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【结 构 式】

【分子编号】69308

【品名】1(S)-amino-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one

【CA登记号】

【 分 子 式 】C11H14N2O

【 分 子 量 】190.245

【元素组成】C 69.45% H 7.42% N 14.72% O 8.41%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(II)

Racemic amine (I) can be resolved by the following alternative procedures: An alternative procedure to compound (VII) begins by condensating amine (II) with N-Boc-L-alanine (IV) in the presence of HOBt.H2O, DIEA and EDC in THF to yield the N-Boc-L-alaninamide derivative (IX) . Similarly, the hydrochloride of amine (II) reacts with N-Boc-L-alanine (IV) in the presence of HOBt.H2O, DIEA and EDC in THF . Intermediate (IX) is then deprotected with either HCl in EtOAc or 1,4-dioxane , or concentrated HCl , and the resulting amine (VII) is obtained as the free base or employed without isolation, respectively. Finally, either hydrochloride (VII) or the nonisolated species obtained from compound (IX) is condensed with 2(S)-hydroxy-3-methylbutyric acid (X) by means of HOBt.H2O, NMM and EDC.HCl in H2O to give semagacestat . Under related conditions, the free base of (VII) couples with acid (XI) in the presence of HOBt.H2O, DIEA and EDC in THF . Alternatively, silylation of 2(S)-hydroxy-3-methylbutyric acid (X) with HMDS in the presence of (NH4)2SO4 at reflux gives trimethylsilyl 3-methyl-2(S)-(trimethylsilyloxy) butanoate (XI), which is first reacted with (COCl)2 in the presence of DMF in CH2Cl2 and then with the mesylate salt (VIII) by means of NMM in CH2Cl2 .

1 Koenig, T.M., Nissen, J.S., Mitchell, D. (Eli Lilly and Company). Lactam compound. EP 1345955, JP 2005538031, WO 2002040508.
2 Audia, J.E., John, V., Latimer, L.H., Tung, J.S., Nissen, J.S., Thorsett, E.D., McDaniel, S.L. (Eli Lilly and Company; Elan Pharmaceuticals, Inc.). Lactam compound. JP 2004517090, WO 2002047671.
3 Koenig, T.M., Audia, J.E., Mitchell, D., Aikins, J.A., Buccilli, L.A., Engel,G.L., McDaniel, S.L. (Eli Lilly and Company). Lactam compound. CA 2425497, EP 1353910, JP 2004521084, WO 2002040451.
4 Audia, J.E., Diseroad, B.A., Varghese, J. et al. (Eli Lilly and Company).Lactam compound. US 2007299053, US 7468365.
5 Mitchell, D., Hay, L.A., Koenig, T.M., McDaniel, S., Nissen, J.S., Audia, J.E.Classical and dynamic resolution of 1-amino-3-methyl-1,3,4,5-tetrahydrobenzo[d]azepin-2-one. Tetrahedron Asymmetry 2005, 16(23): 3814-9.
6 Pu, Y.J., Vaid, R.K., Boini, S.K., Towsley, R.W., Doecke, C.W., Mitchell, D. A practical method for functionalized peptide or amide bond formation in aqueous-ethanol media with EDC as activator. Org Process Res Dev 2009, 13(2): 310-4.
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) 69307 1-amino-3-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one C11H14N2O 详情 详情
(II) 69308 1(S)-amino-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one C11H14N2O 详情 详情
(III) 69309 1(S)-amino-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one C11H14N2O 详情 详情
(IV) 26450 Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid 15761-38-3 C8H15NO4 详情 详情
(V) 13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(VI) 69310 (S)-2-((tert-butoxycarbonyl)amino)propanoic (isobutyl carbonic) anhydride C13H23NO6 详情 详情
(VII) 69311 (S)-2-amino-N-((R)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)propanamide hydrochloride C14H19N3O2.HCl 详情 详情
(VIII) 69312 (S)-2-amino-N-((R)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)propanamide methanesulfonate C14H19N3O2.CH4O3S 详情 详情
(IX) 69313 tert-butyl ((S)-1-(((R)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)amino)-1-oxopropan-2-yl)carbamate C19H27N3O4 详情 详情
(X) 69314 2(S)-hydroxy-3-methylbutyric acid C5H10O3 详情 详情
(XI) 69315 (S)-trimethylsilyl 3-methyl-2-((trimethylsilyl)oxy)butanoate C11H26O3Si2 详情 详情
Extended Information