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【结 构 式】 
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【分子编号】30906 【品名】N-(6-methoxy-1-benzothiophen-2-yl)-N,N-dimethylamine; 6-methoxy-N,N-dimethyl-1-benzothiophen-2-amine 【CA登记号】 |
【 分 子 式 】C11H13NOS 【 分 子 量 】207.29636 【元素组成】C 63.74% H 6.32% N 6.76% O 7.72% S 15.47% |
合成路线1
该中间体在本合成路线中的序号：(I)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：(I)The hydrolysis of 2-(dimethylamino)-6-methoxybenzo[b]thiophene (I) with HCl in refluxing THF gives 6-methoxybenzo[b]thiophen-2(3H)-one (II), which is condensed with 4-methoxybenzaldehyde (III) by means of piperidine in methanol yielding the 3-benzylidene derivative (IV). The rearrangement of (IV) with the same catalyst and solvent affords trans-6-methoxy-2-(4-methoxyphenyl)-2,3-dihydrobenzo[b]thiophene-3-carboxylic acid methyl ester (V), which is hydrolyzed with NaOH in methanol to the corresponding acid (VI). The reaction of (VI) with SOCl2 in dichloromethane gives the acyl chloride (VII), which is condensed with N,O-dimethylhydroxylamine by means of triethylamine in dichloromethane providing the N-methoxy-N-methylamide (VIII). The condensation of (VIII) with the Grignard reagent (IX) in THF affords the dimethyl ether of the target compound (X), which is finally demethylated with AlCl3 and propanethiol in dichloromethane. The intermediate Grignard reagent (IX) has been obtained by condensation of 4-bromophenol (XI) with 1-(2-chloroethyl)piperidine (XII) by means of K2CO3 in hot DMF to give 1-[2-(4-bromophenoxy)ethyl]piperidine (XIII), which is then treated with magnesium in THF to afford (IX).
| 【1】 Stephenson, G.A.; Glasebrook, A.L.; Schmid, C.R.; Misner, J.W.; Synthesis and biological activity of trans-2,3-dihydroraloxifene. Bioorg Med Chem Lett 1999, 9, 8, 1137. |
| 【2】 Glasebrook, A.L.; Schmid, C.R.; Stephenson, G.A.; Misner, J.W.; Synthesis and biological activity of dihydroraloxifene. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 072. |
| 【3】 Misner, J.W.; Schmid, C.R. (Eli Lilly and Company); Intermediates and processes for preparing benzo[b]thiophenes. EP 0979076; WO 9848793 . |
| 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) | 30907 | 6-methoxy-1-benzothiophen-2(3H)-one | C9H8O2S | 详情 | 详情 | |
| (III) | 27251 | 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde | 123-11-5 | C8H8O2 | 详情 | 详情 |
| (IV) | 30908 | 6-methoxy-3-[(Z)-(4-methoxyphenyl)methylidene]-1-benzothiophen-2-one | C17H14O3S | 详情 | 详情 | |
| (V) | 30909 | methyl (2R,3S)-6-methoxy-2-(4-methoxyphenyl)-2,3-dihydro-1-benzothiophene-3-carboxylate | C18H18O4S | 详情 | 详情 | |
| (VI) | 30910 | (2R,3S)-6-methoxy-2-(4-methoxyphenyl)-2,3-dihydro-1-benzothiophene-3-carboxylic acid | C17H16O4S | 详情 | 详情 | |
| (VII) | 30911 | (2R,3R)-6-methoxy-2-(4-methoxyphenyl)-2,3-dihydro-1-benzothiophene-3-carbonyl chloride | C17H15ClO3S | 详情 | 详情 | |
| (VIII) | 30912 | (2R,3S)-N,6-dimethoxy-2-(4-methoxyphenyl)-N-methyl-2,3-dihydro-1-benzothiophene-3-carboxamide | C19H21NO4S | 详情 | 详情 | |
| (IX) | 30913 | bromo[4-[2-(1-piperidinyl)ethoxy]phenyl]magnesium | C13H18BrMgNO | 详情 | 详情 | |
| (X) | 30914 | [(2R,3S)-6-methoxy-2-(4-methoxyphenyl)-2,3-dihydro-1-benzothiophen-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone | C30H33NO4S | 详情 | 详情 | |
| (XI) | 25313 | 4-bromophenol | 106-41-2 | C6H5BrO | 详情 | 详情 |
| (XII) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (XIII) | 30915 | 4-bromophenyl 2-(1-piperidinyl)ethyl ether; 1-[2-(4-bromophenoxy)ethyl]piperidine | C13H18BrNO | 详情 | 详情 |