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【结 构 式】

【分子编号】50810

【品名】benzyl (1R)-1-[([(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin

【CA登记号】

【 分 子 式 】C57H84N6O14

【 分 子 量 】1077.326

【元素组成】C 63.55% H 7.86% N 7.8% O 20.79%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(XIV)

Coupling of benzyloxy isovalery propionic acid (Bzl-Hip-OH) (I) with leucine trimethylsilylethyl ester (II) by means of HOBt and DCC followed by hydrogenation over Pd/C in isopropanol for benzyl protecting group removal provides dipeptide (III), which is then converted into compound (V) by first coupling to Boc-Sta(TBDMS)-OH (IV) by means of DMAP and DCC followed by removal of the TMSe group by means of TBAF. Coupling between Z-D-N-MeLeu-OH (VI) and H-Thr-OTMSe (VII) by means of N-hydroxysuccinimide (NHS) and EDC yields protected dipeptide (VIII), which is then condensed with dipeptide (IX) by means of DMAP and DCC and then treated with HCl in EtOAc for Boc removal to afford tetrapeptide (X) (in turn, dipeptide (IX) can be obtained by coupling between Boc-Pro-OH (XI) and Me2Tyr-ONb (XII) by means of EDC followed by p-nitrobenzyl removal by hydrogenation over Pd/C in HOAc). Coupling of tetrapeptide (X) with compound (V) by means of EDC, HOBt leads to formation of linear peptide (XIII), which is partially deprotected by treatment with TBAF and TFA and then cyclized by means of HOBt, EDC and NMM, providing macrolide (XIV).

1 Rinehart, K.L.; et al.; Total synthesis of didemnins A, B, and C. J Am Chem Soc 1987, 109, 22, 6846.
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) 50799 (2S,4S)-4-(benzyloxy)-2,5-dimethyl-3-oxohexanoic acid C15H20O4 详情 详情
(II) 50800 2-(trimethylsilyl)ethyl (2S)-2-amino-4-methylpentanoate C11H25NO2Si 详情 详情
(III) 50801 2-(trimethylsilyl)ethyl (2S)-2-[[(2S,4S)-4-hydroxy-2,5-dimethyl-3-oxohexanoyl]amino]-4-methylpentanoate C19H37NO5Si 详情 详情
(IV) 50802 (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-[[tert-butyl(dimethyl)silyl]oxy]-5-methylheptanoic acid C19H39NO5Si 详情 详情
(V) 50803 (6R,7S,11S,13S,16S)-7-[[tert-butyl(dimethyl)silyl]oxy]-16-isobutyl-11-isopropyl-2,2,13-trimethyl-6-[(1S)-1-methylpropyl]-4,9,12,14-tetraoxo-3,10-dioxa-5,15-diazaheptadecan-17-oic acid C33H62N2O9Si 详情 详情
(VI) 50772 (2R)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoic acid C15H21NO4 详情 详情
(VII) 50804 2-(trimethylsilyl)ethyl (2S,3R)-2-amino-3-hydroxybutanoate C9H21NO3Si 详情 详情
(VIII) 50805 2-(trimethylsilyl)ethyl (2S,3R)-2-([(2R)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoyl]amino)-3-hydroxybutanoate C24H40N2O6Si 详情 详情
(IX) 50806 (2S)-2-[[[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]carbonyl](methyl)amino]-3-(4-methoxyphenyl)propionic acid C21H30N2O6 详情 详情
(X) 50807 2-(trimethylsilyl)ethyl (2S,3R)-2-([(2R)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoyl]amino)-3-[((2S)-3-(4-methoxyphenyl)-2-[methyl[(2S)pyrrolidinylcarbonyl]amino]propanoyl)oxy]butanoate C40H60N4O9Si 详情 详情
(XI) 16734 (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid C10H17NO4 详情 详情
(XII) 50808   C11H14NNbO3 详情 详情
(XIII) 50809 2-(trimethylsilyl)ethyl (2S,3R)-2-([(2R)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoyl]amino)-3-[[(2S)-2-[[((2S)-1-[(2S,5S,7S,11S,12R)-11-[[tert-butyl(dimethyl)silyl]oxy]-2-isobutyl-7-isopropyl-5,16,16-trimethyl-12-[(1S)-1-methylpropyl]-4 C73H120N6O17Si2 详情 详情
(XIV) 50810 benzyl (1R)-1-[([(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin C57H84N6O14 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XIV)

Removal of the Z protecting group of (XIV) by hydrogenation over Pd/C gives secondary amine (XV), which is then condensed with carboxylic acid derivative (XVI) by means of EDC to furnish benzyl-protected didemnin B (XX) (in turn, synthesis of (XVI) can be performed by coupling of O-benzyl lactyl azide (obtained from ethyl O-benzyl lactate (XVII)) with Pro-OMe (XVIII) to afford methyl ester (XIX), followed by saponification of the methyl ester with NaOH). Finally, didemnin B is obtained by hydrogenation of (XX) over Pd/C for benzyl group removal.

1 Rinehart, K.L.; et al.; Total synthesis of didemnins A, B, and C. J Am Chem Soc 1987, 109, 22, 6846.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIV) 50810 benzyl (1R)-1-[([(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin C57H84N6O14 详情 详情
(XV) 50796 (2R)-N-[(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin-7-yl]-4-methyl-2-(methylamino)pentanamide C49H78N6O12 详情 详情
(XVI) 50798 (2S)-1-[(2S)-2-(benzyloxy)propanoyl]-2-pyrrolidinecarboxylic acid C15H19NO4 详情 详情
(XVII) 50812 ethyl (2S)-2-(benzyloxy)propanoate C12H16O3 详情 详情
(XVIII) 29552 methyl (2S)-2-pyrrolidinecarboxylate 2133-40-6 C6H11NO2 详情 详情
(XIX) 50813 methyl (2S)-1-[(2S)-2-(benzyloxy)propanoyl]-2-pyrrolidinecarboxylate C16H21NO4 详情 详情
(XX) 50811 (2S)-N-[(1R)-1-[([(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin-7-yl]amino)carbonyl]-3-methylbutyl]-1-[(2S)-2-(benzyloxy)propanoyl]-N-methyl-2-pyrrolidinecarboxamide C64H95N7O15 详情 详情

合成路线3

该中间体在本合成路线中的序号:(LXI)

N-Benzyloxycarbonyl-N-methyl-D-leucine (LX) was prepared by methylation of the N-protected D-leucine (LIX) with iodomethane in the presence of NaH. Acylation of macrocyclic amine (XXV) with the N-protected aminoacid (LX) furnished the N-carbobenzoxy didemnin A (LXI). The title compound was then obtained by hydrogenolysis of the N-carbobenzoxy group of (LXI), followed by acylation with pyruvyl proline (XXXII) by means of diisopropyl carbodiimide

1 Edge, A. (Diacrin, Inc.); Method for improving graft acceptance in a recipient by administration of a cytokine profile altering agent. WO 0051630 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXV) 50768 (3S,6R,7S,10R,11S,15S,17S,20S,25aS)-7-amino-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]tetradecahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosine-1,4,8,13,16,18,21(17H)-heptone C42H65N5O11 详情 详情
(XXXII) 62542 (2S)-1-pyruvoyl-2-pyrrolidinecarboxylic acid C8H11NO4 详情 详情
(LIX) 22838 (2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoic acid C14H19NO4 详情 详情
(LXI) 50810 benzyl (1R)-1-[([(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin C57H84N6O14 详情 详情
Extended Information