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【结 构 式】 
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【分子编号】44173 【品名】(2R)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropionic acid 【CA登记号】 |
【 分 子 式 】C22H20N2O5 【 分 子 量 】392.41128 【元素组成】C 67.34% H 5.14% N 7.14% O 20.39% |
合成路线1
该中间体在本合成路线中的序号：(V)Treatment of [U-ring-14C] acetophenone (I) with O-methylhydroxylamine hydrochloride in pyridine/EtOH and catalytic MgSO4 yields labeled acetophenone oxime methyl ether (II), which is then subjected to Didier's enantioselective reduction with BH3·THF and 1S,2R-1-amino-indan-2-ol (III) to provide labeled (S)-(IV). Finally, phenylethylamine (S)-(IV) is coupled to chiral acid (V) with 1-hydroxybenzotriazole hydrate (HOBt), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-methylmorpholine (NMM).
| 【1】 Zhang, Y.S.; Synthesis of 14C-labeled S-(-)-1-phenylethylamine and its application to the synthesis of [14C] CI-1021, a potential antiemetic agent(1). J Label Compd Radiopharm 2000, 43, 11, 1087. |
| 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) | 10317 | Acetophenone | 98-86-2 | C8H8O | 详情 | 详情 |
| (I) | 45337 | C8H8O | 详情 | 详情 | ||
| (II) | 44172 | 1-phenyl-1-ethanone O-methyloxime | C9H11NO | 详情 | 详情 | |
| (II) | 45338 | C9H11NO | 详情 | 详情 | ||
| (III) | 16239 | (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol; Cis-(1S)-1-amino-2,3-dihydro-1H-inden-2-ol | 126456-43-7 | C9H11NO | 详情 | 详情 |
| (IV) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (IV) | 45339 | C8H11N | 详情 | 详情 | ||
| (V) | 44173 | (2R)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropionic acid | C22H20N2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)Treatment of N(alpha)-Cbz-D-tryptophan (I) with diazomethane (CH2N2) in Et2O/CH2Cl2 provides methyl ester derivative (II), which is then cyclized to afford pyrrolo-indole derivative (III) by long treatment with TFA. N-protection of (III) by reaction with benzyl chloroformate (IV) and Na2CO3 in dioxane yields derivative (V), which is then converted into labeled methylated derivative (VI) by first deprotonation with LHDMS followed by treatment with labeled methyl iodide (MeI) in THF. Ring opening of (VI) by means of TFA furnishes protected methyltryptophan (VII), whose Cbz groups are removed by hydrogenolysis over Pd/C in EtOH to yield derivative (VIII). Coupling of (VIII) with carbonate (IX) by means of DMAP in DMF affords derivative (X), which is then subjected to saponification with LiOH in MeOH to provide carboxylic acid derivative (XI). Finally, (XI) is coupled with methylbenzylamine (XII) by means of HOBt, EDC and N-methylmorpholine (NMM).
| 【1】 Ekhato, I.V.; Huang, Y.; Tetrahydro-pyrrolo-[2,3-b]indole-1,2,8-tricarboxylic acid ester in the enantiospecific preparation of alpha-methyltryptophan: Application in the preparation of carbon-14 labeled PD 145942 and PD 154075. J Label Compd Radiopharm 1997, 39, 12, 1019. |
| 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) | 44180 | (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)propionic acid | C19H18N2O4 | 详情 | 详情 | |
| (II) | 44174 | methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)propanoate | C20H20N2O4 | 详情 | 详情 | |
| (III) | 44175 | 1-benzyl 2-methyl (2R,3aS,8aS)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1,2(2H)-dicarboxylate | C20H20N2O4 | 详情 | 详情 | |
| (IV) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (V) | 44176 | 1,8-dibenzyl 2-methyl (2R,3aS,8aR)-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate | C28H26N2O6 | 详情 | 详情 | |
| (VI) | 44177 | 1,8-dibenzyl 2-methyl (2R,3aS,8aS)-2-methyl-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate | C29H28N2O6 | 详情 | 详情 | |
| (VI) | 45341 | 1,8-dibenzyl 2-methyl (2R,3aS,8aS)-2-methyl-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate | C29H28N2O6 | 详情 | 详情 | |
| (VII) | 44178 | benzyl 3-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-methoxy-2-methyl-3-oxopropyl)-1H-indole-1-carboxylate | C29H28N2O6 | 详情 | 详情 | |
| (VII) | 45340 | benzyl 3-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-methoxy-2-methyl-3-oxopropyl)-1H-indole-1-carboxylate | C29H28N2O6 | 详情 | 详情 | |
| (VIII) | 44166 | methyl (2R)-2-amino-3-(1H-indol-3-yl)-2-methylpropanoate | C13H16N2O2 | 详情 | 详情 | |
| (VIII) | 45342 | methyl (2R)-2-amino-3-(1H-indol-3-yl)-2-methylpropanoate | C13H16N2O2 | 详情 | 详情 | |
| (IX) | 44171 | 1-benzofuran-2-ylmethyl 4-nitrophenyl carbonate | C16H11NO6 | 详情 | 详情 | |
| (X) | 44179 | methyl (2R)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropanoate | C23H22N2O5 | 详情 | 详情 | |
| (X) | 45343 | methyl (2R)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropanoate | C23H22N2O5 | 详情 | 详情 | |
| (XI) | 44173 | (2R)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropionic acid | C22H20N2O5 | 详情 | 详情 | |
| (XI) | 45344 | (2R)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropionic acid | C22H20N2O5 | 详情 | 详情 | |
| (XII) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 |