1,3-Benzodioxol-5-amine; 1,3-Benzodioxol-5-ylamine.; 3,4-(Methylenedioxy)aniline -Drug Synthesis Database

【结构式】

【分子编号】10984

【品名】1,3-Benzodioxol-5-amine; 1,3-Benzodioxol-5-ylamine.; 3,4-(Methylenedioxy)aniline

【CA登记号】14268-66-7

【分子式】C₇H₇NO₂

【分子量】137.13812

【元素组成】C 61.31% H 5.14% N 10.21% O 23.33%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(IV)

A synthesis of [14C]-paroxetine labeled at the methylenedioxy group has been described: 4-Nitropyrocatechol (I) is cyclized with [14C]-CH2Br2 by means of cesium carbonate in DMSO, giving 3,4-(methylenedioxy)nitrobenzene (III). The reduction of (III) with H2 over Pd/C in ethanol yields the corresponding aniline (IV), which is treated with HNO2, copper nitrite and cuprous oxide to afford the corresponding phenol (V). The condensation of (V) with (3S,4R)-4-(4-fluorophenyl)-1-methyl-3-(phenylsulfonyloxymethyl)piperidine (VI) by means of sodium methoxide in methanol gives [14C]-labeled 1-methylparoxetine (VII), which is finally demethylated with vinyl chloroformate and potassium carbonate in dichloroethane.

参考文献中间体

合成目标

【1】 Lawrie, K.W.M.; Rustidge, D.C.; The synthesis of [methylene-14C]paroxetine BRL 29060A. J Label Compd Radiopharm 1993, 33, 8, 777.

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)	10982	4-Nitrocatechol; 4-Nitro-1,2-benzenediol; 1,2-Dihydroxy-4-nitrobenzene	3316-09-4	C₆H₅NO₄	详情	详情
(III)	10983	1,2-(Methylenedioxy)-4-nitrobenzene; 5-Nitro-1,3-benzodioxole	2620-44-2	C₇H₅NO₄	详情	详情
(III)	45030	5-nitro-1,3-benzodioxole		C₇H₅NO₄	详情	详情
(IV)	10984	1,3-Benzodioxol-5-amine; 1,3-Benzodioxol-5-ylamine.; 3,4-(Methylenedioxy)aniline	14268-66-7	C₇H₇NO₂	详情	详情
(IV)	45031	1,3-benzodioxol-5-amine; 1,3-benzodioxol-5-ylamine		C₇H₇NO₂	详情	详情
(V)	10985	1,3-Benzodioxol-5-ol; Sesamol	533-31-3	C₇H₆O₃	详情	详情
(V)	45032	1,3-benzodioxol-5-ol		C₇H₆O₃	详情	详情
(VI)	10986	[(3S,4R)-4-(4-fluorophenyl)-1-methylhexahydro-3-pyridinyl]methyl benzenesulfonate		C₁₉H₂₂FNO₃S	详情	详情
(VII)	10987	(3S,4R)-3-[(1,3-Benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-methylhexahydropyridine; 1,3-Benzodioxol-5-yl [(3S,4R)-4-(4-fluorophenyl)-1-methylhexahydro-3-pyridinyl]methyl ether		C₂₀H₂₂FNO₃	详情	详情
(VII)	45033	1,3-benzodioxol-5-yl [(3S,4R)-4-(4-fluorophenyl)-1-methylpiperidinyl]methyl ether; (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-methylpiperidine		C₂₀H₂₂FNO₃	详情	详情
(VIII)	10988	(3S,4R)-3-[(1,3-Benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)hexahydropyridine; 1,3-Benzodioxol-5-yl [(3S,4R)-4-(4-fluorophenyl)hexahydro-3-pyridinyl]methyl ether		C₁₉H₂₀FNO₃	详情	详情
(VIII)	45039	(3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine; 1,3-benzodioxol-5-yl [(3S,4R)-4-(4-fluorophenyl)piperidinyl]methyl ether		C₁₉H₂₀FNO₃	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 diazonium salt prepared from 3,4-methylenedioxyaniline (I) was coupled to methyl acrylate (II) in the presence of Cu2O and HBr to produce the 2-bromo-3-phenylpropionic ester (III). Subsequent displacement of the bromo group of (III) by alpha-mercaptopropionic acid (IV) gave sulfide (V). After conversion of (V) to the corresponding acid chloride with (COCl)2, intramolecular Friedel-Crafts cyclization in the presence of SnCl4 afforded the benzothiepinone (VI) as a mixture of cis and trans isomers. Further treatment of this mixture with sodium methoxide equilibrated the mixture to the more stable trans form (VII). Resolution of the racemic trans ester was achieved by basic hydrolysis, coupling to ethyl (R)-(-)-mandelate (VIII), and fractional crystallization of the desired diastereomer (IX) from EtOAc-hexane. Ester hydrolysis of (IX) under acidic conditions led to the chiral carboxylic acid (X), which was finally condensed with diethyl 4-aminobenzylphosphonate (XI) to furnish the title compound.

参考文献中间体

合成目标

【1】 Oda, T.; et al.; Synthesis of novel 2-benzothiopyran and 3-benzothiepin derivatives and their stimulatory effect on bone formation. J Med Chem 1999, 42, 4, 751.

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)	10984	1,3-Benzodioxol-5-amine; 1,3-Benzodioxol-5-ylamine.; 3,4-(Methylenedioxy)aniline	14268-66-7	C₇H₇NO₂	详情	详情
(II)	14156	methyl acrylate	96-33-3	C₄H₆O₂	详情	详情
(III)	24360	3-(1,3-Benzodioxol-5-yl)-2-bromopropionic acid methyl ester		C₁₁H₁₁BrO₄	详情	详情
(IV)	24361	2-sulfanylpropionic acid; 2-mercaptopropionic acid	57965-30-7	C₃H₆O₂S	详情	详情
(V)	24362	2-[2-(1,3-Benzodioxol-5-yl)-1-(methoxycarbonyl)ethylsulfanyl]propionic acid		C₁₄H₁₆O₆S	详情	详情
(VI)	24363	8-Methyl-9-oxo-5,6,8,9-tetrahydro-1,3-dioxolo[4,5-h][3]benzothiepine-6-carboxylic acid methyl ester		C₁₄H₁₄O₅S	详情	详情
(VII)	24364	8(S)-Methyl-9-oxo-5,6,8,9-tetrahydro-1,3-dioxolo[4,5-h][3]benzothiepine-6(R)-carboxylic acid methyl ester		C₁₄H₁₄O₅S	详情	详情
(VIII)	24365	2-Hydroxy-2-phenylacetic acid methyl ester	4358-87-6	C₉H₁₀O₃	详情	详情
(IX)	24366	8(S)-Methyl-9-oxo-5,6,8,9-tetrahydro-1,3-dioxolo[4,5-h][3]benzothiepine-6(R)-carboxylic acid 1(R)-(methoxycarbonyl)-1-benzyl ester		C₂₂H₂₀O₇S	详情	详情
(X)	24367	8(S)-Methyl-9-oxo-5,6,8,9-tetrahydro-1,3-dioxolo[4,5-h][3]benzothiepine-6(R)-carboxylic acid		C₁₃H₁₂O₅S	详情	详情
(XI)	24368	4-Aminobenzylphosphonic acid diethyl ester	20074-79-7	C₁₁H₁₈NO₃P	详情	详情

合成路线3

该中间体在本合成路线中的序号：(V)

Acylation of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (I) with N-Boc-nipecotic acid (II) by means of EDC/HOBt gives amide (III). Subsequent acidic cleavage of the Boc protecting group yields amine (IV). 3,4-Methylenedioxyaniline (V) is acylated by acryloyl chloride in the presence of Et3N to produce the acrylanilide (VI). Then, Michael addition of piperidine (IV) to the acrylanilide (VI) in boiling toluene provides the title compound.

参考文献中间体

合成目标

【1】 Kakefuda, A.; Okazaki, T.; Watanabe, T.; et al.; Structure-activity relationships of novel 1,2,3,4-tetrahydroisoquinolin derivatives as bradycardic agents. Drugs Fut 2002, 27, Suppl. A.
【2】 Okazaki, T.; Watanabe, T.; Wada, K.; Kakefuda, A.; Masuda, N. (Yamanouchi Pharmaceutical Co., Ltd.); Novel isoquinoline derivs. or salts thereof. EP 1186601; WO 0075133 .

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)	25859	6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline; 6-methoxy-1,2,3,4-tetrahydro-7-isoquinolinyl methyl ether		C₁₁H₁₅NO₂	详情	详情
(II)	57078	Boc-nipecotic acid		C₁₁H₁₉NO₄	详情	详情
(III)	58821	tert-butyl 3-{[6,7-dimethoxy-3,4-dihydro-2(1H)-isoquinolinyl]carbonyl}-1-piperidinecarboxylate		C₂₂H₃₂N₂O₅	详情	详情
(IV)	58822	[6,7-dimethoxy-3,4-dihydro-2(1H)-isoquinolinyl](3-piperidinyl)methanone		C₁₇H₂₄N₂O₃	详情	详情
(V)	10984	1,3-Benzodioxol-5-amine; 1,3-Benzodioxol-5-ylamine.; 3,4-(Methylenedioxy)aniline	14268-66-7	C₇H₇NO₂	详情	详情
(VI)	58823	N-(1,3-benzodioxol-5-yl)acrylamide		C₁₀H₉NO₃	详情	详情

Extended Information