4-(6-Methoxy-1-benzothiophen-2-yl)phenyl methyl ether; 6-Methoxy-2-(4-methoxyphenyl)-1-benzothiophene -Drug Synthesis Database

【结构式】

【分子编号】10121

【品名】4-(6-Methoxy-1-benzothiophen-2-yl)phenyl methyl ether; 6-Methoxy-2-(4-methoxyphenyl)-1-benzothiophene

【CA登记号】63675-74-1

【分子式】C₁₆H₁₄O₂S

【分子量】270.35196

【元素组成】C 71.08% H 5.22% O 11.84% S 11.86%

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：(VII)

The synthesis of radiolabeled raloxifene has been reported: The esterification of 3,5-dibromo-4-hydroxybenzoic acid (I) with methanol/HCl gives the corresponding methyl ester (II), which is condensed with 1-(2-chloroethyl)piperidine (III) by means of K2CO3 in DMF yielding 3,5-dibromo-4-[2-(1-piperidyl)ethoxy]benzoic acid methyl ester (IV). The hydrolysis of (IV) with NaOH in methanol affords the corresponding free acid (V), which by treatment of SOCl2 in toluene is converted to the acyl chloride (VI). The Friedel-Crafts condensation of (VI) with 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (VII) by means of AlCl3 in dichloromethane gives [3,5-dibromo-4-[2-(1-piperidinyl)ethoxy]phenyl]-[6-methoxy-2-(4-methoxy phenyl)benzo[b]thien-3-yl]methanone (VIII), which is demethylated with AlCl3 and ethylmercaptane to dibromoraloxifene (IX). Finally, this compound is submitted to hydrogenolysis with tritium over Pd/C in methanol.

参考文献中间体

合成目标

【1】 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)	10115	3,5-Dibromo-4-hydroxybenzoic acid	3337-62-0	C₇H₄Br₂O₃	详情	详情
(II)	10116	methyl 3,5-dibromo-4-hydroxybenzoate	41727-47-3	C₈H₆Br₂O₃	详情	详情
(III)	10117	1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine	1932-03-2	C₇H₁₄ClN	详情	详情
(IV)	10118	methyl 3,5-dibromo-4-(2-piperidinoethoxy)benzoate		C₁₅H₁₉Br₂NO₃	详情	详情
(V)	10119	3,5-Dibromo-4-(2-piperidinoethoxy)benzoic acid		C₁₄H₁₇Br₂NO₃	详情	详情
(VI)	10120	3,5-Dibromo-4-(2-piperidinoethoxy)benzoyl chloride		C₁₄H₁₆Br₂ClNO₂	详情	详情
(VII)	10121	4-(6-Methoxy-1-benzothiophen-2-yl)phenyl methyl ether; 6-Methoxy-2-(4-methoxyphenyl)-1-benzothiophene	63675-74-1	C₁₆H₁₄O₂S	详情	详情
(VIII)	10122	[3,5-Dibromo-4-[2-(1-piperidinyl)ethoxy]phenyl][6-methoxy-2-(4-methoxyphenyl)-1-benzothiophen-3-yl]methanone		C₃₀H₂₉Br₂NO₄S	详情	详情
(IX)	10123	[3,5-Dibromo-4-[2-(1-piperidinyl)ethoxy]phenyl][6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]methanone		C₂₈H₂₅Br₂NO₄S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Alkylation of 3-methoxybenzenethiol (I) with 4'-methoxyphenacyl bromide (II) afforded sulfide (III). Cyclization of (III) with concomitant rearrangement in the presence of polyphosphoric acid produced a mixture of regioisomers (IV) and (V) that were separated by their different solubility in acetone. Then, Friedel-Crafts acylation of the desired insoluble isomer (IV) with 3,4,5-trimethoxybenzoyl chloride (VI) in the presence of AlCl3 provided the title ketone, which was separated from some demethylated byproduct by means of silica gel chromatography.

参考文献中间体

合成目标

【1】 Lee, B.; et al.; Hepatocyte gene therapy in a large animal: A neonatal bovine model of citrullinemia. Proc Natl Acad Sci USA 1999, 96, 7, 3981.
【2】 Jones, C.D.; et al.; Antiestrogens. 2. Structure-activity studies in a series of 3-aroyl-2-arylbenzo[b]thiophene derivatives leading to [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl] [4-[2-(1-piperidinyl)ethoxy]-phenyl]methanone hydrochloride (LY156758), a remarkably effec. J Med Chem 1984, 27, 8, 1057.
【3】 Carlson, D.G.; Cullinan, G.J.; Fahey, K.J.; Jackson, W.T.; Roehm, N.W.; Spaethe, S.M. (Eli Lilly and Company); Novel benzothiophene cpds. and methods. EP 0732331; JP 1999501932; WO 9628156 .
【4】 Pinney, K.G. (Baylor University); Anti-mitotic agents which inhibit tubulin polymerization. US 5886025 .

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)	25756	3-methoxybenzenethiol	15570-12-4	C₇H₈OS	详情	详情
(II)	21991	2-Methoxyphenacyl bromide; 2-bromo-1-(4-methoxyphenyl)-1-ethanone	2632-13-5	C₉H₉BrO₂	详情	详情
(III)	25757	1-(4-methoxyphenyl)-2-[(3-methoxyphenyl)sulfanyl]-1-ethanone		C₁₆H₁₆O₃S	详情	详情
(IV)	10121	4-(6-Methoxy-1-benzothiophen-2-yl)phenyl methyl ether; 6-Methoxy-2-(4-methoxyphenyl)-1-benzothiophene	63675-74-1	C₁₆H₁₄O₂S	详情	详情
(V)	25758	4-(4-methoxy-1-benzothiophen-2-yl)phenyl methyl ether		C₁₆H₁₄O₂S	详情	详情
(VI)	13571	3,4,5Ttrimethoxybenzoyl chloride	4521-61-3	C₁₀H₁₁ClO₄	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 cyclization of 3-methoxythiophenol (I) with 4-methoxyphenacyl bromide (II) by means of KOH in ethanol gives 2-(4-methoxyphenyl)-6-methoxybenzothiophene (III), which is treated with pyridinium hydrochloride at 220 C to yield 2-(4-hydroxyphenyl)-6-hydroxybenzothiophene (IV). The protection of the hydroxy groups of (IV) by reaction with 4-chlorophenacyl bromide (V) and K2CO3 - 18-crown 6 in refluxing ether affords the bis p-chlorophenacyloxy derivative (VI), which by a Friedel-Kraft's reaction with 4-(2-pyrrolidinoethoxy)benzoyl chloride (VII) by means of AlCl3 in refluxing dichloroethane is converted into 2-[4-(4-chlorophenacyloxy)phenyl]-3-[4-(2-pyrrolidinoethoxy)benzoyl]-6-(4-chlorophenacyloxy)benzothiophene (VIII). Finally, this compound is deprotected by treatment with Zn and acetic acid.

参考文献中间体

合成目标

【1】 Jones, C.D.; Suarez, T.; 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents. DE 2647907; ES 452694; ES 452695; FR 2329271; GB 1570610; JP 52053851; US 4133814 .
【2】 Jones, C.D.; Suarez, T.; 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents. DE 2647907; ES 452694; ES 452695; FR 2329271; GB 1570610; JP 52053851; US 4133814 .
【3】 Blancafort, P.; Castañer, J.; Serradell, M.N.; LY-117018. Drugs Fut 1982, 7, 2, 112.

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)	25756	3-methoxybenzenethiol	15570-12-4	C₇H₈OS	详情	详情
(II)	21991	2-Methoxyphenacyl bromide; 2-bromo-1-(4-methoxyphenyl)-1-ethanone	2632-13-5	C₉H₉BrO₂	详情	详情
(III)	10121	4-(6-Methoxy-1-benzothiophen-2-yl)phenyl methyl ether; 6-Methoxy-2-(4-methoxyphenyl)-1-benzothiophene	63675-74-1	C₁₆H₁₄O₂S	详情	详情
(IV)	36414	2-(4-hydroxyphenyl)-1-benzothiophen-6-ol		C₁₄H₁₀O₂S	详情	详情
(V)	16720	2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone	536-38-9	C₈H₆BrClO	详情	详情
(VI)	36415	1-(4-chlorophenyl)-2-(4-[6-[2-(4-chlorophenyl)-2-oxoethoxy]-1-benzothiophen-2-yl]phenoxy)-1-ethanone		C₃₀H₂₀Cl₂O₄S	详情	详情
(VII)	36416	4-[2-(1-pyrrolidinyl)ethoxy]benzoyl chloride		C₁₃H₁₆ClNO₂	详情	详情
(VIII)	36417	1-(4-chlorophenyl)-2-[(2-[4-[2-(4-chlorophenyl)-2-oxoethoxy]phenyl]-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzoyl]-1-benzothiophen-6-yl)oxy]-1-ethanone		C₄₃H₃₅Cl₂NO₆S	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

Friedel Crafts condensation of benzothiophene (I) with p-fluorobenzoyl chloride (II) yielded the benzoyl benzothiophene (III). Then, substitution of the fluorine atom of (III) with 2-(1-piperidinyl)ethanethiol (VI) (obtained from b-chloroethylpiperidine (IV) and thiourea (V)), afforded sulfide (VII). Finally, deprotection of the methyl ethers of (VII) with BBr3 in cold 1,2-dichloroethane furnished the target compound.

参考文献中间体

合成目标

【1】 Glasebrook, A.W.; Schmid, C.R.; Duke, K.M.; Sluka, J.P.; Novel nonsteroidal selective estrogen receptor modulators. Carbon and heteroatom replacement of oxygen in the ethoxypiperidine region of raloxifene. Bioorg Med Chem Lett 1999, 9, 4, 523.

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)	10121	4-(6-Methoxy-1-benzothiophen-2-yl)phenyl methyl ether; 6-Methoxy-2-(4-methoxyphenyl)-1-benzothiophene	63675-74-1	C₁₆H₁₄O₂S	详情	详情
(II)	17263	4-fluorobenzoyl chloride	403-43-0	C₇H₄ClFO	详情	详情
(III)	21916	(4-fluorophenyl)[6-methoxy-2-(4-methoxyphenyl)-1-benzothiophen-3-yl]methanone		C₂₃H₁₇FO₃S	详情	详情
(IV)	10117	1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine	1932-03-2	C₇H₁₄ClN	详情	详情
(V)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情
(VI)	21919	2-(1-piperidinyl)ethylhydrosulfide; 2-(1-piperidinyl)-1-ethanethiol		C₇H₁₅NS	详情	详情
(VII)	21920	[6-methoxy-2-(4-methoxyphenyl)-1-benzothiophen-3-yl](4-[[2-(1-piperidinyl)ethyl]sulfanyl]phenyl)methanone		C₃₀H₃₁NO₃S₂	详情	详情

Extended Information