|
【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% |
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 |