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【结 构 式】 
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【分子编号】19264 【品名】2-bromo-1-[4-(methylsulfonyl)phenyl]-1-ethanone 【CA登记号】 |
【 分 子 式 】C9H9BrO3S 【 分 子 量 】277.13866 【元素组成】C 39.01% H 3.27% Br 28.83% O 17.32% S 11.57% |
合成路线1
该中间体在本合成路线中的序号：(XII)4) The oxidation of 4-(methylsulfanyl)acetophenone (X) with monoperoxyphthalic acid (MMPP) in dichloro-methane/methanol gives the corresponding sulfone (XI), which is brominated with Br2/AlCl3 in chloroform, yielding the expected phenacyl bromide (XII). Finally, this compound is cyclocondensed with phenylacetic acid (I) by means of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and triethylamine in acetonitrile. 5) Reaction of [4-(methylsulfonyl)phenyl]phenylacetyl-ene (XIII) with CO catalyzed by Rh4(CO)12 in THF at 100 C in a stainless steel autoclave at 100 Atm pressure, followed by a chromatographic separation in a silicagel column to eliminate the undesired regioisomer.
| 【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】 Ducharme, Y.; Gauthier, J.Y.; Prasit, P.; Leblanc, Y.; Wang, Z.; Leger, S.; Therien, M. (Merck Frosst Canada Inc.); Phenyl heterocycles as cyclooxygenase-2 inhibitors. EP 0705254; EP 0739340; EP 0754687; EP 0822190; EP 0980866; JP 1997500372; JP 1997506631; JP 2000038375; US 5474995; WO 9500501; WO 9518799 . |
| 【4】 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 |
|---|---|---|---|---|---|---|
| (I) | 16148 | Benzeneacetic acid; 2-Phenylacetic acid; Phenyl Acetic Acid | 103-82-2 | C8H8O2 | 详情 | 详情 |
| (X) | 19262 | 1-[4-(methylsulfanyl)phenyl]-1-ethanone；4'-Methylthioacetophenon；4’-(methylthio)acetophenone | 1778-09-2 | C9H10OS | 详情 | 详情 |
| (XI) | 19263 | 1-[4-(methylsulfonyl)phenyl]-1-ethanone; 4-methylsulfonylacetophenone | 10297-73-1 | C9H10O3S | 详情 | 详情 |
| (XII) | 19264 | 2-bromo-1-[4-(methylsulfonyl)phenyl]-1-ethanone | C9H9BrO3S | 详情 | 详情 | |
| (XIII) | 19265 | methyl 4-(2-phenylethynyl)phenyl sulfone; methyl(dioxo)[4-(2-phenylethynyl)phenyl]-lambda(6)-sulfane | C15H12O2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)7) The Friedel-Crafts condensation of thioanisole (XX) with acetyl chloride (XXI) by means of AlCl3 in dichlorobenzene gives the corresponding acetophenone (X), which is oxidized with H2O2/WO4Na2 to the ketosulfone (XI). The bromination of (XI) with Br2 in acetic acid/48% HBr affords the phenacyl bromide (XII), which is condensed with phenylacetic acid sodium salt (XXIII) in DMF, giving the phenacyl ester (XXII). Finally, this compound is cyclized by means of diisopropylamine in DMF.
| 【1】 Sorbera, L.A.; Rabasseda, X.; Castañer, J.; Rofecoxib. Drugs Fut 1998, 23, 12, 1287. |
| 【2】 Frey, L.F.; Dolling, U.H.; Desmond, R.; Tillyer, R.D.; Tschaen, D.M. (Merck & Co., Inc.); Process of preparing phenyl heterocycles useful as COX-2 inhibitors. WO 9800416 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 19262 | 1-[4-(methylsulfanyl)phenyl]-1-ethanone；4'-Methylthioacetophenon；4’-(methylthio)acetophenone | 1778-09-2 | C9H10OS | 详情 | 详情 |
| (XI) | 19263 | 1-[4-(methylsulfonyl)phenyl]-1-ethanone; 4-methylsulfonylacetophenone | 10297-73-1 | C9H10O3S | 详情 | 详情 |
| (XII) | 19264 | 2-bromo-1-[4-(methylsulfonyl)phenyl]-1-ethanone | C9H9BrO3S | 详情 | 详情 | |
| (XX) | 19272 | methyl phenyl sulfide; 1-(methylsulfanyl)benzene | 100-68-5 | C7H8S | 详情 | 详情 |
| (XXI) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
| (XXII) | 19274 | 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl 2-phenylacetate | C17H16O5S | 详情 | 详情 | |
| (XXIII) | 19275 | sodium 2-phenylacetate | 114-70-5 | C8H7NaO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The Friedel Crafts acylation of thioanisole (I) with acetyl chloride (II) and AlCl3 in chloroform gives 4-(methylsulfanyl)acetophenone (III), which is oxidized with monoperoxyphthalic acid (MMPP) in methanol/dichloromethane to yield 4-(methylsulfonyl)acetophenone (IV). The bromination of (IV) with Br2 and AlCl3 in chloroform affords 4-(methylsulfonyl)phenacyl bromide (V), which is finally cyclized by means of DBU and TEA in acetonitrile to provide the target furanone derivative.
| 【1】 Thérien, M.; Gauthier, J.Y.; Leblanc, Y.; Leger, S.; Perrier, H.; Prasit, P.; Wang, Z.; Synthesis of rofecoxib, (MK 0966, Vioxx(R)) 4-(4'-methylsulfonylphenyl)-3-phenyl-2(5H)-furanone), a selective and orally active inhibitor of cyclooxygenase-2. Synthesis (Stuttgart) 2001, 12, 1778. |
| 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) | 19272 | methyl phenyl sulfide; 1-(methylsulfanyl)benzene | 100-68-5 | C7H8S | 详情 | 详情 |
| (II) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
| (III) | 19262 | 1-[4-(methylsulfanyl)phenyl]-1-ethanone；4'-Methylthioacetophenon；4’-(methylthio)acetophenone | 1778-09-2 | C9H10OS | 详情 | 详情 |
| (IV) | 19263 | 1-[4-(methylsulfonyl)phenyl]-1-ethanone; 4-methylsulfonylacetophenone | 10297-73-1 | C9H10O3S | 详情 | 详情 |
| (V) | 19264 | 2-bromo-1-[4-(methylsulfonyl)phenyl]-1-ethanone | C9H9BrO3S | 详情 | 详情 | |
| (VI) | 16148 | Benzeneacetic acid; 2-Phenylacetic acid; Phenyl Acetic Acid | 103-82-2 | C8H8O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)6-Chloronicotinic acid (I) is converted to the corresponding acid chloride (II) employing either SOCl2 or PCl5/POCl3. Treatment of acid chloride (II) with EtOH and Et3N, followed by reduction of the resultant ethyl ester with LiAlH4, furnishes 6-chloro-3-pyridylmethanol (III). Alcohol (III) is alternatively prepared by NaBH4 reduction of acid chloride (II). Chlorination of (III) by using SOCl2 gives the chloromethyl pyridine (IV), and further chloride displacement with KCN leads to nitrile (V). Substitution of the remaining chloride group of (V) upon heating with pyrrolidine (VI) furnishes the pyrrolidinyl pyridine (VII). Then hydrolysis of the nitrile function of (VII) under acidic conditions provides carboxylic acid (VIII). Bromination of 4-(methylsulfonyl)acetophenone (IX) in the presence of AlCl3 produces the phenacyl bromide (X). Finally, condensation between acid (VIII) and bromo ketone (X) under basic conditions gives rise to the title diaryl furanone
| 【1】 Almansa, C.; Alfon, J.; Cavalcanti, F.L.; Gomez, L.; Miralles, A.; Synthesis and SAR of 4-pyrrolidinylarylheterocycles as COX-2 selective inhibitors. Drugs Fut 2002, 27, Suppl. A. |
| 【2】 Almansa Rosales, C.; Gonzalez Gonzalez, C.; Torres Barreda, M.C. (J. Uriach & Cia., SA); Novel heterocyclic cpds. with anti-inflammatory activity. EP 1281709; ES 2166710; WO 0183475 . |
| 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) | 12996 | 6-Chloronicotinic acid | 5326-23-8 | C6H4ClNO2 | 详情 | 详情 |
| (II) | 30256 | 6-chloronicotinoyl chloride | 58757-38-3 | C6H3Cl2NO | 详情 | 详情 |
| (III) | 60372 | (6-chloro-3-pyridinyl)methanol | C6H6ClNO | 详情 | 详情 | |
| (IV) | 60373 | 2-chloro-5-(chloromethyl)pyridine | C6H5Cl2N | 详情 | 详情 | |
| (V) | 60374 | 2-(6-chloro-3-pyridinyl)acetonitrile | C7H5ClN2 | 详情 | 详情 | |
| (VI) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (VII) | 60375 | 2-[6-(1-pyrrolidinyl)-3-pyridinyl]acetonitrile | C11H13N3 | 详情 | 详情 | |
| (VIII) | 60376 | 2-[6-(1-pyrrolidinyl)-3-pyridinyl]acetic acid | C11H14N2O2 | 详情 | 详情 | |
| (IX) | 19263 | 1-[4-(methylsulfonyl)phenyl]-1-ethanone; 4-methylsulfonylacetophenone | 10297-73-1 | C9H10O3S | 详情 | 详情 |
| (X) | 19264 | 2-bromo-1-[4-(methylsulfonyl)phenyl]-1-ethanone | C9H9BrO3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)
| 【1】 Sharma NR.Rawat GS. 2004. Synthesis of rofecoxib and study of Lactone ring stability. Asia J Chem, 16: 978～982 |
| 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) | 19262 | 1-[4-(methylsulfanyl)phenyl]-1-ethanone；4'-Methylthioacetophenon；4’-(methylthio)acetophenone | 1778-09-2 | C9H10OS | 详情 | 详情 |
| (II) | 19263 | 1-[4-(methylsulfonyl)phenyl]-1-ethanone; 4-methylsulfonylacetophenone | 10297-73-1 | C9H10O3S | 详情 | 详情 |
| (III) | 19264 | 2-bromo-1-[4-(methylsulfonyl)phenyl]-1-ethanone | C9H9BrO3S | 详情 | 详情 | |
| (IV) | 16148 | Benzeneacetic acid; 2-Phenylacetic acid; Phenyl Acetic Acid | 103-82-2 | C8H8O2 | 详情 | 详情 |
| (V) | 19274 | 2-[4-(methylsulfonyl)phenyl]-2-oxoethyl 2-phenylacetate | C17H16O5S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)
| 【1】 Ao GZ, Wang WD．Zhang YH. 2002．Synthesis of selective COX-2 inhibitor rofecoxib. 中国医药工业杂志, 33: 267～268(本论文作者来自于Center of Drug Discovery．China Pharmaceutical University, Nanjing, Peop Rep China) |
| 【2】 Desmond R, Dolling UH, Frey LF,et aL. 1998. Process of preparing phenyl heterocycles useful as COX-2 inhibitors. W0 9800416(本专利属于Merck＆Co．Inc，USA) |
| 【3】 Therien M. Gauthier JY, Leblanc Y et aL. 2001. Syntheais of Rofecoxib, (MK 0966, Vioxx 4-(4'-methyl-sulfonylphenyl) -3-phenyl-2(5H)-furanone), a selective ancl orally active inhibitor of cycloocygeruse-2. Synthesis, (12):1778～1779(本论文作者来自于Merck Frosst Centre for Therapeutic Research，Dorval, QC, Can) |
| 【4】 Wu AH，Wang QH，Wang QL et al. 2002．Synthesis of new cyclooxygenase-2 inhibitor: rofcoxib．中国药物化学杂志，12: 37～38(本论文作者来自于School of Pharmaceutical Engineering，Shenyang Pharmaceutical University, Shenyang, Peop Rep China) |
| 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) | 19272 | methyl phenyl sulfide; 1-(methylsulfanyl)benzene | 100-68-5 | C7H8S | 详情 | 详情 |
| (II) | 19262 | 1-[4-(methylsulfanyl)phenyl]-1-ethanone；4'-Methylthioacetophenon；4’-(methylthio)acetophenone | 1778-09-2 | C9H10OS | 详情 | 详情 |
| (III) | 19263 | 1-[4-(methylsulfonyl)phenyl]-1-ethanone; 4-methylsulfonylacetophenone | 10297-73-1 | C9H10O3S | 详情 | 详情 |
| (IV) | 19264 | 2-bromo-1-[4-(methylsulfonyl)phenyl]-1-ethanone | C9H9BrO3S | 详情 | 详情 | |
| (V) | 16148 | Benzeneacetic acid; 2-Phenylacetic acid; Phenyl Acetic Acid | 103-82-2 | C8H8O2 | 详情 | 详情 |