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【结 构 式】 
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【分子编号】26283 【品名】methyl (2S)-3-(1-methoxy-1H-indol-3-yl)-2-(methylamino)propanoate 【CA登记号】 |
【 分 子 式 】C14H18N2O3 【 分 子 量 】262.3086 【元素组成】C 64.11% H 6.92% N 10.68% O 18.3% |
合成路线1
该中间体在本合成路线中的序号：(XXII)Condensation of phenylacetic acid (XI) with methoxyamine gave hydroxamate (XII). After N-chlorination of (XII) with tert-butyl hypochlorite, Ag(I)-catalyzed ring closure of the intermediate (XIII) produced N-(methoxy)oxindole (XIV). Amide reduction of (XIV) with LiAlH4 gave hemiaminal (XV), which was converted to the racemic tryptophan derivative (XVII) by reaction with alpha-acetamidoacrylic acid (XVI) in AcOH-Ac2O. Optical resolution of (XVII) by enantioselective enzymatic hydrolysis of the acetamide group using Acylase I from Aspergillus sp. afforded N1'-methoxy-L-tryptophan (XVIII), which was protected as the N-Boc derivative (XIX) and N-methylated by means of MeI and NaH yielding (XX). The resulting N-methyl amino acid (XX) was esterified upon treatment with (trimethylsilyl)diazomethane giving (XXI), and the N-Boc group was removed with HCl in EtOAc to provide the tryptophan derivative (XXII).
| 【1】 Boger, D.L.; et al.; Total synthesis of HUN-7293. J Am Chem Soc 1999, 121, 26, 6197. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15455 | (aminooxy)methane; O-methylhydroxylamine | 67-62-9 | CH5NO | 详情 | 详情 | |
| (XI) | 16148 | Benzeneacetic acid; 2-Phenylacetic acid; Phenyl Acetic Acid | 103-82-2 | C8H8O2 | 详情 | 详情 |
| (XII) | 26273 | N-methoxy-2-phenylacetamide | C9H11NO2 | 详情 | 详情 | |
| (XIII) | 26274 | N-chloro-N-methoxy-2-phenylacetamide | C9H10ClNO2 | 详情 | 详情 | |
| (XIV) | 26275 | 1-methoxy-1,3-dihydro-2H-indol-2-one | C9H9NO2 | 详情 | 详情 | |
| (XV) | 26276 | 1-methoxy-2-indolinol | C9H11NO2 | 详情 | 详情 | |
| (XVI) | 26277 | 2-(acetamido)acrylic acid | 5429-56-1 | C5H7NO3 | 详情 | 详情 |
| (XVII) | 26278 | N-acetyl-1-methoxytryptophan | C14H16N2O4 | 详情 | 详情 | |
| (XVIII) | 26279 | (2S)-2-amino-3-(1-methoxy-1H-indol-3-yl)propionic acid | C12H14N2O3 | 详情 | 详情 | |
| (XIX) | 26280 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1-methoxy-1H-indol-3-yl)propionic acid | C17H22N2O5 | 详情 | 详情 | |
| (XX) | 26281 | (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(1-methoxy-1H-indol-3-yl)propionic acid | C18H24N2O5 | 详情 | 详情 | |
| (XXI) | 26282 | methyl (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(1-methoxy-1H-indol-3-yl)propanoate | C19H26N2O5 | 详情 | 详情 | |
| (XXII) | 26283 | methyl (2S)-3-(1-methoxy-1H-indol-3-yl)-2-(methylamino)propanoate | C14H18N2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXII)A more effective preparation of (XXII) was further developed starting from N-methyltryptophan (XXIII). Protection as the N-Fmoc derivative (XXIV) and then esterification with (trimethylsilyl)diazomethane yielded (XXV). Reduction of (XXV) with triethylsilane and TFA produced indoline (XXVI), which was reoxidized to the corresponding N-hydroxyindole with Na2WO4 and H2O2, and then O-methylated with Me2SO4 to give (XXVII). Finally, Fmoc deprotection of (XXVII) with Et2NH provided aminoester (XXII).
| 【1】 Boger, D.L.; et al.; Total synthesis of HUN-7293. J Am Chem Soc 1999, 121, 26, 6197. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40597 | 9-[[(chlorocarbonyl)oxy]methyl]-9H-fluorene | 28920-43-6 | C15H11ClO2 | 详情 | 详情 | |
| (XXII) | 26283 | methyl (2S)-3-(1-methoxy-1H-indol-3-yl)-2-(methylamino)propanoate | C14H18N2O3 | 详情 | 详情 | |
| (XXIII) | 26284 | N-alpha-Methyl-L-tryptophan; L-Abrine; (2S)-3-(1H-Indol-3-yl)-2-(methylamino)propionic acid; N-Methyl-L-tryptophan | 526-31-8 | C12H14N2O2 | 详情 | 详情 |
| (XXIV) | 26285 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]-3-(1H-indol-3-yl)propionic acid | C27H24N2O4 | 详情 | 详情 | |
| (XXV) | 26286 | methyl (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]-3-(1H-indol-3-yl)propanoate | C28H26N2O4 | 详情 | 详情 | |
| (XXVI) | 26287 | methyl (2S)-3-(2,3-dihydro-1H-indol-3-yl)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]propanoate | C28H28N2O4 | 详情 | 详情 | |
| (XXVII) | 26288 | methyl (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]-3-(1-methoxy-1H-indol-3-yl)propanoate | C29H28N2O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXII)Dipeptide (XLIV) was prepared by coupling N-Boc-L-leucine (XLII) with tryptophan derivative (XXII), followed by basic hydrolysis of the resulting dipeptide ester (XLIII). Dipeptides (XLIV) and (XLI) were then coupled in the presence of HATU to afford tetrapeptide (XLV), which was separated from minor amounts of a tryptophan-epimerized byproduct by semipreparative RP-HPLC. Tetrapeptide ester (XLV) was then hydrolyzed to acid (XLVI) with LiOH in aqueous tert-butanol.
| 【1】 Boger, D.L.; et al.; Total synthesis of HUN-7293. J Am Chem Soc 1999, 121, 26, 6197. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXII) | 26283 | methyl (2S)-3-(1-methoxy-1H-indol-3-yl)-2-(methylamino)propanoate | C14H18N2O3 | 详情 | 详情 | |
| (XLI) | 26302 | methyl (2S)-2-[[(2S,4R)-2-amino-4-methyloctanoyl](methyl)amino]propanoate | C14H28N2O3 | 详情 | 详情 | |
| (XLII) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (XLIII) | 26303 | methyl (2S)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoyl](methyl)amino]-3-(1-methoxy-1H-indol-3-yl)propanoate | C25H37N3O6 | 详情 | 详情 | |
| (XLIV) | 26304 | (2S)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoyl](methyl)amino]-3-(1-methoxy-1H-indol-3-yl)propionic acid | C24H35N3O6 | 详情 | 详情 | |
| (XLV) | 26305 | methyl (6S,9S,12S,15S)-6-isobutyl-9-[(1-methoxy-1H-indol-3-yl)methyl]-2,2,8,14,15-pentamethyl-12-[(2R)-2-methylhexyl]-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecan-16-oate | C38H61N5O8 | 详情 | 详情 | |
| (XLVI) | 26308 | N-(Tert-butoxycarbonyl)-L-leucyl-(N-alpha-methyl-N-1-methoxy)-L-tryptophyl-L-(2-amino-4(R)-methyloctanoyl)-(N-methyl)-L-alanine; N-(Tert-butoxycarbonyl)-L-leucyl-(N-alpha-methyl-N-1-methoxy)-L-tryptophyl-L-(2-amino-4(R)-methyloctanoyl)-(N-methyl)-L-alanine | C37H59N5O8 | 详情 | 详情 |