methyl (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenylcarbamate -Drug Synthesis Database

【结构式】

【分子编号】34049

【品名】methyl (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenylcarbamate

【CA登记号】

【分子式】C₁₈H₁₇Cl₂NO₂

【分子量】350.24392

【元素组成】C 61.73% H 4.89% Cl 20.24% N 4% O 9.14%

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：(X)

A stereoselective synthesis of sertraline has been described: The silylation of 1,2-dihydronaphthalen-1(R)-ol (I) with tert-butyldiphenylsilyl chloride (TBDPS-Cl) gives the corresponding silyl ether (II), which is brominated with Br2 and triethylamine (TEA) in dichloromethane yielding the 4-bromo-compound (III). The condensation of (III) with 3,4-dichlorophenyltrimethyltin (IV), by means of a palladium catalyst affords the silylated phenylnaphthalenol (V), which is deprotected with TBAF and acetic acid to provide 4-(3,4-dichlorophenyl)-1,2-dihydronaphthalen-1(R)-ol (VI). The regioselective hydrogenation with H2 over chiral iridium or rhodium catalysts gives the (1R-trans)-tetrahydronaphthol (VII), which is treated with diphenylphosphoryl azide (DPPA) and DBU in THF yielding the (1S-cis)-azide (VIII). The reduction of (VIII) with H2 over Pd/C in ethanol affords the corresponding amine (IX), which is treated with ethyl chloroformate to give the expected carbamate (X). Finally, this compound is reduced with LiAlH(OMe)3 in THF. 2,4-Dichlorophenyltrimethyltin (IV) is prepared by reaction of 3,4-dichlorophenol (XI) with triflic anhydride in pyridine/CH2Cl2 to give triflate (XII), which is converted to (IV) by reaction with hexamethylditin and Pd(PPh3)4 in THF. The silylated naphthalenol (V) can also be obtained by condensation of (III) with the phenylboronic acid (XIII) in the presence of a palladium catalyst.

参考文献中间体

合成目标

【1】 Rovis, T.; Lautens, M.; Selective functionalization of 1,2-dihydronaphthalenols leads to a concise, stereoselective synthesis of sertraline. Tetrahedron 1999, 55, 29, 8967.

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)	34037	1,2-dihydronaphthalen-1(R)-ol; (1R)-1,2-dihydro-1-naphthalenol		C₁₀H₁₀O	详情	详情
(II)	34038	tert-butyl(diphenyl)silyl (1R)-1,2-dihydro-1-naphthalenyl ether; tert-butyl[(1R)-1,2-dihydro-1-naphthalenyloxy]diphenylsilane		C₂₆H₂₈OSi	详情	详情
(III)	34039	(1R)-4-bromo-1,2-dihydro-1-naphthalenyl tert-butyl(diphenyl)silyl ether; [[(1R)-4-bromo-1,2-dihydro-1-naphthalenyl]oxy](tert-butyl)diphenylsilane		C₂₆H₂₇BrOSi	详情	详情
(IV)	34042	(3,4-dichlorophenyl)(trimethyl)stannane; 3,4-dichlorophenyltrimethyltin		C₉H₁₂Cl₂Sn	详情	详情
(V)	34041	tert-butyl(diphenyl)silyl (1R)-4-(3,4-dichlorophenyl)-1,2-dihydro-1-naphthalenyl ether; tert-butyl[[(1R)-4-(3,4-dichlorophenyl)-1,2-dihydro-1-naphthalenyl]oxy]diphenylsilane		C₃₂H₃₀Cl₂OSi	详情	详情
(VI)	34045	(1R)-4-(3,4-dichlorophenyl)-1,2-dihydro-1-naphthalenol; 4-(3,4-dichlorophenyl)-1,2-dihydronaphthalen -1(R)-o		C₁₆H₁₂Cl₂O	详情	详情
(VII)	34046	(1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenol		C₁₆H₁₄Cl₂O	详情	详情
(VIII)	34047	(1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenyl azide; (1S,4S)-1-azido-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalene		C₁₆H₁₃Cl₂N₃	详情	详情
(IX)	34048	(1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine; (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenylamine		C₁₆H₁₅Cl₂N	详情	详情
(X)	34049	methyl (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenylcarbamate		C₁₈H₁₇Cl₂NO₂	详情	详情
(XI)	34044	3,4-Dichlorophenol	95-77-2	C₆H₄Cl₂O	详情	详情
(XII)	34043	3,4-dichlorophenyl trifluoromethanesulfonate		C₇H₃Cl₂F₃O₃S	详情	详情
(XIII)	34040	3,4-Dichlorophenylboronic acid	151169-75-4	C₆H₅BCl₂O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

The reaction of intermediate 4-(3,4-dichlorophenyl)-4-phenylbutyric acid (I) (see scheme number 09017202a intermediate (VII)) with (COCl)2 in dichloromethane gives the acyl chloride (II), which is condensed with methyl carbamate (III) in hot toluene to yield N-[4-(3,4-dichlorophenyl)-4-phenylbutyryl]carbamic acid methyl ester (IV). The reduction of (IV) with DIBAL in toluene/dichloromethane affords the hydroxybutyl derivative (V), which is cyclized by means of TiCl4 in dichloromethane to provide N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthyl]carbamic acid methyl ester as a mixture of the cis and trans isomers, easily separated by chromatography. Finally, the desired cis isomer (VI) is reduced with LiAlH4 in THF to afford the target (rac)-sertraline.

参考文献中间体

合成目标

【1】 DeNinno, M.P.; et al.; The preparation and intra- and intermolecular addition reactions of acyclic N-acylimines: Applications to the synthesis of (±)-sertraline. J Org Chem 2001, 66, 21, 6988.

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)	30581	4-(3,4-dichlorophenyl)-4-phenylbutyric acid		C₁₆H₁₄Cl₂O₂	详情	详情
(II)	30582	4-(3,4-dichlorophenyl)-4-phenylbutanoyl chloride		C₁₆H₁₃Cl₃O	详情	详情
(III)	40724	methyl carbamate; carbamic acid methyl ester	598-55-0	C₂H₅NO₂	详情	详情
(IV)	58595	methyl 4-(3,4-dichlorophenyl)-4-phenylbutanoylcarbamate		C₁₈H₁₇Cl₂NO₃	详情	详情
(V)	58596	methyl 4-(3,4-dichlorophenyl)-1-hydroxy-4-phenylbutylcarbamate		C₁₈H₁₉Cl₂NO₃	详情	详情
(VI)	34049	methyl (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenylcarbamate		C₁₈H₁₇Cl₂NO₂	详情	详情

Extended Information