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【结 构 式】 
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【分子编号】19260 【品名】4-[4-(methylsulfanyl)phenyl]-3-phenyl-2(5H)-furanone 【CA登记号】 |
【 分 子 式 】C17H14O2S 【 分 子 量 】282.36296 【元素组成】C 72.31% H 5% O 11.33% S 11.36% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The synthesis of rofecoxib can be performed by several different ways: 1) The condensation of phenylacetic acid (I) with ethyl bromoacetate (II) by means of triethylamine in THF yields 2-(phenylacetoxy)acetic acid ethyl ester (III), which is cyclized to the hydroxyfuranone (IV) by means of potassium tert-butoxide in tert-butanol. The reaction of (IV) with triflic anhydride and diisopropylethylamine in dichloro-methane affords the corresponding triflate (V), which by reaction with LiBr in hot acetone yields the bromofuranone (VI). The condensation of (VI) with 4-(methylsulfanyl)phenylboronic acid (VII) by means of Na2CO3 and Pd(Ph3P)4 in hot toluene gives 4-[4-(methylsulfanyl)-phenyl]-3-phenylfuran-2(5H)-one (VIII), which is finally oxidized with 2KHSO5.KHSO4.K2SO4 (oxone). 2) The intermediate (VIII) can also be obtained by condensation of triflate (V) with boronic acid (VII) by means of Na2CO3 and Pd(Ph3P)4 in hot toluene. 3) The intermediate (VIII) can also be synthesized by the reaction of triflate (V) with tetramethylammonium chloride, giving the chlorofuranone (IX), which is then condensed with boronic acid (VII) as before.
| 【1】 Sorbera, L.A.; Rabasseda, X.; Castañer, J.; Rofecoxib. Drugs Fut 1998, 23, 12, 1287. |
| 【2】 Tillyer, R.; Desmond, R.; Dolling, U.; Marcune, B.; Tschaen, D. (Merck & Co., Inc.); Process for making phenyl heterocycles useful as COX-2 inhibitors. WO 9608482 . |
| 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) | 16148 | Benzeneacetic acid; 2-Phenylacetic acid; Phenyl Acetic Acid | 103-82-2 | C8H8O2 | 详情 | 详情 |
| (II) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (III) | 19255 | 2-ethoxy-2-oxoethyl 2-phenylacetate | C12H14O4 | 详情 | 详情 | |
| (IV) | 19256 | 4-hydroxy-3-phenyl-2(5H)-furanone | 23782-85-6 | C10H8O3 | 详情 | 详情 |
| (V) | 19257 | 5-oxo-4-phenyl-2,5-dihydro-3-furanyl trifluoromethyl sulfate | C11H7F3O6S | 详情 | 详情 | |
| (VI) | 19258 | 4-bromo-3-phenyl-2(5H)-furanone | C10H7BrO2 | 详情 | 详情 | |
| (VII) | 18561 | 4-(methylsulfanyl)phenylboronic acid | 98546-51-1 | C7H9BO2S | 详情 | 详情 |
| (VIII) | 19260 | 4-[4-(methylsulfanyl)phenyl]-3-phenyl-2(5H)-furanone | C17H14O2S | 详情 | 详情 | |
| (IX) | 19261 | 4-chloro-3-phenyl-2(5H)-furanone | C10H7ClO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)6) The reaction of 4-bromothioanisole (XIV) with furan-2(5H)-one (XV) by means of tert-BuLi/CuI in ethyl ether, followed by silylation with trimethylsilyl chloride gives 4-[4-(methylsulfanyl)phenyl]-2-(trimethylsilyloxy)-3,4-dihydrofuran (XVI), which is desilylated with palladium acetate in acetonitrile to afford the furanone (XVII). The iodination of (XVII) with I2 in pyridine yields 3-iodo-4-[4-(methylsulfanyl)phenyl]furan-2(5H)-one (XVIII), which is condensed with phenylboronic acid (XIX) by means of triphenylarsine and a Pd catalyst in refluxing benzene, giving 4-[4-(methylsulfanyl)phenyl]-3-phenylfuran-2(5H)-one (VIII), already described in Scheme 1. Finally, this compound is oxidized with monoperoxyphthalic acid magnesium salt in dichloromethane/methanol.
| 【1】 Sorbera, L.A.; Rabasseda, X.; Castañer, J.; Rofecoxib. Drugs Fut 1998, 23, 12, 1287. |
| 【2】 Atkinson, J.G.; Wang, Z. (Merck Frosst Canada Inc.); Stilbene derivs. useful as cyclooxygenase-2 inhibitors. EP 0788476; JP 1998507765; WO 9613483 . |
| 【3】 Hancock, B.; Winters, C.; Gertz, B.; Ehrich, E. (Merck & Co., Inc.; Merck Frosst Canada Inc.); Compsns. for a once a day treatment of cyclooxygenase-2 mediated diseases. JP 1999512754; WO 9744028 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 19260 | 4-[4-(methylsulfanyl)phenyl]-3-phenyl-2(5H)-furanone | C17H14O2S | 详情 | 详情 | |
| (XIV) | 19266 | 4-bromophenyl methyl sulfide; 1-bromo-4-(methylsulfanyl)benzene | 104-95-0 | C7H7BrS | 详情 | 详情 |
| (XV) | 19267 | 2(5H)-furanone；furan-2(5H)-one；2-Buten-1,4-olide | 497-23-4 | C4H4O2 | 详情 | 详情 |
| (XVI) | 19268 | trimethyl([4-[4-(methylsulfanyl)phenyl]-4,5-dihydro-2-furanyl]oxy)silane; 4-[4-(methylsulfanyl)phenyl]-4,5-dihydro-2-furanyl trimethylsilyl ether | C14H20O2SSi | 详情 | 详情 | |
| (XVII) | 19269 | 4-[4-(methylsulfanyl)phenyl]-2(5H)-furanone | C11H10O2S | 详情 | 详情 | |
| (XVIII) | 19270 | 3-iodo-4-[4-(methylsulfanyl)phenyl]-2(5H)-furanone | C11H9IO2S | 详情 | 详情 | |
| (XIX) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)
| 【1】 Majo VJ, Prabhakaran J, Simpson NR, et al. 2005. A general method for the synthesis of aryl[11C] methylsulfone; potential PET probes for imaging cycloox3vgenase-2 expression. Baoorg Med Chem Lett,15: 4268～4271 |
| 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) | 18561 | 4-(methylsulfanyl)phenylboronic acid | 98546-51-1 | C7H9BO2S | 详情 | 详情 |
| (II) | 66641 | 3,4-dibromofuran-2(5H)-one | 149418-41-7 | C4H2Br2O2 | 详情 | 详情 |
| (III) | 66642 | 3-bromo-4-(4-(methylthio)phenyl)furan-2(5H)-one | C11H9BrO2S | 详情 | 详情 | |
| (IV) | 19260 | 4-[4-(methylsulfanyl)phenyl]-3-phenyl-2(5H)-furanone | C17H14O2S | 详情 | 详情 | |
| (V) | 66643 | 4-(4-(methylsulfinyl)phenyl)-3-phenylfuran-2(5H)-one | C17H14O3S | 详情 | 详情 | |
| (VI) | 66644 | (4-(5-oxo-4-phenyl-2,5-dihydrofuran-3-yl)phenyl) butanethioate | C20H18O3S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)
| 【1】 Zhang J, Blazecka PG, Belmont D, et al. 2002. Reinvestigation of mucohalic acids, versatile and useful building blocks for highly functionalized, β-unsaturated, -butyrolactones. Org Lett,41 4559～4561（本论文作者来自于Global Research & Development, Ann Arbor lAboratories, Chemical Research and Development, Pfizer, Inc) |
| 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) | 66608 | 3,4-dibromo-5-hydroxyfuran-2(5H)-one | 766-38-1 | C4H2Br2O3 | 详情 | 详情 |
| (II) | 66641 | 3,4-dibromofuran-2(5H)-one | 149418-41-7 | C4H2Br2O2 | 详情 | 详情 |
| (III) | 18561 | 4-(methylsulfanyl)phenylboronic acid | 98546-51-1 | C7H9BO2S | 详情 | 详情 |
| (IV) | 66642 | 3-bromo-4-(4-(methylthio)phenyl)furan-2(5H)-one | C11H9BrO2S | 详情 | 详情 | |
| (V) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (VI) | 19260 | 4-[4-(methylsulfanyl)phenyl]-3-phenyl-2(5H)-furanone | C17H14O2S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)
| 【1】 Rossi R, Bellina F, Raugei E. 2000. Selective synthesis of unsymmetrical 3,4-disubstituted and 4-substituted 2(5H)-furanones. Synlett, (12): 1749～1752. |
| 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) | 66608 | 3,4-dibromo-5-hydroxyfuran-2(5H)-one | 766-38-1 | C4H2Br2O3 | 详情 | 详情 |
| (II) | 66641 | 3,4-dibromofuran-2(5H)-one | 149418-41-7 | C4H2Br2O2 | 详情 | 详情 |
| (III) | 66651 | 3-bromo-4-(4-(methylthio)phenyl)furan-2(5H)-one | C8H10SSn | 详情 | 详情 | |
| (IV) | 66642 | 3-bromo-4-(4-(methylthio)phenyl)furan-2(5H)-one | C11H9BrO2S | 详情 | 详情 | |
| (V) | 19260 | 4-[4-(methylsulfanyl)phenyl]-3-phenyl-2(5H)-furanone | C17H14O2S | 详情 | 详情 |