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【结 构 式】

【分子编号】29589

【品名】(1S,2R,6R,7R,11R,12R)-7-benzyl-12-(benzyloxy)-4,4-dimethyl-3,5-dioxa-8,10-diazatetracyclo[9.2.2.0(1,10).0(2,6)]pentadecan-9-one

【CA登记号】

【 分 子 式 】C27H32N2O4

【 分 子 量 】448.56216

【元素组成】C 72.3% H 7.19% N 6.25% O 14.27%

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:(X)

The chiral bicyclic alcohol (I) was converted to the benzyl ether (II) using benzyl bromide and NaH. Subsequent reduction of the ester group of (III) with LiBH4 provided primary alcohol (III), and further Swern oxidation yielded aldehyde (IV). Pinacol coupling of (IV) with D-phenylalaninal (V) by means of VCl3 - (THF)3 and Zn furnished diol (VI) with 85% diastereoselectivity. This was protected as the acetonide (VIII) upon treatment with 2,2-dimethoxypropane (VII) and camphorsulfonic acid. Selective removal of the two N-benzyloxycarbonyl groups of (VIII) by hydrogenation in the presence of Pd/C and NH3 gave diamine (IX), which was cyclized to the urea (X) employing carbonyldiimidazole and pyridine.

1 Han, W.; Pelletier, J.C.; Hodge, C.N.; Tricyclic ureas: A new class of HIV-1 protease inhibitors. Bioorg Med Chem Lett 1998, 8, 24, 3615.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(I) 29582 7-benzyl 1-(tert-butyl) (1S,3R,4R)-3-hydroxy-7-azabicyclo[2.2.1]heptane-1,7-dicarboxylate C19H25NO5 详情 详情
(II) 29583 7-benzyl 1-(tert-butyl) (1S,3R,4R)-3-(benzyloxy)-7-azabicyclo[2.2.1]heptane-1,7-dicarboxylate C26H31NO5 详情 详情
(III) 29584 benzyl (1S,3R,4R)-3-(benzyloxy)-1-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate C22H25NO4 详情 详情
(IV) 29585 benzyl (1S,3R,4R)-3-(benzyloxy)-1-formyl-7-azabicyclo[2.2.1]heptane-7-carboxylate C22H23NO4 详情 详情
(V) 27884 benzyl (1R)-1-benzyl-2-oxoethylcarbamate C17H17NO3 详情 详情
(VI) 29586 benzyl (1S,3R,4R)-3-(benzyloxy)-1-((1R,2R,3R)-3-[[(benzyloxy)carbonyl]amino]-1,2-dihydroxy-4-phenylbutyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate C39H42N2O7 详情 详情
(VII) 10722 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane 77-76-9 C5H12O2 详情 详情
(VIII) 29587 benzyl (1S,3R,4R)-3-(benzyloxy)-1-[(4R,5R)-5-((1R)-1-[[(benzyloxy)carbonyl]amino]-2-phenylethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-7-azabicyclo[2.2.1]heptane-7-carboxylate C42H46N2O7 详情 详情
(IX) 29588 (1R)-1-[(4R,5R)-5-[(3R,4R)-3-(benzyloxy)-7-azabicyclo[2.2.1]hept-1-yl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenylethylamine; (1R)-1-[(4R,5R)-5-[(3R,4R)-3-(benzyloxy)-7-azabicyclo[2.2.1]hept-1-yl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenyl-1-ethanamine C26H34N2O3 详情 详情
(X) 29589 (1S,2R,6R,7R,11R,12R)-7-benzyl-12-(benzyloxy)-4,4-dimethyl-3,5-dioxa-8,10-diazatetracyclo[9.2.2.0(1,10).0(2,6)]pentadecan-9-one C27H32N2O4 详情 详情

合成路线2

该中间体在本合成路线中的序号:(X)

After N-alkylation of (X) with the protected bromomethylindazole (XI) to give (XII), acid hydrolysis of the acetonide yielded diol (XIII). In order to invert the undesired configuration at C4, the 4-hydroxyl group of (XIII) was selectively oxidized under Swern conditions to produce hydroxyketone (XIV). Subsequent reduction of (XIV) with ethanolic NaBH4 provided the required (4S,5R)-diol (XV). The silylethoxymethyl protecting group was finally removed with tetrabutylammonium fluoride in THF to afford the title compound.

1 Han, W.; Pelletier, J.C.; Hodge, C.N.; Tricyclic ureas: A new class of HIV-1 protease inhibitors. Bioorg Med Chem Lett 1998, 8, 24, 3615.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 29589 (1S,2R,6R,7R,11R,12R)-7-benzyl-12-(benzyloxy)-4,4-dimethyl-3,5-dioxa-8,10-diazatetracyclo[9.2.2.0(1,10).0(2,6)]pentadecan-9-one C27H32N2O4 详情 详情
(XI) 29590 5-(bromomethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazole; [5-(bromomethyl)-1H-indazol-1-yl]methyl 2-(trimethylsilyl)ethyl ether C14H21BrN2OSi 详情 详情
(XII) 29591 (1S,2R,6R,7R,11R,12R)-7-benzyl-12-(benzyloxy)-4,4-dimethyl-8-[(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-5-yl)methyl]-3,5-dioxa-8,10-diazatetracyclo[9.2.2.0(1,10).0(2,6)]pentadecan-9-one C41H52N4O5Si 详情 详情
(XIII) 29592 (1S,2R,3R,4R,8R,9R)-4-benzyl-9-(benzyloxy)-2,3-dihydroxy-5-[(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-5-yl)methyl]-5,7-diazatricyclo[6.2.2.0(1,7)]dodecan-6-one C38H48N4O5Si 详情 详情
(XIV) 29593 (1S,2R,4R,8R,9R)-4-benzyl-9-(benzyloxy)-2-hydroxy-5-[(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-5-yl)methyl]-5,7-diazatricyclo[6.2.2.0(1,7)]dodecane-3,6-dione C38H46N4O5Si 详情 详情
(XV) 29594 (1S,2R,3S,4R,8R,9R)-4-benzyl-9-(benzyloxy)-2,3-dihydroxy-5-[(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-5-yl)methyl]-5,7-diazatricyclo[6.2.2.0(1,7)]dodecan-6-one C38H48N4O5Si 详情 详情
Extended Information