3-(3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one -Drug Synthesis Database

【结构式】

【分子编号】24899

【品名】3-(3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one

【CA登记号】

【分子式】C₁₅H₁₈ClNO₃

【分子量】295.76556

【元素组成】C 60.91% H 6.13% Cl 11.99% N 4.74% O 16.23%

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：(VIII)

The reaction of 3,4-dimethoxyphenylacetic acid (I) with SOCl2 in methylene chloride gives the corresponding acyl chloride (II), which is treated with aminoacetaldehyde dimethylacetal (III) and triethylamine in methylene chloride yielding N-(2,2-diethoxyethyl)-3,4-dimethoxyphenylacetamide (IV). The cyclization of (IV) by means of HCl in acetic acid atfords 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (V), which is alkylated with 1-bromo-3-chloro propane (VI) by means of potassium tert-butoxide in DMSO to give 3-(3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (VII). The reaction of (VII) with N-methyl-2-(3,4-dimethoxyphenyl)ethylamine (VIII) at 100 C affords 7,8-dimethoxy-3-[3-[N-methyl-N-[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]-1,3-dihydro-2H-3-benzazepin-2-one (IX), which is finally hydrogenated with H2 over Pd/C in acetic acid.

参考文献中间体

合成目标

【1】 Reiffen, M.; et al. (Dr. Karl Thomae GmbH); Benzazepines, process for their preparation and their application as pharmaceutical preparations. DE 3119874; EP 0065229; GB 2099425; JP 57193462 .
【2】 Reiffen, M. (Dr. Karl Thomae GmbH); Process for the prepaation of benzazepine derivatives. CA 1207764; DD 215541; DE 3242345 .
【3】 Prous, J.; Castaner, J.; Ul-FS-49. Drugs Fut 1985, 10, 8, 639.

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)	24049	2-(3,4-dimethoxyphenyl)acetic acid	93-40-3	C₁₀H₁₂O₄	详情	详情
(II)	20594	2-(3,4-dimethoxyphenyl)acetyl chloride		C₁₀H₁₁ClO₃	详情	详情
(III)	10331	2,2-Diethoxy-1-ethanamine; 2,2-Diethoxyethylamine; Aminoacetaldehyde diethyl acetal	645-36-3	C₆H₁₅NO₂	详情	详情
(IV)	24284	N-(2,2-diethoxyethyl)-2-(3,4-dimethoxyphenyl)acetamide		C₁₆H₂₅NO₅	详情	详情
(V)	24285	7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one		C₁₂H₁₃NO₃	详情	详情
(VI)	10358	1-Bromo-3-chloropropane	109-70-6	C₃H₆BrCl	详情	详情
(VII)	18398	1-(tert-butyl) 3-ethyl (3R,4R)-4-phenyl-1,3-piperidinedicarboxylate		C₁₉H₂₇NO₄	详情	详情
(VIII)	24899	3-(3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one		C₁₅H₁₈ClNO₃	详情	详情
(IX)	24901	3-[3-[(3,4-dimethoxyphenethyl)(methyl)amino]propyl]-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one		C₂₆H₃₄N₂O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

Reduction of 4,5-dimethoxybenzocyclobutane-1-carbonitrile (I) with BH3 in THF gives 4,5-dimethoxybenzocyclobutan-1-ylmethylamine (II), which is treated with ethyl chloroformate (III) and triethylamine in dichloromethane to yield carbamate (IV). Reduction of carbamate (IV) by means of LiAlH4 in THF provides racemic N-(4,5-dimethoxybenzocyclobutan-1-yl)-N-methylamine (V), which is submitted to optical resolution with camphorsulfonic acid (CSA) to afford the desired (S)-enantiomer (VI). Reaction of the known 3-(3-chloropropyl)-7,8-dimethoxy-2,3-dihydro-1H-3-benzazepin-2-one (VII) with NaI in acetone yields the corresponding 3-iodopropyl derivative (VIII), which is condensed with the chiral amine (VI) by means of K2CO3 in acetone to afford adduct (IX). Finally, this compound is hydrogenated with H2 over Pd(OH)2 in AcOH.

参考文献中间体

合成目标

【2】 Peglion, J.-L.; Vian, J.; Vilaine, J.-P.; Villeneuve, N.; Janiak, P.; Bidouard, J.-P. (ADIR et Cie.); Benzocyclobutyl- or indanyl-alkyl-amino-alkyl substd. 3-benzazepin-2-ones useful in the treatment of cardiovascular diseases. EP 0534859; FR 2681862; JP 1993213890; US 5296482 .
【1】 Sorbera, L.A.; Castaner, J.; Ivabradine Hydrochloride. Drugs Fut 2003, 28, 7, 652.

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)	62954	3,4-bis(methyloxy)bicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile		C₁₁H₁₁NO₂	详情	详情
(II)	62955	[3,4-bis(methyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-yl]methanamine; [3,4-bis(methyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-yl]methylamine		C₁₁H₁₅NO₂	详情	详情
(III)	11229	1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate	541-41-3	C₃H₅ClO₂	详情	详情
(IV)	62956	ethyl [3,4-bis(methyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-yl]methylcarbamate		C₁₄H₁₉NO₄	详情	详情
(V)	62957	N-{[3,4-bis(methyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-N-methylamine; [3,4-bis(methyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine		C₁₂H₁₇NO₂	详情	详情
(VI)	62958	N-{[3,4-bis(methyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-N-methylamine; [3,4-bis(methyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine		C₁₂H₁₇NO₂	详情	详情
(VII)	24899	3-(3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one		C₁₅H₁₈ClNO₃	详情	详情
(VIII)	62959	3-(3-iodopropyl)-7,8-bis(methyloxy)-1,3-dihydro-2H-3-benzazepin-2-one		C₁₅H₁₈INO₃	详情	详情
(IX)	62960	3-{3-[{[3,4-bis(methyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino]propyl}-7,8-bis(methyloxy)-1,3-dihydro-2H-3-benzazepin-2-one		C₂₇H₃₄N₂O₅	详情	详情

Extended Information