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【结 构 式】

【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%

与该中间体有关的原料药合成路线共 2 条

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
Extended Information