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【结 构 式】

【药物名称】Isoprofen, UP-517-03

【化学名称】2-(2-Isopropylindan-5-yl)propionic acid

【CA登记号】57144-56-6, 58453-65-9 (sodium salt)

【 分 子 式 】C15H20O2

【 分 子 量 】232.32545

【开发单位】

【药理作用】 

合成路线1

The Friedel-Kraft's reaction of 2-isopropylindan (I) with ethyloxalyl chloride (II) by means of AlCl3 in methylene chloride gives ethyl 2-(2-isopropyl-5-indanyl)-2-oxoacetate (III), which is hydrolyzed with NaOH in refluxing ethanol to the corresponding free acid (IV). The reaction of (IV) with methylmagnesium iodide in ether yields 2-(2-isopropyl-5-indanyl)-2-hydroxypropionic acid (V), which is dehydrated with H2SO4 in refluxing dioxane affording 2-(2-isopropyl-5-indanyl)acrylic acid (VI) (1,2,4). Finally this compound is reduced with H2 over Raney-Ni or Pd/C in methanol or dioxane

1 Blancafort, P.; Serradell, M.N.; Castaner, J.; Arrigoni, Martelli, E.; Isoprofen. Drugs Fut 1981, 6, 8, 471.
2 Payne, T.G. (Hexachimie SA); CH 605564 .
3 Teulon, J,M,; et al. (Hexachimie SA); BE 824522; CA 1063618; CH 603533; CH 605567; DD 117209; DD 118271; DD 123319; DE 2504689; FR 2260334; GB 1492175; JP 76125367; JP 76125368; NL 7501518; NL 7501519; US 4069326; US 4088787; US 4182896; ZA 7500707 .
4 Teulon, J.M.; et al.; Antiinflammatory and analgesic diastereoisomeric derivatives of indan-5-acetic acid. J Med Chem 1978, 21, 4, 901.
5 Payne, T.G. (Hexachimie SA); CH 605565 .
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) 60960 2-isopropylindane C12H16 详情 详情
(II) 11043 Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride 4755-77-5 C4H5ClO3 详情 详情
(III) 60961 ethyl 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)-2-oxoacetate C16H20O3 详情 详情
(IV) 60962 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)-2-oxoacetic acid C14H16O3 详情 详情
(V) 60963 2-hydroxy-2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)propanoic acid C15H20O3 详情 详情
(VI) 60964 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)acrylic acid C15H18O2 详情 详情

合成路线2

The Friedel-Kraft's reaction of 2-isopropylindan (I) with acetic anhydride in methylene chloride gives 2-isopropyl-5-acetylindan (VII), which by with sulfur and morpholine (A) at 140 C gives 2-(2-isopropyl-5-indanyl)acetylmorpholinothioamide (XI), which is hydrolyzed to 2-(2-isopropyl-5-indanyl)acetic acid (XII). The esterification of (XII) with ethanol - H2SO4 yields the corresponding ethyl ester (XIII), which is condensed with diethyl carbonate (XIV) by means of sodium ethoxide in refluxing ethanol affording diethyl (2-isopropyl-5-indanyl)malonate (XV), which is methylated with methyl iodide and sodium ethoxide in refluxing ethanol to give diethyl methyl-(2-isopropyl-5-indanyl)malonate (XVI). Finally this compound is hydrolyzed and decarboxylated by treatment with NaOH in refluxing hydrazine hydrate Compound (XII) can also be obtained by a Wolf-Kistner reduction of ketoacid (IV) in refluxing hydrazine hydrate

1 Teulon, J,M,; et al. (Hexachimie SA); BE 824522; CA 1063618; CH 603533; CH 605567; DD 117209; DD 118271; DD 123319; DE 2504689; FR 2260334; GB 1492175; JP 76125367; JP 76125368; NL 7501518; NL 7501519; US 4069326; US 4088787; US 4182896; ZA 7500707 .
2 Blancafort, P.; Serradell, M.N.; Castaner, J.; Arrigoni, Martelli, E.; Isoprofen. Drugs Fut 1981, 6, 8, 471.
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) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(I) 60960 2-isopropylindane C12H16 详情 详情
(IV) 60962 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)-2-oxoacetic acid C14H16O3 详情 详情
(VII) 60965 1-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)-1-ethanone C14H18O 详情 详情
(XI) 60966 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)-1-(4-morpholinyl)-1-ethanethione C18H25NOS 详情 详情
(XII) 60967 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)acetic acid C14H18O2 详情 详情
(XIII) 60968 ethyl 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)acetate C16H22O2 详情 详情
(XIV) 17470 diethyl carbonate; diethylcarbonate 105-58-8 C5H10O3 详情 详情
(XV) 60969 diethyl 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)malonate C19H26O4 详情 详情
(XVI) 60970 ethyl 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)propanoate C17H24O2 详情 详情

合成路线3

The Friedel-Kraft's reaction of 2-isopropylindan (I) with acetic anhydride in methylene chloride gives 2-isopropyl-5-acetylindan (VII), which is reduced with KBH4 in methanol yielding 2-isopropyl-5-(1-hydroxyethyl)indan (VIII). The treatment of (VIII) with SOCl2 in benzene affords 2-isopropyl-5-(1-chloroethyl)indan (IX), which by reaction with NaCN in hot HMPA yields 2-(2-isopropyl-5-indanyl)propionitrile (X). Finally this compound is hydrolyzed with H2SO4 in refluxing acetic acid - water

1 Teulon, J.M.; et al.; Antiinflammatory and analgesic diastereoisomeric derivatives of indan-5-acetic acid. J Med Chem 1978, 21, 4, 901.
2 Teulon, J,M,; et al. (Hexachimie SA); BE 824522; CA 1063618; CH 603533; CH 605567; DD 117209; DD 118271; DD 123319; DE 2504689; FR 2260334; GB 1492175; JP 76125367; JP 76125368; NL 7501518; NL 7501519; US 4069326; US 4088787; US 4182896; ZA 7500707 .
3 Blancafort, P.; Serradell, M.N.; Castaner, J.; Arrigoni, Martelli, E.; Isoprofen. Drugs Fut 1981, 6, 8, 471.
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) 60960 2-isopropylindane C12H16 详情 详情
(VII) 60965 1-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)-1-ethanone C14H18O 详情 详情
(VIII) 60971 1-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)-1-ethanol C14H20O 详情 详情
(IX) 60972 5-(1-chloroethyl)-2-isopropylindane C14H19Cl 详情 详情
(X) 60973 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)propanenitrile C15H19N 详情 详情
Extended Information