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【结 构 式】 
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【分子编号】37674 【品名】Bromo(4-methoxyphenyl)magnesium; 4-Methoxyphenylmagnesium bromide 【CA登记号】352-13-6 |
【 分 子 式 】C7H7BrMgO 【 分 子 量 】211.34098 【元素组成】C 39.78% H 3.34% Br 37.81% Mg 11.5% O 7.57% |
合成路线1
该中间体在本合成路线中的序号：(IV)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：(IV)The condensation beta-tetralone (I) with phenyl 4-methoxybenzoate (II) by means of NaNH2 in THF gives 3,4-dihydro-1-(4-methoxybenzoyl)-2(1H)-naphthalenone (III), which is then submitted to a Grignard reaction with 4-methoxyphenylmagnesium bromide (IV) in hot THF yielding 3,4-dihydro-2-(4-methoxyphenyl)-1-naphthyl-4-methoxyphenyl ketone (V). The cleavage of one methoxy group of (V) with sodium ethylmercaptide (A) in dry DMF affords 3,4-dihydro-2-(4-methoxyphenyl)-1-naphthyl-4-hydroxyphenyl ketone (VI), which is finally condensed with N-(2-chloroethyl)pyrrolidine (VII) by means of K2CO3 in refluxing 2-butanone.
| 【1】 Jones, C.D.; et al.; Synthesis and antiestrogenic activity of [3,4-dihydro-2-(4-methoxyphenyl)-1-naphthalenyl][4-[2-(1-pyrrolidinyl)ethoxyphenyl]methanone]methane sulfonic acid salt. J Med Chem 1979, 22, 8, 962-966. |
| 【2】 Castaner, J.; Hillier, K.; Trioxifene mesylate. Drugs Fut 1980, 5, 5, 259. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 39110 | Sodium 1-ethanethiolate; Sodium ethylmercaptide | 811-51-8 | C2H5NaS | 详情 | 详情 |
| (I) | 39106 | 3,4-Dihydro-2(1H)-naphthalenone; beta-Tetralone | 530-93-8 | C10H10O | 详情 | 详情 |
| (II) | 39107 | Phenyl 4-methoxybenzoate | C14H12O3 | 详情 | 详情 | |
| (III) | 39108 | 1-(4-Methoxybenzoyl)-3,4-dihydro-2(1H)-naphthalenone; 3,4-Dihydro-1-(4-methoxybenzoyl)-2(1H)-naphthalenone | C18H16O3 | 详情 | 详情 | |
| (IV) | 37674 | Bromo(4-methoxyphenyl)magnesium; 4-Methoxyphenylmagnesium bromide | 352-13-6 | C7H7BrMgO | 详情 | 详情 |
| (V) | 39109 | (4-Methoxyphenyl)[2-(4-methoxyphenyl)-3,4-dihydro-1-naphthalenyl]methanone; 3,4-Dihydro-2-(4-methoxyphenyl)-1-naphthyl-4-methoxyphenyl ketone | C25H22O3 | 详情 | 详情 | |
| (VI) | 39111 | (4-Hydroxyphenyl)[2-(4-methoxyphenyl)-3,4-dihydro-1-naphthalenyl]methanone; 3,4-Dihydro-2-(4-methoxyphenyl)-1-naphthyl-4-hydroxyphenyl ketone | C24H20O3 | 详情 | 详情 | |
| (VII) | 33922 | 1-(2-Chloroethyl)pyrrolidine; N-(2-Chloroethyl)pyrrolidine | C6H12ClN | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The intermediate 4-(4-methoxyphenyl)-2-methylpyridine (IV) was obtained by two different procedures. Acylation of 2-picoline (I) with ethyl chloroformate, followed by addition of the Grignard reagent (II), prepared from 4-bromoanisole and magnesium, furnished the 4-aryl dihydropyridine (III). Aromatization of (III) by heating at 200 C with sulfur in decahydronaphthalene produced the phenylpyridine (IV). In an alternative method, 2-methylpyridine (I) was converted to the N-aminopyridinium salt (V) by reaction with hydroxylamine-O-sulfonic acid. This was then condensed with dehydroacetic acid (VI) under acidic conditions to produce the bipyridinium derivative (VII), which was isolated as the tetrafluoroborate salt. Alternatively, addition of 4-methoxyphenylmagnesium bromide (II) to (VII) yielded the phenyl bipyridinone (VIII), which upon elimination of the dimethylpyridone moiety in refluxing DMF generated the intermediate phenyl pyridine (IV). Methyl ether cleavage of (IV) in refluxing HBr afforded phenol (IX). This was then alkylated with 3-chloro-3-methylbutyne (X) to yield the aryl propargyl ether (XI) ,which was subjected to a Claisen rearrangement in hot ortho-dichlorobenzene to produce chromene (XII).
| 【1】 Manley, P.W. (Novartis AG; Novartis Deutschland GmbH); 2,2-Dialkyl- and 2,2-dialkyl-3, 4-dihydro-3-hydroxy-2H-1-benzopyrans, their use as pharmaceuticals. EP 0623129; WO 9412493 . |
| 【2】 Manley, P.W. (Novartis AG); 2,2-Dialkyl- and 2,2-dialkyl-3, 4-dihydro-3-hydroxy-2H-1-benzopyrans. US 5574049 . |
| 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) | 17590 | 2-methylpyridine; 2-picoline | 109-06-8 | C6H7N | 详情 | 详情 |
| (II) | 37674 | Bromo(4-methoxyphenyl)magnesium; 4-Methoxyphenylmagnesium bromide | 352-13-6 | C7H7BrMgO | 详情 | 详情 |
| (III) | 50053 | ethyl 4-(4-methoxyphenyl)-2-methyl-1(4H)-pyridinecarboxylate | C16H19NO3 | 详情 | 详情 | |
| (IV) | 50055 | 4-(4-methoxyphenyl)-2-methylpyridine; methyl 4-(2-methyl-4-pyridinyl)phenyl ether | C13H13NO | 详情 | 详情 | |
| (V) | 50051 | 1-amino-2-methylpyridinium hydrogen sulfate | C6H10N2O4S | 详情 | 详情 | |
| (VI) | 43660 | 3-acetyl-6-methyl-2H-pyran-2,4(3H)-dione | 520-45-6 | C8H8O4 | 详情 | 详情 |
| (VII) | 50052 | C13H15BF4N2O | 详情 | 详情 | ||
| (VIII) | 50054 | C20H22N2O2 | 详情 | 详情 | ||
| (IX) | 50056 | 4-(2-methyl-4-pyridinyl)phenol | C12H11NO | 详情 | 详情 | |
| (X) | 22416 | 3-chloro-3-methyl-1-butyne | 1111-97-3 | C5H7Cl | 详情 | 详情 |
| (XI) | 50057 | 1,1-dimethyl-2-propynyl 4-(2-methyl-4-pyridinyl)phenyl ether; 4-[4-[(1,1-dimethyl-2-propynyl)oxy]phenyl]-2-methylpyridine | C17H17NO | 详情 | 详情 | |
| (XII) | 50058 | 4-(2,2-dimethyl-2H-chromen-6-yl)-2-methylpyridine | C17H17NO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)The condensation of desoxybenzoin (I) with tetrahydropyranyl ether (II) in aq. 48% NaOH containing TEBAC gives 1,2-diphenyl-4-(tetrahydropyranyloxy)-1-butanone (III), which by a Grignard condensation with 4-methoxyphenylmagnesium bromide (IV) in THF yields the monoprotected triphenylbutanediol (V). The deprotection of (V) with H2SO4 in ethanol/water at room temperature affords the triphenylbutane-1,4-diol (VI), which is cyclized with H2SO4 in hot ethanol/water to provide 2-(4-methoxyphenyl)-2,3-diphenyltetrahydrofuran (VII). The reaction of (VII) with 48% HBr in refluxing acetic acid gives a mixture of (E)- and (Z)-4-(4-hydroxyphenyl)-3,4-diphenyl-1-butanol that is separated by chemical working up to obtain the desired (Z)-isomer (VIII). The condensation of the phenolic OH of (VIII) with benzyl protected 2-bromoethanol (IX) by means of NaOH and tetrabutylammonium bromide in refluxing toluene/water gives the benzyloxyethyl ether (X). The reaction of the aliphatic OH group of (X) with PPh3 and CCl4 in acetonitrile yields the corresponding chloro derivative (XI), which is finally debenzylated by hydrogenation with H2 over Pd/C in ethyl acetate/ethanol.
| 【1】 Toivola, R.J.; Karjalainen, A.J.; Kurkela, K.O.A.; Soderwall, M.-L.; Kangas, L.V.M.; Blanco, G.L.; Sundquist, H.K. (Orion Corporation); Tri-phenyl alkene derivs. and their oestrogenic, anti-oestrogenic and progestanic uses. US 4996225; US 5491173 . |
| 【2】 Härkönen, P.; Miettinen, T.; Mäntylä, E.; Kangas, L.; DeGregorio, M. (Orion Corporation); Serum cholesterol lowering agent. WO 9732574 . |
| 【3】 Laine, A.; Degregorio, M.; Harkonen, P.; Wiebe, V.; Vaananen, K.; Kangas, L.V.M. (Orion Corporation); Triphenylethylenes for the prevention and treatment of osteoporosis. WO 9607402 . |
| 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) | 41003 | 1,2-diphenyl-1-ethanone; Deoxybenzoin-2-phenylacetophenone; Dexybenzoin | 451-40-1 | C14H12O | 详情 | 详情 |
| (II) | 26934 | 2-bromoethyl tetrahydro-2H-pyran-2-yl ether | C7H13BrO2 | 详情 | 详情 | |
| (III) | 52021 | 1,2-diphenyl-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanone | C21H24O3 | 详情 | 详情 | |
| (IV) | 37674 | Bromo(4-methoxyphenyl)magnesium; 4-Methoxyphenylmagnesium bromide | 352-13-6 | C7H7BrMgO | 详情 | 详情 |
| (V) | 52022 | 1-(4-methoxyphenyl)-1,2-diphenyl-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanol | C28H32O4 | 详情 | 详情 | |
| (VI) | 52023 | 1-(4-methoxyphenyl)-1,2-diphenyl-1,4-butanediol | C23H24O3 | 详情 | 详情 | |
| (VII) | 52024 | 2-(4-methoxyphenyl)-2,3-diphenyltetrahydrofuran; 4-(2,3-diphenyltetrahydro-2-furanyl)phenyl methyl ether | C23H22O2 | 详情 | 详情 | |
| (VIII) | 52025 | 4-[(Z)-4-hydroxy-1,2-diphenyl-1-butenyl]phenol | C22H20O2 | 详情 | 详情 | |
| (IX) | 35528 | 1-[(2-bromoethoxy)methyl]benzene; benzyl 2-bromoethyl ether | 1462-37-9 | C9H11BrO | 详情 | 详情 |
| (X) | 52026 | (Z)-4-[4-[2-(benzyloxy)ethoxy]phenyl]-3,4-diphenyl-3-buten-1-ol | C31H30O3 | 详情 | 详情 | |
| (XI) | 52027 | 1-[2-(benzyloxy)ethoxy]-4-[(Z)-4-chloro-1,2-diphenyl-1-butenyl]benzene; benzyl 2-[4-[(Z)-4-chloro-1,2-diphenyl-1-butenyl]phenoxy]ethyl ether | C31H29ClO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XVI)Condensation of desoxybenzoin (I) with 2-(tetra-hydropyranyloxy)ethyl bromide (XIV) by means of aqueous NaOH and TEBAC as before gives 1,2-diphenyl-4-(tetrahydropyranyloxy)-1-butanone (XV), which by a Grignard condensation with 4-methoxyphenylmagnesium bromide (XVI) -prepared from 4-bromoanisole (XVII) and Mg in THF- provides the triphenylbutanol derivative (XVIII). Cleavage of the THP-protecting group of compound (XVIII) with H2SO4 in ethanol/water at room temperature affords the butane-1,4-diol derivative (XIX), which is cyclized by means of H2SO4 in hot ethanol/ water to yield 2-(4-methoxyphenyl)-2,3-diphenyltetrahydrofuran (XX). Finally, this compound is treated with 48% HBr in refluxing AcOH to give 4-(4-hydroxyphenyl)-3,4-diphenyl-3-buten-1-ol (X) as a (Z):(E)-isomeric mixture, from which the desired (Z)-isomer is separated by chemical work up.
| 【1】 Sorbera, L.A.; Castaner, J.; Bayes, M.; Ospemifene. Drugs Fut 2004, 29, 1, 38. |
| 【2】 Toivola, R.J.; Karjalainen, A.J.; Kurkela, K.O.A.; Soderwall, M.-L.; Kangas, L.V.M.; Blanco, G.L.; Sundquist, H.K. (Orion Corporation); Tri-phenyl alkene derivs. and their oestrogenic, anti-oestrogenic and progestanic uses. US 4996225; US 5491173 . |
| 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) | 41003 | 1,2-diphenyl-1-ethanone; Deoxybenzoin-2-phenylacetophenone; Dexybenzoin | 451-40-1 | C14H12O | 详情 | 详情 |
| (X) | 52025 | 4-[(Z)-4-hydroxy-1,2-diphenyl-1-butenyl]phenol | C22H20O2 | 详情 | 详情 | |
| (XIV) | 26934 | 2-bromoethyl tetrahydro-2H-pyran-2-yl ether | C7H13BrO2 | 详情 | 详情 | |
| (XV) | 52021 | 1,2-diphenyl-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanone | C21H24O3 | 详情 | 详情 | |
| (XVI) | 37674 | Bromo(4-methoxyphenyl)magnesium; 4-Methoxyphenylmagnesium bromide | 352-13-6 | C7H7BrMgO | 详情 | 详情 |
| (XVII) | 63436 | 1-bromo-4-methoxybenzene; 4-bromophenyl methyl ether | C7H7BrO | 详情 | 详情 | |
| (XVIII) | 52022 | 1-(4-methoxyphenyl)-1,2-diphenyl-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanol | C28H32O4 | 详情 | 详情 | |
| (XIX) | 52023 | 1-(4-methoxyphenyl)-1,2-diphenyl-1,4-butanediol | C23H24O3 | 详情 | 详情 | |
| (XX) | 52024 | 2-(4-methoxyphenyl)-2,3-diphenyltetrahydrofuran; 4-(2,3-diphenyltetrahydro-2-furanyl)phenyl methyl ether | C23H22O2 | 详情 | 详情 | |
| (XXI) | 30343 | 1-(4-methoxyphenyl)-2-phenyl-1-ethanone | C15H14O2 | 详情 | 详情 | |
| (XXII) | 63437 | 1-(4-methoxyphenyl)-2-phenyl-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanone | C22H26O4 | 详情 | 详情 | |
| (XXIII) | 17616 | bromo(phenyl)magnesium; Phenyl Magnesium Bromide | 100-58-3 | C6H5BrMg | 详情 | 详情 |