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【结 构 式】 
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【分子编号】17341 【品名】5-methyl-4-isoxazolecarbonyl chloride 【CA登记号】67305-24-2 |
【 分 子 式 】C5H4ClNO2 【 分 子 量 】145.545 【元素组成】C 41.26% H 2.77% Cl 24.36% N 9.62% O 21.99% |
合成路线1
该中间体在本合成路线中的序号：(X)Leflunomide can be obtained by several related ways: 1) The reaction of diketene (I) with 4-(trifluoromethyl)-aniline (II) in hot acetonitrile gives N-[4-(trifluoro-methyl) phenyl]acetoacetamide (III) , which by reaction with triethyl orthoformate (IV) in refluxing acetic anhydride yields the corresponding ethoxymethylene derivative (V). Finally, this compound is cyclized with hydroxylamine in refluxing ethanol/water. 2) The reaction of ethyl acetoacetate (VI) with triethyl orthoformate (IV) as before gives the corresponding ethoxymethylene derivative (VII), which by cyclization with hydroxylamine as before affords 5-methylisoxazole-4-carboxylic acid ethyl ester (VIII). The hydrolysis of (VIII) under acidic conditions yields the free acid (IX), which is converted into the acid chloride (X) by standard methods. Finally, this compound is condensed with 4-(trifluoro-methyl)aniline (II) by means of triethylamine in acetonitrile. 3) The formation of leflunomide from acid (IX) or its derivatives such as ethyl (VIII) or other esters can also be performed through other standard procedures of amide formation. 4) The N-[4-(trifluoromethyl)phenyl]acetoacetamide (III) can also be obtained by reaction of 4-(trifluoro-methyl) aniline (II) with 2,2,6-trimethyl-4H-1,3-dioxin-4-one (XI) in refluxing xylene.
| 【1】 Fossa, P.; Schenone, P.; Filippelli, W.; Lucarelli, C.; Menozzi, G.; Russo, S.; Marmo, E.; 5-Substd. 4-isoxazolecarboxamides with platelet antiaggregating and other activities. Farmaco 1991, 46, 6, 789-802. |
| 【2】 Kammerer, F.-J.; Schleyerbach, R. (Aventis SA); Isoxazole deriv., process for its preparation, medicine containing it and intermediates required in the process. DE 2854439; EP 0013376; US 4284786; US 4351841 . |
| 【3】 Treatment of platelet derived growth factor related disorders such as cancers using inhibitors of platelet derived growth receptor. EP 1000617; US 5700823; WO 9519169 . |
| 【4】 Gershon, N.; Avrutov, I.; Liberman, A. (Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals USA, Inc.); A method for synthesizing leflunomide. WO 0160363 . |
| 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) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
| (II) | 17333 | 4-(trifluoromethyl)aniline; p-Trifluoromethylaniline; 4-(trifluoromethyl)phenylamine; 4-aminobenzotrifluoride | 455-14-1 | C7H6F3N | 详情 | 详情 |
| (III) | 17334 | 3-oxo-N-[4-(trifluoromethyl)phenyl]butanamide | C11H10F3NO2 | 详情 | 详情 | |
| (IV) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
| (V) | 17336 | (E)-2-acetyl-3-ethoxy-N-[4-(trifluoromethyl)phenyl]-2-propenamide | C14H14F3NO3 | 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) | 17338 | ethyl (E)-2-acetyl-3-ethoxy-2-propenoate | C9H14O4 | 详情 | 详情 | |
| (VIII) | 17339 | ethyl 5-methyl-4-isoxazolecarboxylate | C7H9NO3 | 详情 | 详情 | |
| (IX) | 17340 | 5-methyl-4-isoxazolecarboxylic acid | 42831-50-5 | C5H5NO3 | 详情 | 详情 |
| (X) | 17341 | 5-methyl-4-isoxazolecarbonyl chloride | 67305-24-2 | C5H4ClNO2 | 详情 | 详情 |
| (XI) | 13327 | 2,2,6-Trimethyl-4H-1,3-dioxin-4-one；2,2,6-trimethyl-1,3-dioxin-4-one；2,2,6-trimethyl-m-Dioxin-4-one;3-(1-hydroxy-1-methylethoxy)-d-lactone Crotonicacid | 5394-63-8 | C7H10O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)5-Methylisoxazole-4-carboxylic acid (I) was converted to the corresponding acid chloride (II) upon refluxing with SOCl2. Coupling of acid chloride (II) with 4-(trifluoromethyl)aniline (III) produced anilide (IV). Finally, isoxazole ring opening in the presence of NaOH gave rise to the title cyano amide.
| 【1】 Bartlett, R.R.; Kämmerer, F.-J. (Aventis SA); Isoxazole-4-carboxamides and hydroxyalkylidene-cyanoacetamides, drugs containing these cpds. and use of such drugs. EP 0527736; JP 1993506425; JP 1999322700; JP 1999343285; US 5494911; US 5532259; WO 9117748 . |
| 【2】 Coghlan, M.J.; Luly, J.R.; Wiedeman, P.E. (Abbott Laboratories Inc.); Immunosuppressive agents. WO 9424095 . |
| 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) | 17340 | 5-methyl-4-isoxazolecarboxylic acid | 42831-50-5 | C5H5NO3 | 详情 | 详情 |
| (II) | 17341 | 5-methyl-4-isoxazolecarbonyl chloride | 67305-24-2 | C5H4ClNO2 | 详情 | 详情 |
| (III) | 17333 | 4-(trifluoromethyl)aniline; p-Trifluoromethylaniline; 4-(trifluoromethyl)phenylamine; 4-aminobenzotrifluoride | 455-14-1 | C7H6F3N | 详情 | 详情 |
| (IV) | 54580 | 5-methyl-N-[4-(trifluoromethyl)phenyl]-4-isoxazolecarboxamide | C12H9F3N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)Alternatively, aniline (I) was coupled with 5-methylisoxazole-4-carbonyl chloride (IV) to provide the isoxazolecarboxamide (V). The isoxazole ring was then opened with NaOH to furnish the target cyanopropenamide.
| 【1】 Ghosh, S.; Zheng, Y.; Jun, X.; Narla, R.K.; Mahajan, S.; Navara, C.; Mao, C.; Sudbeck, E.A.; Uckun, F.M.; alpha-Cyano-beta-hydroxy-beta-methyl-N-[4-(trifluoromethoxy)phenyl]propenamide: An inhibitor of the epidermal growth factor receptor tyrosine kinase with potent cytotoxic activity. Clin Cancer Res 1998, 4, 11, 2657. |