【结 构 式】 |
【分子编号】18780 【品名】4-(trifluoromethoxy)phenol 【CA登记号】828-27-3 |
【 分 子 式 】C7H5F3O2 【 分 子 量 】178.1107096 【元素组成】C 47.2% H 2.83% F 32% O 17.97% |
合成路线1
该中间体在本合成路线中的序号:(VIII)The precursor 2-methoxy-5-trifluoromethoxybenzaldehyde (III) was prepared as follows. Alkylation of 4-(trifluoromethoxy)phenol (VIII) by means of iodomethane and K2CO3 or dimethyl carbonate and DMAP furnished 4-(trifluoromethoxy)anisole (IX). Formylation of (IX) to the target aldehyde (III) was achieved by treatment with dichloromethyl methyl ether and TiCl4 or with hexamethylenetetraamine and trifluoroacetic acid.
【1】 Lowe, J.A. III; Rosen, T.J. (Pfizer Inc.); Fluoroalkoxybenzylamino derivs. of nitrogen containing heterocycles. EP 0589924; JP 1994506473; WO 9300331 . |
【2】 Snyder, W.M.; Godek, D.M.; Stewart, A.M. (Pfizer Inc.); Formylation process for aromatic aldehydes. WO 9424081 . |
合成路线2
该中间体在本合成路线中的序号:(XXIV)Reaction of mesylate (XVII) with triazole sodium salt (XVIII) gave (XIX). Ozonization of olefinic double bond, followed by treatment with Me2S and K2CO3 provided ketone (XX). Then, haloform reaction with NaOBr gave acid (XXI), and reduction with LiAlH4 in cold Et2O afforded primary alcohol (XXII). Alcohol (XXII) was converted to mesylate (XXIII), and this was condensed with 4-(trifluoromethoxy)phenol (XXIV) to give ether (XXV). Deprotection of the trityl group with formic acid in EtOAc and subsequent reaction with methanesulfonyl chloride provided mesylate (XXVI), which was finally condensed with mercaptoimidazole (XXVII) to furnish the target compound.
【1】 Tsukuda, T.; Watanabe, M.; Ontsuka, H.; Hattori, K.; Shirai, M.; Shimma, N.; Synthesis of novel antifungal agents (2). Bioorg Med Chem Lett 1998, 8, 14, 1825. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XVII) | 18762 | 1-Ethoxyethylene; Ethyl vinyl ether;Ethoxyethene | 109-92-2 | C4H8O | 详情 | 详情 |
(XVIII) | 16341 | 1H-1,2,4-triazol-1-ylsodium | C2H2N3Na | 详情 | 详情 | |
(XIX) | 18775 | 2-[(1S,2R,3R,4R)-4-isopropenyl-2-methoxy-1-methyl-3-(1H-1,2,4-triazol-1-ylmethyl)cyclohexyl]ethyl trityl ether; 1-([(1R,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexyl]methyl)-1H-1,2,4-triazole | C35H41N3O2 | 详情 | 详情 | |
(XX) | 18776 | 1-[(1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexyl]-1-ethanone | C34H39N3O3 | 详情 | 详情 | |
(XXI) | 18777 | (1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexanecarboxylic acid | C33H37N3O4 | 详情 | 详情 | |
(XXII) | 18778 | [(1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexyl]methanol | C33H39N3O3 | 详情 | 详情 | |
(XXIII) | 18779 | [(1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexyl]methyl methanesulfonate | C34H41N3O5S | 详情 | 详情 | |
(XXIV) | 18780 | 4-(trifluoromethoxy)phenol | 828-27-3 | C7H5F3O2 | 详情 | 详情 |
(XXV) | 18781 | 1-([(1R,2R,3S,6R)-2-methoxy-3-methyl-6-[[4-(trifluoromethoxy)phenoxy]methyl]-3-[2-(trityloxy)ethyl]cyclohexyl]methyl)-1H-1,2,4-triazole; 2-((1S,2R,3R,4R)-2-methoxy-1-methyl-3-(1H-1,2,4-triazol-1-ylmethyl)-4-[[4-(trifluoromethoxy)phenoxy]methyl]cyclohexyl)ethyl trityl ether | C40H42F3N3O4 | 详情 | 详情 | |
(XXVI) | 18782 | 2-((1S,2R,3R,4R)-2-methoxy-1-methyl-3-(1H-1,2,4-triazol-1-ylmethyl)-4-[[4-(trifluoromethoxy)phenoxy]methyl]cyclohexyl)ethyl methanesulfonate | C22H30F3N3O6S | 详情 | 详情 | |
(XXVII) | 18783 | 1-methyl-1H-imidazol-2-ylhydrosulfide; 1-methyl-1H-imidazole-2-thiol | 60-56-0 | C4H6N2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(XXIV)Reaction of mesylate (XVII) with triazole sodium salt (XVIII) gave (XIX). Ozonization of olefinic double bond, followed by treatment with Me2S and K2CO3 provided ketone (XX). Then, haloform reaction with NaOBr gave acid (XXI), and reduction with LiAlH4 in cold Et2O afforded primary alcohol (XXII). Alcohol (XXII) was converted to mesylate (XXIII), and this was condensed with 4-(trifluoromethoxy)phenol (XXIV) to give ether (XXV). Deprotection of the trityl group with formic acid in EtOAc and subsequent reaction with methanesulfonyl chloride provided mesylate (XXVI), which was finally condensed with morpholine (XXVII) to furnish the target compound.
【1】 Tsukuda, T.; Watanabe, M.; Ontsuka, H.; Hattori, K.; Shirai, M.; Shimma, N.; Synthesis of novel antifungal agents (2). Bioorg Med Chem Lett 1998, 8, 14, 1825. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XVII) | 18762 | 1-Ethoxyethylene; Ethyl vinyl ether;Ethoxyethene | 109-92-2 | C4H8O | 详情 | 详情 |
(XVIII) | 16341 | 1H-1,2,4-triazol-1-ylsodium | C2H2N3Na | 详情 | 详情 | |
(XIX) | 18775 | 2-[(1S,2R,3R,4R)-4-isopropenyl-2-methoxy-1-methyl-3-(1H-1,2,4-triazol-1-ylmethyl)cyclohexyl]ethyl trityl ether; 1-([(1R,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexyl]methyl)-1H-1,2,4-triazole | C35H41N3O2 | 详情 | 详情 | |
(XX) | 18776 | 1-[(1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexyl]-1-ethanone | C34H39N3O3 | 详情 | 详情 | |
(XXI) | 18777 | (1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexanecarboxylic acid | C33H37N3O4 | 详情 | 详情 | |
(XXII) | 18778 | [(1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexyl]methanol | C33H39N3O3 | 详情 | 详情 | |
(XXIII) | 18779 | [(1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexyl]methyl methanesulfonate | C34H41N3O5S | 详情 | 详情 | |
(XXIV) | 18780 | 4-(trifluoromethoxy)phenol | 828-27-3 | C7H5F3O2 | 详情 | 详情 |
(XXV) | 18781 | 1-([(1R,2R,3S,6R)-2-methoxy-3-methyl-6-[[4-(trifluoromethoxy)phenoxy]methyl]-3-[2-(trityloxy)ethyl]cyclohexyl]methyl)-1H-1,2,4-triazole; 2-((1S,2R,3R,4R)-2-methoxy-1-methyl-3-(1H-1,2,4-triazol-1-ylmethyl)-4-[[4-(trifluoromethoxy)phenoxy]methyl]cyclohexyl)ethyl trityl ether | C40H42F3N3O4 | 详情 | 详情 | |
(XXVI) | 18782 | 2-((1S,2R,3R,4R)-2-methoxy-1-methyl-3-(1H-1,2,4-triazol-1-ylmethyl)-4-[[4-(trifluoromethoxy)phenoxy]methyl]cyclohexyl)ethyl methanesulfonate | C22H30F3N3O6S | 详情 | 详情 | |
(XXVII) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(I)The condensation of 4-(trifluoromethoxy)phenol (I) with 4-fluorophenyl(methyl)sulfone (II) by means of K2CO3 in hot DMSO gives the diphenyl ether (III), which is condensed with 2,2-dimethyl-1,3-dioxolane-(R)-carboxylic acid methyl ester (IV) by means of BuLi in THF to afford the ethanone (V). The reduction of (V) with NaBH4 in ethanol yields the ethanol derivative (VI), which is dehydrated to the ethylene (VII) by means of MsCl, TEA and NaHCO3. The addition of hydroxylamine to the double bond of (VII) provides the hydroxyamine derivative (VIII) as a diastereomeric mixture that is separated by flash chromatography, affording the desired enantiomer (IX). Finally, this compound is formylated by treatment with 2,2,2-trifluoroethyl formate (X) (obtained by reaction of 2,2,2-trifluoroethanol (XI) with hot formic acid (XII)) in refluxing MTBE.
【1】 Curtin, M.L.; Wada, C.K.; Holms, J.H.; et al.; Phenoxyphenyl sulfone N-forylhydroxylamines (retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors. J Med Chem 2002, 45, 1, 219. |
【2】 Curtin, M.L.; Davidsen, S.K.; Michaelides, M.R.; Steinman, D.H.; Dai, Y.; Heyman, H.R.; Holmes, J.H. (Abbott Laboratories Inc.); Reverse hydroxamate inhibitors of matrix metalloproteinases. WO 0044739 . |
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) | 18780 | 4-(trifluoromethoxy)phenol | 828-27-3 | C7H5F3O2 | 详情 | 详情 |
(II) | 46256 | 4-fluorophenyl methyl sulfone; (4-fluorophenyl)(methyl)dioxo-lambda(6)-sulfane | C7H7FO2S | 详情 | 详情 | |
(III) | 46241 | methyl(dioxo)[4-[4-(trifluoromethoxy)phenoxy]phenyl]-lambda(6)-sulfane; methyl 4-[4-(trifluoromethoxy)phenoxy]phenyl sulfone | C14H11F3O4S | 详情 | 详情 | |
(IV) | 20917 | methyl (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylate | 52373-72-5 | C7H12O4 | 详情 | 详情 |
(V) | 46257 | 1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)-1-ethanone | C20H19F3O7S | 详情 | 详情 | |
(VI) | 46258 | (1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)-1-ethanol | C20H21F3O7S | 详情 | 详情 | |
(VII) | 46259 | (Z)-2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethenyl 4-[4-(trifluoromethoxy)phenoxy]phenyl sulfone; (4S)-2,2-dimethyl-4-[(Z)-2-([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)ethenyl]-1,3-dioxolane | C20H19F3O6S | 详情 | 详情 | |
(VIII) | 46260 | (4S)-4-[1-(hydroxyamino)-2-([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)ethyl]-2,2-dimethyl-1,3-dioxolane; N-[1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)ethyl]hydroxylamine | C20H22F3NO7S | 详情 | 详情 | |
(IX) | 46261 | N-[(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)ethyl]hydroxylamine; (4S)-4-[(1S)-1-(hydroxyamino)-2-([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)ethyl]-2,2-dimethyl-1,3-dioxolane | C20H22F3NO7S | 详情 | 详情 | |
(X) | 46245 | 2,2,2-trifluoroethyl formate | C3H3F3O2 | 详情 | 详情 | |
(XI) | 19483 | 2,2,2-trifluoro-1-ethanol | 75-89-8 | C2H3F3O | 详情 | 详情 |
(XII) | 14590 | Formic acid | 64-18-6 | CH2O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号:(X)Ethyl nipecotate (I) was protected as the tert-butyl carbamate (II) upon treatment with Boc2O in THF. The lithium enolate of ester (II) was then sulfenylated with the disulfide (IV), prepared by oxidation of 4-fluorothiophenol (III), yielding thioether (V). This was further oxidized to the corresponding sulfone (VI) using meta-chloroperbenzoic acid. Acid cleavage of the Boc protecting group of (VI) gave piperidine (VII), which was converted to the N-cyclopropyl amine (IX) by reductive alkylation with [(1-ethoxycyclopropyl)oxy]trimethylsilane (VIII) in the presence of NaBH3CN. Displacement of the aryl fluoride of (IX) with 4-(trifluoromethoxy)phenol (X) under basic conditions afforded the diaryl ether (XI). After saponification of the ester group of (XI), the resultant carboxylic acid (XII) was coupled to O-(tetrahydropyranyl)hydroxylamine by means of EDC to produce the protected hydroxamate (XIII). Finally, removal of the tetrahydropyranyl protecting group of (XIII) with HCl in dioxan afforded the title compound.
【1】 Villamil, C.I.; et al.; Design and synthesis of 4,4-disubstituted piperidine alpha-sulphone hydroxamates as potent and selective MMP inhibitors: The discovery of SC-77964. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 258. |
【2】 Aromatic sulfone hydroxamic acid metalloprotease inhibitor. WO 0050396 . |
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) | 17410 | Ethyl isonipecotate; ethyl 4-piperidinecarboxylate | 1126-09-6 | C8H15NO2 | 详情 | 详情 |
(II) | 49847 | 1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine | 142851-03-4 | C13H23NO4 | 详情 | 详情 |
(III) | 22971 | 4-fluorobenzenethiol; 4-fluorophenylhydrosulfide; 4-Fluorothiophenol | 371-42-6 | C6H5FS | 详情 | 详情 |
(IV) | 52287 | bis(4-fluorophenyl) disulfide; 1-fluoro-4-[(4-fluorophenyl)disulfanyl]benzene | C12H8F2S2 | 详情 | 详情 | |
(V) | 52288 | 1-(1,1-dimethylethyl) 4-ethyl 4-[(4-fluorophenyl)sulfanyl]-1,4-piperidinedicarboxylate | C19H26FNO4S | 详情 | 详情 | |
(VI) | 52289 | 1-(1,1-dimethylethyl) 4-ethyl 4-[(4-fluorophenyl)sulfonyl]-1,4-piperidinedicarboxylate | C19H26FNO6S | 详情 | 详情 | |
(VII) | 52290 | ethyl 4-[(4-fluorophenyl)sulfonyl]-4-piperidinecarboxylate | C14H18FNO4S | 详情 | 详情 | |
(VIII) | 52291 | Cyclopropanone ethyl trimethylsilyl acetal; (1-Ethoxycyclopropoxy)trimethylsilane | C8H18O2Si | 详情 | 详情 | |
(IX) | 52292 | ethyl 1-cyclopropyl-4-[(4-fluorophenyl)sulfonyl]-4-piperidinecarboxylate | C17H22FNO4S | 详情 | 详情 | |
(X) | 18780 | 4-(trifluoromethoxy)phenol | 828-27-3 | C7H5F3O2 | 详情 | 详情 |
(XI) | 52293 | ethyl 1-cyclopropyl-4-{[4-({4-[(trifluoromethyl)oxy]phenyl}oxy)phenyl]sulfonyl}-4-piperidinecarboxylate | C24H26F3NO6S | 详情 | 详情 | |
(XII) | 52294 | 1-cyclopropyl-4-{[4-({4-[(trifluoromethyl)oxy]phenyl}oxy)phenyl]sulfonyl}-4-piperidinecarboxylic acid | C22H22F3NO6S | 详情 | 详情 | |
(XIII) | 52295 | 1-cyclopropyl-N-(tetrahydro-2H-pyran-2-yloxy)-4-{[4-({4-[(trifluoromethyl)oxy]phenyl}oxy)phenyl]sulfonyl}-4-piperidinecarboxamide | C27H31F3N2O7S | 详情 | 详情 |