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【结 构 式】 
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【药物名称】L-784512 【化学名称】3-(3,4-Difluorophenoxy)-5(R)-methyl-4-[4-(methylsulfonyl) phenyl]-5-(2,2,2-trifluoroethyl)furan-2(5H)-one 【CA登记号】189955-09-7, 189955-44-0 (undefined isomer) 【 分 子 式 】C20H15F5O5S 【 分 子 量 】462.39555 |
【开发单位】Merck & Co. (Originator) 【药理作用】Antiinflammatory Drugs, Cyclooxygenase-2 Inhibitors |
合成路线1
Alkylation of 2-(S)-tert-butyl-5-(S)-methyl-1,3-dioxolan-4-one (I) with 1,1,1-trifluoro-2-iodoethane (II) in the presence of LDA in THF at -72 C provided trifluoroethyl compound (III). Condensation of (III) with 4-(methylthio)phenyllithium (IV), prepared from 4-bromothioanisole and BuLi, gave (V), which was hydrolyzed with p-toluenesulfonic acid in boiling water to afford ketone (VI). Subsequent oxidation of sulfide group with KHSO5 (Oxone(R)) in the presence of Oct3NMeCl (Aliquat 336(R)) produced sulfone (VII). Esterification of (VII) with chloroacetic acid using 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide methyl-p-toluenesulfonate (CMC) as the condensing agent provided chloroacetate (VIII). Finally, condensation with 3,4-difluorophenol (IX) in the presence of DBU in acetonitrile gave the intermediate ether (X), which cyclized to produce the target furanone.
| 【1】 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 . |
| 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) | 18805 | (2S,5S)-2-(tert-butyl)-5-methyl-1,3-dioxolan-4-one | C8H14O3 | 详情 | 详情 | |
| (II) | 18806 | 1,1,1-trifluoro-2-iodoethane | 353-83-3 | C2H2F3I | 详情 | 详情 |
| (III) | 18807 | (2S,5R)-2-(tert-butyl)-5-methyl-5-(2,2,2-trifluoroethyl)-1,3-dioxolan-4-one | C10H15F3O3 | 详情 | 详情 | |
| (IV) | 18808 | [4-(methylsulfanyl)phenyl]lithium | C7H7LiS | 详情 | 详情 | |
| (V) | 18809 | (2S,5R)-2-(tert-butyl)-5-methyl-4-[4-(methylsulfanyl)phenyl]-5-(2,2,2-trifluoroethyl)-1,3-dioxolan-4-ol | C17H23F3O3S | 详情 | 详情 | |
| (VI) | 18810 | (2R)-4,4,4-trifluoro-2-hydroxy-2-methyl-1-[4-(methylsulfanyl)phenyl]-1-butanone | C12H13F3O2S | 详情 | 详情 | |
| (VII) | 18811 | (2R)-4,4,4-trifluoro-2-hydroxy-2-methyl-1-[4-(methylsulfonyl)phenyl]-1-butanone | C12H13F3O4S | 详情 | 详情 | |
| (VIII) | 18812 | (1R)-3,3,3-trifluoro-1-methyl-1-[4-(methylsulfonyl)benzoyl]propyl 2-chloroacetate | C14H14ClF3O5S | 详情 | 详情 | |
| (IX) | 16739 | 3,4-difluorophenol | 2713-33-9 | C6H4F2O | 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 |
合成路线2
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 |