-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】(3R,4S,5R,5aS,7R,8R)-3-Benzyl-7-benzyloxy-4,5-dihydroxy-2-(1H-indazol-5-ylmethyl)perhydro-5a,8-ethanopyrrolo[1,2-c][1,3]diazepin-1-one

【CA登记号】

【分子式】C₃₂H₃₄N₄O₄

【分子量】538.65218

【开发单位】Bristol-Myers Squibb (Originator)

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, HIV Protease Inhibitors

合成路线1 合成路线2

合成路线1

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.

参考文献中间体

【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

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.

参考文献中间体

【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	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

Drug NewChemical Entity Original Patent(1)