[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl][4-(2-piperidinoethoxy)phenyl]methanone -Drug Synthesis Database

【结构式】

【分子编号】17321

【品名】[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl][4-(2-piperidinoethoxy)phenyl]methanone

【CA登记号】

【分子式】C₂₈H₂₇NO₄S

【分子量】473.59272

【元素组成】C 71.01% H 5.75% N 2.96% O 13.51% S 6.77%

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：(I)

The two major metabolites of raloxifene, the glucuronide conjugates (VI) and (VIII) are synthesized as follows: The partial silylation of raloxifene (I) with tert-butyldimethylsilyl chloride (TBDMS-Cl) by means of dimethylaminopyridine (DMAP) in THF/DMF gives a mixture of the monosilylated compounds (II) and (III), which are separated by chromatography. Compounds (II) and (III) are independently condensed with methyl 1,2,3,4-tetra-O-acetyl-D-glucuronate (IV) by means of BF3.OEt2 in dichloromethane yielding protected glucuronides (V) and (VII), respectively. Finally, both compounds are deprotected by a treatment first with LiOH in dioxane to hydrolyzed the ester groups, and then with tetrabutylammonium fluoride in THF to eliminate the silyl groups, thus obtaining the desired metabolites (VI) and (VIII), respectively.

参考文献中间体

合成目标

【1】 Glasebrook, A.L.; Frolik, C.A.; Dodge, J.A.; Cho, S.; Phillips, D.L.; Lugar, C.W.; Osborne, J.J.; Synthesis and estrogen receptor binding affinities of the major human metabolites of raloxifene (LY139481). Bioorg Med Chem Lett 1997, 7, 8, 993.
【2】 Dodge, J.A.; Stocksdale, M.G.; Jones, C.D.; A chemical probe for the estrogen receptor: Synthesis of the H-3 isotopomer of raloxifene. J Label Compd Radiopharm 1995, 36, 1, 43.

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)	17321	[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl][4-(2-piperidinoethoxy)phenyl]methanone		C₂₈H₂₇NO₄S	详情	详情
(II)	17322	[6-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone		C₃₄H₄₁NO₄SSi	详情	详情
(III)	17323	[2-(4-[[tert-butyl(dimethyl)silyl]oxy]phenyl)-6-hydroxy-1-benzothiophen-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone		C₃₄H₄₁NO₄SSi	详情	详情
(IV)	17324	methyl (2S,3R,4S,5R)-3,4,5,6-tetrakis(acetoxy)tetrahydro-2H-pyran-2-carboxylate	7355-18-2	C₁₅H₂₀O₁₁	详情	详情
(V)	17325	methyl (2S,3R,4S,5R,6S)-3,4,5-tris(acetoxy)-6-[4-(6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]-1-benzothiophen-2-yl)phenoxy]tetrahydro-2H-pyran-2-carboxylate		C₄₁H₄₃NO₁₃S	详情	详情
(VI)	17326	methyl (2S,3R,4S,5R,6S)-3,4,5-tris(acetoxy)-6-[(2-(4-hydroxyphenyl)-3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]-1-benzothiophen-6-yl)oxy]tetrahydro-2H-pyran-2-carboxylate		C₄₁H₄₃NO₁₃S	详情	详情
(VII)	17327	(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-[4-(6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]-1-benzothiophen-2-yl)phenoxy]tetrahydro-2H-pyran-2-carboxylic acid		C₃₄H₃₅NO₁₀S	详情	详情
(VIII)	17328	(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-[(2-(4-hydroxyphenyl)-3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]-1-benzothiophen-6-yl)oxy]tetrahydro-2H-pyran-2-carboxylic acid		C₃₄H₃₅NO₁₀S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Keoxifene has been synthesized using the following process: A portion of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-pipendinoethoxy)benzoyl]benzo[b]thiophene hydrochloride (I) was combined with denatured alcohol and 5N sodium hydroxide, and stirred under a nitrogen atmosphere. The reaction mixture was evaporated to dryness under vacuum, and the residue dissolved in water and washed with diethyl ether. The water layer was degassed under vacuum, and then nitrogen was bubbled through it to remove all traces of ether. The mixture was then acidified with 1N hydrochloric acid, and then made basic with excess sodium bicarbonate The precipitate was collected by filtration and washed with cold water to obtain crude product, which was purified on a column of silica gel. The column was eluted first with 700 ml of 5% methanol in chloroform, followed by 1l of 10% methanol in chloroform. The impurities came off first, and the product-containing fractions were combined and evaporated under vacuum to obtain a yellow oil. The oil was dissolved in acetone seeded and chilled in a freezer to obtain the purified product.

参考文献中间体

合成目标

【1】 Peters, M.K.; Jones, C.D.; Benzothiophene compounds and process for preparing them. EP 0062053; GB 2097788 .
【2】 Pento, J.T.; Keoxifene. Drugs Fut 1984, 9, 7, 516.

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)	30520	[6-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-2-(4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]phenyl)-1-benzothiophen-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone		C₃₄H₃₉NO₄S₃	详情	详情
(II)	17321	[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl][4-(2-piperidinoethoxy)phenyl]methanone		C₂₈H₂₇NO₄S	详情	详情

Extended Information