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【结 构 式】 
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【分子编号】63858 【品名】methyl (3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-9-{(5S,7R,9S)-5-ethyl-5-hydroxy-9-(methoxycarbonyl)-7-({[(4-methylphenyl)sulfonyl]oxy}methyl)-3-[(4-nitrophenyl)sulfonyl]-1,2,3,4,5,6,7,8,9,10-decahydroazacycloundecino[5,4-b]indol-9-yl}-5-hydr; ethyl 2-[3-{[(1S)-2-({4-[2-(aminomethyl)-4-chlorophenoxy]butyl}amino)-1-benzylethyl]amino}-6-chloro-2-oxo-1(2H)-pyrazinyl]acetate 【CA登记号】 |
【 分 子 式 】C59H69N5O16S2 【 分 子 量 】1168.35296 【元素组成】C 60.65% H 5.95% N 5.99% O 21.91% S 5.49% |
合成路线1
该中间体在本合成路线中的序号：(LII)The trifluoroacetate ester group of (L) is deprotected by treatment with triethylamine in MeOH to give (LI). Subsequent deprotection of the N-sulfonyl group with mercaptoethanol and DBU liberates the secondary amine which finally undergoes cyclization to the title compound upon intramolecular displacement of the tosylate group (8, 9).
| 【1】 Schneider, C.; First de novo synthesis of the bisindole alkaloid vinblastine. Angew Chem. Int Ed 2002, 41, 22, 4217. |
| 【2】 Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.; Fukuyama, T.; Stereocontrolled total synthesis of (+)-vinblastine. J Am Chem Soc 2002, 124, 10, 2137. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (LI) | 63825 | methyl (3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-9-{(5S,7R,9S)-5-ethyl-9-(methoxycarbonyl)-7-({[(4-methylphenyl)sulfonyl]oxy}methyl)-3-[(4-nitrophenyl)sulfonyl]-5-[(2,2,2-trifluoroacetyl)oxy]-1,2,3,4,5,6,7,8,9,10-decahydroazacycloundecino[5,4 | C61H68F3N5O17S2 | 详情 | 详情 | |
| (LII) | 63858 | methyl (3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-9-{(5S,7R,9S)-5-ethyl-5-hydroxy-9-(methoxycarbonyl)-7-({[(4-methylphenyl)sulfonyl]oxy}methyl)-3-[(4-nitrophenyl)sulfonyl]-1,2,3,4,5,6,7,8,9,10-decahydroazacycloundecino[5,4-b]indol-9-yl}-5-hydr; ethyl 2-[3-{[(1S)-2-({4-[2-(aminomethyl)-4-chlorophenoxy]butyl}amino)-1-benzylethyl]amino}-6-chloro-2-oxo-1(2H)-pyrazinyl]acetate | C59H69N5O16S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)The reaction of N-(2(S)-benzyl-3-hydroxypropyl)carbamic acid tert-butyl ester (VIII), with sodium azide and PPh3 gives the corresponding 3-azido derivative (IX), which is deprotected to afford 3-azido-2(S)-benzylpropylamine (X). The condensation of (X) with the intermediate bromopyrazinone (VII) by means of TEA in hot ethanol provides the secondary amine (XI), which is chlorinated with NCS in hot dichloroethane to give the chloropyrazinone (XII). The reduction of the azido group of (XII) by means of SnCl2 in methanol/THF yields the primary amine (XIII), which is condensed with the Boc protected 2-(5-bromopentyloxy)-5-chlorobenzylamine (XIV) by means of triethylamine in DMF to afford the linear precursor (XV). The deprotection of the NH2 group of (XV) by means of HCl provides the benzylamine derivative (XVI), which is treated with LiOH in THF to furnish the aminoacid precursor (XVII). Finally this compound is cyclized by means of EDC and HOAt to obtain the target macrolactam (1, 2).
| 【1】 Nantermet, P.G.; Selnick, H.G.; Potent thrombin inhibitors via a 20-membered ring olefin metathesis macrocyclization. Tetrahedron Lett 2003, 44, 11, 2401. |
| 【2】 Selnick, H.G.; Newton, R.C.; Newton, C.L.; Barrow, J.C.; Nantermet, P.G. (Merck & Co., Inc.); Thrombin inhibitors. WO 0311222 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 63820 | propyl 2-[3-bromo-2-oxo-1(2H)-pyrazinyl]acetate | C9H11BrN2O3 | 详情 | 详情 | |
| (VIII) | 54624 | tert-butyl (1S)-1-benzyl-2-hydroxyethylcarbamate | C14H21NO3 | 详情 | 详情 | |
| (IX) | 63851 | tert-butyl (1S)-2-azido-1-benzylethylcarbamate | C14H20N4O2 | 详情 | 详情 | |
| (X) | 63852 | (1S)-2-azido-1-benzylethylamine; (2S)-1-azido-3-phenyl-2-propanamine | C9H12N4 | 详情 | 详情 | |
| (XI) | 63853 | propyl 2-[3-{[(1S)-2-azido-1-benzylethyl]amino}-2-oxo-1(2H)-pyrazinyl]acetate | C18H22N6O3 | 详情 | 详情 | |
| (XII) | 63854 | propyl 2-[3-{[(1S)-2-azido-1-benzylethyl]amino}-6-chloro-2-oxo-1(2H)-pyrazinyl]acetate | C18H21ClN6O3 | 详情 | 详情 | |
| (XIII) | 63855 | propyl 2-[3-{[(1S)-2-amino-1-benzylethyl]amino}-6-chloro-2-oxo-1(2H)-pyrazinyl]acetate | C18H23ClN4O3 | 详情 | 详情 | |
| (XIV) | 63856 | tert-butyl 2-[(5-bromopentyl)oxy]-5-chlorobenzylcarbamate | C17H25BrClNO3 | 详情 | 详情 | |
| (XV) | 63857 | ethyl 2-[3-[((1S)-1-benzyl-2-{[4-(2-{[(tert-butoxycarbonyl)amino]methyl}-4-chlorophenoxy)butyl]amino}ethyl)amino]-6-chloro-2-oxo-1(2H)-pyrazinyl]acetate | C33H43Cl2N5O6 | 详情 | 详情 | |
| (XVI) | 63858 | methyl (3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-9-{(5S,7R,9S)-5-ethyl-5-hydroxy-9-(methoxycarbonyl)-7-({[(4-methylphenyl)sulfonyl]oxy}methyl)-3-[(4-nitrophenyl)sulfonyl]-1,2,3,4,5,6,7,8,9,10-decahydroazacycloundecino[5,4-b]indol-9-yl}-5-hydr; ethyl 2-[3-{[(1S)-2-({4-[2-(aminomethyl)-4-chlorophenoxy]butyl}amino)-1-benzylethyl]amino}-6-chloro-2-oxo-1(2H)-pyrazinyl]acetate | C59H69N5O16S2 | 详情 | 详情 | |
| (XVII) | 63859 | 2-[3-{[(1S)-2-({4-[2-(aminomethyl)-4-chlorophenoxy]butyl}amino)-1-benzylethyl]amino}-6-chloro-2-oxo-1(2H)-pyrazinyl]acetic acid | C26H31Cl2N5O4 | 详情 | 详情 |