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【结 构 式】 
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【分子编号】26934 【品名】2-bromoethyl tetrahydro-2H-pyran-2-yl ether 【CA登记号】 |
【 分 子 式 】C7H13BrO2 【 分 子 量 】209.08302 【元素组成】C 40.21% H 6.27% Br 38.22% O 15.3% |
合成路线1
该中间体在本合成路线中的序号：(V)Alkylation of 3,4-dichlorophenylacetonitrile (VI) with (tetrahydropyranyloxy)ethyl bromide (V) (prepared by protection of 2-bromoethanol (IV) with dihydropyran) furnished nitrile (VII). Catalytic hydrogenation of (VII) in the presence of Raney-Ni and Et3N gave the primary amine (VIII). After acidic hydrolysis of the tetrahydropyranyl group of (VIII), the resultant amino alcohol was resolved by means of D-tartaric acid providing the (S)-enantiomer (IX). Reaction of amine (IX) with ethyl chloroformate afforded carbamate (X), which was further reduced to the N-methyl amine (XI) employing LiAlH4. Subsequent acylation of (XI) with benzoyl chloride furnished benzamide (XII). Mesylate (XIII) was then prepared by treatment of alcohol (XII) with methanesulfonyl chloride and triethylamine. Finally, condensation between piperidine (III) and mesylate (XIII) led to the title compound
| 【1】 Emonds-Alt, X.; Goulaouic, P.; Proietto, V.; Van Broeck, D. (Sanofi-Synthelabo); Arylalkylamines, process for their preparation and pharmaceutical compsns. containing them. EP 0474561; FR 2666335; FR 2678267; JP 1992261155; US 5236921; US 5350852 . |
| 【2】 Emonds-Alt, X.; Proietto, V.; Van Broeck, D.; Vilain, P.; Advenier, C.; Neliat, G.; Le Fur, G.; Breliere, J.-C.; Pharmacological profile and chemical synthesis of SR 48968, a non-peptide antagonist of the neurokinin A (NK2) receptor. Bioorg Med Chem Lett 1993, 3, 5, 925. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 59283 | N-(4-phenyl-4-piperidinyl)acetamide | C13H18N2O | 详情 | 详情 | |
| (IV) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (V) | 26934 | 2-bromoethyl tetrahydro-2H-pyran-2-yl ether | C7H13BrO2 | 详情 | 详情 | |
| (VI) | 26935 | 2-(3,4-dichlorophenyl)acetonitrile | 3218-49-3 | C8H5Cl2N | 详情 | 详情 |
| (VII) | 26936 | 2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile | C15H17Cl2NO2 | 详情 | 详情 | |
| (VIII) | 26937 | 2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanamine | C15H21Cl2NO2 | 详情 | 详情 | |
| (IX) | 26939 | (3S)-4-amino-3-(3,4-dichlorophenyl)-1-butanol | C10H13Cl2NO | 详情 | 详情 | |
| (X) | 26940 | ethyl (2S)-2-(3,4-dichlorophenyl)-4-hydroxybutylcarbamate | C13H17Cl2NO3 | 详情 | 详情 | |
| (XI) | 26941 | (3S)-3-(3,4-dichlorophenyl)-4-(methylamino)-1-butanol | C11H15Cl2NO | 详情 | 详情 | |
| (XII) | 26942 | N-[(2S)-2-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methylbenzamide | C18H19Cl2NO2 | 详情 | 详情 | |
| (XIII) | 62380 | (3S)-4-(benzoylamino)-3-(3,4-dichlorophenyl)butyl methanesulfonate | C18H19Cl2NO4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Alkylation of 3,4-dichlorophenylacetonitrile (I) with 2-(tetrahydropyranyloxy)ethyl bromide (II) in the presence of NaH in THF afforded nitrile (III). This was further alkylated with ethyl 3-bromopropionate (IV) using LDA to produce the cyano ester adduct (V). Catalytic hydrogenation of the cyano group of (V) in the presence of Raney-nickel, with concomitant intramolecular cyclization of the intermediate amino ester, gave rise to the piperidinone (VI). This was further reduced to piperidine (VII) using LiAlH4 in THF. After acidic deprotection of the tetrahydropyranyl group of (VII), the racemic amine was resolved by means of tartaric acid to furnish the desired enantiomer (VIII). Acylation of piperidine (VIII) with 3-isopropoxyphenylacetic acid (IX) employing BOP as the coupling reagent yielded amide (X). Conversion of (X) to the mesylate (XI) was carried out by treatment with methanesulfonyl chloride and Et3N. Then, N-alkylation of 4-phenylquinuclidine (XII) with mesylate (XI) produced the corresponding ammonium salt, which was finally subjected to anion exchange of the mesylate for a chloride group by treatment with HCl.
| 【1】 Emonds-Alt, X.; Gueule, P.; Proietto, V.; Van Broeck, D. (Sanofi-Synthelabo); Quaternary basic amides as tachykinines antagonists. EP 0591040; FR 2696178; JP 1998175976; US 5583134; US 5712288 . |
| 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) | 26935 | 2-(3,4-dichlorophenyl)acetonitrile | 3218-49-3 | C8H5Cl2N | 详情 | 详情 |
| (II) | 26934 | 2-bromoethyl tetrahydro-2H-pyran-2-yl ether | C7H13BrO2 | 详情 | 详情 | |
| (III) | 26936 | 2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile | C15H17Cl2NO2 | 详情 | 详情 | |
| (IV) | 29132 | ethyl 3-bromopropanoate | 539-74-2 | C5H9BrO2 | 详情 | 详情 |
| (V) | 59767 | ethyl 4-cyano-4-(3,4-dichlorophenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hexanoate | C20H25Cl2NO4 | 详情 | 详情 | |
| (VI) | 59768 | 5-(3,4-dichlorophenyl)-5-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-2-piperidinone | C18H23Cl2NO3 | 详情 | 详情 | |
| (VII) | 59769 | 2-[3-(3,4-dichlorophenyl)-3-piperidinyl]ethyl tetrahydro-2H-pyran-2-yl ether; 3-(3,4-dichlorophenyl)-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]piperidine | C18H25Cl2NO2 | 详情 | 详情 | |
| (VIII) | 59770 | 2-[(3S)-3-(3,4-dichlorophenyl)piperidinyl]-1-ethanol | C13H17Cl2NO | 详情 | 详情 | |
| (IX) | 59771 | 2-(3-isopropoxyphenyl)acetic acid | C11H14O3 | 详情 | 详情 | |
| (X) | 59772 | 1-[(3S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)piperidinyl]-2-(3-isopropoxyphenyl)-1-ethanone | C24H29Cl2NO3 | 详情 | 详情 | |
| (XI) | 59773 | 2-{(3S)-3-(3,4-dichlorophenyl)-1-[2-(3-isopropoxyphenyl)acetyl]piperidinyl}ethyl methanesulfonate | C25H31Cl2NO5S | 详情 | 详情 | |
| (XII) | 59774 | 4-phenyl-1-azabicyclo[2.2.2]octane | C13H17N | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)This compound has been obtained by two related ways: 1) The condensation of 4-acetylbiphenyl oxime (I) with 2-(2-bromoethoxy)tetrahydropyran (II) by means of K2CO3 in hot dimethylacetamide gives the oxime derivative (III), which is treated with TsOH in methanol yielding 4-acetylbiphenyl O-(2-hydroxyethyl)oxime (IV). The condensation of (IV) with 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione (V) by means of diethyl azodicarboxylate (DEAD) and PPh3 in THF affords (VI), the trityl derivative of the target compound, which is finally treated with hot aqueous ethanol to eliminate the trityl group. 2) The condensation of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione (VIII) with N-(2-hydroxyethoxy)phthalimide (VII) by means DEAD gives the adduct (IX), which is treated with hydrazine to eliminate the phthalimido group yielding the substituted hydroxylamine (X). Finally, this compound is condensed with 4-acetylbiphenyl (XI) by means of TEA.
| 【1】 Yanagisawa, H.; Fujita, T.; Fujimoto, K.; Yoshioka, T.; Wada, K.; Oguchi, M.; Fujiwara, T.; Horikoshi, H. (Sankyo Co., Ltd.); Oxime derivs., their preparation and their therapeutic use. CA 2159938; EP 0708098; JP 1997048779; US 5703096; US 5780490; US 5972959 . |
| 【2】 Isobe, A.; Fujita, S.; Fujiwara, T.; Yanagisawa, H.; Takamura, M.; Yamada, E.; Hagisawa, Y.; Yachi, M.; Novel oximes having 5-benzyl-2,4-thiazolidinedione as antihyperglycemic agents: Synthesis and structure-activity relationship. Bioorg Med Chem Lett 2000, 10, 4, 373. |
| 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) | 36912 | 1-[1,1'-biphenyl]-4-yl-1-ethanone oxime | C14H13NO | 详情 | 详情 | |
| (II) | 26934 | 2-bromoethyl tetrahydro-2H-pyran-2-yl ether | C7H13BrO2 | 详情 | 详情 | |
| (III) | 36913 | 1-[1,1'-biphenyl]-4-yl-1-ethanone O-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]oxime | C21H25NO3 | 详情 | 详情 | |
| (IV) | 36914 | 1-[1,1'-biphenyl]-4-yl-1-ethanone O-(2-hydroxyethyl)oxime | C16H17NO2 | 详情 | 详情 | |
| (V) | 18803 | 5-(4-hydroxybenzyl)-3-trityl-1,3-thiazolidine-2,4-dione | C29H23NO3S | 详情 | 详情 | |
| (VI) | 36915 | 5-[4-[2-([[(E)-1-[1,1'-biphenyl]-4-ylethylidene]amino]oxy)ethoxy]benzyl]-3-trityl-1,3-thiazolidine-2,4-dione | C45H38N2O4S | 详情 | 详情 | |
| (VII) | 36908 | 2-(2-hydroxyethoxy)-1H-isoindole-1,3(2H)-dione | C10H9NO4 | 详情 | 详情 | |
| (VIII) | 26462 | 5-(4-hydroxybenzyl)-1,3-thiazolidine-2,4-dione | 74772-78-4 | C10H9NO3S | 详情 | 详情 |
| (IX) | 36909 | 2-(2-[4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy]ethoxy)-1H-isoindole-1,3(2H)-dione | C20H16N2O6S | 详情 | 详情 | |
| (X) | 36910 | 5-[4-[2-(aminooxy)ethoxy]benzyl]-1,3-thiazolidine-2,4-dione | C12H14N2O4S | 详情 | 详情 | |
| (XI) | 36916 | 1-[1,1'-biphenyl]-4-yl-1-ethanone | 92-91-1 | C14H12O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)This compound has been obtained by two related ways: 1) The condensation of 3-acetyl-6-phenylpyridine oxime (I) with 2-(2-bromoethoxy)tetrahydropyran (II) by means of K2CO3 in hot dimethylacetamide gives the oxime derivative (III), which is treated with TsOH in methanol yielding 3-acetyl-6-phenylpyridine O-(2-hydroxyethyl)oxime (IV). The condensation of (IV) with 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione (V) by means of diethyl azodicarboxylate (DEAD) and PPh3 in THF affords (VI), the trityl derivative of the target compound, which is finally treated with hot aqueous ethanol to eliminate the trityl group. 2) The condensation of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione (VIII) with N-(2-hydroxyethoxy)phthalimide (VII) by means DEAD gives the adduct (IX), which is treated with hydrazine to eliminate the phthalimido group yielding the substituted hydroxylamine (X). Finally, this compound is condensed with 3-acetyl-6-phenylpyridine (XI) by means of TEA.
| 【1】 Yanagisawa, H.; Fujita, T.; Fujimoto, K.; Yoshioka, T.; Wada, K.; Oguchi, M.; Fujiwara, T.; Horikoshi, H. (Sankyo Co., Ltd.); Oxime derivs., their preparation and their therapeutic use. CA 2159938; EP 0708098; JP 1997048779; US 5703096; US 5780490; US 5972959 . |
| 【2】 Isobe, A.; Fujita, S.; Fujiwara, T.; Yanagisawa, H.; Takamura, M.; Yamada, E.; Hagisawa, Y.; Yachi, M.; Novel oximes having 5-benzyl-2,4-thiazolidinedione as antihyperglycemic agents: Synthesis and structure-activity relationship. Bioorg Med Chem Lett 2000, 10, 4, 373. |
| 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) | 36904 | 1-(6-phenyl-3-pyridinyl)-1-ethanone oxime | C13H12N2O | 详情 | 详情 | |
| (II) | 26934 | 2-bromoethyl tetrahydro-2H-pyran-2-yl ether | C7H13BrO2 | 详情 | 详情 | |
| (III) | 36905 | 1-(6-phenyl-3-pyridinyl)-1-ethanone O-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]oxime | C20H24N2O3 | 详情 | 详情 | |
| (IV) | 36906 | 1-(6-phenyl-3-pyridinyl)-1-ethanone O-(2-hydroxyethyl)oxime | C15H16N2O2 | 详情 | 详情 | |
| (V) | 18803 | 5-(4-hydroxybenzyl)-3-trityl-1,3-thiazolidine-2,4-dione | C29H23NO3S | 详情 | 详情 | |
| (VI) | 36907 | 5-[4-[2-([[(E)-1-(6-phenyl-3-pyridinyl)ethylidene]amino]oxy)ethoxy]benzyl]-3-trityl-1,3-thiazolidine-2,4-dione | C44H37N3O4S | 详情 | 详情 | |
| (VII) | 36908 | 2-(2-hydroxyethoxy)-1H-isoindole-1,3(2H)-dione | C10H9NO4 | 详情 | 详情 | |
| (VIII) | 26462 | 5-(4-hydroxybenzyl)-1,3-thiazolidine-2,4-dione | 74772-78-4 | C10H9NO3S | 详情 | 详情 |
| (IX) | 36909 | 2-(2-[4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy]ethoxy)-1H-isoindole-1,3(2H)-dione | C20H16N2O6S | 详情 | 详情 | |
| (X) | 36910 | 5-[4-[2-(aminooxy)ethoxy]benzyl]-1,3-thiazolidine-2,4-dione | C12H14N2O4S | 详情 | 详情 | |
| (XI) | 36911 | 1-(6-phenyl-3-pyridinyl)-1-ethanone | C13H11NO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The reaction of 2-bromoethanol (I) with dihydropyran by means of a strong acid ion exchange resin gives the tetrahydropyranyl ether (II), which is condensed with 2-(3,4-dichlorophenyl)acetonitrile (III) by means of NaH in THF yielding thebutyronitrile (IV). The reduction of (IV) with H2 over RaNi in ethanol/NH4OH affords the butylamine (V), which is deprotected with HCl in methanol providing racemic 2-(3,4-dichlorophenyl)-4-hydroxybutylamine (VI). The optical resolution of (VI) with D-tartaric acid affords the corresponding (S) isomer (VII), which is treated with ethyl chloroformate and triethylamine in dichloromethane to give the carbamate (VIII). The reduction of (VIII) with LiAlH4 in THF yields N-[2(S)-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methylamine (IX), which is acylated with benzoyl chloride (X) and triethylamine in dichloromethane to affords the amide (XI). Oxidation of the hydroxyl group of (XI) with Dess-Martin periodinane yields the corresponding aldehyde (XII), which is reductocondensed with 4-[N-(trifluoroacetyl)-N-[3-(trifluoroacetamido)propyl]amino]piperidine (XIII) by means of NaBH3CN in methanol/acetic acid providing the bis(trifluoroacetylated) intermediate (XIV). The deprotection of (XIV) with KOH in methanol/water gives the diamine intermediate (XV), which is finally cyclized with carbonyldiimidazole (CDI) in chloroform.
| 【1】 Miller, S.C. (AstraZeneca plc); Therapeutic heterocycles which antagonize neurokinin receptors. JP 1997501439; US 5567700; US 5990130; US 6124279; WO 9505377 . |
| 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) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (II) | 26934 | 2-bromoethyl tetrahydro-2H-pyran-2-yl ether | C7H13BrO2 | 详情 | 详情 | |
| (III) | 26935 | 2-(3,4-dichlorophenyl)acetonitrile | 3218-49-3 | C8H5Cl2N | 详情 | 详情 |
| (IV) | 26936 | 2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile | C15H17Cl2NO2 | 详情 | 详情 | |
| (V) | 26937 | 2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanamine | C15H21Cl2NO2 | 详情 | 详情 | |
| (VI) | 26938 | 4-amino-3-(3,4-dichlorophenyl)-1-butanol | C10H13Cl2NO | 详情 | 详情 | |
| (VII) | 26939 | (3S)-4-amino-3-(3,4-dichlorophenyl)-1-butanol | C10H13Cl2NO | 详情 | 详情 | |
| (VIII) | 26940 | ethyl (2S)-2-(3,4-dichlorophenyl)-4-hydroxybutylcarbamate | C13H17Cl2NO3 | 详情 | 详情 | |
| (IX) | 26941 | (3S)-3-(3,4-dichlorophenyl)-4-(methylamino)-1-butanol | C11H15Cl2NO | 详情 | 详情 | |
| (X) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (XI) | 26942 | N-[(2S)-2-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methylbenzamide | C18H19Cl2NO2 | 详情 | 详情 | |
| (XII) | 26943 | N-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide | C18H17Cl2NO2 | 详情 | 详情 | |
| (XIII) | 26944 | 2,2,2-trifluoro-N-(4-piperidinyl)-N-[3-[(2,2,2-trifluoroacetyl)amino]propyl]acetamide | C12H17F6N3O2 | 详情 | 详情 | |
| (XIV) | 26945 | N-[(2S)-2-(3,4-dichlorophenyl)-4-[4-((2,2,2-trifluoroacetyl)[3-[(2,2,2-trifluoroacetyl)amino]propyl]amino)-1-piperidinyl]butyl]-N-methylbenzamide | C30H34Cl2F6N4O3 | 详情 | 详情 | |
| (XV) | 26946 | N-[(2S)-4-[4-[(3-aminopropyl)amino]-1-piperidinyl]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide | C26H36Cl2N4O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)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7
该中间体在本合成路线中的序号：(XIV)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 |