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【结 构 式】

【药物名称】LY-450139;Semagacestat

【化学名称】N2-[2(S)-Hydroxy-3-methylbutyryl]-N1-[3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepin-1(S)-yl]-L-alaninamide;2(S)-Hydroxy-3-methyl-N-[1(S)-methyl-2-oxo-2-[2,3,4,5-tetrahydro-3-methyl-2-oxo-1H-3-benzazepin-1(S)-ylamino]ethyl]butyramide

【CA登记号】425386-60-3

【 分 子 式 】C19H27N3O4

【 分 子 量 】361.4354

【开发单位】Eli Lilly and Company (US)

【药理作用】γ-Secretase Inhibitor;Treatment of Alzheimer’s Disease
合成路线1合成路线2

合成路线1

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 .

参考文献 中间体
【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

合成路线2

Amination of 2-phenylethyl bromide (XII) with methylamine in THF gives N-methylphenethylamine (XIII) , which upon N-acylation with chloroacetyl chloride (XIV) in the presence of NaHCO3 in CH2Cl2 or methyl t-butyl ether yields the chloroacetamide derivative (XV) . Cyclization of intermediate (XV) by Friedel-Crafts alkylation by means of AlCl3 in 1,2-dichlorobenzene at 165 °C gives 3-methyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (XVI) . Alternatively, compound (XVI) can be obtained from 2,3,4,5-tetrahydro-1H-3-benzazepin-2-one (XVII) by N-methylation with methyl iodide by means of NaH in DMF . Treatment of lactam (XVI) with isoamyl nitrite (i-AmONO) in the presence of NaHMDS or LiHMDS in THF yields the 1-hydroxyiminobenzazepinone (XVIII), which is finally hydrogenated with H2 over Pd/C in the presence of HCl in EtOH at 50 °C or with H2 over Raney-Ni in the presence of NH3 in EtOH at 100 °C .
Alternatively, phenylacetyl chloride (XIX) is condensed with N-(2,2-dimethoxyethyl)-N-methylamine (XX) by means of NaHCO3 in methyl t-butyl ether/H2O to furnish the phenylacetamide derivative (XXI), which upon cyclization in the presence of H2SO4 at 110 °C affords the benzazepin-2-one derivative (XXII). Treatment of intermediate (XXII) with i-AmONO in the presence of LiHMDS in THF gives the hydroxyimino derivative (XXIII), which is finally hydrogenated with H2 over Pd/C in the presence of HCl in EtOH at 50 °C .

参考文献 中间体
【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.
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
(XII) 20730 1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide 103-63-9 C8H9Br 详情 详情
(XIII) 69316 N-methyl-2-phenylethanamine；N-Phenethylmethylamine;N-methylphenethylamine 589-08-2 C9H13N 详情 详情
(XIV) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(XV) 69317 2-chloro-N-methyl-N-phenethylacetamide C11H14ClNO 详情 详情
(XVI) 69318 3-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one；3-methyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one 73644-95-8 C11H13NO 详情 详情
(XVII) 69319 4,5-Dihydro-1H-benzo[d]azepin-2(3H)-one;1,3,4,5-Tetrahydrobenzo[d]azepin-2-one;1,3,4,5-Tetrahydro-2H-3-benzazepin-2-one;2,3,4,5-tetrahydro-1H-3-benzazepin-2-one 15987-50-5 C10H11NO 详情 详情
(XVIII) 69320 (E)-1-(hydroxyimino)-3-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one C11H12N2O2 详情 详情
(XIX) 25890 2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride 103-80-0 C8H7ClO 详情 详情
(XX) 36650 2,2-dimethoxy-N-methyl-1-ethanamine;1,1-Dimethoxy-2-(methylamino)-ethane;Methylaminoacetaldehyde dimethyl acetal;N-(2,2-dimethoxyethyl)-N-methylamine 122-07-6 C5H13NO2 详情 详情
(XXI) 69321 N-(2,2-dimethoxyethyl)-N-methyl-2-phenylacetamide C13H19NO3 详情 详情
(XXII) 69322 3-methyl-1H-benzo[d]azepin-2(3H)-one C11H11NO 详情 详情
(XXIII) 69323 (E)-1-(hydroxyimino)-3-methyl-1H-benzo[d]azepin-2(3H)-one C11H10N2O2 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(2)