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【结 构 式】 
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【分子编号】46497 【品名】4-[(3aR,9bR)-9-methoxy-1,3a,4,9b-tetrahydrochromeno[3,4-c]pyrrol-2(3H)-yl]butanenitrile 【CA登记号】 |
【 分 子 式 】C16H20N2O2 【 分 子 量 】272.34708 【元素组成】C 70.56% H 7.4% N 10.29% O 11.75% |
合成路线1
该中间体在本合成路线中的序号：(XXV)Alternatively, the reaction of the cyclic sulfate (VIII) with potassium phthalimide (XVIII) gives the N-substituted phthalimide (XIX), whose sulfate group is cleaved with sulfuric acid to yield the alcohol (XX). The reaction of (XX) with the perhydroisoquinoline (XV) by means of K2CO3 in acetonitrile/methanol affords the oxazoline (XXI), whose ring is opened with thiophenol (XVII) and KHCO3 in THF, providing a mixture of the two sulfides (XXII) and (XXIII) that are not isolated. The cleavage of the phthalimido group with refluxing ethanolamine followed by a treatment with benzoic acid gives a mixture of ammonium salts that is separated by crystallization, yielding the desired isomer (XXIV). The reaction of (XXIV) with acid chloride (XII) affords the precursor (XXV), which is finally deacetylated with NaOH to provide the target compound.
| 【1】 Albizati, K.F.; et al.; A synthesis of the HIV-protease inhibitor nelfinavir from D-tartaric acid. Tetrahedron Lett 2001, 42, 37, 6481. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 55023 | [(4R,5R)-5-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2,2-dioxo-1,3,2lambda~6~-dioxathiolan-4-yl]methyl 4-methylbenzenesulfonate | C18H20O10S3 | 详情 | 详情 | |
| (XII) | 46596 | 3-(chlorocarbonyl)-2-methylphenyl acetate | C10H9ClO3 | 详情 | 详情 | |
| (XV) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
| (XVII) | 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 |
| (XVIII) | 27890 | Potassium phthalimide | 1074-82-4 | C8H4KNO2 | 详情 | 详情 |
| (XIX) | 55029 | potassium 2-[(1S,2S)-3-{[(4-methylphenyl)sulfonyl]oxy}-1-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2-(sulfonatooxy)propyl]-1,3-dioxoisoindoline | C26H24KNO12S3 | 详情 | 详情 | |
| (XX) | 55030 | (2S,3S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-hydroxy-4-{[(4-methylphenyl)sulfonyl]oxy}butyl 4-methylbenzenesulfonate | C26H25NO9S2 | 详情 | 详情 | |
| (XXI) | 55031 | methyl 2-((4S)-4-{(1R)-2-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-hydroxyethyl}-4,5-dihydro-1,3-oxazol-2-yl)benzoate | C27H39N3O5 | 详情 | 详情 | |
| (XXII) | 55032 | (3S,4aS,8aS)-N-(tert-butyl)-2-[(2R,3R)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-hydroxy-4-(phenylsulfanyl)butyl]decahydro-3-isoquinolinecarboxamide | C32H41N3O4S | 详情 | 详情 | |
| (XXIII) | 55033 | (3S,4aS,8aS)-N-(tert-butyl)-2-[(2S,3S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-hydroxy-4-(phenylsulfanyl)butyl]decahydro-3-isoquinolinecarboxamide | C32H41N3O4S | 详情 | 详情 | |
| (XXIV) | 55034 | (2R,3R)-4-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-3-hydroxy-1-(phenylsulfanyl)-2-butanaminium benzoate | C31H45N3O4S | 详情 | 详情 | |
| (XXV) | 46497 | 4-[(3aR,9bR)-9-methoxy-1,3a,4,9b-tetrahydrochromeno[3,4-c]pyrrol-2(3H)-yl]butanenitrile | C16H20N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)Cycloaddition of the azomethine ylide resulting from N-trimethylsilylmethyl-N-methoxymethyl-(R)-alpha-methylbenzylamine (II) to 5-methoxycoumarin (I) produced the chiral cis-benzopyranopyrrole system (III). Lactone reduction by means of LiAlH4 or LiBH4 afforded diol (IV). After conversion of the primary alcohol of (IV) to either the corresponding chloride or the mesylate, cyclization in the presence of potassium tert-butoxide generated the tricyclic compound (V). The alpha-methylbenzyl group of (V) was removed by catalytic hydrogenation to give amine (VI), which was alkylated with 4-bromobutyronitrile yielding (VII). Reduction of the cyano group of (VII) using LiAlH4 in the presence AlCl3 or by catalytic hydrogenation in the presence of Raney-Ni produced the primary amine (VIII).
| 【1】 Meyer, M.D.; Altenbach, R.J.; Basha, F.; Carroll, W.A.; Drizin, I.; Kerwin, J.F.; Wendt, M.D.; Haight, A.R.; Zhang, W. (Abbott Laboratories Inc.); Benzopyranopyrrole and benzopyranopyridine alpha-1 adrenergic cpds.. EP 0942911; US 5891882; US 6046207; WO 9824791 . |
| 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) | 46491 | 5-methoxy-2H-chromen-2-one | C10H8O3 | 详情 | 详情 | |
| (II) | 46492 | (1R)-N-(methoxymethyl)-1-phenyl-N-[(trimethylsilyl)methyl]-1-ethanamine; N-(methoxymethyl)-N-[(1R)-1-phenylethyl]-N-[(trimethylsilyl)methyl]amine | C14H25NOSi | 详情 | 详情 | |
| (III) | 46493 | (3aR,9bR)-9-methoxy-2-[(1R)-1-phenylethyl]-2,3,3a,9b-tetrahydrochromeno[3,4-c]pyrrol-4(1H)-one | C20H21NO3 | 详情 | 详情 | |
| (IV) | 46494 | 2-[(3R,4R)-4-(hydroxymethyl)-1-[(1R)-1-phenylethyl]pyrrolidinyl]-3-methoxyphenol | C20H25NO3 | 详情 | 详情 | |
| (V) | 46495 | (3aR,9bR)-9-methoxy-2-[(1R)-1-phenylethyl]-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole; (3aR,9bR)-2-[(1R)-1-phenylethyl]-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrol-9-yl methyl ether | C20H23NO2 | 详情 | 详情 | |
| (VI) | 46496 | (3aR,9bR)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrol-9-yl methyl ether; (3aR,9bR)-9-methoxy-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole | C12H15NO2 | 详情 | 详情 | |
| (VII) | 46497 | 4-[(3aR,9bR)-9-methoxy-1,3a,4,9b-tetrahydrochromeno[3,4-c]pyrrol-2(3H)-yl]butanenitrile | C16H20N2O2 | 详情 | 详情 | |
| (VIII) | 46498 | 4-[(3aR,9bR)-9-methoxy-1,3a,4,9b-tetrahydrochromeno[3,4-c]pyrrol-2(3H)-yl]-1-butanamine; 4-[(3aR,9bR)-9-methoxy-1,3a,4,9b-tetrahydrochromeno[3,4-c]pyrrol-2(3H)-yl]butylamine | C16H24N2O2 | 详情 | 详情 |