|
【结 构 式】 
|
【分子编号】11131 【品名】4-(Trifluoromethoxy)aniline; 4-(Trifluoromethoxy)phenylamine 【CA登记号】461-82-5 |
【 分 子 式 】C7H6F3NO 【 分 子 量 】177.1259896 【元素组成】C 47.47% H 3.41% F 32.18% N 7.91% O 9.03% |
合成路线1
该中间体在本合成路线中的序号：(I)By condensation of 4-(trifluoromethoxy)aniline (I) with potassium thiocyanate (II) by means of Br2 in acetic acid.
| 【1】 Mizoule, J. (Pharmindustrie); New medicament containing 2-amino-6-trifluoromethoxybenzothiazole. EP 0050551 . |
| 【2】 Castaner, J.; Rabasseda, X.; Mealy, N.; Riluzole. Drugs Fut 1994, 19, 10, 920. |
合成路线2
该中间体在本合成路线中的序号：(I)Treatment of 4-(trifluoromethoxy)aniline (I) with thiocyanogen, generated from KSCN and Br2 in cold AcOH, afforded riluzole (II). Regioselective alkylation of (II) with 2-(methylthio)ethyl chloride (III) in refluxing methyl ethyl ketone then gave the title compound.
| 【1】 Barreau, M.; Audiau, F.; Jimonet, P.; et al.; Riluzole series. Synthesis and in vivo "antiglutamate" activity of 6-substituted-2-benzothiazolamines and 3-substituted-2-imino-benzothiazolines. J Med Chem 1999, 42, 15, 2828. |
| 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) | 11131 | 4-(Trifluoromethoxy)aniline; 4-(Trifluoromethoxy)phenylamine | 461-82-5 | C7H6F3NO | 详情 | 详情 |
| (II) | 34884 | 6-(trifluoromethoxy)-1,3-benzothiazol-2-ylamine; 6-(trifluoromethoxy)-1,3-benzothiazol-2-amine | 1744-22-5 | C8H5F3N2OS | 详情 | 详情 |
| (III) | 16149 | 2-Chloroethyl methyl sulfide; 1-Chloro-2-(methylsulfanyl)ethane | 542-81-4 | C3H7ClS | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Treatment of 4-(trifluoromethoxy)aniline (I) with thiocyanogen, generated from KSCN and Br2 in cold AcOH, afforded riluzole (II). Regioselective alkylation of (II) with 2-(methylthio)ethyl chloride (III) in refluxing methyl ethyl ketone then gave compound (IV), which was finally oxidized to the title sulfoxide by means of m-chloroperbenzoic acid.
| 【1】 Barreau, M.; Audiau, F.; Jimonet, P.; et al.; Riluzole series. Synthesis and in vivo "antiglutamate" activity of 6-substituted-2-benzothiazolamines and 3-substituted-2-imino-benzothiazolines. J Med Chem 1999, 42, 15, 2828. |
| 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) | 11131 | 4-(Trifluoromethoxy)aniline; 4-(Trifluoromethoxy)phenylamine | 461-82-5 | C7H6F3NO | 详情 | 详情 |
| (II) | 34884 | 6-(trifluoromethoxy)-1,3-benzothiazol-2-ylamine; 6-(trifluoromethoxy)-1,3-benzothiazol-2-amine | 1744-22-5 | C8H5F3N2OS | 详情 | 详情 |
| (III) | 16149 | 2-Chloroethyl methyl sulfide; 1-Chloro-2-(methylsulfanyl)ethane | 542-81-4 | C3H7ClS | 详情 | 详情 |
| (IV) | 34885 | 3-[2-(methylsulfanyl)ethyl]-6-(trifluoromethoxy)-1,3-benzothiazol-2(3H)-imine | C11H11F3N2OS2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Two synthetic ways have been reported for the compound. Coupling of cyanoacetic acid (II) to 4-(trifluoromethoxy)aniline (I) in the presence of diisopropylcarbodiimide formed the cyanoacetamide (III), which was treated with NaH and then acylated with acetyl chloride to yield the title compound.
| 【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. |
| 【2】 Ghosh, S.; Uckun, F.M.; Zheng, Y. (Parker Hughes Institute); Inhibitors of the EGF-receptor tyrosine kinase and their use. WO 0056703 . |
合成路线5
该中间体在本合成路线中的序号：(I)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. |
合成路线6
该中间体在本合成路线中的序号：(V)Chlorination of 4-(trifluoromethoxy)aniline (V) employing N-chlorosuccinimide affords the 2-chloro aniline (VI). Diazotization of aniline (VI) and subsequent quenching with potassium iodide gives rise to the aryl iodide (VII). This is converted into the arylboronic acid (VIII) by lithiation with butyllithium, followed by reaction with triisopropyl borate. Suzuki coupling between chloropyridine (IV) and boronic acid (VIII) leads to the phenylpyridine (IX). Reduction of the nitro group of (IX) employing sodium dithionite provides the diaminopyridine (X). This is finally condensed with triethyl orthopropionate to produce the target imidazopyridine compound.
| 【1】 Arvanitis, A.G.; Rescinito, J.T.; Arnold, C.R.; Wilde, R.G.; Fitzgerald, L.W.; Zaczek, R.; Hartig, P.R.; Grossman, S.; Arneric, S.P.; Gilligan, P.J.; Olson, R.E.; Robertson, D.W.; Imidazo[4,5-c]pyridines as corticotropin releasing factor receptor ligands. Bioorg Med Chem Lett 2003, 13, 1, 129. |
| 【2】 Wilde, R.G.; Bakthavatchalam, R.; Beck, J.P.; Arvanitis, A. (Bristol-Myers Squibb Co.); Imidazopyrimidinyl and imidazopyridinyl derivs.. EP 1244666; JP 2003516992; WO 0144248 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 63241 | N-(2-chloro-3-nitro-4-pyridinyl)-N-[(1S)-1-methylbutyl]amine; 2-chloro-N-[(1S)-1-methylbutyl]-3-nitro-4-pyridinamine | C10H14ClN3O2 | 详情 | 详情 | |
| (V) | 11131 | 4-(Trifluoromethoxy)aniline; 4-(Trifluoromethoxy)phenylamine | 461-82-5 | C7H6F3NO | 详情 | 详情 |
| (VI) | 63242 | 2-chloro-4-(trifluoromethoxy)aniline; 2-chloro-4-(trifluoromethoxy)phenylamine | C7H5ClF3NO | 详情 | 详情 | |
| (VII) | 63243 | 2-chloro-1-iodo-4-(trifluoromethoxy)benzene; 3-chloro-4-iodophenyl trifluoromethyl ether | C7H3ClF3IO | 详情 | 详情 | |
| (VIII) | 63244 | 2-chloro-4-(trifluoromethoxy)phenylboronic acid | C7H5BClF3O3 | 详情 | 详情 | |
| (IX) | 63245 | 2-[2-chloro-4-(trifluoromethoxy)phenyl]-N-[(1S)-1-methylbutyl]-3-nitro-4-pyridinamine; N-{2-[2-chloro-4-(trifluoromethoxy)phenyl]-3-nitro-4-pyridinyl}-N-[(1S)-1-methylbutyl]amine | C17H17ClF3N3O3 | 详情 | 详情 | |
| (X) | 63246 | N-{3-amino-2-[2-chloro-4-(trifluoromethoxy)phenyl]-4-pyridinyl}-N-[(1S)-1-methylbutyl]amine; 2-[2-chloro-4-(trifluoromethoxy)phenyl]-N~4~-[(1S)-1-methylbutyl]-3,4-pyridinediamine | C17H19ClF3N3O | 详情 | 详情 |