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【结 构 式】 
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【药物名称】Nabumetone, BRL-14777, Nabuser, Listran, Relafen, Relifen, Arthaxan, Relifex 【化学名称】4-(6-Methoxy-2-naphthalenyl)-2-butanone 【CA登记号】42924-53-8 【 分 子 式 】C15H16O2 【 分 子 量 】228.29357 |
【开发单位】GlaxoSmithKline (Originator), Procter & Gamble (Not Determined), Meda (Licensee), Uriach (Licensee) 【药理作用】Antiarthritic Drugs, Osteoarthritis, Treatment of, Rheumatoid Arthritis, Treatment of, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Non-Steroidal Antiinflammatory Drugs |
合成路线1
The condensation of 6-methoxy-2-naphthaldehyde (I) with ethyl aceto-acetate (II) gives ethyl 2-(6-methoxy-2-naphthylmethylene)acetoacetate (III), which is reduced to ethyl 2-(6-methoxy-2-naphthylmethyl)acetoacetate (IV). Finally, this compound is hydrolyzed and decarboxylated in acidic medium.
| 【1】 Rose, C.J.; Miller, D. (SmithKline Beecham plc); A1 14777 by hydrogenation. CA 1134384 . |
| 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) | 29956 | 6-Methoxy-2-naphthaldehyde | 3453-33-6 | C12H10O2 | 详情 | 详情 |
| (II) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (III) | 29957 | ethyl (Z)-2-acetyl-3-(6-methoxy-2-naphthyl)-2-propenoate | C18H18O4 | 详情 | 详情 | |
| (IV) | 29958 | ethyl 2-[(6-methoxy-2-naphthyl)methyl]-3-oxobutanoate | C18H20O4 | 详情 | 详情 |
合成路线2
The condensation of 6-methoxy-2-naphthaldehyde (I) with acetone by means of NaOH in water gives 4-(6-methoxy-2-naphtyl)-3-buten-2-one (II), which is reduced with H2 over Pd/C in ethyl acetate.
| 【1】 Goudie, A.C. Ert al.; 4-(6-Methoxy-2-naphtyl)butan-2-one and related analogues, a novel structural class of antiinflammatory compounds. J Med Chem 1978, 21, 12, 1260. |
| 【2】 Kyburz, E.; Aschwanden, W. (F. Hoffmann-La Roche AG); 1-(p-Methoxy-p-hydroxy, and p-benzyloxybenzoyl)-2-pyrrolidinones. DD 141828; EP 0005143; EP 0044088; ES 477587; ES 483756; JP 54117468 . |
| 【3】 Neuman, M.; Blancafort, P.; Castaner, J.; Serradell, M.N.; Nabumetone. Drugs Fut 1981, 6, 1, 35. |
| 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) | 29956 | 6-Methoxy-2-naphthaldehyde | 3453-33-6 | C12H10O2 | 详情 | 详情 |
| (II) | 32194 | (E)-4-(6-methoxy-2-naphthyl)-3-buten-2-one | C15H14O2 | 详情 | 详情 |
合成路线3
The reduction of methyl 6-methoxy-2-naphtyl acetate (III) with LiAlH4 in refluxing ether gives 2-(6-methoxy-2-naphthyl)ethanol (IV), which by treatment with PBr3 in refluxing benzene is converted into 2-(6-methoxy-2-naphthyl)ethyl bromide (V). The reaction of (V) with KCN in refluxing ethanol - water affords 3-(6-methoxy-2-naphthyl)propionitrile (VI), which is finally treated with methylmagnesium iodide in refluxing ethanol.
| 【1】 Goudie, A.C. Ert al.; 4-(6-Methoxy-2-naphtyl)butan-2-one and related analogues, a novel structural class of antiinflammatory compounds. J Med Chem 1978, 21, 12, 1260. |
| 【2】 Neuman, M.; Blancafort, P.; Castaner, J.; Serradell, M.N.; Nabumetone. Drugs Fut 1981, 6, 1, 35. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 32195 | 6-Methoxy-2-naphtyl acetate; 1-(6-Methoxy-2-naphthyl)acetone | C14H14O2 | 详情 | 详情 | |
| (IV) | 32196 | 2-(6-Methoxy-2-naphthyl)-1-ethanol | C13H14O2 | 详情 | 详情 | |
| (V) | 32197 | 6-(2-Bromoethyl)-2-naphthyl methyl ether; 2-(6-Methoxy-2-napthyl)ethyI bromide; 2-(2-Bromoethyl)-6-methoxynaphthalene | C13H13BrO | 详情 | 详情 | |
| (VI) | 32198 | 3-(6-Methoxy-2-naphthyl)propanenitrile; 3-(6-Methoxy-2-naphthyl)propionitrile | C14H13NO | 详情 | 详情 |
合成路线4
A short, simple and economical process for large-scale preparation of nabumetone has been reported: Condensation of commercially available 2-acetyl-6-methoxynaphthalene (2-acetylnaroline) (I) with ethyl acetate (II) by means of potassium sec-butoxide (sec-BuOK) in DMSO gives the ketoenol (III), which is reduced with H2 over Pd/C in ethyl acetate with a catalytic amount of sulfuric acid.
| 【1】 Nageshwar, D.; Devi, A.S.; Reddy, G.O.; Sarma, M.R.; Reddy, G.B.; Vyas, K.; Prabhakar, C.; Reddy, C.M.; Babu, J.M.; Process research and structural studies on nabumetone. Org Process Res Dev 1999, 3, 2, 121. |
合成路线5
The bromination of beta-naphthol (I) gives the 1,6-dibromo-beta-naphthol (II), which is partially debrominated with Sn and BrH, yielding 1-bromo-beta-naphthol (III). The methylation of (III) with methanol/sulfuric acid affords the corresponding methyl ether (IV), which is treated with Mg and DMF to provide 6-methoxynaphthalene-2-carbaldehyde (V). The condensation of (V) with ethyl acetoacetate (VI) gives the expected adduct (VII), which is reduced with H2 over Pd/C to provide 2-acetyl-3-(6-methoxy-2-naphthyl)propionic acid ethyl ester (VIII). Finally, this compound is decarboxylated with aqueous HCl.
| 【1】 Zhang, G.; et al.; A study on the synthesis of a new anti-inflammatory agent - nabumetone. J Shenyang Coll Pharm 1988, 5, 4, 259. |
| 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) | 44396 | 2-naphthol | 135-19-3 | C10H8O | 详情 | 详情 |
| (II) | 44397 | 1,6-dibromo-2-naphthol | 16239-18-2 | C10H6Br2O | 详情 | 详情 |
| (III) | 44398 | 6-bromo-2-naphthol | 15231-91-1 | C10H7BrO | 详情 | 详情 |
| (IV) | 44399 | 2-bromo-6-methoxynaphthalene; 6-bromo-2-naphthyl methyl ether | 5111-65-9 | C11H9BrO | 详情 | 详情 |
| (V) | 29956 | 6-Methoxy-2-naphthaldehyde | 3453-33-6 | C12H10O2 | 详情 | 详情 |
| (VI) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (VII) | 29957 | ethyl (Z)-2-acetyl-3-(6-methoxy-2-naphthyl)-2-propenoate | C18H18O4 | 详情 | 详情 | |
| (VIII) | 29958 | ethyl 2-[(6-methoxy-2-naphthyl)methyl]-3-oxobutanoate | C18H20O4 | 详情 | 详情 |
合成路线6
The condensation of 2-bromo-6-methoxynaphthalene (I) with 3-buten-2-one (II) by means of PdCl2, PPh3 and K2CO3 in DMF at 132 C gives 4-(6-methoxy-2-naphthyl)-3-buten-2-one (III), which is then hydrogenated with H2 over Pd/C in DMF. The same condensation can be performed with PdCl2 , PPh3 and NaHCO3 in 1-methyl-2-pyrrolidone at 130 C. The reaction of 4-hydroxy-2-butanone (IV) with acetic anhydride or acetyl chloride gives 4-acetyl-2-butanone (V), which is condensed with 2-bromo-6-methoxynaphthalene (I) by means of PdCl2, PPh3 and K2CO3 in DMF at 132 C to yield the previously reported 4-(6-methoxy-2-naphthyl)-3-buten-2-one (III).
| 【1】 Aslam, M.; et al.; Convenient synthesis of nabumetone. Synthesis 1989, 869. |
| 【2】 Fritch, J.R.; Rios, D.E.; Smith, J.C.; Aslam, M. (Celanese AG); Use of 4-substd. 2-butanones to prepare nabumetone. WO 9640608 . |
| 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) | 44399 | 2-bromo-6-methoxynaphthalene; 6-bromo-2-naphthyl methyl ether | 5111-65-9 | C11H9BrO | 详情 | 详情 |
| (II) | 30324 | 3-buten-2-one; methyl vinyl ketone | 78-94-4 | C4H6O | 详情 | 详情 |
| (III) | 32194 | (E)-4-(6-methoxy-2-naphthyl)-3-buten-2-one | C15H14O2 | 详情 | 详情 | |
| (IV) | 46053 | 4-hydroxy-2-butanone | C4H8O2 | 详情 | 详情 | |
| (V) | 46054 | 3-oxobutyl acetate | C6H10O3 | 详情 | 详情 |
合成路线7
By condensation of 2-bromo-6-methoxynaphthalene (I) with 3-buten-2-ol (VI) catalyzed by Pd(OAc)2 or PdCl2, along with PPh3 and NaHCO3 in 1-methyl-2-pyrrolidone at 140 C. The reaction of 2-bromo-6-methoxynaphthalene (I) with Mg in THF gives the expected Grignard reagent (VII), which is then condensed with 3-buten-2-one (II) by means of ZnCl2-amine complex in the same solvent.
| 【1】 Aslam, M.; et al.; Convenient synthesis of nabumetone. Synthesis 1989, 869. |
| 【2】 Wang, S.-M.; Chen, Z.-X.; Novel synthesis of nabumetone. Chin J Pharm 1989, 20, 4, 146. |
| 【3】 Davenport, K.G.; Aslam, M. (Celanese AG); Method of preparation of nabumetone. EP 0376516 . |