• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【药物名称】Mavoglurant;AFQ-056;Rezonic;Zunrisa

【化学名称】(–)-(3aR,4S,7aR)-4-Hydroxy-4-[2-(3-methylphenyl)ethynyl]perhydroindole-1-carboxylic acid methyl ester

【CA登记号】

【 分 子 式 】C19H23NO3

【 分 子 量 】313.3908

【开发单位】Novartis AG (CH)

【药理作用】Metabotropic Glutamate mGlu5 Receptor Antagonist;Treatment of Fragile X Syndrome;Treatment of Dyskinesia

合成路线1

Protection of 1,5,6,7-tetrahydroindol-4-one (I) with Boc2O by means of t-BuOK in refluxing THF gives the corresponding N-Boc-indolone (II), which is then reduced with H2 over Pt/C in MeOH to yield (3aR*, 4S*,7aR*)-cis-N-Boc-4-hydroxyoctahydroindole (III). Swern oxidation of alcohol (III) using (COCl)2, DMSO and Et3N in THF affords the racemic perhydroindolone (IV), which is resolved using chiral chromatography to the (3aR,7aR)-enantiomer (V). Alternatively, enantioselective acetylation of racemic alcohol (III) with vinyl acetate in the presence of immobilized Candida antarctica lipase (Novozyme 435), followed by flash chromatographic separation of the undesired (3aS,4R,7aS)-acetate provides unreacted (3aR,4S,7aR)-alcohol (VI), which is then oxidized to ketone (V) under Swern conditions. Treatment of 1-ethynyl-3-methylbenzene (VII) with BuLi in THF at –20 °C and subsequent enantioselective condensation with ketone (V) leads to propargylic alcohol (VIII), which is then N-deprotected with HCl in EtOAc to produce the amine (IX). Finally, amine (IX) is acylated with methyl chloroformate (X) in the presence of Et3N in CH2Cl2 .
Alternatively, Michael addition of aziridine (XI) to 2-cyclohexenone (XII) in toluene gives 3-(1-aziridinyl)cyclohexanone (XIII), which is submitted to aziridine ring opening by treatment with methyl chloroformate in toluene to provide methyl N-2-chloroethyl-N-(3-oxocyclohexyl)carba-mate (XIV). Intramolecular cyclization of carbamate (XIV) in the presence of pyrrolidine and Et3N in CH2Cl2 affords racemic methyl 4-oxooctahydroindole-1-carboxylate (XV), which is then subjected to chiral chromatographic separation, resulting in the (3aR,7aR)-enantiomer (XVI). Finally, 1-ethynyl-3-methylbenzene (VII) is stereospecifically added to ketone (XVI) in the presence of n-Hex-Li in THF .

1 Auberson, Y., Ofner, S., Gasparini, F. (Novartis AG; Novartis Pharma GmbH). Acetylene derivatives having mGluR5 antagonistic activity. EP 1453512, JP 2005514381, JP 200830326, US 200506591, US 7348353, US 2008146647, US 2008303226, WO 2003047581.
2 Kuesters, E., Acemoglu, M., Lustenberger, P., Sedelmeier, G., Schmidt, B.,Penn, G. (Novartis AG). Processes for the preparation of 4-oxo-octahydroindole-1-carbocylic acid methyl ester and derivatives thereof. CN 102119151, EP 2315748, JP 2011530566, KR 2011042222, US 2011144352, US 8084487, WO 2010018154.
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) 68376 6,7-dihydro-1H-indol-4(5H)-one;1,5,6,7-tetrahydro-4h-indol-4-one;4-0xo-4,5,6,7-tetrahydroindole;4-Oxo-1,5,6,7-tetrahydroindole 13754-86-4 C8H9NO 详情 详情
(II) 68377 tert-butyl 4-oxo-4,5,6,7-tetrahydro-1H-indole-1-carboxylate   C13H17NO3 详情 详情
(III) 68378 racemic N-Boc-4-hydroxyoctahydroindole;racemic tert-butyl 4-hydroxyoctahydro-1H-indole-1-carboxylate   C13H23NO3 详情 详情
(IV) 68379 racemic tert-butyl 4-oxooctahydro-1H-indole-1-carboxylate   C13H21NO3 详情 详情
(V) 68380 (3aR,7aR)-tert-butyl 4-oxooctahydro- 1H-indole-1-carboxylate   C13H21NO3 详情 详情
(VI) 68381 (3aR,4S,7aR)-cis-N-Boc-4- hydroxyoctahydroindole;(3aR,4S,7aR)-tert-butyl 4- hydroxyoctahydro-1H-indole-1-carboxylate   C13H23NO3 详情 详情
(VII) 68382 1-ethynyl-3-methylbenzene;3-Ethynyltoluene;3-Methylphenylacetylene;3'-Methylphenylacetylene 766-82-5 C9H8 详情 详情
(VIII) 68384 (3aR,4S,7aR)-tert-butyl 4-hydroxy-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate   C22H29NO3 详情 详情
(IX) 68383 (3aR,4S,7aR)-4-(m-tolylethynyl)octahydro-1H-indol-4-ol hydrochloride   C17H21NO.HCl 详情 详情
(X) 16993 methyl chlorocarbonate;Carbonochloridic acid methyl ester;[(chlorocarbonyl)oxy]methane;methyl chloroformate 79-22-1 C2H3ClO2 详情 详情
(XI) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情
(XII) 26253 2-cyclohexen-1-one;Cyclohex-2-enone;2-cyclohexenone 930-68-7 C6H8O 详情 详情
(XIII) 68385 3-(1-aziridinyl)cyclohexanone;3-(aziridin-1-yl)cyclohexanone   C8H13NO 详情 详情
(XIV) 68386 methyl N-2-chloroethyl-N-(3-oxocyclohexyl) carbamate;methyl (2-chloroethyl)(3-oxocyclohexyl)carbamate   C10H16ClNO3 详情 详情
(XV) 68387 racemic methyl 4-oxooctahydroindole-1-carboxylate   C10H15NO3 详情 详情
(XVI) 68388 (3aR,7aR)-methyl 4-oxooctahydro-1H-indole-1-carboxylate   C10H15NO3 详情 详情
Extended Information