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【结 构 式】

【药物名称】DMP-850

【化学名称】(4R,5S,6S,7R)-1-(3-Amino-1H-indazol-5-ylmethyl)-3,4,7-tribenzyl-5,6-dihydroxyperhydro-1,3-diazepine-2-one

【CA登记号】

【 分 子 式 】C34H35N5O3

【 分 子 量 】561.68975

【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

The oxidation of N-(benzyloxycarbonyl)-D-phenylalaninol (I) with NaOCl catalized by 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) and NaBr in water gives the corresponding aldehyde (II), which is dimerized by means of the Coulton's reagent (VCl3/Zn/THF) to the pinacol (III)(1). The silylation of (III) with triethylsilyl chloride and imidazole in DMF yields the silylated diol (IV), which is submitted to hydrogenolysis with H2 over Pd/C in toluene to afford the free diamine (V). The cyclization of (V) with carbonyldimidazole (CDI) in toluene followed by desilylation with 1N HCl gives (4R,5S,6S,7R)-4,7-dibenzyl-5,6-dihydroxyperhydro-1,3-diazepin-2-one (VI), which is treated with 2,2-dimethoxypropane (VII) and p-toluenesulfonic acid in DMF yielding the corresponding acetonide (VIII). The methylation of (VIII) with methyl triflate in refluxing dichloroethane affords the cyclic isourea (IX), which is alkylated with 3-cyano-4-fluorobenzyl bromide (X)/NaH in DMF giving the N-monobenzyl derivative (XI). A new alkylation of (XI) with benzyl bromide (XII) in refluxing acetonitrile yields the disubstituted cyclic urea (XIII), which is finally treated with hydrazine in refluxing butanol to generate the indazole ring and treated with HCl in methanol to eliminate the acetonide group.

1 Rodgers, J.D.; Lam, P.Y.S.; Johnson, B.L.; Wang, H.; Li, R.; Ru, Y.; Ko, S.S.; Seitz, S.P.; Trainor, G.L.; Anderson, P.S.; Klabe, R.M.; Bacheler, L.T.; Cordova, B.; Garber, S.; Reid, C.; Wright, M.R.; Chang, C.-H.; Erickson-Viitanen, S.; Design and selection of DMP 850 and DMP 851: The next generation of cyclic urea HIV protease inhibitors. Chem Biol 1998, 5, 10, 597.
2 Pierce, M.E.; et al.; Stereoselective synthesis of HIV-1 protease inhibitor, DMP 323. J Org Chem 1996, 61, 2, 444.
3 Rodgers, J.D.; Sun, J.-H. (DuPont Pharmaceuticals Co.); Method for preparing N-monosubstd. and N,N'-disubstd. unsymmetrical cyclic ureas. AU 96059868; EP 0837855; EP 1029859; US 5532357; WO 9640652 .
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) 27228 benzyl (1R)-1-benzyl-2-hydroxyethylcarbamate C17H19NO3 详情 详情
(II) 27220 benzyl (1R)-1-benzyl-3-oxopropylcarbamate C18H19NO3 详情 详情
(III) 19618 benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-2,3-dihydroxy-5-phenylpentylcarbamate C34H36N2O6 详情 详情
(IV) 27221 benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-5-phenyl-2,3-bis[(triethylsilyl)oxy]pentylcarbamate C46H64N2O6Si2 详情 详情
(V) 27222 (1R,2S,3S,4R)-4-amino-1-benzyl-5-phenyl-2,3-bis[(triethylsilyl)oxy]pentylamine C30H52N2O2Si2 详情 详情
(VI) 27223 (4R,5S,6S,7R)-4,7-dibenzyl-5,6-dihydroxy-1,3-diazepan-2-one C19H22N2O3 详情 详情
(VII) 10722 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane 77-76-9 C5H12O2 详情 详情
(VIII) 27049 (3aS,4R,8R,8aS)-4,8-dibenzyl-2,2-dimethylhexahydro-6H-[1,3]dioxolo[4,5-e][1,3]diazepin-6-one C22H26N2O3 详情 详情
(IX) 27224 (3aS,4R,8R,8aS)-4,8-dibenzyl-2,2-dimethyl-4,5,8,8a-tetrahydro-3aH-[1,3]dioxolo[4,5-e][1,3]diazepin-6-yl methyl ether C23H28N2O3 详情 详情
(X) 27225 5-(bromomethyl)-2-fluorobenzonitrile C8H5BrFN 详情 详情
(XI) 27226 5-[[(3aS,4R,8R,8aS)-4,8-dibenzyl-6-methoxy-2,2-dimethyl-3a,4,8,8a-tetrahydro-5H-[1,3]dioxolo[4,5-e][1,3]diazepin-5-yl]methyl]-2-fluorobenzonitrile C31H32FN3O3 详情 详情
(XII) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(XIII) 27227 5-[[(3aS,4R,8R,8aS)-4,7,8-tribenzyl-2,2-dimethyl-6-oxohexahydro-5H-[1,3]dioxolo[4,5-e][1,3]diazepin-5-yl]methyl]-2-fluorobenzonitrile C37H36FN3O3 详情 详情
Extended Information