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【结 构 式】 
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【分子编号】12290 【品名】N-[(1S)-1-Phenylethyl]-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amine; (3R)-N-[(1S)-1-Phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine 【CA登记号】 |
【 分 子 式 】C20H22N2 【 分 子 量 】290.40816 【元素组成】C 82.72% H 7.64% N 9.65% |
合成路线1
该中间体在本合成路线中的序号：(III)The synthesis of Bay u 3405 was carried out as follows: Reductive amination of 3-oxo-1,2,3,4-tetrahydrocarbazole (I) with S-phenethylamine (II) afforded a mixture of diastereomeric amines, of which the desired isomer (III) crystallized in high diastereomeric purity as the hydrogensulfate. Cleavage of the phenethyl group by transfer hydrogenolysis with amminium formate and palladium on charcoal yielded the enantiomerically pure (3R)-3-amino-1,2,3,4-tetrahydrocarbazole (IV). Sulfonylation of (IV) with 4-fluorobenzenesulfonyl chloride (V) to the sulfonamide (VI) followed by addition of acrylonitrile and subsequent hydrolysis gave Bay u 3405.
| 【1】 Raz, A.; Needleman, P.; Minkes, M.; Thromboxanes: Selective biosynthesis and distinct biological properties. Science 1976, 193, 163-5. |
| 【2】 Svensson, J.; Hamberg, M.; Samuelsson, B.; Thromboxanes: A new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci USA 1975, 72, 8, 2994-8. |
| 【3】 Gardiner, P.J.; Boberg, M.; Fiedler, V.B.; Perzborn, E.; Boshagen, H.; Buhner, K.; Muller, U.; Rosentreter, U.; Seuter, F.; Weber, H.; Norman, P.; Ritter, W.; Bay u 3405. Drugs Fut 1991, 16, 8, 701. |
| 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) | 12288 | 1,2,4,9-Tetrahydro-3H-carbazol-3-one | C12H11NO | 详情 | 详情 | |
| (II) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (III) | 12290 | N-[(1S)-1-Phenylethyl]-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amine; (3R)-N-[(1S)-1-Phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine | C20H22N2 | 详情 | 详情 | |
| (IV) | 12291 | (3R)-2,3,4,9-Tetrahydro-1H-carbazol-3-ylamine; (3R)-2,3,4,9-Tetrahydro-1H-carbazol-3-amine | C12H14N2 | 详情 | 详情 | |
| (V) | 12292 | 4-Fluorobenzenesulfonyl chloride | 349-88-2 | C6H4ClFO2S | 详情 | 详情 |
| (VI) | 12293 | 4-Fluoro-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]benzenesulfonamide | C18H17FN2O2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)The synthesis of [14C]-labeled Bay-u-3405 by two closely related ways has been described: 1) [14C]-Labeled aniline (I) is diazotized and reduced with sodium sulfite, yielding the labeled hydrazine (II), which is condensed with the monoketal of cyclohexane-1,4-dione (III) under Fisher's indole synthesis (ZnCl2) to afford the tetrahydrocarbazole (IV). The hydrolysis of (IV) with HCl in THF/water yields 1,2,3,4-tetrahydrocarbazol-3-one (V), which is submitted to a reductive condensation with (S)-1-phenylethylamine (VI) by means of tetrabutylammonium borohydride, yielding preferentially the secondary amine (VII), which, after purification, is dealkylated with ammonium formate and Pd/C to afford 1,2,3,4-tetrahydrocarbazole-3(R)-amine (VIII). The acylation of (VIII) with 4-fluorophenylsulfonyl chloride (IX) gives the corresponding sulfonamide (X), which is condensed with acrylonitrile by means of NaH, yielding 3-[3(R)-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydrocarbazol-9-yl]pro pionitrile (XI). Finally, this compound is hydrolyzed in the usual way. 2) The condensation of the sulfonamide (X) with methyl acrylate by means of NaH as before gives 3-[3(R)-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydrocarbazol-9-yl]propionic acid methyl ester (XII), which is finally hydrolyzed in the usual way.
| 【1】 Pleiss, U.; Radtke, M.; Rosentreter, U.; Boberg, M.; Synthesis of (+)-(3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-[5,6,7,8,12,13-u-C-14]carbazolepropanoic acid, [C-14]BAY u 3405. J Label Compd Radiopharm 1994, 34, 12, 1207. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (I) | 45117 | C6H7N | 详情 | 详情 | ||
| (II) | 11818 | Phenyl hydrazine; 1-Phenylhydrazine | 100-63-0 | C6H8N2 | 详情 | 详情 |
| (II) | 45118 | C6H8N2 | 详情 | 详情 | ||
| (III) | 11377 | 1,4-Dioxaspiro[4.5]decan-8-one | 4746-97-8 | C8H12O3 | 详情 | 详情 |
| (IV) | 12297 | 1,2,3,4-Tetrahydrospiro[9H-carbazole-3,2'-1,3-dioxolane] | C14H15NO2 | 详情 | 详情 | |
| (IV) | 45119 | C14H15NO2 | 详情 | 详情 | ||
| (V) | 12288 | 1,2,4,9-Tetrahydro-3H-carbazol-3-one | C12H11NO | 详情 | 详情 | |
| (V) | 45120 | C12H11NO | 详情 | 详情 | ||
| (VI) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (VII) | 12290 | N-[(1S)-1-Phenylethyl]-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amine; (3R)-N-[(1S)-1-Phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine | C20H22N2 | 详情 | 详情 | |
| (VII) | 45121 | C20H22N2 | 详情 | 详情 | ||
| (VIII) | 12291 | (3R)-2,3,4,9-Tetrahydro-1H-carbazol-3-ylamine; (3R)-2,3,4,9-Tetrahydro-1H-carbazol-3-amine | C12H14N2 | 详情 | 详情 | |
| (VIII) | 45122 | C12H14N2 | 详情 | 详情 | ||
| (IX) | 12292 | 4-Fluorobenzenesulfonyl chloride | 349-88-2 | C6H4ClFO2S | 详情 | 详情 |
| (X) | 12293 | 4-Fluoro-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]benzenesulfonamide | C18H17FN2O2S | 详情 | 详情 | |
| (X) | 45123 | C18H17FN2O2S | 详情 | 详情 | ||
| (XI) | 12304 | N-[(3R)-9-(2-cyanoethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-4-fluorobenzenesulfonamide | C21H20FN3O2S | 详情 | 详情 | |
| (XI) | 45124 | C21H20FN3O2S | 详情 | 详情 | ||
| (XII) | 12305 | methyl 3-((3R)-3-[[(4-fluorophenyl)sulfonyl]amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl)propanoate | C22H23FN2O4S | 详情 | 详情 | |
| (XII) | 45125 | C22H23FN2O4S | 详情 | 详情 |