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【结 构 式】 
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【分子编号】51512 【品名】2-(4-cyanoanilino)acetic acid 【CA登记号】 |
【 分 子 式 】C9H8N2O2 【 分 子 量 】176.1748 【元素组成】C 61.36% H 4.58% N 15.9% O 18.16% |
合成路线1
该中间体在本合成路线中的序号：(VII)Nitration of 1-(4-chlorophenyl)-1-cyclopropanecarboxylic acid (I) with fuming HNO3 produced the 3-nitro derivative (II). The chloride group of (III) was then displaced with methylamine to give the nitro aniline (III). Coupling of (III) with pyrrolidine (IV) by means of TBTU yielded amide (V). The nitro group of (V) was reduced by catalytic hydrogenation over Pd/C to afford the phenylenediamine (VI), which was subsequently acylated by N-(4-cyanophenyl)glycine (VII), yielding amide (VIII). Benzimidazole (IX) was then obtained by cyclization of (VIII) in refluxing HOAc. Pinner reaction of nitrile (IX) with ethanolic HCl produced the imidate (X), which was finally converted to the target amidine by treatment with ammonium carbonate.
| 【1】 Kauffmann, I.; Ries, U.; Priepke, H.; Hauel, N.; Stassen, J.M.; Nar, H.; Wienen, W. (Boehringer Ingelheim Pharma KG); Benzimidazoles, production thereof and use thereof as medicaments. DE 19829964; EP 1095025; WO 0001704 . |
| 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) | 51507 | 1-(4-Chlorophenyl)-1-cyclopropanecarboxylic acid | 72934-37-3 | C10H9ClO2 | 详情 | 详情 |
| (II) | 51508 | 1-(4-chloro-3-nitrophenyl)cyclopropanecarboxylic acid | C10H8ClNO4 | 详情 | 详情 | |
| (III) | 51509 | 1-[4-(methylamino)-3-nitrophenyl]cyclopropanecarboxylic acid | C11H12N2O4 | 详情 | 详情 | |
| (IV) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (V) | 51510 | [1-[4-(methylamino)-3-nitrophenyl]cyclopropyl](1-pyrrolidinyl)methanone | C15H19N3O3 | 详情 | 详情 | |
| (VI) | 51511 | [1-[3-amino-4-(methylamino)phenyl]cyclopropyl](1-pyrrolidinyl)methanone | C15H21N3O | 详情 | 详情 | |
| (VII) | 51512 | 2-(4-cyanoanilino)acetic acid | C9H8N2O2 | 详情 | 详情 | |
| (VIII) | 51513 | 2-(4-cyanoanilino)-N-[2-(methylamino)-5-[1-(1-pyrrolidinylcarbonyl)cyclopropyl]phenyl]acetamide | C24H27N5O2 | 详情 | 详情 | |
| (IX) | 51514 | 4-[([1-methyl-5-[1-(1-pyrrolidinylcarbonyl)cyclopropyl]-1H-benzimidazol-2-yl]methyl)amino]benzonitrile | C24H25N5O | 详情 | 详情 | |
| (X) | 51515 | ethyl 4-[([1-methyl-5-[1-(1-pyrrolidinylcarbonyl)cyclopropyl]-1H-benzimidazol-2-yl]methyl)amino]benzenecarboximidoate | C26H31N5O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)4-Methylamino-3-nitrobenzoic acid (I) is converted into acid chloride (II) by using SOCl2, and subsequently condensed with ethyl 3-(2-pyridylamino)propionate (III) to produce amide (IV). Reduction of the nitro group of (IV) by catalytic hydrogenation yields the phenylenediamine (V). After acylation of diamine (V) with N-(4-cyanophenyl)glycine (VI), cyclization of the resulting amino amide in refluxing AcOH leads to benzimidazole (VII). The cyano group of (VII) is then transformed into amidine (VIII) employing the Pinner reaction. Finally, acylation of the amidino group of (VIII) with hexyl chloroformate gives rise to the target amidine carbamate derivative
| 【1】 Hauel, N.H.; et al.; Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 2002, 45, 9, 1757. |
| 【2】 Hauel, N.; Wienen, W.; Ries, U.; Priepke, H.; Stassen, J.M. (Boehringer Ingelheim Pharma KG); Disubstd. bicyclic heterocycles, their production and use as medicaments. DE 19706229; DE 19751939; EP 0966454; JP 2001509815; US 2003004181; US 6087380; US 6469039; WO 9837075 . |
| 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) | 60793 | 4-(methylamino)-3-nitrobenzoic acid | C8H8N2O4 | 详情 | 详情 | |
| (II) | 60794 | 4-(methylamino)-3-nitrobenzoyl chloride | C8H7ClN2O3 | 详情 | 详情 | |
| (III) | 60795 | ethyl 3-(2-pyridinylamino)propanoate | C10H14N2O2 | 详情 | 详情 | |
| (IV) | 60796 | ethyl 3-[[4-(methylamino)-3-nitrobenzoyl](2-pyridinyl)amino]propanoate | C18H20N4O5 | 详情 | 详情 | |
| (V) | 60797 | ethyl 3-[[3-amino-4-(methylamino)benzoyl](2-pyridinyl)amino]propanoate | C18H22N4O3 | 详情 | 详情 | |
| (VI) | 51512 | 2-(4-cyanoanilino)acetic acid | C9H8N2O2 | 详情 | 详情 | |
| (VII) | 60798 | ethyl 3-[({2-[(4-cyanoanilino)methyl]-1-methyl-1H-benzimidazol-5-yl}carbonyl)(2-pyridinyl)amino]propanoate | C27H26N6O3 | 详情 | 详情 | |
| (VIII) | 60799 | ethyl 3-[{[2-({4-[amino(imino)methyl]anilino}methyl)-1-methyl-1H-benzimidazol-5-yl]carbonyl}(2-pyridinyl)amino]propanoate | C27H29N7O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)Lithiation of 2-bromopyridine (II) with BuLi, followed by addition to 1-phenylcyclopropanecarbonitrile (I), gave rise to ketone (III). Electrophilic nitration of the phenyl ring of (III) produced the nitro derivative (IV). The nitro group of (IV) was subsequently reduced by catalytic hydrogenation over Raney Ni to afford aniline (V), which was further acylated with trifluoroacetic anhydride, yielding amide (VI). A second nitration reaction in (VI) with HNO3-H2SO4 provided the nitro anilide (VII). Amide (VII) N-alkylation by means of iodomethane and K2CO3 gave the corresponding N-methyl derivative (VIII). The trifluoroacetamide function of (VIII) was then hydrolyzed under basic conditions to furnish the nitro aniline (IX), which was reduced to the phenylenediamine (X) by catalytic hydrogenation in the presence of Raney Ni. Acylation of (X) by N-(4-cyanophenyl)glycine (XI) yielded amide (XII). Benzimidazole (XIII) was then obtained by cyclization of (XII) in refluxing HOAc. The keto group of (XIII) was converted to the oxime derivative (XV) by condensation with ethyl (aminooxy)acetate (XIV). Finally, Pinner reaction of nitrile (XV) with ethanolic HCl, followed by treatment of the resulting imidate with ammonium carbonate provided the target amidine.
| 【1】 Kauffmann, I.; Ries, U.; Priepke, H.; Hauel, N.; Stassen, J.M.; Nar, H.; Wienen, W. (Boehringer Ingelheim Pharma KG); Benzimidazoles, production thereof and use thereof as medicaments. DE 19829964; EP 1095025; WO 0001704 . |
| 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) | 51516 | 1-Phenyl-1-cyclopropanecarbonitrile | 935-44-4 | C10H9N | 详情 | 详情 |
| (II) | 29052 | 2-Bromopyridine；α-bromopyridine;α-bromoazine | 109-04-6 | C5H4BrN | 详情 | 详情 |
| (III) | 51517 | (1-phenylcyclopropyl)(2-pyridinyl)methanone | C15H13NO | 详情 | 详情 | |
| (IV) | 51518 | [1-(4-nitrophenyl)cyclopropyl](2-pyridinyl)methanone | C15H12N2O3 | 详情 | 详情 | |
| (V) | 51519 | [1-(4-aminophenyl)cyclopropyl](2-pyridinyl)methanone | C15H14N2O | 详情 | 详情 | |
| (VI) | 51520 | 2,2,2-trifluoro-N-[4-[1-(2-pyridinylcarbonyl)cyclopropyl]phenyl]acetamide | C17H13F3N2O2 | 详情 | 详情 | |
| (VII) | 51521 | 2,2,2-trifluoro-N-[2-nitro-4-[1-(2-pyridinylcarbonyl)cyclopropyl]phenyl]acetamide | C17H12F3N3O4 | 详情 | 详情 | |
| (VIII) | 51522 | 2,2,2-trifluoro-N-methyl-N-[2-nitro-4-[1-(2-pyridinylcarbonyl)cyclopropyl]phenyl]acetamide | C18H14F3N3O4 | 详情 | 详情 | |
| (IX) | 51523 | [1-[4-(methylamino)-3-nitrophenyl]cyclopropyl](2-pyridinyl)methanone | C16H15N3O3 | 详情 | 详情 | |
| (X) | 51524 | [1-[3-amino-4-(methylamino)phenyl]cyclopropyl](2-pyridinyl)methanone | C16H17N3O | 详情 | 详情 | |
| (XI) | 51512 | 2-(4-cyanoanilino)acetic acid | C9H8N2O2 | 详情 | 详情 | |
| (XII) | 51525 | 2-(4-cyanoanilino)-N-[2-(methylamino)-5-[1-(2-pyridinylcarbonyl)cyclopropyl]phenyl]acetamide | C25H23N5O2 | 详情 | 详情 | |
| (XIII) | 51526 | 4-[([1-methyl-5-[1-(2-pyridinylcarbonyl)cyclopropyl]-1H-benzimidazol-2-yl]methyl)amino]benzonitrile | C25H21N5O | 详情 | 详情 | |
| (XIV) | 51527 | ethyl 2-(aminooxy)acetate | C4H9NO3 | 详情 | 详情 | |
| (XV) | 51528 | ethyl 2-([[(E)-(1-[2-[(4-cyanoanilino)methyl]-1-methyl-1H-benzimidazol-5-yl]cyclopropyl)(2-pyridinyl)methylidene]amino]oxy)acetate | C29H28N6O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)The alkylation of 2-methylbenzimidazole (I) with 4-chloro-3-nitrobenzyl chloride (II) provided adduct (III). Displacement of the chlorine atom of (III) with methylamine furnished the nitro aniline (IV), which was further reduced to phenylenediamine (V) by catalytic hydrogenation over Raney-Ni. Acylation of (V) by N-(4-cyanophenyl)glycine (VI) using N,N'-carbonyldiimidazole as the activating reagent yielded amide (VII). The bis-benzimidazole compound (VIII) was then produced by cyclization of (VII) in refluxing HOAc. Finally, Pinner reaction of nitrile (VIII) with ethanolic HCl, followed by treatment of the resulting imidate with ammonium carbonate, provided the target amidine.
| 【1】 Kauffmann, I.; Ries, U.; Priepke, H.; Hauel, N.; Stassen, J.M.; Nar, H.; Wienen, W. (Boehringer Ingelheim Pharma KG); Benzimidazoles, production thereof and use thereof as medicaments. DE 19829964; EP 1095025; WO 0001704 . |
| 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) | 51529 | 2-Methylbenzimidazole | 615-15-6 | C8H8N2 | 详情 | 详情 |
| (II) | 51530 | 1-chloro-4-(chloromethyl)-2-nitrobenzene | C7H5Cl2NO2 | 详情 | 详情 | |
| (III) | 51531 | 1-(4-chloro-3-nitrobenzyl)-2-methyl-1H-benzimidazole | C15H12ClN3O2 | 详情 | 详情 | |
| (IV) | 51532 | N-methyl-4-[(2-methyl-1H-benzimidazol-1-yl)methyl]-2-nitroaniline; N-methyl-N-[4-[(2-methyl-1H-benzimidazol-1-yl)methyl]-2-nitrophenyl]amine | C16H16N4O2 | 详情 | 详情 | |
| (V) | 51533 | N-[2-amino-4-[(2-methyl-1H-benzimidazol-1-yl)methyl]phenyl]-N-methylamine; N(1)-methyl-4-[(2-methyl-1H-benzimidazol-1-yl)methyl]-1,2-benzenediamine | C16H18N4 | 详情 | 详情 | |
| (VI) | 51512 | 2-(4-cyanoanilino)acetic acid | C9H8N2O2 | 详情 | 详情 | |
| (VII) | 51534 | 2-(4-cyanoanilino)-N-[2-(methylamino)-5-[(2-methyl-1H-benzimidazol-1-yl)methyl]phenyl]acetamide | C25H24N6O | 详情 | 详情 | |
| (VIII) | 51535 | 4-[([1-methyl-5-[(2-methyl-1H-benzimidazol-1-yl)methyl]-1H-benzimidazol-2-yl]methyl)amino]benzonitrile | C25H22N6 | 详情 | 详情 |