1-amino-3-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one -Drug Synthesis Database

【结构式】

【分子编号】69307

【品名】1-amino-3-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-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 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

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

合成目标

【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

该中间体在本合成路线中的序号：(I)

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

合成目标

【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