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【结 构 式】

【分子编号】10770

【品名】(5aR,6S,7S,8R,9S,9aR,10aR)-6,8-bis[[(benzyloxy)carbonyl](methyl)amino]-2-[(E)-2-(dimethylamino)ethenyl]-7,9-dihydroxy-4-oxo-5a,6,7,8,9,9a-hexahydro-4H-pyrano[2,3-b][1,4]benzodioxin-4(10aH)-yl acetate

【CA登记号】

【 分 子 式 】C35H41N3O12

【 分 子 量 】695.72356

【元素组成】C 60.42% H 5.94% N 6.04% O 27.6%

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)

1) The condensation of N,N'-di(benzyloxycarbonyl)actinamine (I) with the L-glucose nitrosodimer (II) in DMF gives the oxime adduct (III), which is cyclized by means of aqueous HCl yielding the hemiketal triacetate (IV). The treatment of (IV) with anhydrous KHCO3 in acetonitrile affords the enone acetate (V), which is deacetylated with K2HPO4 in methanol to give N,N'-di(benzyloxycarbonyl)dehydrospectinomycin (VI). The hydrogenation of (VI) with H2 over Pd/BaSO4 in pyridine - isopropanol yields free spectinomycin (VII), which is protected again with benzyloxycarbonyl chloride as usual to give N,N'-di(benzyloxycarbonyl)spectinomycin (VIII). The formylation of (VIII) with formic acid - acetic anhydride gives the 2,6-di-O-formyl derivative (IX), which by treatment with acetic anhydride and dimethylaminopyridine (DMAP) is converted into the enol acetate (X). The reaction of (X) with dibromodimethylhydantoin (DBMH) in refluxing CCl4 under visible light illumination affords the unsaturated ketone (XI), which is treated with dimethylformamide dimethyl acetal in hot DMF, yielding the dimethylaminovinylene compound (XII).

1 White, D.R.; Mizsak, S.A.; Birkenmeyer, R.D.; Thomas, R.C.; Wiley, V.H.; The stereospecific synthesis of spectinomycin. Tetrahedron Lett 1979, 30, 2737-40.
2 White, D.R. (Pharmacia Corp.); 6'-Alkylspectinomycins. DE 3308196; US 4532336 .
3 Cain, G.A.; White, D.R.; The synthesis of trospectomycin (6'-n-propylspectinomycin, U-63,366F). Tetrahedron Lett 1989, 30, 12, 1469-72.
4 White, D.R.; Maring, C.J.; Cain, G.A.; Synthesis and in vitro antibacterial properties of alkylspectinomycin analogs. J Antibiot 1983, 36, 3, 339-42.
5 Castaner, J.; Patoia, L.; Trospectomycin Sulfate. Drugs Fut 1991, 16, 4, 323.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11984 N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine; Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal 4637-24-5 C5H13NO2 详情 详情
(I) 10759 (1R,3S,4R,6S)-3-[Carboxy(methyl)amino]-2,4,5,6-tetrahydroxycyclohexyl(methyl)carbamic acid C10H18N2O8 详情 详情
(II) 10760 (2S,3R,4S,5S,6S)-3-(acetoxy)-2-[(acetoxy)methyl]-5-[[[[(2S,3S,4S,5R,6S)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-2-chlorotetrahydro-2H-pyran-3-yl](oxo)-lambda(5)-azanylidene]methylene](oxo)-lambda(5)-azanyl]-6-chlorotetrahydro-2H-pyran-4-yl acetate C25H32Cl2N2O16 详情 详情
(III) 10761 (2S,3S,4S,6R)-3-(acetoxy)-2-[(acetoxy)methyl]-6-([(2R,3S,5R,6S)-3,5-bis[[(benzyloxy)carbonyl](methyl)amino]-2,4,6-trihydroxycyclohexyl]oxy)-5-(hydroxyimino)tetrahydro-2H-pyran-4-yl acetate C36H45N3O16 详情 详情
(IV) 10762 (2S,3S,4R,4aS,5aS,6R,7R,8S,9R,9aS,10aR)-3-(acetoxy)-2-[(acetoxy)methyl]-6,8-bis[[(benzyloxy)carbonyl](methyl)amino]-4a,7,9-trihydroxydecahydro-2H-pyrano[2,3-b][1,4]benzodioxin-4-yl acetate C36H44N2O16 详情 详情
(V) 10763 (5aR,6S,7S,8R,9S,9aR,10aR)-6,8-bis[[(benzyloxy)carbonyl](methyl)amino]-7,9-dihydroxy-2-methyl-4-oxo-5a,6,7,8,9,9a-hexahydro-4H-pyrano[2,3-b][1,4]benzodioxin-4(10aH)-yl acetate C32H36N2O12 详情 详情
(VI) 10764 benzyl (4aR,5aR,6S,7S,8R,9S,9aR,10aR)-6-[[(benzyloxy)carbonyl](methyl)amino]-4a,7,9-trihydroxy-2-methyl-4-oxo-4a,5a,6,7,8,9,9a,10a-octahydro-4H-pyrano[2,3-b][1,4]benzodioxin-8-yl(methyl)carbamate C30H34N2O11 详情 详情
(VII) 10765 (2R,4aR,5aR,6S,7S,8R,9S,9aR,10aS)-4a,7,9-Trihydroxy-2-methyl-6,8-bis(methylamino)decahydro-4H-pyrano[2,3-b][1,4]benzodioxin-4-one C14H24N2O7 详情 详情
(VIII) 10766 benzyl (2R,4aR,5aR,6S,7S,8R,9S,9aR,10aS)-6-[[(benzyloxy)carbonyl](methyl)amino]-4a,7,9-trihydroxy-2-methyl-4-oxodecahydro-2H-pyrano[2,3-b][1,4]benzodioxin-8-yl(methyl)carbamate C30H36N2O11 详情 详情
(IX) 10767 benzyl (2R,4aR,5aR,6R,7R,8R,9S,9aS,10aS)-6-[[(benzyloxy)carbonyl](methyl)amino]-7,9-bis(formyloxy)-4a-hydroxy-2-methyl-4-oxodecahydro-2H-pyrano[2,3-b][1,4]benzodioxin-8-yl(methyl)carbamate C32H36N2O13 详情 详情
(X) 10768 (2R,4aS,5aR,6R,7R,8R,9S,9aS,10aS)-6,8-bis[[(benzyloxy)carbonyl](methyl)amino]-7,9-bis(formyloxy)-4a-hydroxy-2-methyl-4a,5a,6,7,8,9,9a,10a-octahydro-2H-pyrano[2,3-b][1,4]benzodioxin-4-yl acetate C34H38N2O14 详情 详情
(XI) 10769 (5aR,6R,7R,8R,9S,9aS,10aR)-6,8-bis[[(benzyloxy)carbonyl](methyl)amino]-7,9-bis(formyloxy)-2-methyl-4-oxo-5a,6,7,8,9,9a-hexahydro-4H-pyrano[2,3-b][1,4]benzodioxin-4(10aH)-yl acetate C34H36N2O14 详情 详情
(XII) 10770 (5aR,6S,7S,8R,9S,9aR,10aR)-6,8-bis[[(benzyloxy)carbonyl](methyl)amino]-2-[(E)-2-(dimethylamino)ethenyl]-7,9-dihydroxy-4-oxo-5a,6,7,8,9,9a-hexahydro-4H-pyrano[2,3-b][1,4]benzodioxin-4(10aH)-yl acetate C35H41N3O12 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XII)

Reduction of (XII) with sodium cyanoborohydride in methanolic HCl gives the 2-dimethylaminoethyl compound (XIII), which is treated with m-chloroperbenzoic acid in ethylacetate - Skellysolve B to afford the vinyl derivative (XIV). The reaction of (XIV) with ethylmagnesium bromide and CuBr2 in THF affords the protected propyl-dehydrospectinomycin (XV), which is hydrogenated with lithium tri-sec-butyl borohydride in THF to afford the propyl-spectinomycin (XVI). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in methanol. 2) The silylation of the dimethylaminovinylene compound (XII) with trimethylsilylchloride and hexamethyldisilazane in THF gives the silylated compound (XVII), which is treated with ethylmagnesium bromide to yield the 1-butenyl derivative (XVIII). The elimination of the silyl groups of (XVIII) with HF in acetonitrile affords N,N'-di(benzyloxycarbonyl)tetradehydrotrospectomycin (XIX), which is then hydrogenated with H2 over Pd/BaSO4 as before.

1 White, D.R.; Mizsak, S.A.; Birkenmeyer, R.D.; Thomas, R.C.; Wiley, V.H.; The stereospecific synthesis of spectinomycin. Tetrahedron Lett 1979, 30, 2737-40.
2 White, D.R. (Pharmacia Corp.); 6'-Alkylspectinomycins. DE 3308196; US 4532336 .
3 Cain, G.A.; White, D.R.; The synthesis of trospectomycin (6'-n-propylspectinomycin, U-63,366F). Tetrahedron Lett 1989, 30, 12, 1469-72.
4 White, D.R.; Maring, C.J.; Cain, G.A.; Synthesis and in vitro antibacterial properties of alkylspectinomycin analogs. J Antibiot 1983, 36, 3, 339-42.
5 Castaner, J.; Patoia, L.; Trospectomycin Sulfate. Drugs Fut 1991, 16, 4, 323.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 10770 (5aR,6S,7S,8R,9S,9aR,10aR)-6,8-bis[[(benzyloxy)carbonyl](methyl)amino]-2-[(E)-2-(dimethylamino)ethenyl]-7,9-dihydroxy-4-oxo-5a,6,7,8,9,9a-hexahydro-4H-pyrano[2,3-b][1,4]benzodioxin-4(10aH)-yl acetate C35H41N3O12 详情 详情
(XIII) 10771 (5aR,6S,7S,8R,9S,9aR,10aR)-6,8-bis[[(benzyloxy)carbonyl](methyl)amino]-2-[2-(dimethylamino)ethyl]-7,9-dihydroxy-4-oxo-5a,6,7,8,9,9a-hexahydro-4H-pyrano[2,3-b][1,4]benzodioxin-4(10aH)-yl acetate C35H43N3O12 详情 详情
(XIV) 10772 (5aR,6S,7S,8R,9S,9aR,10aR)-6,8-bis[[(benzyloxy)carbonyl](methyl)amino]-7,9-dihydroxy-4-oxo-2-vinyl-5a,6,7,8,9,9a-hexahydro-4H-pyrano[2,3-b][1,4]benzodioxin-4(10aH)-yl acetate C33H36N2O12 详情 详情
(XV) 10773 (5aR,6S,7S,8R,9S,9aR,10aR)-6,8-bis[[(benzyloxy)carbonyl](methyl)amino]-2-butyl-7,9-dihydroxy-4-oxo-5a,6,7,8,9,9a-hexahydro-4H-pyrano[2,3-b][1,4]benzodioxin-4(10aH)-yl acetate C35H42N2O12 详情 详情
(XVI) 10774 benzyl (2R,4aR,5aR,6S,7S,8R,9S,9aR,10aS)-6-[[(benzyloxy)carbonyl](methyl)amino]-2-butyl-4a,7,9-trihydroxy-4-oxodecahydro-2H-pyrano[2,3-b][1,4]benzodioxin-8-yl(methyl)carbamate C33H42N2O11 详情 详情
(XVII) 10775 (5aR,6S,7S,8R,9S,9aR,10aR)-6,8-bis[[(benzyloxy)carbonyl](methyl)amino]-2-[(E)-2-(dimethylamino)ethenyl]-4-oxo-7,9-bis[(trimethylsilyl)methyl]-5a,6,7,8,9,9a-hexahydro-4H-pyrano[2,3-b][1,4]benzodioxin-4(10aH)-yl acetate C43H61N3O10Si2 详情 详情
(XVIII) 10776 benzyl (4aR,5aR,6S,7S,8R,9S,9aR,10aR)-6-[[(benzyloxy)carbonyl](methyl)amino]-2-[(E)-1-butenyl]-4a-hydroxy-4-oxo-7,9-bis[(trimethylsilyl)methyl]-4a,5a,6,7,8,9,9a,10a-octahydro-4H-pyrano[2,3-b][1,4]benzodioxin-8-yl(methyl)carbamate C38H50N2O9Si 详情 详情
(XIX) 10777 benzyl (4aR,5aR,6S,7S,8R,9S,9aR,10aR)-6-[[(benzyloxy)carbonyl](methyl)amino]-2-[(E)-1-butenyl]-4a,7,9-trihydroxy-4-oxo-4a,5a,6,7,8,9,9a,10a-octahydro-4H-pyrano[2,3-b][1,4]benzodioxin-8-yl(methyl)carbamate C33H38N2O11 详情 详情
Extended Information