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【结 构 式】 
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【分子编号】32473 【品名】5,5-dimethyl-2,4-imidazolidinedione 【CA登记号】77-71-4 |
【 分 子 式 】C5H8N2O2 【 分 子 量 】128.1308 【元素组成】C 46.87% H 6.29% N 21.86% O 24.97% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of 2-(4-nitrophenyl)ethanol (I) with 5,5-dimethylimidazolidine-2,4-dione (II) by means of PPh3 and DIAD in THF gives 5,5-dimethyl-3-[2-(4-nitrophenyl)ethyl]imidazolidine-2,4-dione (III), which is reduced with H2 over Pd/C in ethanol yielding the 4-aminophenyl derivative (IV). The condensation of (IV) with 2-(3-chloropropyl)malonic acid diethyl ester (V) by means of NaNO2 and NaOAc in water affords the hydrazone (VI), which is isomerized and cyclized in refluxing butanol giving the indolecarboxylic ester (VII). The methylation of the free amino group of (VII) with formaldehyde and NaCNBH3 yields the dimethylamino derivative (VIII), which is transesterified with benzyl alcohol and titanium tetraisopropoxide affording the benzyl ester (IX). The debenzylation of (IX) with H2 over Pd/C gives the free acid (X), which is finally converted into the target amide with benzylamine, TBTU and DIPEA in DMF.
| 【1】 Robertson, A.D.; Dodsworth, S.; Sang, P.Y.; Glen, R.; Moloney, G.P.; Mathews, N.; Martin, G.R.; MacLennan, S.; Knight, C.; A novel series of 2,5-substituted tryptamine derivatives as vascular 5HT(1B/1D) receptor antagonists. J Med Chem 1997, 40, 15, 2347-62. |
| 【2】 Mathews, N.; Martin, G.R.; Moloney, G.P.; et al.; Synthesis and serotonergic activity of substituted 2,N-benzylcarboxamido-5-(2-ethyl-1-dioxoimidazolidinyl)-N,N-dimethyltryptamine derivatives: Novel antagonists for the vascular 5-HT1B-like receptor. J Med Chem 1999, 42, 14, 2504. |
| 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) | 32472 | 2-(4-nitrophenyl)-1-ethanol | 100-27-6 | C8H9NO3 | 详情 | 详情 |
| (II) | 32473 | 5,5-dimethyl-2,4-imidazolidinedione | 77-71-4 | C5H8N2O2 | 详情 | 详情 |
| (III) | 32474 | 5,5-dimethyl-3-(4-nitrophenethyl)-2,4-imidazolidinedione | C13H15N3O4 | 详情 | 详情 | |
| (IV) | 32475 | 3-(4-aminophenethyl)-5,5-dimethyl-2,4-imidazolidinedione | C13H17N3O2 | 详情 | 详情 | |
| (V) | 32476 | diethyl 2-(3-chloropropyl)malonate | 18719-43-2 | C10H17ClO4 | 详情 | 详情 |
| (VI) | 32477 | ethyl 5-chloro-2-((Z)-2-[4-[2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]phenyl]hydrazono)pentanoate | C20H27ClN4O4 | 详情 | 详情 | |
| (VII) | 32478 | ethyl 3-(2-aminoethyl)-5-[2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-1H-indole-2-carboxylate | C20H26N4O4 | 详情 | 详情 | |
| (VIII) | 32479 | ethyl 3-[2-(dimethylamino)ethyl]-5-[2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-1H-indole-2-carboxylate | C22H30N4O4 | 详情 | 详情 | |
| (IX) | 32480 | benzyl 3-[2-(dimethylamino)ethyl]-5-[2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-1H-indole-2-carboxylate | C27H32N4O4 | 详情 | 详情 | |
| (X) | 32481 | 3-[2-(dimethylamino)ethyl]-5-[2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-1H-indole-2-carboxylic acid | C20H26N4O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)Suzuki coupling between 4-methoxyphenylboronic acid (I) and 1-bromo-4-(trifluoromethoxy)benzene (II) gave the biphenyl derivative (III). Methyl ether cleavage in (III) by means of BBr3 provided the biphenyl alcohol (IV), which was condensed with (S)-benzyl glycidyl ether (V) under basic conditions, yielding the chiral glycerol diether (VI). Mitsunobu coupling of alcohol (VI) with the di-Boc-protected hydroxylamine (VII) using DEAD/PPh3 afforded carbamate (VIII). Subsequent catalytic hydrogenolysis of the benzyl ether of (VIII) gave alcohol (IX). Condensation of this alcohol (IX) with 5,5-dimethylhydantoin (X) under Mitsunobu conditions, followed by acidic cleavage of the Boc protecting groups, furnished the hydroxylamine derivative (XI). This was finally N-formylated by treatment with formic acetic anhydride.
| 【1】 Curtin, M.L.; et al.; Discovery and characterization of the potent, selective and orally bioavailable MMP inhibitor ABT-770. Bioorg Med Chem Lett 2001, 11, 12, 1557. |
| 【2】 Dellaria, J.F. Jr.; Gong, J.; Steinman, D.H.; Michaelides, M.R.; Giesler, J.; Davidsen, S.K.; Curtin, M.L.; Florjancic, A.S.; Xu, L.; Guo, Y.; Holms, J.H.; Wada, C.K.; Heyman, H.R. (Abbott Laboratories Inc.); Reverse hydroxamate inhibitors of matrix metalloproteinases. JP 2001523272; WO 9906361 . |
| 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) | 39246 | 4-methoxyphenylboronic acid | 5720-07-0 | C7H9BO3 | 详情 | 详情 |
| (II) | 52466 | 4-Bromophenyl trifluoromethyl ether; 4-(Trifluoromethoxy)bromobenzene; 4-Bromo-(trifluoromethoxy)-benzene; 4-Bromo-alpha,alpha,alpha-trifluoroanisole; 4-Bromotrifluoromethoxybenzene; 1-Bromo-4-(trifluoromethoxy)benzene | 407-14-7 | C7H4BrF3O | 详情 | 详情 |
| (III) | 52467 | 4-(methyloxy)-4'-[(trifluoromethyl)oxy]-1,1'-biphenyl; methyl 4'-[(trifluoromethyl)oxy][1,1'-biphenyl]-4-yl ether | C14H11F3O2 | 详情 | 详情 | |
| (IV) | 52468 | 4'-[(trifluoromethyl)oxy][1,1'-biphenyl]-4-ol | C13H9F3O2 | 详情 | 详情 | |
| (V) | 12350 | Benzyl (2R)oxiranylmethyl ether; (2R)-2-[(Benzyloxy)methyl]oxirane | 14618-80-5 | C10H12O2 | 详情 | 详情 |
| (VI) | 52469 | 1-[(phenylmethyl)oxy]-3-({4'-[(trifluoromethyl)oxy][1,1'-biphenyl]-4-yl}oxy)-2-propanol | C23H21F3O4 | 详情 | 详情 | |
| (VII) | 34722 | 2-[([[(tert-butoxycarbonyl)amino]oxy]carbonyl)oxy]-2-methylpropane | C10H19NO5 | 详情 | 详情 | |
| (VIII) | 52470 | 4-({2-[{[(1,1-dimethylethyl)oxy]carbonyl}({[(1,1-dimethylethyl)oxy]carbonyl}oxy)amino]-3-[(phenylmethyl)oxy]propyl}oxy)-4'-[(trifluoromethyl)oxy]-1,1'-biphenyl | C33H38F3NO8 | 详情 | 详情 | |
| (IX) | 52471 | 4-({2-[{[(1,1-dimethylethyl)oxy]carbonyl}({[(1,1-dimethylethyl)oxy]carbonyl}oxy)amino]-3-hydroxypropyl}oxy)-4'-[(trifluoromethyl)oxy]-1,1'-biphenyl | C26H32F3NO8 | 详情 | 详情 | |
| (X) | 32473 | 5,5-dimethyl-2,4-imidazolidinedione | 77-71-4 | C5H8N2O2 | 详情 | 详情 |
| (XI) | 52472 | 3-[2-(hydroxyamino)-3-({4'-[(trifluoromethyl)oxy][1,1'-biphenyl]-4-yl}oxy)propyl]-5,5-dimethyl-2,4-imidazolidinedione | C21H22F3N3O5 | 详情 | 详情 |