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【结 构 式】 
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【分子编号】41003 【品名】1,2-diphenyl-1-ethanone; Deoxybenzoin-2-phenylacetophenone; Dexybenzoin 【CA登记号】451-40-1 |
【 分 子 式 】C14H12O 【 分 子 量 】196.24868 【元素组成】C 85.68% H 6.16% O 8.15% |
合成路线1
该中间体在本合成路线中的序号：(I)Deoxybenzoin (I) is converted to the corresponding oxime (II) by treatment with NH2OH·HCl under basic conditions either with sodium acetate in aqueous ethanol or in toluene in presence of potassium hydroxide in absolute ethanol. Deprotonation of the oxime under nitrogen with 2eq of butyllithium in THF followed by cyclization in ethyl acetate or acetic anhydride affords isoxazoline (III). Finally, treatment of (III) with cold chlorosulfonic acid followed by reaction of the intermediate sulfonyl chloride with aqueous ammonia affords the desired product.
| 【1】 Leeson, P.; Castañer, J.; Castañer, R.M.; Sorbera, L.A.; Valdecoxib and Parecoxib Sodium. Drugs Fut 2001, 26, 2, 133. |
| 【2】 Carter, J.S.; Talley, J.J.; Brown, D.L.; et al.; 4-[5-Methyl-3-phenylisoxazol]4-yl]-benzenesulfonamide, valdecoxib: A potent and selective inhibitor of COX-2. J Med Chem 2000, 43, 5, 775. |
| 【3】 Talley, J.J.; Brown, D.L.; Nagarajan, S.; Carter, J.S.; Weier, R.M.; Stealey, M.A.; Collins, P.W.; Seibert, K.; Graneto, M.J.; Xu, X.; Partis, R. (Pharmacia Corp.); Substd. isoxazoles for the treatment of inflammation. EP 0809636; JP 1999503722; US 5633272; WO 9625405 . |
| 【4】 Talley, J.J.; Sikorski, J.A.; Devadas, B.; Graneto, M.J.; Carter, J.S.; Norman, B.H.; Lu, H.-F.; Brown, D.L. (Pharmacia Corp.); Substd. sulfonylphenylheterocycles as cyclooxygenase-2 and 5-lipoxygenase inhibitors. EP 0828736; EP 0995747; US 5643933; WO 9638442 . |
| 【5】 Talley, J.J. (Pharmacia Corp.); Isoxazole cpds. as cyclooxygenase inhibitors. US 5859257 . |
合成路线2
该中间体在本合成路线中的序号：(I)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3
该中间体在本合成路线中的序号：(I)The condensation of desoxybenzoin (I) with 2-(benzyloxy)ethyl bromide (II) by means of aqueous 48% NaOH containing triethylbenzylammonium chloride (TEBAC) gives 4-(benzyloxy)-1,2-diphenyl-1-butanone (III), which by reaction with the Grignard reagent (IV) - prepared from 4-(tetrahydropyranyloxy)phenyl bromide (V) and Mg in THF - yields the triphenylbutanol derivative (VI). Elimination of the THP-protecting group of compound (VI) by means of H2SO4 in ethanol/water at room temperature affords the triphenylbutanol derivative (VII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to provide the butane-1,4-diol derivative (VIII). Cyclization of the butane-1,4-diol (VIII) by means of H2SO4 in hot ethanol/water gives 2-(4-hydroxyphenyl)-2,3-diphenyltetrahydrofuran (IX), which is treated with 48% HBr in refluxing AcOH to yield a mixture of (E)- and (Z)-4-(4-hydroxyphenyl)-3,4-diphenyl-3-buten-1-ol (X), which is separated by chemical work up. The phenolic OH group of the desired (Z)-isomer (X) is condensed with 2-(benzyloxy)ethyl bromide (II) by means of NaOH and tetrabutylammonium bromide in refluxing toluene/ water to afford the benzyloxyethyl ether (XII). Reaction of the aliphatic OH group of ether (XII) with PPh3 and CCl4 in acetonitrile provides the corresponding chloro derivative (XIII), which is finally debenzylated with H2 over Pd/C in ethyl acetate/ethanol.
| 【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 . |
| 【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) | 35528 | 1-[(2-bromoethoxy)methyl]benzene; benzyl 2-bromoethyl ether | 1462-37-9 | C9H11BrO | 详情 | 详情 |
| (III) | 63429 | 4-(benzyloxy)-1,2-diphenyl-1-butanone | C23H22O2 | 详情 | 详情 | |
| (IV) | 31255 | bromo[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]magnesium | C11H13BrMgO2 | 详情 | 详情 | |
| (V) | 63430 | 4-bromophenyl tetrahydro-2H-pyran-2-yl ether; 2-(4-bromophenoxy)tetrahydro-2H-pyran | C11H13BrO2 | 详情 | 详情 | |
| (VI) | 63431 | 4-(benzyloxy)-1,2-diphenyl-1-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-1-butanol | C34H36O4 | 详情 | 详情 | |
| (VII) | 63432 | 4-[4-(benzyloxy)-1-hydroxy-1,2-diphenylbutyl]phenol | C29H28O3 | 详情 | 详情 | |
| (VIII) | 63433 | 1-(4-hydroxyphenyl)-1,2-diphenyl-1,4-butanediol | C22H22O3 | 详情 | 详情 | |
| (IX) | 63434 | 4-(2,3-diphenyltetrahydro-2-furanyl)phenol | C22H20O2 | 详情 | 详情 | |
| (X) | 52025 | 4-[(Z)-4-hydroxy-1,2-diphenyl-1-butenyl]phenol | C22H20O2 | 详情 | 详情 | |
| (XII) | 52026 | (Z)-4-[4-[2-(benzyloxy)ethoxy]phenyl]-3,4-diphenyl-3-buten-1-ol | C31H30O3 | 详情 | 详情 | |
| (XIII) | 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4
该中间体在本合成路线中的序号：(I)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 |
合成路线5
该中间体在本合成路线中的序号：(I)Treatment of deoxybenzoin (I) with hydroxylamine hydrochloride produces the corresponding oxime (II). Condensation of the dilithium derivative of (II) with methyl chloroacetate (III) generates the dihydroisoxazole (IV). Subsequent chlorosulfonation of (IV), followed by treatment with ammonia, furnishes sulfonamide (V). Then, displacement of the chloro group of (V) with silver nitrate gives rise to the target nitrate ester. Alternatively, chloride (V) is converted to alcohol (VI) by displacement with formic acid, followed by alkaline hydrolysis. Then, reaction of alcohol (VI) with in situ generated acetyl nitrate yields the corresponding nitrate.
| 【1】 Schroeder, J.D.; et al.; NMI-1093: A nitric oxide-enhanced cyclooxygenase-2 selective inhibitor with cardioprotective potential. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 316. |
| 【2】 Garvey, D.S.; Tam, S.W.; Letts, L.G.; Schroeder, J.D.; Bandarage, U.K.; Fang, X.; Bandarage, R.R. (NitroMed Inc.); Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compsns. and methods of use. WO 0145703 . |
| 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) | 41004 | 1,2-diphenyl-1-ethanone oxime | C14H13NO | 详情 | 详情 | |
| (III) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 详情 | 详情 |
| (IV) | 57848 | 5-(chloromethyl)-3,4-diphenyl-4,5-dihydro-5-isoxazolol | C16H14ClNO2 | 详情 | 详情 | |
| (V) | 57849 | 4-[5-(chloromethyl)-3-phenyl-4-isoxazolyl]benzenesulfonamide | C16H13ClN2O3S | 详情 | 详情 | |
| (VI) | 57850 | 4-[5-(hydroxymethyl)-3-phenyl-4-isoxazolyl]benzenesulfonamide | C16H14N2O4S | 详情 | 详情 |