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【结 构 式】 
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【分子编号】17929 【品名】ethyl 3-ethoxy-3-iminopropanoate 【CA登记号】2318-25-4 |
【 分 子 式 】C7H13NO3 【 分 子 量 】159.18516 【元素组成】C 52.82% H 8.23% N 8.8% O 30.15% |
合成路线1
该中间体在本合成路线中的序号：(VI)Conjugated addition of 2-nitroaniline (I) to acrylonitrile (II) in the presence of Triton B in dioxane yielded propionitrile (III), which was hydrogenated to the phenylenediamine (IV). Treatment of ethyl cyanoacetate (V) with a cold saturated solution of HCl in absolute ethanol gave ethyl ethoxycarbonylacetimidate hydrochloride (VI). Reaction of this acetimidate (VI) with phenylenediamine (IV) in refluxing ethanol afforded the benzimidazole (VII), which was converted to the diester (VIII) on treatment with ethanolic HCl. Dieckmann condensation of diester (VIII) in the presence of sodium ethoxide furnished the tricyclic ketoester (IX), which was finally condensed with 2,6-difluoroaniline (X) in refluxing xilene to afford the target carboxamide.
| 【1】 Maryanoff, B.E.; et al.; Potential anxiolytic agents. Pyrido[1, 2-a]benzimidazoles: A new structural class of ligands for the benzodiazepine binding site on GABA-A receptors. J Med Chem 1995, 38, 1, 16. |
| 【2】 Maryanoff, B.E.; McComsey, D.F.; Winston, H. (Ortho-McNeil Pharmaceutical, Inc.); 3-Oxo-pyrido(1,2-a)benzimidazole-4-carboxyl and 4-oxo-azepino(1,2-a)benzimidazole-5-carboxyl derivs. useful in treating central nervous system disorders. EP 0656002; WO 9404532 . |
| 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) | 11608 | o-Nitroaniline; 2-Nitroaniline; 2-Nitrophenylamine | 88-74-4 | C6H6N2O2 | 详情 | 详情 |
| (II) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (III) | 17926 | 3-(2-nitroanilino)propanenitrile | C9H9N3O2 | 详情 | 详情 | |
| (IV) | 17927 | 3-(2-aminoanilino)propanenitrile | C9H11N3 | 详情 | 详情 | |
| (V) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (VI) | 17929 | ethyl 3-ethoxy-3-iminopropanoate | 2318-25-4 | C7H13NO3 | 详情 | 详情 |
| (VII) | 17930 | ethyl 2-[1-(2-cyanoethyl)-1H-benzimidazol-2-yl]acetate | C14H15N3O2 | 详情 | 详情 | |
| (VIII) | 17931 | ethyl 3-[2-(2-ethoxy-2-oxoethyl)-1H-benzimidazol-1-yl]propanoate | C16H20N2O4 | 详情 | 详情 | |
| (IX) | 17932 | ethyl 3-oxo-1,2,3,5-tetrahydropyrido[1,2-a]benzimidazole-4-carboxylate | C14H14N2O3 | 详情 | 详情 | |
| (X) | 17933 | 2,6-Difluorophenylamine; 2,6-Difluoroaniline | 5509-65-9 | C6H5F2N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Addition of acrylonitrile (II) to 3,4-difluoro-2-nitroaniline (I) gave the anilinopropionitrile (III). Subsequent hydrogenation of the nitro group of (III) over Pd/C led to the phenylenediamine (IV), which was condensed with carbethoxyacetimidate-HCl (V) to produce the benzimidazole (VI). After conversion of the nitrile group of (VI) to ester (VII) with ethanolic HCl, Dieckmann condensation using NaOEt furnished the cyclic ketoester (VIII). Finally, reaction of (VIII) with 2,6-difluoroaniline (IX) in xylene yielded the target carboxamide.
| 【1】 Maryanoff, B.E.; et al.; Potential anxiolytic agents. Pyrido[1, 2-a]benzimidazoles: A new structural class of ligands for the benzodiazepine binding site on GABA-A receptors. J Med Chem 1995, 38, 1, 16. |
| 【2】 Nortey, S.O.; Sanfilippo, P.J.; Dubinsky, B.; Maryanoff, B.E.; McComsey, D.F.; Reitz, A.B.; Shank, R.P.; McNally, J.J.; Potential anxiolytic agents. 3. Novel A-ring modified pyrido[1,2-a]benzimidazoles. Bioorg Med Chem Lett 1999, 9, 11, 1547. |
| 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) | 31347 | 3,4-difluoro-2-nitrophenylamine; 3,4-difluoro-2-nitroaniline | C6H4F2N2O2 | 详情 | 详情 | |
| (II) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (III) | 31348 | 3-(3,4-difluoro-2-nitroanilino)propanenitrile | C9H7F2N3O2 | 详情 | 详情 | |
| (IV) | 31349 | 3-(2-amino-3,4-difluoroanilino)propanenitrile | C9H9F2N3 | 详情 | 详情 | |
| (V) | 17929 | ethyl 3-ethoxy-3-iminopropanoate | 2318-25-4 | C7H13NO3 | 详情 | 详情 |
| (VI) | 31350 | ethyl 2-[1-(2-cyanoethyl)-4,5-difluoro-1H-benzimidazol-2-yl]acetate | C14H13F2N3O2 | 详情 | 详情 | |
| (VII) | 31351 | ethyl 3-[2-(2-ethoxy-2-oxoethyl)-4,5-difluoro-1H-benzimidazol-1-yl]propanoate | C16H18F2N2O4 | 详情 | 详情 | |
| (VIII) | 31352 | ethyl 6,7-difluoro-3-oxo-1,2,3,5-tetrahydropyrido[1,2-a]benzimidazole-4-carboxylate | C14H12F2N2O3 | 详情 | 详情 | |
| (IX) | 17933 | 2,6-Difluorophenylamine; 2,6-Difluoroaniline | 5509-65-9 | C6H5F2N | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)The reduction of 3,4-dinitrobenzoic acid amide (I) with H2 over Pd/C in methanol gives 3,4-diaminobenzoic acid (II), which is cyclized with 3-ethoxy-3-iminopropionic acid ethyl ester (IV) (obtained by reaction of cyanacetic acid ethyl ester (III) with ethanolic HCl) in hot acetic acid to yield 2-(5-carbamoyl-1H-benzimidazol-2-yl)acetic acid ethyl ester (V). The reaction of 3-methoxy-4-nitrobenzoic acid (VII) with aqueous methylamine in a sealed tube at 100 C gives 3-(methylamino)-4-nitrobenzoic acid (VIII), which is reduced with H2 over Pd/C in methanol/THF to yield 4-amino-3-(methylamino)benzoic acid (VI). The cyclization of (VI) with (V) by means of 1,3-dimethylperhydropyrimidin-2-one (DMPU) at 190 C affords the substituted bis-benzimidazolylmethyl (IX). The reaction of (IX) with 2-amino-3-phosponopropionic acid tris-trimethylsilyl ester (X) (prepared by esterification of 2-amino-3-phosphonopropionic acid (XI) with N-methyl-N-(trimethylsilyl)trifluoroacetamide (XII)) by means of (PyBroP) in DMF provides the carboxamide (XIII). Finally, the cleavage of the trimethylsilyl ester groups by means of TFA furnishes the target phosphonic acid.
| 【1】 Rice, K.; Wang, V.R.; Hataye, J.M.; Shelton, E.J.; Spender, J.R. (Celera Genomics); Novel cpds. and compsns. for treating hepatitis C infections. WO 0020400 . |
| 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) | 55559 | 3,4-dinitrobenzamide | C7H5N3O5 | 详情 | 详情 | |
| (II) | 55560 | 3,4-diaminobenzamide | C7H9N3O | 详情 | 详情 | |
| (III) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (IV) | 17929 | ethyl 3-ethoxy-3-iminopropanoate | 2318-25-4 | C7H13NO3 | 详情 | 详情 |
| (V) | 55561 | ethyl 2-[5-(aminocarbonyl)-1H-benzimidazol-2-yl]acetate | C12H13N3O3 | 详情 | 详情 | |
| (VI) | 14729 | 4-amino-3-(methylamino)benzoic acid | C8H10N2O2 | 详情 | 详情 | |
| (VII) | 21085 | 3-methoxy-4-nitrobenzoic acid；4-Nitro-3-methoxybenzoic acid | 5081-36-7 | C8H7NO5 | 详情 | 详情 |
| (VIII) | 14728 | 3-(methylamino)-4-nitrobenzoic acid | C8H8N2O4 | 详情 | 详情 | |
| (IX) | 55562 | 2-{[5-(aminocarbonyl)-1H-benzimidazol-2-yl]methyl}-1-methyl-1H-benzimidazole-6-carboxylic acid | C18H15N5O3 | 详情 | 详情 | |
| (X) | 55563 | 3-{bis[(trimethylsilyl)oxy]phosphoryl}alanine | C9H24NO5PSi2 | 详情 | 详情 | |
| (XI) | 55565 | DL-2-Amino-3-phosphonopropionic acid; 2-Amino-3-phosphonopropionic acid | 20263-06-3 | C3H8NO5P | 详情 | 详情 |
| (XII) | 21859 | 2,2,2-trifluoro-N-methyl-N-(trimethylsilyl)acetamide | C6H12F3NOSi | 详情 | 详情 | |
| (XIII) | 55564 | N-[(2-{[5-(aminocarbonyl)-1H-benzimidazol-2-yl]methyl}-1-methyl-1H-benzimidazol-6-yl)carbonyl]-3-{bis[(trimethylsilyl)oxy]phosphoryl}alanine | C27H37N6O7PSi2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The cyclization of the phenylenediamine (I) with 3-ethoxy-3-iminopropionic acid ethyl ester (II) in refluxing ethanol gives the 2-(benzimidazol-2-yl)acetate (III), which is submitted to a new cyclization with 2-aminobenzonitrile (IV) by means of LiHMDS in THF to afford the target quinolinone.
| 【1】 Harris, A.; Renhowe, P.; Machajewski, T.; Shafer, C.; Wernette-Hammond, M.-E.; Pecchi, S.; Taylor, C.; McCrea, B.; McBride, C.; Jazan, E. (Chiron Corp.); Quinolinone derivs.. WO 0222598 . |
| 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) | 53573 | 2-amino-4-[(3S)-3-(dimethylamino)pyrrolidinyl]phenylamine; 4-[(3S)-3-(dimethylamino)pyrrolidinyl]-1,2-benzenediamine | n/a | C12H20N4 | 详情 | 详情 |
| (II) | 17929 | ethyl 3-ethoxy-3-iminopropanoate | 2318-25-4 | C7H13NO3 | 详情 | 详情 |
| (III) | 53574 | ethyl 2-{5-[(3S)-3-(dimethylamino)pyrrolidinyl]-1H-benzimidazol-2-yl}acetate | n/a | C17H24N4O2 | 详情 | 详情 |
| (IV) | 19493 | 2-aminobenzonitrile | 1885-29-6 | C7H6N2 | 详情 | 详情 |