|
【结 构 式】 
|
【分子编号】27228 【品名】benzyl (1R)-1-benzyl-2-hydroxyethylcarbamate 【CA登记号】 |
【 分 子 式 】C17H19NO3 【 分 子 量 】285.3428 【元素组成】C 71.56% H 6.71% N 4.91% O 16.82% |
合成路线1
该中间体在本合成路线中的序号：(I)Swern oxidation of N-(benzyloxycarbonyl)-(R)-phenylalaninol (I) gave aldehyde (II), which was subjected to a vanadium-mediated pinacol coupling to yield diol (III). Protection of the hydroxyl groups of (III) by reaction with [2-(trimethylsilyl)-ethoxy]methyl chloride (SEMCl) (IV) and DIEA in DMF provided trimethylsilyl)ethoxymethyl ether (V), whose N-benzyloxycarbonyl groups were removed by hydrogenolysis over Pd/C to afford diamine (VI). Finally, cyclization of diamine (VI) with carbonyldiimidazole produced the cyclic urea (VII).
| 【3】 Lam, P.Y.; Eyermann, C.J.; Hodge, C.N.; Jadhav, P.K.; DeLucca, G.V. (DuPont Pharmaceuticals Co.); Cyclic ureas and analogues useful as retroviral protease inhibitors. EP 0607334; EP 0686151; EP 0765873; JP 1995500324; JP 1996509700; US 5610294; WO 9307128; WO 9419329 . |
| 【1】 Hodge, C.N.; et al.; Improved cyclic urea inhibitors of the HIV-1 protease: Synthesis, potency, resistance profile, human pharmacokinetics and X-ray crystal structure of DMP 450. Chem Biol 1996, 3, 4, 301. |
| 【2】 Lam, P.Y.S.; et al.; Cyclic HIV protease inhibitors. Synthesis, conformational analysis, P2/P2' structure-activity relationship, and molecular recognition of cyclic ureas. J Med Chem 1996, 39, 18, 3514. |
| 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) | 27884 | benzyl (1R)-1-benzyl-2-oxoethylcarbamate | C17H17NO3 | 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) | 27243 | [2-(chloromethoxy)ethyl](trimethyl)silane | 76513-69-4 | C6H15ClOSi | 详情 | 详情 |
| (V) | 19920 | benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-5-phenyl-2,3-bis[[2-(trimethylsilyl)ethoxy]methoxy]pentylcarbamate | C46H64N2O8Si2 | 详情 | 详情 | |
| (VI) | 19921 | (1R,2S,3S,4R)-4-amino-1-benzyl-5-phenyl-2,3-bis[[2-(trimethylsilyl)ethoxy]methoxy]pentylamine; (2R,3S,4S,5R)-1,6-diphenyl-3,4-bis[[2-(trimethylsilyl)ethoxy]methoxy]-2,5-hexanediamine | C30H52N2O4Si2 | 详情 | 详情 | |
| (VII) | 19922 | (4R,5S,6S,7R)-4,7-dibenzyl-5,6-bis[[2-(trimethylsilyl)ethoxy]methoxy]-1,3-diazepan-2-one | C31H50N2O5Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The synthesis of DMP-851 has been performed as follows: The oxidation of N-(benzyloxycarbonyl)-D-phenylalaninol (I) with NaOCl catalized by 2,2,6,6-tetramethyl-1-piperidinyloxyl 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). 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 affording the free diamine (V). The cyclization of (V) with carbonyldiimidazole (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) [Pierce, M.E. et al. J Org Chem 1996, 61(2): 444]. The methylation of (VIII) with methyl triflate in refluxing dichloroethane affords the cyclic isourea (IX), which is alkylated with butyl iodide/NaH in DMF giving the N-monobutyl derivative (X). A new alkylation of (X) with 3-cyano-4-fluorobenzyl bromide (XI) in refluxing acetonitrile yields the disubstituted cyclic urea (XII), 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. |
| 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) | 27884 | benzyl (1R)-1-benzyl-2-oxoethylcarbamate | C17H17NO3 | 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) | 27885 | (3aS,4R,8R,8aS)-4,8-dibenzyl-5-butyl-2,2-dimethyl-4,5,8,8a-tetrahydro-3aH-[1,3]dioxolo[4,5-e][1,3]diazepin-6-yl methyl ether | C27H36N2O3 | 详情 | 详情 | |
| (XI) | 27225 | 5-(bromomethyl)-2-fluorobenzonitrile | C8H5BrFN | 详情 | 详情 | |
| (XII) | 27886 | 5-[[(3aS,4R,8R,8aS)-4,8-dibenzyl-7-butyl-2,2-dimethyl-6-oxohexahydro-5H-[1,3]dioxolo[4,5-e][1,3]diazepin-5-yl]methyl]-2-fluorobenzonitrile | C34H38FN3O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)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 |