Isoprofen, UP-517-03, -Drug Synthesis Database

【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 合成路线2 合成路线3

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

参考文献中间体

【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

参考文献中间体

【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

参考文献中间体

【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	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