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【结 构 式】 
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【分子编号】21916 【品名】(4-fluorophenyl)[6-methoxy-2-(4-methoxyphenyl)-1-benzothiophen-3-yl]methanone 【CA登记号】 |
【 分 子 式 】C23H17FO3S 【 分 子 量 】392.4505832 【元素组成】C 70.39% H 4.37% F 4.84% O 12.23% S 8.17% |
合成路线1
该中间体在本合成路线中的序号：(V)Two related new syntheses of raloxifene have been described: 1) The acylation of N-(6-methoxy-1-benzothiophen-2-yl)-N,N-dimethylamine (I) with 4-fluorobenzoyl chloride (II) by heating at 100 C in chlorobenzene gives the 3-acyl derivative (III), which is condensed with 4-methoxyphenylmagnesium bromide (IV) in THF yielding 3-(4-fluorobenzoyl)-6-methoxy-2-(4-methoxyphenyl)-1-benzothiophene (V). The condensation of (V) with 1-(2-hydroxyethyl)piperidine (VI) by means of NaH in DMF affords the ether (VII), which is finally demethylated with AlCl3 and ethanethiol. 2) The intermediate (III) can also be condensed first with 1-(2-hydroxyethyl)piperidine (VI) by means of NaH as before giving the piperidinoethyl ether (VIII), which is then condensed with the Grignard reagent (IV) affording the previously reported ether (VII).
| 【1】 Bradley, D.A.; et al.; Synergistic methodologies for the synthesis of 3-aroyl-2-arylbenzo[b]thiophene-based selective estrogen receptor modulators. Two concise syntheses of raloxifene. Tetrahedron Lett 1999, 40, 28, 5155. |
| 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) | 30906 | N-(6-methoxy-1-benzothiophen-2-yl)-N,N-dimethylamine; 6-methoxy-N,N-dimethyl-1-benzothiophen-2-amine | C11H13NOS | 详情 | 详情 | |
| (II) | 17263 | 4-fluorobenzoyl chloride | 403-43-0 | C7H4ClFO | 详情 | 详情 |
| (III) | 37673 | [2-(dimethylamino)-6-methoxy-1-benzothiophen-3-yl](4-fluorophenyl)methanone | C18H16FNO2S | 详情 | 详情 | |
| (IV) | 37674 | Bromo(4-methoxyphenyl)magnesium; 4-Methoxyphenylmagnesium bromide | 352-13-6 | C7H7BrMgO | 详情 | 详情 |
| (V) | 21916 | (4-fluorophenyl)[6-methoxy-2-(4-methoxyphenyl)-1-benzothiophen-3-yl]methanone | C23H17FO3S | 详情 | 详情 | |
| (VI) | 37675 | 2-(1-piperidinyl)-1-ethanol | 3040-44-6 | C7H15NO | 详情 | 详情 |
| (VII) | 37677 | [6-methoxy-2-(4-methoxyphenyl)-1-benzothiophen-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone | C30H31NO4S | 详情 | 详情 | |
| (VIII) | 37676 | [2-(dimethylamino)-6-methoxy-1-benzothiophen-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone | C25H30N2O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)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.
| 【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 |