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【结 构 式】 
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【分子编号】22288 【品名】4-fluoro-2-nitrophenylamine; 4-fluoro-2-nitroaniline 【CA登记号】364-78-3 |
【 分 子 式 】C6H5FN2O2 【 分 子 量 】156.1163832 【元素组成】C 46.16% H 3.23% F 12.17% N 17.94% O 20.5% |
合成路线1
该中间体在本合成路线中的序号：(I)Michael addition of acrylonitrile (II) to 4-fluoro-2-nitroaniline (I) in the presence of Triton B provided nitrile (III). The nitro group of (III) was then reduced to the amine (IV) by hydrogenation over Pd/C. Further cyclization of amine (IV) with ethyl (ethoxycarbonyl)acetimidate (V) furnished the benzimidazole (VI). Diester (VII) (prepared by refluxing the nitrile (VI) with ethanolic HCl), was submitted to Dieckmann cyclization in the presence of NaOEt to produce the pyridobenzimidazole (VIII). Reaction of the ester group of (VIII) with 2-fluoroaniline (IX) in boiling xylene yielded the corresponding anilide (X), which was finally alkylated with ethoxymethyl chloride (XI) in the presence of NaH and crown ether.
| 【1】 Sanfilippo, P.J.; Reitz, A.B.; Kordik, C.P.; Dubinsky, B.; Rosenthal, D.I.; Vaidya, A.H.; Jordan, A.D.; Wu, W.-N.; Potential anxiolytic agents. Part 4: Novel orally-active N(5)-substituted pyrido[1,2-a]benzimidazoles with high GABA-A receptor affinity. Bioorg Med Chem Lett 2002, 12, 17, 2381. |
| 【2】 Cohen, J.H.; et al.; Process research for the synthesis of RWJ-51204, a novel anxiolytic agent. Org Process Res Dev 1999, 3, 4, 260. |
| 【3】 Reitz, A.B.; Jordan, A.D.; Sanfilippo, P.J.; Scott, M.K. (Ortho-McNeil Pharmaceutical, Inc.); 5-Heteroatom-containing alkyl substd.-3-oxo-pyrido(1,2-a)benzimidazole-4-carboxamide derivs. useful in treating central nervous system disorders. EP 0935598; US 5817668; WO 9815553 . |
| 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) | 22288 | 4-fluoro-2-nitrophenylamine; 4-fluoro-2-nitroaniline | 364-78-3 | C6H5FN2O2 | 详情 | 详情 |
| (III) | 22290 | 3-(4-fluoro-2-nitroanilino)propanenitrile | C9H8FN3O2 | 详情 | 详情 | |
| (IV) | 22291 | 3-(2-amino-4-fluoroanilino)propanenitrile | C9H10FN3 | 详情 | 详情 | |
| (VI) | 22293 | ethyl 2-[1-(2-cyanoethyl)-5-fluoro-1H-benzimidazol-2-yl]acetate | C14H14FN3O2 | 详情 | 详情 | |
| (VII) | 22294 | ethyl 3-[2-(2-ethoxy-2-oxoethyl)-5-fluoro-1H-benzimidazol-1-yl]propanoate | C16H19FN2O4 | 详情 | 详情 | |
| (VIII) | 22295 | ethyl 7-fluoro-3-oxo-1,2,3,5-tetrahydropyrido[1,2-a]benzimidazole-4-carboxylate | C14H13FN2O3 | 详情 | 详情 | |
| (IX) | 22296 | 2-fluorophenylamine; 2-fluoroaniline | 348-54-9 | C6H6FN | 详情 | 详情 |
| (X) | 22297 | 7-fluoro-N-(2-fluorophenyl)-3-oxo-1,2,3,5-tetrahydropyrido[1,2-a]benzimidazole-4-carboxamide | C18H13F2N3O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Synthesis of intermediate (VII): Conversion of 3-fluoroaniline (I) into 2-amino-5-fluorobenzothiazole (III) can be achieved by first coupling with isocyanate (II) followed by hydrolysis with NaOH, reaction with Br2 and finally heating treatment. Dimerization of substituted benzothiazole (III) by means of refluxing aqueous KOH yields disulfide derivative (IV), which is then condensed with substituted benzoyl chloride (V) in refluxing pyridine to afford derivative (VI). Finally, (VI) is converted into intermediate (VII) by treatment with SnCl2 dihydrate in refluxing HCl/EtOH. Alternatively, intermediate (VII) can be synthesized as follows: substituted aniline (VIII) is first brominated via a Sandmeyer reaction with NaNO2 in HBr and CuBr, and then the nitro group is reduced with SnCl2 in refluxing EtOH to provide derivative (IX). Condensation of (IX) with substituted benzoyl chloride (V) in refluxing pyridine yields amide (X), which is then first treated with Lawesson's reagent and HMPA and then with NaH in NMP to afford benzothiazole derivative (XI). Finally, the nitro group of (XI) is reduced with SnCl2 in refluxing EtOH to yield intermediate (VII). Synthesis of EN 295753: The desired compound can finally be obtained by coupling of intermediate (VII) with Boc-Lys(Boc)-OH (XII) by means of carbodiimide WSC.HCl and HOBt in CH2Cl2, followed by Boc removal with HCl (gas) in CH2Cl2.
| 【1】 Hutchinson, I.; et al.; Antitumor benzothiazoles. 16. Synthesis and pharmaceutical properties of antitumor 2-(4-aminophenyl)benzothiazole amino acid produgs. J Med Chem 2002, 45, 3, 744. |
| 【2】 Chua, M.-S.; Westwell, A.D.; Hutchinson, I.P.; Stevens, M.F.G.; Poole, T.D. (Cancer Research Campaign Technology Ltd.); Substd. 2-arylbenzazole cpds. and their use as antitumour agents. WO 0114354 . |
| 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) | 20697 | 3-fluoroaniline; 3-fluorophenylamine | 372-19-0 | C6H6FN | 详情 | 详情 |
| (II) | 23530 | benzoyl isothiocyanate | 532-55-8 | C8H5NOS | 详情 | 详情 |
| (III) | 47594 | 5-fluoro-1,3-benzothiazol-2-amine; 5-fluoro-1,3-benzothiazol-2-ylamine | C7H5FN2S | 详情 | 详情 | |
| (IV) | 47595 | 2-[(2-amino-4-fluorophenyl)disulfanyl]-5-fluoroaniline; 2-[(2-amino-4-fluorophenyl)disulfanyl]-5-fluorophenylamine | C12H10F2N2S2 | 详情 | 详情 | |
| (V) | 47596 | 3-methyl-4-nitrobenzoyl chloride | 35675-46-8 | C8H6ClNO3 | 详情 | 详情 |
| (VI) | 47597 | N-[5-fluoro-2-([4-fluoro-2-[(3-methyl-4-nitrobenzoyl)amino]phenyl]disulfanyl)phenyl]-3-methyl-4-nitrobenzamide | C28H20F2N4O6S2 | 详情 | 详情 | |
| (VII) | 47598 | 1-(5-fluoro-1,3-benzothiazol-2-yl)-3-methyl-1lambda(5)-pyridin-4-amine; 1-(5-fluoro-1,3-benzothiazol-2-yl)-3-methyl-1lambda(5)-pyridin-4-ylamine | C13H12FN3S | 详情 | 详情 | |
| (VIII) | 22288 | 4-fluoro-2-nitrophenylamine; 4-fluoro-2-nitroaniline | 364-78-3 | C6H5FN2O2 | 详情 | 详情 |
| (IX) | 47599 | 2-bromo-5-fluoroaniline; 2-bromo-5-fluorophenylamine | 1003-99-2 | C6H5BrFN | 详情 | 详情 |
| (X) | 47600 | N-(2-bromo-5-fluorophenyl)-3-methyl-4-nitrobenzamide | C14H10BrFN2O3 | 详情 | 详情 | |
| (XI) | 47602 | methyl 3-(1-trityl-1H-imidazol-4-yl)propanoate | C26H24N2O2 | 详情 | 详情 | |
| (XII) | 37991 | (2S)-2,6-bis[(tert-butoxycarbonyl)amino]hexanoic acid | 2483-46-7 | C16H30N2O6 | 详情 | 详情 |
| (XIII) | 47601 | tert-butyl (1S)-5-[(tert-butoxycarbonyl)amino]-1-([[1-(5-fluoro-1,3-benzothiazol-2-yl)-3-methyl-1lambda(5)-pyridin-4-yl]amino]carbonyl)pentylcarbamate | C29H40FN5O5S | 详情 | 详情 |