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【结 构 式】

【分子编号】62626

【品名】(3aS,4S,5aR,9aR,9bS)-2,2-dimethyloctahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridin-4-yl benzyl ether; (3aS,4S,5aR,9aR,9bS)-4-(benzyloxy)-2,2-dimethyloctahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridine

【CA登记号】

【 分 子 式 】C18H25NO4

【 分 子 量 】319.40084

【元素组成】C 67.69% H 7.89% N 4.39% O 20.04%

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:(XII)

The reaction of benzyl alpha-D-mannopyranoside (I) with Tbdms-Cl and imidazole gives the silyl ether (II), which is treated with 2,2-dimethoxypropane (III) and CSA in dichloromethane to yield the acetonide (IV). The oxidation of the free OH group of (IV) with PCC in dichloromethane affords the ketone (V), which is reduced with NaBH4 to provide benzyl 6-O-(tert-butyldimethylsilyl)-2,3-O-isopropylidene-alpha-D-talopyranoside (VI) with inverted configuration at C4. The reaction of (VI) with Tf2O and pyridine gives the triflate (VII), which is treated with NaN3 in DMF to yield the 4-azido derivative (VIII) with a new inversion of configuration at C4. The reaction of (VIII) with TBAF, followed by oxidation with PCC afforded the carbaldehyde (IX), which is condensed with the phosphorane (X) to provide the unsaturated azidoaldehyde (XI). The treatment of (XI) with H2 over Pd/C in methanol produces the reduction of the double bond, the reduction of the azide group to amine, and subsequent reductive cyclization of the resulting aminoaldehyde to give the perhydropyranopyridine derivative (XII). Further reductive debenzylation of (XII) with H2 over Pd/C in AcOH produces the formation of a lactol in equilibrium with the open chain aminoaldehyde (XIII), which undergoes a reductive amination to form the acetonide of swainsonine (XIV). Finally, this acetonide is decomposed by reaction with TFA to afford the target swainsonine.

1 Bashyal, B.P.; et al.; Synthesis of the alpha-mannosidase inhibitors swainsonine [(1S,2R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizine and 1,4-dideoxy-1,4-imino-D-mannitol from mannose. Tetrahedron 1987, 43, 13, 3083.
2 Fleet, G.W.J.; et al.; Enantiospecific synthesis of swainsonine (1S,2R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizine, from D-mannose. Tetrahedron Lett 1984, 25, 17, 1853.
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) 62617 (2S,3S,4S,5S,6R)-2-(benzyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol C13H18O6 详情 详情
(II) 62618 (2S,3S,4S,5S,6R)-2-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)tetrahydro-2H-pyran-3,4,5-triol C29H36O6Si 详情 详情
(III) 10722 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane 77-76-9 C5H12O2 详情 详情
(IV) 62619 (3aS,4S,6R,7R,7aS)-4-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-ol C32H40O6Si 详情 详情
(V) 62620 (3aS,4S,6R,7aR)-4-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethyldihydro-4H-[1,3]dioxolo[4,5-c]pyran-7(6H)-one C32H38O6Si 详情 详情
(VI) 62621 (3aS,4S,6R,7S,7aS)-4-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-ol C32H40O6Si 详情 详情
(VII) 62622 (3aS,4S,6R,7S,7aR)-4-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl trifluoromethanesulfonate C33H39F3O8SSi 详情 详情
(VIII) 62623 [(3aS,4S,6S,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]methyl tert-butyl(diphenyl)silyl ether; {[(3aS,4S,6S,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]methoxy}(tert-butyl)diphenylsilane C32H39N3O5Si 详情 详情
(IX) 62624 (3aS,4S,6S,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-carbaldehyde C16H19N3O5 详情 详情
(X) 55468 2-(triphenylphosphoranylidene)acetaldehyde C20H17OP 详情 详情
(XI) 62625 (E)-3-[(3aS,4S,6R,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]-2-propenal C18H21N3O5 详情 详情
(XII) 62626 (3aS,4S,5aR,9aR,9bS)-2,2-dimethyloctahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridin-4-yl benzyl ether; (3aS,4S,5aR,9aR,9bS)-4-(benzyloxy)-2,2-dimethyloctahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridine C18H25NO4 详情 详情
(XIII) 62627 (4S,5S)-5-[(2R,3R)-3-hydroxypiperidinyl]-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde C11H19NO4 详情 详情
(XIV) 62616 (3aR,9R,9aR,9bS)-2,2-dimethyloctahydro[1,3]dioxolo[4,5-a]indolizin-9-ol C11H19NO3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XXI)

The reaction of benzyl-alpha-D-mannoside (I) with Ts-Cl in pyridine gives the 6-O-tosylate (II), which is treated with 2,2-dimethoxypropane (III), trimethyl orthoacetate and naphthalenesulfonic acid to yield the acetonide (IV). The silylation of the remaining OH group of (IV) with Tms-Cl and TEA in THF affords the silyl ether (V), which is condensed with allylmagnesium bromide (VI) in ethyl ether to provide the olefinic compound (VII). The desilylation of (VII) by means of TBAF in THF gives the secondary alcohol (VIII); which is oxidized by means of (COCl)2, DMSO and TEA in dichloromethane to yield the ketone derivative (IX). The oxidation of the terminal double bond of (IX) by means of RuO2 and NaIO4 in CCl4/acetonitrile affords the carboxylic acid (X), which is methylated with diazomethane to provide the corresponding methyl ester (XI). Alternatively the propionic ester (XI) can also be obtained by the following sequence: The condensation of the silyl ether (V) with the sodium salt of diethyl malonate (XII) in refluxing toluene gives the malonyl derivative (XIII), which is treated with NaCl at 145 C, yielding the lactone (XIV). The methanolysis of (XIV) with KOH in methanol affords the hydroxyester (XV), which is finally oxidized with PCC in dichloromethane to provide the target ketoester (XI), already reported. The reduction of the carbonyl group of (XI) by means of NaBH4 in ethanol gives the hydroxyester (XVI), which is treated with triflic anhydride and pyridine to yield the corresponding triflate (XVII). The reaction of (XVII) with sodium azide in DMF affords the azido derivative (XVIII), which is reduced with H2 over Pd/C to provide the expected amino derivative (XIX). The cyclization of (XIX) in refluxing toluene gives the lactam (XX), which is finally reduced to the target perhydro-pyrano[3,2-b]pyridine (XXI) intermediate.

1 Bermejo Gonzalez, F.; et al.; Efficient preparation of a valuable intermediate in the synthesis of (-)-swainsonine. Bull Chem Soc Jpn 1992, 65, 2, 567.
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) 62617 (2S,3S,4S,5S,6R)-2-(benzyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol C13H18O6 详情 详情
(II) 62659 [(2R,3S,4S,5S,6S)-6-(benzyloxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl]methyl 4-methylbenzenesulfonate C20H24O8S 详情 详情
(III) 10722 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane 77-76-9 C5H12O2 详情 详情
(IV) 62660 [(3aS,4S,6R,7R,7aS)-4-(benzyloxy)-7-hydroxy-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]methyl 4-methylbenzenesulfonate C23H28O8S 详情 详情
(V) 62661 {(3aS,4S,6R,7R,7aR)-4-(benzyloxy)-2,2-dimethyl-7-[(trimethylsilyl)oxy]tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl}methyl 4-methylbenzenesulfonate C26H36O8SSi 详情 详情
(VI) 61128   C4H8 详情 详情
(VII) 62662 (3aS,4S,6R,7R,7aR)-4-(benzyloxy)-6-(3-butenyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl trimethylsilyl ether; {[(3aS,4S,6R,7R,7aR)-4-(benzyloxy)-6-(3-butenyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl]oxy}(trimethyl)silane C22H34O5Si 详情 详情
(VIII) 62663 (3aS,4S,6R,7R,7aS)-4-(benzyloxy)-6-(3-butenyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-ol C19H26O5 详情 详情
(IX) 62664 (3aS,4S,6R,7aR)-4-(benzyloxy)-6-(3-butenyl)-2,2-dimethyldihydro-4H-[1,3]dioxolo[4,5-c]pyran-7(6H)-one C19H24O5 详情 详情
(X) 62665 3-[(3aS,4S,6R,7aR)-4-(benzyloxy)-2,2-dimethyl-7-oxotetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoic acid C18H22O7 详情 详情
(XI) 62667 methyl 3-[(3aS,4S,6R,7aR)-4-(benzyloxy)-2,2-dimethyl-7-oxotetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoate C19H24O7 详情 详情
(XII) 16336 [2-ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]sodium C7H11NaO4 详情 详情
(XIII) 62666 diethyl 2-({(3aS,4S,6R,7R,7aR)-4-(benzyloxy)-2,2-dimethyl-7-[(trimethylsilyl)oxy]tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl}methyl)malonate C26H40O9Si 详情 详情
(XIV) 62669 (3aS,4S,5aR,9aR,9bR)-4-(benzyloxy)-2,2-dimethylhexahydro[1,3]dioxolo[4,5-d]pyrano[3,2-b]pyran-8(4H)-one C18H22O6 详情 详情
(XV) 62668 methyl 3-[(3aS,4S,6R,7R,7aS)-4-(benzyloxy)-7-hydroxy-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoate C19H26O7 详情 详情
(XVI) 62670 methyl 3-[(3aS,4S,6R,7S,7aS)-4-(benzyloxy)-7-hydroxy-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoate C19H26O7 详情 详情
(XVII) 62671 methyl 3-((3aS,4S,6R,7S,7aR)-4-(benzyloxy)-2,2-dimethyl-7-{[(trifluoromethyl)sulfonyl]oxy}tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl)propanoate C20H25F3O9S 详情 详情
(XVIII) 62672 methyl 3-[(3aS,4S,6R,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoate C19H25N3O6 详情 详情
(XIX) 62673 methyl 3-[(3aS,4S,6R,7R,7aS)-7-amino-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoate C19H27NO6 详情 详情
(XX) 62674 (3aS,4S,5aR,9aR,9bS)-4-(benzyloxy)-2,2-dimethylhexahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridin-8(5aH)-one C18H23NO5 详情 详情
(XXI) 62626 (3aS,4S,5aR,9aR,9bS)-2,2-dimethyloctahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridin-4-yl benzyl ether; (3aS,4S,5aR,9aR,9bS)-4-(benzyloxy)-2,2-dimethyloctahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridine C18H25NO4 详情 详情
Extended Information