365-48-2 | C3H6O2S | 详情 | 详情 |
(VIII) | 28812 | ethyl 4-(3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-1,3-thiazolidin-2-yl]propyl)benzoate | C23H33NO4S | 详情 | 详情 | |
(IX) | 28813 | 4-(3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-1,3-thiazolidin-2-yl]propyl)benzoic acid | C21H29NO4S | 详情 | 详情 | |
(X) | 28814 | methyl 4-(3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-1,3-thiazolidin-2-yl]propyl)benzoate | C22H31NO4S | 详情 | 详情 | |
(XI) | 28815 | (1S,4R)-7,7-dimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylic acid | C9H12O4 | 详情 | 详情 | |
(XII) | 28816 | 1-[2-(2-[3-[4-(methoxycarbonyl)phenyl]propyl]-4-oxo-1,3-thiazolidin-3-yl)ethyl]cyclohexyl (1S,4R)-7,7-dimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylate | C31H41NO7S | 详情 | 详情 | |
(XIII) | 28817 | 1-[2-((2R)-2-[3-[4-(methoxycarbonyl)phenyl]propyl]-4-oxo-1,3-thiazolidin-3-yl)ethyl]cyclohexyl (1S,4R)-7,7-dimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylate | C31H41NO7S | 详情 | 详情 |