4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone; 4-(3',4'-Dichlorophenyl)-1-tetralone -Drug Synthesis Database

【结构式】

【分子编号】30583

【品名】4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone; 4-(3',4'-Dichlorophenyl)-1-tetralone

【CA登记号】79580-19-3

【分子式】C₁₆H₁₂Cl₂O

【分子量】291.17608

【元素组成】C 66% H 4.15% Cl 24.35% O 5.49%

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：(IX)

The Friedel-Kraft's reaction of benzene (I) and 3,4-dichlorobenzoyl chloride (II) by means of AlCl3 in dichloromethane gives 3,4-dichlorobenzophenone (III), which is condensed with diethyl succinate (IV) by means of potassium tert-butoxide in tert-butyl alcohol yielding ethyl 3-ethoxycarbonyl-4-(3,4-dichlorophenyl)-4-phenylbut-3-enoate (V). Hydrolysis of (V) with HBr in refluxing acetic acid affords 4-(3,4-dichlorophenyl)-4-phenylbut-3-enoic acid (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate giving 4-(3,4-dichlorophenyl)-4-phenylbutanoic acid (VII), which is converted into the corresponding acyl chloride (VIII) with refluxing SOCl2. Cyclization of (VIII) with AlCl3 in CS2 yields 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalenone (IX), which is treated with methylamine and TiCl4 in THF affording the corresponding Schiff base (X). Finally, this compound is reduced with H2 over Pd/C in THF.

参考文献中间体

合成目标

【1】 Kraska, A.R.; Welch, W.M. Jr.; Koe, B.K.; Harbert, C.A. (Pfizer Inc.); Antidepressant derivatives of cis-4-phenyl-1,2,3,4-tetrahydro-1-naphtalenamine. EP 0030081; JP 1981086137; US 4536518 .
【2】 Castaner, J.; Serradell, M.N.; Sertraline. Drugs Fut 1984, 9, 4, 277.

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)	13364	Benzene	71-43-2	C₆H₆	详情	详情
(II)	26356	3,4-dichlorobenzoyl chloride	3024-72-4	C₇H₃Cl₃O	详情	详情
(III)	30578	(3,4-dichlorophenyl)(phenyl)methanone	6284-79-3	C₁₃H₈Cl₂O	详情	详情
(IV)	12313	diethyl succinate	123-25-1	C₈H₁₄O₄	详情	详情
(V)	30579	diethyl 2-[(Z)-(3,4-dichlorophenyl)(phenyl)methylidene]succinate		C₂₁H₂₀Cl₂O₄	详情	详情
(VI)	30580	(E)-4-(3,4-dichlorophenyl)-4-phenyl-3-butenoic acid		C₁₆H₁₂Cl₂O₂	详情	详情
(VII)	30581	4-(3,4-dichlorophenyl)-4-phenylbutyric acid		C₁₆H₁₄Cl₂O₂	详情	详情
(VIII)	30582	4-(3,4-dichlorophenyl)-4-phenylbutanoyl chloride		C₁₆H₁₃Cl₃O	详情	详情
(IX)	30583	4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone; 4-(3',4'-Dichlorophenyl)-1-tetralone	79580-19-3	C₁₆H₁₂Cl₂O	详情	详情
(X)	30584	N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]-N-methylamine; N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine		C₁₇H₁₅Cl₂N	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The reaction of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-one (I) with methylamine by means of TiCl4 in toluene gives the corresponding imine (II), which is reduced with H2 over 5% Pd/graphite, yielding a 12:1 mixture of (??(cis)(III) and (?)(trans)(III). This mixture was resolved by a treatment with (D)-mandelic acid, crystallization of the resulting salt, and treatment with NaOH in toluene/water to afford the target (+)(S,S)(cis)-sertraline.

参考文献中间体

合成目标

【1】 Gershon, N.; Nidam, T.; Mendelovich, M.; Pilarsky, G. (Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals USA, Inc.); Novel process for preparing (+)-cis-sertraline. WO 0168566 .

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)	30583	4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone; 4-(3',4'-Dichlorophenyl)-1-tetralone	79580-19-3	C₁₆H₁₂Cl₂O	详情	详情
(II)	30584	N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]-N-methylamine; N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine		C₁₇H₁₅Cl₂N	详情	详情
(III)	58591	N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenyl]-N-methylamine; 4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydro-1-naphthalenamine		C₁₇H₁₇Cl₂N	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

The condensation of 1-naphthol (I) with an excess of o-dichlorobenzene (II) at 100 C by means of anhydrous AlCl3 gives 4-(3,4-dichlorophenyl)-1-tetralone (III), which is allowed to react with N-methylhydroxylamine (IV) and NaOAc in refluxing ethanol, yielding the nitrone (V). The reduction of (V) with H2 over RaNi in methanol affords a racemic cis/trans (9:1) mixture of methylamines, which by crystallization of its hydrochloride in ethanol provides pure (racemic)-(cis)-(VI). Finally, the target (1S)-(cis)-compound is obtained by optical resolution of (VI) with (R)-(-)-mandelic acid.

参考文献中间体

合成目标

【1】 Vukics, K.; et al.; Improved industrial synthesis of antidepressant sertraline. Org Process Res Dev 2002, 6, 1, 82.

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)	22935	alpha-naphthol; 1-naphthol	90-15-3	C₁₀H₈O	详情	详情
(II)	58592	1,2-Dichlorobenzene; chloroben; chloroden; cloroben; Dichloricide; Dichlorobenzol; dilantin db; dilatin db; dizene; dowtherm e; o-Dichlorobenzene; o-Dichlorobenzol; termitkil	95-50-1	C₆H₄Cl₂	详情	详情
(III)	30583	4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone; 4-(3',4'-Dichlorophenyl)-1-tetralone	79580-19-3	C₁₆H₁₂Cl₂O	详情	详情
(IV)	12690	(Hydroxyamino)methane; N-Methylhydroxylamine	593-77-1	CH₅NO	详情	详情
(V)	58593	[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene](methyl)ammoniumolate		C₁₇H₁₅Cl₂NO	详情	详情
(VI)	58594	N-[(1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenyl]-N-methylamine; (1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydro-1-naphthalenamine		C₁₇H₁₇Cl₂N	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

The reaction of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-one (I) with methylamine and formic acid in DMF gives the corresponding methylimine (II), which is reduced with H2 over Pd/C to yield (rac)(cis)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine (rac)(cis)(III). Finally, this compound is submitted to optical resolution by means of mandelic acid to afford the target (1S)(cis)-sertraline.

参考文献中间体

合成目标

【1】 Laitinen, I.; Pietikaeinen, P. (Orion Corporation); Process for the production of sertraline and intermediates useful therefor. US 2003013768 .

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)-(cis)-(III)	58594	N-[(1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenyl]-N-methylamine; (1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydro-1-naphthalenamine		C₁₇H₁₇Cl₂N	详情	详情
(I)	30583	4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone; 4-(3',4'-Dichlorophenyl)-1-tetralone	79580-19-3	C₁₆H₁₂Cl₂O	详情	详情
(II)	30584	N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]-N-methylamine; N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine		C₁₇H₁₅Cl₂N	详情	详情

Extended Information