5-methoxy-1,1-bis(phenylsulfanyl)-3,4-dihydro-2(1H)-naphthalenone -Drug Synthesis Database

【结构式】

【分子编号】44372

【品名】5-methoxy-1,1-bis(phenylsulfanyl)-3,4-dihydro-2(1H)-naphthalenone

【CA登记号】

【分子式】C₂₃H₂₀O₂S₂

【分子量】392.5426

【元素组成】C 70.38% H 5.14% O 8.15% S 16.34%

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：(II)

The reaction of 5-methoxy-2-tetralone (I) with benzenethiosulfonic acid S-phenyl ester and sodium acetate in methanol gives 1,1-bis(phenylsulfanyl)-2-tetralone (II), which is condensed with 2-(bromomethyl)acrylic acid tert-butyl ester (III) by means of n-BuLi and diisopropylamine (DIA) in THF to yield the acrylic acid derivative (IV). Desulfurization of (IV) with Al/Hg in THF/water affords compound (V), which is treated with O-methylhydroxylamine and Na2HPO4 in methanol, providing the methoxyimino compound (VI). The reduction of (VI) with Zn/HOAc provides the methoxyamino compound (VII). The cyclization of (VII) by means of potassium hydrogen phosphate gives 1,6-dimethoxy-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylic acid tert-butyl ester as a diastereomeric mixture that is separated by chromatography to furnish the desired diastereomer (VIII). Hydrolysis of the tert-butoxy ester group of (VIII) by means of TFA yields the carboxylic acid (IX), which is treated with diazomethane to afford the methyl ester (X). Selective demethoxylation of (X) with Zn/HOAc provides the octahydrobenzoquinoline (XI).

参考文献中间体

合成目标

【1】 Nordmann, R.; Petcher, T.J.; Octahydrobenzo[g]quinolines: Potent dopamine agonists which show the relationship between ergolines and apomorphine. J Med Chem 1985, 28, 3, 367.
【2】 Petcher, T.J.; Nordmann, R. (Novartis AG); Novel pharmaceutically active 1,2,3,4,4a,5,10,10a-octahydrobenzo(g)quinoline derivs.. EP 0077754; ES 8606281; ES 8706120 .

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)	14647	5-methoxy-3,4-dihydro-2(1H)-naphthalenone	32940-15-1	C₁₁H₁₂O₂	详情	详情
(II)	44372	5-methoxy-1,1-bis(phenylsulfanyl)-3,4-dihydro-2(1H)-naphthalenone		C₂₃H₂₀O₂S₂	详情	详情
(III)	44373	tert-butyl 2-(bromomethyl)acrylate		C₈H₁₃BrO₂	详情	详情
(IV)	44374	tert-butyl 2-[[8-methoxy-3-oxo-4,4-bis(phenylsulfanyl)-1,2,3,4-tetrahydro-2-naphthalenyl]methyl]acrylate		C₃₁H₃₂O₄S₂	详情	详情
(V)	44375	tert-butyl 2-[(8-methoxy-3-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)methyl]acrylate		C₁₉H₂₄O₄	详情	详情
(VI)	44376	tert-butyl 2-[[8-methoxy-3-(methoxyimino)-1,2,3,4-tetrahydro-2-naphthalenyl]methyl]acrylate		C₂₀H₂₇NO₄	详情	详情
(VII)	44377	tert-butyl 2-[[8-methoxy-3-(methoxyamino)-1,2,3,4-tetrahydro-2-naphthalenyl]methyl]acrylate		C₂₀H₂₉NO₄	详情	详情
(VIII)	44378	tert-butyl (3S,4aR,10aR)-1,6-dimethoxy-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylate		C₂₀H₂₉NO₄	详情	详情
(IX)	44379	(3S,4aR,10aR)-1,6-dimethoxy-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylic acid		C₁₆H₂₁NO₄	详情	详情
(X)	44380	methyl (3S,4aR,10aR)-1,6-dimethoxy-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylate		C₁₇H₂₃NO₄	详情	详情
(XI)	44381	methyl (3S,4aR,10aR)-6-methoxy-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylate		C₁₆H₂₁NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

The selective monoreduction of the already known (see scheme 14265002a) 1-[3-methoxy-5-(methylsulfonyl)-4-propoxyphenyl]-4-(3,4,5-trimethoxyphenyl)butane-1,4-dione (I) with LiAlH(O-t-Bu)3 in THF gives the hydroxybutanone (II) as a racemic mixture that is separated by esterification with (-)-(R)-mandelic acid, separation of diastereomers and hydrolysis with KOH in ethanol yielding (S)-(III) and (R)-(IV) as pure enantiomers. The reduction of both (S)-(III) and (R)-(IV) with NaBH4 in hot ethanol gives (S)-(V) and (R)-(VI) diols that are cyclized by means of TFA in chloroform to afford trans-(S,S)- and trans-(R,R)-target compounds. Both compounds are impurified with about 25% of the corresponding cis-isomer that is separated by chromatography.

参考文献中间体

合成目标

【1】 Chabala, J.C.; Buglanesi, R.L.; Ponpipom, M.M.; Enantioselective cyclization of chiral butane-1, 4-diols to chiral tetrahydrofurans: Synthesis of chiral trans-2-(3-methoxy-5-methylsulfonyl-4-propoxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (L-659,989), a potent PAF-receptor antagonist. Tetrahedron Lett 1988, 29, 48, 6211.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	44366	1-[3-methoxy-5-(methylsulfonyl)-4-propoxyphenyl]-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione	C₂₄H₃₀O₉S	详情	详情
(II)	44367	4-hydroxy-4-[3-methoxy-5-(methylsulfonyl)-4-propoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-1-butanone	C₂₄H₃₂O₉S	详情	详情
(III)	44371	(4S)-4-hydroxy-4-[3-methoxy-5-(methylsulfonyl)-4-propoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-1-butanone	C₂₄H₃₂O₉S	详情	详情
(IV)	44372	5-methoxy-1,1-bis(phenylsulfanyl)-3,4-dihydro-2(1H)-naphthalenone	C₂₃H₂₀O₂S₂	详情	详情
(V)	44373	tert-butyl 2-(bromomethyl)acrylate	C₈H₁₃BrO₂	详情	详情
(VI)	44374	tert-butyl 2-[[8-methoxy-3-oxo-4,4-bis(phenylsulfanyl)-1,2,3,4-tetrahydro-2-naphthalenyl]methyl]acrylate	C₃₁H₃₂O₄S₂	详情	详情

Extended Information