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【结 构 式】 
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【分子编号】18815 【品名】4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde 【CA登记号】3446-89-7 |
【 分 子 式 】C8H8OS 【 分 子 量 】152.21692 【元素组成】C 63.13% H 5.3% O 10.51% S 21.07% |
合成路线1
该中间体在本合成路线中的序号：(I)Reaction of 4-methylthiobenzaldehyde (I) with acetone (A) affords in a 90% yield E-4-methylmercaptophenyl-3-buten-2-one (II), which is oxidized by sodium periodate to the sulfoxide (III) in a 55% yield without forming any sulfone as byproduct. The sulfoxide then reacts with 4-hydroxycumarin without solvent at 140 C to form methylsulfinylwarifarin. The compound is purified by extraction from ether with a 1% sodium hydroxide solution and then precipitated with 10% hydrochloric acid. The yield of the last step is 30% of theory.
| 【1】 Rehse, K.; Methylsulfinylwarfarin. Drugs Fut 1985, 10, 3, 205. |
| 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) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (I) | 18815 | 4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde | 3446-89-7 | C8H8OS | 详情 | 详情 |
| (II) | 29061 | (E)-4-[4-(methylsulfanyl)phenyl]-3-buten-2-one | C11H12OS | 详情 | 详情 | |
| (III) | 29062 | (E)-4-[4-(methylsulfinyl)phenyl]-3-buten-2-one | C11H12O2S | 详情 | 详情 | |
| (IV) | 29063 | 4-Hydroxycoumarine; 4-Hydroxy-2H-chromen-2-one; 4-hydroxy-2H-1-benzopyran-2-one; 4-oxocoumarin-3,4-dihydro-4-hydroxycoumarin; 4-hydroxy-2H-1-benzopyran-2-one | 1076-38-6 | C9H6O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)4-[(tert-Butyldimethylsilyloxy)methyl]pyridine (II) was prepared by silylation of 4-hydroxymethylpyridine (I) with tert-butyldimethylsilyl chloride and imidazole. Deprotonation of (II) by means of LDA in cold THF, followed by condensation with 4-fluorobenzaldehyde (III), furnished the protected diol adduct (IV), which was further desilylated upon treatment with tetrabutylammonium fluoride in THF. Oxidation of the resultant diol (V) under Swern conditions provided diketone (VI). The triaryl imidazole (VIII) was then obtained by condensation of diketone (VI) with 4-(methylsulfanyl)benzaldehyde (VII) in the presence of ammonium acetate in refluxing HOAc. Finally, oxidation of the thioether function of (VIII) with K-2S2O8 furnished the title sulfoxide.
| 【1】 Adams, J.L.; Gallagher, T.F.; Lee, J.C.; White, J.R. (GlaxoSmithKline plc); Imidazole derivs. and their use as cytokine inhibitors. EP 0623126; EP 0943616; JP 1995503017; US 5686455; WO 9314081 . |
| 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) | 32835 | 4-pyridinylmethanol | 586-95-8 | C6H7NO | 详情 | 详情 |
| (II) | 22829 | 4-([[tert-butyl(dimethyl)silyl]oxy]methyl)pyridine; tert-butyl(dimethyl)silyl 4-pyridinylmethyl ether | C12H21NOSi | 详情 | 详情 | |
| (III) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (IV) | 55081 | 2-{[tert-butyl(dimethyl)silyl]oxy}-1-(4-fluorophenyl)-2-(4-pyridinyl)-1-ethanol | C19H26FNO2Si | 详情 | 详情 | |
| (V) | 55082 | 1-(4-fluorophenyl)-2-(4-pyridinyl)-1,2-ethanediol | C13H12FNO2 | 详情 | 详情 | |
| (VI) | 37913 | 1-(4-fluorophenyl)-2-(4-pyridinyl)-1,2-ethanedione | C13H8FNO2 | 详情 | 详情 | |
| (VII) | 18815 | 4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde | 3446-89-7 | C8H8OS | 详情 | 详情 |
| (VIII) | 55083 | 4-{5-(4-fluorophenyl)-2-[4-(methylsulfanyl)phenyl]-1H-imidazol-4-yl}pyridine; 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-imidazol-2-yl]phenyl methyl sulfide | C21H16FN3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)In a related procedure, 4-fluorobenzoyl chloride (IX) was converted to the corresponding Weinreb amide (X) upon treatment with N,O-dimethylhydroxylamine. Condensation of (X) with the lithium derivative of 4-[(tert-butyldimethylsilyloxy)methyl]pyridine (II) furnished the silylated hydroxy ketone (XI). This was then condensed with 4-(methylthio)benzaldehyde (VII) in the presence of cupric acetate as oxidant and ammonium acetate to produce the intermediate triaryl imidazole (VIII), which was finally oxidized as above.
| 【1】 Gallagher, T.F.; et al.; Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase. Bioorg Med Chem 1997, 5, 1, 49. |
| 【2】 Gallagher, T.F.; et al.; 2,4,5-Triarylimidazole inhibitors of IL-1 biosynthesis. Bioorg Med Chem Lett 1995, 5, 11, 1171. |
| 【3】 Adams, J.L.; Gallagher, T.F.; Lee, J.C.; White, J.R. (GlaxoSmithKline plc); Imidazole derivs. and their use as cytokine inhibitors. EP 0623126; EP 0943616; JP 1995503017; US 5686455; WO 9314081 . |
| 【4】 Adams, J.L.; Gallagher, T.F.; Lee, J.C.; White, J.R. (GlaxoSmithKline plc); Imidazoles for treating cytokine mediated disease. WO 9503297 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 22829 | 4-([[tert-butyl(dimethyl)silyl]oxy]methyl)pyridine; tert-butyl(dimethyl)silyl 4-pyridinylmethyl ether | C12H21NOSi | 详情 | 详情 | |
| (VII) | 18815 | 4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde | 3446-89-7 | C8H8OS | 详情 | 详情 |
| (VIII) | 55083 | 4-{5-(4-fluorophenyl)-2-[4-(methylsulfanyl)phenyl]-1H-imidazol-4-yl}pyridine; 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-imidazol-2-yl]phenyl methyl sulfide | C21H16FN3S | 详情 | 详情 | |
| (IX) | 17263 | 4-fluorobenzoyl chloride | 403-43-0 | C7H4ClFO | 详情 | 详情 |
| (X) | 29514 | 4-fluoro-N-methoxy-N-methylbenzamide | C9H10FNO2 | 详情 | 详情 | |
| (XI) | 22831 | 2-[[tert-butyl(dimethyl)silyl]oxy]-1-(4-fluorophenyl)-2-(4-pyridinyl)-1-ethanone | C19H24FNO2Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)Condensation of p-fluorobenzaldehyde (I) with propionic anhydride (II) by means of sodium propionate at 140 C affords p-fluoro-alpha-methylcinnamic acid (III), which is then hydrogenated over Pd/C in EtOH to provide p-fluoro-alpha-methylhydrocinnamic acid (IV). Derivative (IV) is subjected to cyclization by treatment with polyphosphoric acid (PPA) to give 6-fluoro-2-methylindanone (V), which is converted into 5-fluoro-2-methylindenyl-3-acetic acid (VII) by first condensation with cyanoacetic acid (VI) by means of acetic acid and ammonium acetate in refluxing toluene, followed by hydrolysis with KOH in hot ethanol. Condensation of derivative (VII) with p-methylthiobenzaldehyde (VIII) by means of sodium methoxide in hot MeOH affords 5-fluoro-2-methyl-1-[p-(methylsulfanyl)benzylidene]-3-indenyl acetic acid (IX), which is then oxidized in MeOH/acetone by means of an aqueous solution of sodium periodate to yield methylsulfinylbenzylidene derivative (X). Finally, the target product is obtained by further oxidation of (X) with H2O2 in the presence of sodium methoxide and sodium bicarbonate in MeOH/acetonitrile at -10 C.
| 【1】 Mayle, M.J.; Menander, K.B. (Cell Pathways, Inc.); A method for treating patients with acne by administering a cyclic GMP PDE inhibitor. WO 0044372 . |
| 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) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (II) | 20095 | propionic anhydride | 123-62-6 | C6H10O3 | 详情 | 详情 |
| (III) | 48870 | (Z)-3-(4-fluorophenyl)-2-methyl-2-propenoic acid | C10H9FO2 | 详情 | 详情 | |
| (IV) | 48871 | 3-(4-fluorophenyl)-2-methylpropionic acid | C10H11FO2 | 详情 | 详情 | |
| (V) | 48872 | 6-Fluoro-2-methylindanone | C10H9FO | 详情 | 详情 | |
| (VI) | 12591 | Cyanoacetic Acid; 2-Cyanoacetic acid | 372-09-8 | C3H3NO2 | 详情 | 详情 |
| (VII) | 48874 | 2-(5-fluoro-2-methyl-1H-inden-3-yl)acetic acid | C12H11FO2 | 详情 | 详情 | |
| (VIII) | 18815 | 4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde | 3446-89-7 | C8H8OS | 详情 | 详情 |
| (IX) | 51940 | 2-(5-fluoro-2-methyl-1-[(E)-[4-(methylsulfanyl)phenyl]methylidene]-1H-inden-3-yl)acetic acid | C20H17FO2S | 详情 | 详情 | |
| (X) | 51941 | 2-(5-fluoro-2-methyl-1-[(E)-[4-(methylsulfinyl)phenyl]methylidene]-1H-inden-3-yl)acetic acid | C20H17FO3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The condensation of 4-(methylsulfanyl)benzaldehyde (I) with 4-fluorophenylacetic acid (II) in refluxing acetic anhydride containing one equivalent of triethylamine, followed by aqueous hydrolysis, provided the diarylpropenoic acid (III). Curtius rearrangement of acid (III) by treatment with diphenylphosphoryl azide in cold toluene, and subsequent hydrolysis of the intermediate isocyanate afforded diarylethanone (IV), which was then brominated in a solution of HBr in acetic acid to give bromoketone (V). The cyclization of this bromoketone with 2-chlorothiobenzamide (VI) in refluxing acetonitrile gave rise to thiazole (VII), and then, oxidation with meta-chloroperbenzoic acid in dichloromethane provided the target sulfone.
| 【1】 Talley, J.J.; Carter, J.S.; Collins, P.W.; Kramer, S.W.; Penning, T.D.; Rogier, D.J. Jr.; Rogers, R.S. (Pharmacia Corp.); Substd. thiazoles for the treatment of inflammation. EP 0772606; JP 1998504542; US 5668161; WO 9603392 . |
| 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) | 18815 | 4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde | 3446-89-7 | C8H8OS | 详情 | 详情 |
| (II) | 18999 | 4-Fluorophenylacetic acid; 2-(4-Fluorophenyl)acetic acid | 405-50-5 | C8H7FO2 | 详情 | 详情 |
| (III) | 19000 | (E)-2-(4-fluorophenyl)-3-[4-(methylsulfanyl)phenyl]-2-propenoic acid | C16H13FO2S | 详情 | 详情 | |
| (IV) | 19001 | 1-(4-fluorophenyl)-2-[4-(methylsulfanyl)phenyl]-1-ethanone | C15H13FOS | 详情 | 详情 | |
| (V) | 19002 | 2-bromo-1-(4-fluorophenyl)-2-[4-(methylsulfanyl)phenyl]-1-ethanone | C15H12BrFOS | 详情 | 详情 | |
| (VI) | 19003 | 2-chlorobenzenecarbothioamide | 15717-17-6 | C7H6ClNS | 详情 | 详情 |
| (VII) | 19004 | 4-[2-(2-chlorophenyl)-4-(4-fluorophenyl)-1,3-thiazol-5-yl]phenyl methyl sulfide; 2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfanyl)phenyl]-1,3-thiazole | C22H15ClFNS2 | 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 precursor deoxybenzoin (V) was prepared via Perkin condensation of 4-fluorophenylacetic acid (I) with 4-(methylsulfanyl)benzaldehyde (II) to yield the alpha-phenylcinnamic acid derivative (III), followed by Curtius rearrangement of the corresponding acylazide, and further hydrolysis of the intermediate isocyanate (IV) with HCl in t-BuOH. Alternatively, Friedel-Crafts acylation of fluorobenzene with acid chloride (VI) yielded deoxyenzoin (V). Bromoketone (VII) was then obtained by bromination of (V) in the presence of HBr and AcOH. Subsequent condensation of (VII) with 2-chlorothiobenzamide (VIII) formed thiazole (IX). Finally, the sulfide group of (IX) was oxidized to sulfone using m-chloroperbenzoic acid.
| 【1】 Carter, J.S.; et al.; Design and synthesis of sulfonyl-substituted 4,5-diaylthiazoles as selective cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett 1999, 9, 8, 1167. |
| 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) | 18999 | 4-Fluorophenylacetic acid; 2-(4-Fluorophenyl)acetic acid | 405-50-5 | C8H7FO2 | 详情 | 详情 |
| (II) | 18815 | 4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde | 3446-89-7 | C8H8OS | 详情 | 详情 |
| (III) | 19000 | (E)-2-(4-fluorophenyl)-3-[4-(methylsulfanyl)phenyl]-2-propenoic acid | C16H13FO2S | 详情 | 详情 | |
| (IV) | 25754 | (E)-1-(4-fluorophenyl)-2-[4-(methylsulfanyl)phenyl]ethenyl isocyanate; 1-fluoro-4-[(E)-1-isocyanato-2-[4-(methylsulfanyl)phenyl]ethenyl]benzene | C16H12FNOS | 详情 | 详情 | |
| (V) | 19001 | 1-(4-fluorophenyl)-2-[4-(methylsulfanyl)phenyl]-1-ethanone | C15H13FOS | 详情 | 详情 | |
| (VI) | 25755 | 2-[4-(methylsulfanyl)phenyl]acetyl chloride | C9H9ClOS | 详情 | 详情 | |
| (VII) | 19002 | 2-bromo-1-(4-fluorophenyl)-2-[4-(methylsulfanyl)phenyl]-1-ethanone | C15H12BrFOS | 详情 | 详情 | |
| (VIII) | 19003 | 2-chlorobenzenecarbothioamide | 15717-17-6 | C7H6ClNS | 详情 | 详情 |
| (IX) | 19004 | 4-[2-(2-chlorophenyl)-4-(4-fluorophenyl)-1,3-thiazol-5-yl]phenyl methyl sulfide; 2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfanyl)phenyl]-1,3-thiazole | C22H15ClFNS2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XI)Horner-Emmons reaction of 4-(methylthio)benzaldehyde (XI) with phosphonate (XII) in the presence of Et3N and MgBr2 afforded unsaturated ester (XIII). Oxidation to sulfone (XIV) was effected with H2O2 and a catalytic amount of Na2WO4. Subsequent reduction of the ester group with DIBAL-H in CH2Cl2 at -78 C produced allyl alcohol (XV), which was converted to iodide (XVI) on treatment with I2, Ph3P and imidazole in acetonitrile. Reaction of this iodide with methyl chlorodifluoro-acetate in the presence of KF and CuI in DMF at 90 C yielded trifluoromethyl compound (XVIII). Alternatively, alcohol (XV) could be converted to (XVIII) with chlorodifluoroacetic anhydride followed by conversion of the intermediate ester (XVII) to trifluoroethyl compound in the presence of KF and CuI. Sharpless asymmetric dihydroxylation of olefin (XVIII) with potassium ferricyanide or iodine and a catalytic amount of K3OsO4 as the oxidants and the chiral ligand hydroquinidine 1,4-phthalazinediyl diether ((DHQD)2PHAL) yielded diol (XXI) with a 79% e.e. In a related procedure, diol (XXI) was obtained by reduction of ester (XIII) and treatment of the resulting allyl alcohol (XIX) with chlordifluoroacetic anhydride to give olefin (XX). Sharpless oxidation of (XX) then produced a mixture of diols with a sulfide, sulfoxide and sulfone groups, which was oxidized with H2O2 and Na2WO4 to the sulfone (XXI) with a 82% e.e. Recrystallization from isopropyl acetate-hexane raised the e.e. to > 98%. Then, Swern oxidation of diol (XXI) provided hydroxyketone (VII). Subsequent esterification with 3,4-difluorophenoxyacetic acid (XXII) in the presence of CMC and DMAP gave ester (X), which was cyclized to the target furanone by treatment with DBU using isopropyl trifluoroacetate as a water scavenger.
| 【1】 Tan, L.; et al.; An efficient asymmetric synthesis of a potent COX-2 inhibitor L-784,512. Tetrahedron Lett 1998, 39, 23, 3961. |
| 【2】 Belley, M.; Gauthier, J.Y.; Grimm, E.; Leblanc, Y.; Li, C.-S.; Therien, M.; Lau, C.-K.; Prasit, P.; Roy, P. (Merck Frosst Canada Inc.); (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors. EP 0863891; JP 1999500146; US 5981576; WO 9714691 . |
| 【3】 Black, C.; Leger, S.; Prasit, P.; Wang, Z.; Hamel, P.; Han, Y.; Hughes, G. (Merck Frosst Canada Inc.); 3,4-Diaryl-2-hydroxy-2,5-dihydrofurans as prodrugs to Cox-2 inhibitors. EP 0904269; JP 1999500748; US 5698584; WO 9716435 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 18811 | (2R)-4,4,4-trifluoro-2-hydroxy-2-methyl-1-[4-(methylsulfonyl)phenyl]-1-butanone | C12H13F3O4S | 详情 | 详情 | |
| (X) | 18814 | (1R)-3,3,3-trifluoro-1-methyl-1-[4-(methylsulfonyl)benzoyl]propyl 2-(3,4-difluorophenoxy)acetate | C20H17F5O6S | 详情 | 详情 | |
| (XI) | 18815 | 4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde | 3446-89-7 | C8H8OS | 详情 | 详情 |
| (XII) | 18816 | ethyl 2-(diethoxyphosphoryl)propanoate | 3699-66-9 | C9H19O5P | 详情 | 详情 |
| (XIII) | 18817 | ethyl (E)-2-methyl-3-[4-(methylsulfanyl)phenyl]-2-propenoate | C13H16O2S | 详情 | 详情 | |
| (XIV) | 18818 | ethyl (E)-2-methyl-3-[4-(methylsulfonyl)phenyl]-2-propenoate | C13H16O4S | 详情 | 详情 | |
| (XV) | 18819 | (E)-2-methyl-3-[4-(methylsulfonyl)phenyl]-2-propen-1-ol | C11H14O3S | 详情 | 详情 | |
| (XVI) | 18820 | 4-[(E)-3-iodo-2-methyl-1-propenyl]phenyl methyl sulfone; [4-[(E)-3-iodo-2-methyl-1-propenyl]phenyl](methyl)dioxo-lambda(6)-sulfane | C11H13IO2S | 详情 | 详情 | |
| (XVII) | 18821 | methyl 4-[(E)-4,4,4-trifluoro-2-methyl-1-butenyl]phenyl sulfone; (E)-2-methyl-3-[4-(methylsulfonyl)phenyl]-2-propenyl 2-chloro-2,2-difluoroacetate | C13H13ClF2O4S | 详情 | 详情 | |
| (XVIII) | 18822 | methyl(dioxo)[4-[(E)-4,4,4-trifluoro-2-methyl-1-butenyl]phenyl]-lambda(6)-sulfane | C12H13F3O2S | 详情 | 详情 | |
| (XIX) | 18823 | (E)-2-methyl-3-[4-(methylsulfanyl)phenyl]-2-propen-1-ol | C11H14OS | 详情 | 详情 | |
| (XX) | 18824 | 1-(methylsulfanyl)-4-[(E)-4,4,4-trifluoro-2-methyl-1-butenyl]benzene; methyl 4-[(E)-4,4,4-trifluoro-2-methyl-1-butenyl]phenyl sulfide | C12H13F3S | 详情 | 详情 | |
| (XXI) | 18825 | (1R,2R)-4,4,4-trifluoro-2-methyl-1-[4-(methylsulfonyl)phenyl]-1,2-butanediol | C12H15F3O4S | 详情 | 详情 | |
| (XXII) | 18826 | 2-(3,4-difluorophenoxy)acetic acid | C8H6F2O3 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(III)Reaction of benzaldehyde (I) with trimethylsilyl cyanide and ZnI2 gave O-trimethylsilyl cyanohydrin (II). Subsequent condensation of (II) with 4-(methylthio)benzaldehyde (III) in the presence of lithium hexamethyldisilazide, followed by quenching of the intermediate (IV) with KHF2 and HCl, provided benzoin (V). This was oxidized either under Swern conditions, or with Bi2O3 in acetic to afford the corresponding benzil (VI). Condensation of (VI) with trifluoroacetaldehyde ethyl hemiacetal (VII) produced imidazole (VIII). Finally, oxidation of the sulfide group of (VIII) with hydrogen peroxide in AcOH provided the target sulfone.
| 【1】 Barta, T.E.; Collins, P.W.; Weier, R.M.; Stealey, M.A.; Antiinflammatory 4,5-diarylimidazoles as selective cyclooxygenase inhibitors. Bioorg Med Chem Lett 1998, 8, 24, 3443. |
| 【2】 Weier, R.M.; Collins, P.W.; Stealey, M.A.; Barta, T.E.; Huff, R.M. (Pharmacia Corp.); 4,5-Substd. imidazolyl cpds. for the treatment of inflammation. EP 0772601; US 5620999; WO 9603387 . |
| 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) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (II) | 26578 | 2-phenyl-3-(trimethylsilyl)propanenitrile | C12H17NSi | 详情 | 详情 | |
| (III) | 18815 | 4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde | 3446-89-7 | C8H8OS | 详情 | 详情 |
| (IV) | 26579 | 3-hydroxy-3-[4-(methylsulfanyl)phenyl]-2-phenyl-2-[(trimethylsilyl)methyl]propanenitrile | C20H25NOSSi | 详情 | 详情 | |
| (V) | 26580 | 2-hydroxy-2-[4-(methylsulfanyl)phenyl]-1-phenyl-1-ethanone | C15H14O2S | 详情 | 详情 | |
| (VI) | 26581 | 1-[4-(methylsulfanyl)phenyl]-2-phenyl-1,2-ethanedione | C15H12O2S | 详情 | 详情 | |
| (VII) | 26582 | 1-ethoxy-2,2,2-trifluoro-1-ethanol | 433-27-2 | C4H7F3O2 | 详情 | 详情 |
| (VIII) | 26583 | methyl 4-[5-phenyl-2-(trifluoromethyl)-1H-imidazol-4-yl]phenyl sulfide | C17H13F3N2S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(X)An related procedure was based on the formation of the intermediate stilbene sulfone (XII) by Wittig reaction. Thus, condensation of phosphonium salt (IX) with aldehyde (X) in the presence of LiOEt gave stilbene (XI) as a mixture of geometric isomers. Then, oxidation of the sulfide group of (XI) with Oxone provided stilbene sulfone (XII). Alternatively, phosphonium salt (XIV), prepared from benzyl chloride (XIII) and triphenyl phosphine, was condensed with benzaldehyde to yield (XII). The oxidation of stilbene (XII) with KMnO4 produced benzil (XV). Finally, cyclization of (XV) with hemiacetal (VII) furnished the title imidazole.
| 【1】 Barta, T.E.; Collins, P.W.; Weier, R.M.; Stealey, M.A.; Antiinflammatory 4,5-diarylimidazoles as selective cyclooxygenase inhibitors. Bioorg Med Chem Lett 1998, 8, 24, 3443. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 | |
| (VII) | 26582 | 1-ethoxy-2,2,2-trifluoro-1-ethanol | 433-27-2 | C4H7F3O2 | 详情 | 详情 |
| (IX) | 26584 | benzyl(triphenyl)phosphonium iodide | 15853-35-7 | C25H22IP | 详情 | 详情 |
| (X) | 18815 | 4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde | 3446-89-7 | C8H8OS | 详情 | 详情 |
| (XI) | 26585 | methyl 4-[(Z)-2-phenylethenyl]phenyl sulfide | C15H14S | 详情 | 详情 | |
| (XII) | 26586 | methyl 4-[(Z)-2-phenylethenyl]phenyl sulfone | C15H14O2S | 详情 | 详情 | |
| (XIII) | 26587 | 4-(chloromethyl)phenyl methyl sulfone | C8H9ClO2S | 详情 | 详情 | |
| (XIV) | 26588 | [4-(methylsulfonyl)benzyl](triphenyl)phosphonium chloride | C26H24ClO2PS | 详情 | 详情 | |
| (XV) | 26589 | 1-[4-(methylsulfonyl)phenyl]-2-phenyl-1,2-ethanedione | C15H12O4S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(II)Aldol condensation between 5'-fluoro-2'-hydroxyacetophenone (I) and 4-(methylthio)benzaldehyde (II) produces chalcone (III). Oxidative cyclization of (III) in hot DMSO in the presence of iodine leads to the flavone compound (IV). Further oxidation of the methylthio group of (IV) employing oxone furnishes sulfone (V). Conversion of flavone (V) into the 3-iodo derivative (VI) is carried out by treatment with iodine and bis(trifluoroacetoxy)iodobenzene. Finally, Suzuki coupling of the iodoflavone (VI) with lithium trimethoxy-3-pyridylboronate (VII) provides the desired 2,3-diaryl benzopyranone
| 【1】 Joo, Y.H.; Kim, J.K.; Kang, S-H.; Noh, M-S.; Ha, J-Y.; Choi, J.K.; Lim, K.M.; Lee, C.H.; Chung, S.; Diarylbenzopyran derivatives as a selective inhibitor of cyclooxygenase-2. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 313. |
| 【2】 Kim, J.K.; Choi, J.K.; Lee, C.H.; Joo, Y.H.; Noh, M.-S.; Ha, J.-Y.; Lim, K.M.; Kang, S.-H. (Pacific Corp.); Diarylbenzopyran derivs. as cyclooxygenase-2 inhibitors. EP 1105384; JP 2002523410; US 6340694; WO 0010993 . |
| 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) | 60391 | 1-(5-fluoro-2-hydroxyphenyl)-1-ethanone | 394-32-1 | C8H7FO2 | 详情 | 详情 |
| (II) | 18815 | 4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde | 3446-89-7 | C8H8OS | 详情 | 详情 |
| (III) | 60392 | (E)-1-(5-fluoro-2-hydroxyphenyl)-3-[4-(methylsulfanyl)phenyl]-2-propen-1-one | C16H13FO2S | 详情 | 详情 | |
| (IV) | 60393 | 6-fluoro-2-[4-(methylsulfanyl)phenyl]-4H-chromen-4-one | C16H11FO2S | 详情 | 详情 | |
| (V) | 60394 | 6-fluoro-2-[4-(methylsulfonyl)phenyl]-4H-chromen-4-one | C16H11FO4S | 详情 | 详情 | |
| (VI) | 60395 | 6-fluoro-3-iodo-2-[4-(methylsulfonyl)phenyl]-4H-chromen-4-one | C16H10FIO4S | 详情 | 详情 | |
| (VII) | 30006 | Trimethoxy(3-pyridyl)boranuide lithium salt | C8H13BLiNO3 | 详情 | 详情 |