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【结 构 式】 
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【分子编号】12304 【品名】N-[(3R)-9-(2-cyanoethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-4-fluorobenzenesulfonamide 【CA登记号】 |
【 分 子 式 】C21H20FN3O2S 【 分 子 量 】397.4732232 【元素组成】C 63.46% H 5.07% F 4.78% N 10.57% O 8.05% S 8.07% |
合成路线1
该中间体在本合成路线中的序号：(A)The reaction of 1,2,3,5-tetra-O-acetyl-beta-D-ribofuranose (I) with dry HCl in ether-acetic anhydride gives 1-chloro-2,3,5-tri-O-acetyl-beta-D-ribofuranose (II), which by reaction with silver isocyanate in dry xylene is converted into 2,3,5-tri-O-acetyl-beta-D-ribofuranosylisocyanate (III). The reaction of (III) with 2-methylisourea (IV) in dry CHCl3 affords 1-(2,3,5-tri-O-acetyl-3-D-ribofuranosyl)-4-methylisobiuret (V), which is cyclized by reaction with ethyl orthoformate at 135 C yielding 1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-4-methoxy-2-oxo-1,2-dihydro-1,3,5-triazine (VI). Finally, this compound is treated with ammonia in dry methanol.
| 【1】 Sorm, F.; Piskala, A.; Nucleic acid components and their analogues. LI. Synthesis of 1-glycosyl derivatives of 5-azauracil and 5-azacytosine. Coll Czech Chem Commun 1964, 29, 2060-76. |
| 【2】 Von Hoff, D.D.; Azacitidine. Drugs Fut 1980, 5, 8, 392. |
| 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) | 12304 | N-[(3R)-9-(2-cyanoethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-4-fluorobenzenesulfonamide | C21H20FN3O2S | 详情 | 详情 | |
| (I) | 33835 | (2R,3R,4R,5S)-4,5-bis(acetoxy)-2-[(acetoxy)methyl]tetrahydro-3-furanyl acetate | 13035-61-5 | C13H18O9 | 详情 | 详情 |
| (II) | 39189 | (2R,3S,4R,5S)-4-(acetoxy)-2-[(acetoxy)methyl]-5-chlorotetrahydro-3-furanyl acetate | C11H15ClO7 | 详情 | 详情 | |
| (III) | 39190 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-isocyanatotetrahydro-3-furanyl acetate | C12H15NO8 | 详情 | 详情 | |
| (IV) | 26657 | O-methyl isourea; [Amino(imino)methoxy]methane | 52328-05-9 | C2H6N2O | 详情 | 详情 |
| (V) | 39191 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-[([[(E)-amino(methoxy)methylidene]amino]carbonyl)amino]tetrahydro-3-furanyl acetate | C14H21N3O9 | 详情 | 详情 | |
| (VI) | 39192 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-[4-methoxy-2-oxo-1,3,5-triazin-1(2H)-yl]tetrahydro-3-furanyl acetate | C15H19N3O9 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)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 |