2-bromo-3,4-dihydro-1(2H)-naphthalenone -Drug Synthesis Database

【结构式】

【分子编号】20721

【品名】2-bromo-3,4-dihydro-1(2H)-naphthalenone

【CA登记号】

【分子式】C₁₀H₉BrO

【分子量】225.08486

【元素组成】C 53.36% H 4.03% Br 35.5% O 7.11%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(V)

A new synthesis of CGS-14824A is given: The reaction of 3-bromo-1-phenylpropane (I) with KCN gives 4-phenylbutyronitrile (II), which is hydrolyzed to the corresponding butyric acid (III). The cyclization of (III) with polyphosphoric acid affords 1-tetralone (IV), which is brominated to 2-bromo-1-tetralone (V) and treated with hydroxylamine to give the oxime (VI). The Beckman rearrangement of (VI) yields 3-bromo-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is treated with sodium azide to afford the azide derivative (VIII). The N-alkylation of (VIII) with ethyl bromoacetate (IX) by means of KOH and tetrabutylammonium bromide in THF gives the N-alkylated azide (X), which is reduced by catalytic hydrogenation to the corresponding amine (XI). The hydrolysis of the ester group of (XI) with NaOH yields the free acetic acid derivative (XII), which is finally reductocondensed with ethyl 2-oxo-4-phenylbutyrate (XIII) by means of sodium cyanoborohydride.

参考文献中间体

合成目标

【1】 Chaudhuri, N.K.; Patera, R.; Markus, B.; Sung, M.-S.; Synthesis of 14C-labeled 3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid hydrochloride ([14C]CGS 14824A). J Label Compd Radiopharm 1987, 24, 10, 1177-84.

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)	20884	1-(3-bromopropyl)benzene	637-59-2	C₉H₁₁Br	详情	详情
(II)	20885	4-phenylbutanenitrile	2046-18-6	C₁₀H₁₁N	详情	详情
(III)	20886	Benzenebutyric acid; 4-Phenylbutyric acid	1821-12-1	C₁₀H₁₂O₂	详情	详情
(IV)	20720	3,4-dihydro-1(2H)-naphthalenone	529-34-0	C₁₀H₁₀O	详情	详情
(V)	20721	2-bromo-3,4-dihydro-1(2H)-naphthalenone		C₁₀H₉BrO	详情	详情
(VI)	20722	2-bromo-3,4-dihydro-1(2H)-naphthalenone oxime		C₁₀H₁₀BrNO	详情	详情
(VII)	20723	3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one		C₁₀H₁₀BrNO	详情	详情
(VIII)	20891	3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one		C₁₀H₁₀N₄O	详情	详情
(IX)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(X)	20893	ethyl 2-(3-azido-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate		C₁₄H₁₆N₄O₃	详情	详情
(XI)	20894	ethyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate	109010-60-8	C₁₄H₁₈N₂O₃	详情	详情
(XII)	20895	2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetic acid		C₁₂H₁₄N₂O₃	详情	详情
(XIII)	20896	Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester	64920-29-2	C₁₂H₁₄O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

The condensation of N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylamine (I) with 2-bromo-1-tetralone (II) by means of K2CO3 in DMF gives the tertiary amine (III), which is reduced with NaBH4 in ethanol to the hydroxyamine (IV). The cyclization of (IV) by means of methanesulfonic acid yields a mixture of cis and trans tetracyclic compounds that is separated by chromatography. The desired trans isomer (V) is monodemethylated by means of EtS-Na in DMF affording a mixture of 11-methoxy,12-hydroxy and 12-methoxy-11-hydroxy compounds that is separated by crystallization. The desired 12-methoxy-11-hydroxy compound (VI) is dehydroxylated by means of 5-chloro-1-phenyltetrazole (CPT) and NaH in hot DMF giving the 12-methoxy compound (VII), which is chlorinated with SO2Cl2 in dichloromethane to afford the racemic 11-chloro-12-methoxy compound rac-(VIII). Optical resolution of rac-(VIII) with (+)-di-p-toluoyl-D-tartaric acid [(+)-DPT] gives (-)(6aS,13bR)(VIII), which is finally demethylated to the target compound with 48% HBr in refluxing acetic acid.

参考文献中间体

合成目标

【1】 Berger, J.G.; et al.; Synthesis and receptor affinities of some conformationally restricted analogues of the dopamine D1 selective ligand (5R)-8-chloro-2,3,4, 5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol. J Med Chem 1989, 32, 8, 1913-21.

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)	18938	2-(3,4-dimethoxyphenyl)-N-methyl-1-ethanamine; N-(3,4-dimethoxyphenethyl)-N-methylamine	3490-06-0	C₁₁H₁₇NO₂	详情	详情
(II)	20721	2-bromo-3,4-dihydro-1(2H)-naphthalenone		C₁₀H₉BrO	详情	详情
(III)	36619	2-[(3,4-dimethoxyphenethyl)(methyl)amino]-3,4-dihydro-1(2H)-naphthalenone		C₂₁H₂₅NO₃	详情	详情
(IV)	36620	2-[(3,4-dimethoxyphenethyl)(methyl)amino]-1,2,3,4-tetrahydro-1-naphthalenol		C₂₁H₂₇NO₃	详情	详情
(V)	36621	(3aS,9bR)-11-methoxy-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepin-12-yl methyl ether; (3aS,9bR)-11,12-dimethoxy-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepine		C₂₁H₂₅NO₂	详情	详情
(VI)	36622	(3aS,9bR)-11-methoxy-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepin-12-ol		C₂₀H₂₃NO₂	详情	详情
(VII)	36623	(3aS,9bR)-11-methoxy-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepine; (3aS,9bR)-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepin-11-yl methyl ether		C₂₀H₂₃NO	详情	详情
(VIII)	31779	(3aS,9bR)-12-chloro-11-methoxy-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepine; (3aS,9bR)-12-chloro-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepin-11-yl methyl ether		C₂₀H₂₂ClNO	详情	详情

合成路线3

该中间体在本合成路线中的序号：(V)

2) The chiral intermediates the amine (I) and the acid (II) have been obtained as follows: 2a) The bromination of 1-tetralone (IV) with Br2 in methanol gives the 2-bromotetralone (V), which is treated with hydroxylamine yielding the corresponding oximae (VI). The isomerization of (V) with polyphosphoric acid (PPA) at 80 C affords the benzazepinone (VII), which is treated with potassium phthalimide (VIII) in DMF to give the corresponding phthalimido derivative (IX). The reaction of (IX) with tert-butyl bromoacetate (X) by means of potassium tert-butoxide in DMF yields the benzazepinoacetic ester (XI), which is treated with hot ethanolamine to eliminate the phthalimido group yielding racemic (I). Finally, this racemate is submitted to optical resolution with L-(+)-tartaric acid to afford the chiral (S)-intermediate (I).

参考文献中间体

合成目标

【1】 Waldeck, H.; Höltje, D.; Messinger, J.; Antel, J.; Wurl, M.; Thormählen, D. (Kali-Chemie AG); Benzazepin-, benzoxazepin- and benzothiazepin-N-acetic acid-derivs., their preparation and their pharmaceutical compsns.. CA 2172354; EP 0733642; JP 1996269011; US 5677297 .
【2】 Rozsa, S.; Gy Papp, J.; Thormahlen, D.; Waldeck, H. (Solvay SA); Drugs for increasing gastrointestinal blood supply. DE 19638020; EP 0830863; JP 1998101565 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
rac-(I)	20728	tert-butyl 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate		C₁₆H₂₂N₂O₃	详情	详情
(I)	20717	tert-butyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate		C₁₆H₂₂N₂O₃	详情	详情
(IV)	20720	3,4-dihydro-1(2H)-naphthalenone	529-34-0	C₁₀H₁₀O	详情	详情
(V)	20721	2-bromo-3,4-dihydro-1(2H)-naphthalenone		C₁₀H₉BrO	详情	详情
(VI)	20722	2-bromo-3,4-dihydro-1(2H)-naphthalenone oxime		C₁₀H₁₀BrNO	详情	详情
(VII)	20723	3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one		C₁₀H₁₀BrNO	详情	详情
(VIII)	10926	(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium		C₈H₄KNO₂	详情	详情
(IX)	20725	2-(2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-1H-isoindole-1,3(2H)-dione		C₁₈H₁₄N₂O₃	详情	详情
(X)	17430	2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate	5292-43-3	C₆H₁₁BrO₂	详情	详情
(XI)	20727	tert-butyl 2-[3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate		C₂₅H₂₆N₂O₅	详情	详情

合成路线4

该中间体在本合成路线中的序号：(V)

2a) The chiral intermediate amine (I) has been obtained as follows: The bromination of 1-tetralone (IV) with Br2 in methanol gives the 2-bromotetralone (V), which is treated with hydroxylamine yielding the corresponding oximae (VI). The isomerization of (V) with polyphosphoric acid (PPA) at 80 C affords the benzazepinone (VII), which is treated with potassium phthalimide (VIII) in DMF to give the corresponding phthalimido derivative (IX). The reaction of (IX) with tert-butyl bromoacetate (X) by means of potassium tert-butoxide in DMF yields the benzazepinoacetic ester (XI), which is treated with hot ethanolamine to eliminate the phthalimido group yielding racemic (I). Finally, this racemate is submitted to optical resolution with L-(+)-tartaric acid to afford the chiral (S)-intermediate (I).

参考文献中间体

合成目标

【1】 Sorbera, L.A.; Leeson, P.A.; Castañer, J.; SLV-306. Drugs Fut 2002, 27, 1, 27.
【2】 Waldeck, H.; Höltje, D.; Messinger, J.; Antel, J.; Wurl, M.; Thormählen, D. (Kali-Chemie AG); Benzazepin-, benzoxazepin- and benzothiazepin-N-acetic acid-derivs., their preparation and their pharmaceutical compsns.. CA 2172354; EP 0733642; JP 1996269011; US 5677297 .
【3】 Rozsa, S.; Gy Papp, J.; Thormahlen, D.; Waldeck, H. (Solvay SA); Drugs for increasing gastrointestinal blood supply. DE 19638020; EP 0830863; JP 1998101565 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
rac-(I)	20728	tert-butyl 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate		C₁₆H₂₂N₂O₃	详情	详情
(I)	20717	tert-butyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate		C₁₆H₂₂N₂O₃	详情	详情
(IV)	20720	3,4-dihydro-1(2H)-naphthalenone	529-34-0	C₁₀H₁₀O	详情	详情
(V)	20721	2-bromo-3,4-dihydro-1(2H)-naphthalenone		C₁₀H₉BrO	详情	详情
(VI)	20722	2-bromo-3,4-dihydro-1(2H)-naphthalenone oxime		C₁₀H₁₀BrNO	详情	详情
(VII)	20723	3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one		C₁₀H₁₀BrNO	详情	详情
(VIII)	10926	(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium		C₈H₄KNO₂	详情	详情
(IX)	20725	2-(2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-1H-isoindole-1,3(2H)-dione		C₁₈H₁₄N₂O₃	详情	详情
(X)	17430	2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate	5292-43-3	C₆H₁₁BrO₂	详情	详情
(XI)	20727	tert-butyl 2-[3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate		C₂₅H₂₆N₂O₅	详情	详情

Extended Information