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【结 构 式】 
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【分子编号】19105 【品名】(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylamine; (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine 【CA登记号】 |
【 分 子 式 】C8H16N2 【 分 子 量 】140.22852 【元素组成】C 68.52% H 11.5% N 19.98% |
合成路线1
该中间体在本合成路线中的序号：(IV)The reaction of 2,3-dihydro-1H-benzimidazol-2-one (I) with trichloromethyl chloroformate (II) in THF gives 2-oxo-2,3-dihydro-1H-benzimidazol-2-ylcarbonyl chloride (III), which is then condensed with endo-8-methyl-8-azabicyclo[3,2,1]octan-3-amine (IV) in THF.
| 【1】 Turconi, M.; Schiantarelli, P.; Borsini, F.; Rizzi, C.A.; Ladinsky, H.; Donetti, A.; Azabicycloalkyl benzimidazolones: Interaction with serotonergic 5-HT3 and 5-HT4 receptors and potential therapeutic implications. Drugs Fut 1991, 16, 11, 1011. |
| 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) | 42923 | 1,3-dihydro-2H-benzimidazol-2-one | 615-16-7 | C7H6N2O | 详情 | 详情 |
| (II) | 42918 | Chloroformic acid trichloromethyl ester; di-Phosgene; Chloroformic Acid, Trichloromethyl Ester; Trichloromethyl chloroformate; Diphosgene | 503-38-8 | C2Cl4O2 | 详情 | 详情 |
| (III) | 42924 | 2-oxo-2,3-dihydro-1H-benzimidazole-1-carbonyl chloride | C8H5ClN2O2 | 详情 | 详情 | |
| (IV) | 19105 | (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylamine; (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine | C8H16N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The condensation of 2-nitrophenyl isocyanate (V) with endo-8-methyl-8-azabicyclo[3,2,1]octan-3-amine (IV) in THF/cyclohexane gives the corresponding 2-nitrophenylurea (VI), which is reduced with H2 over Pd/C in ethanol to yield the 2-aminophenylurea (VII). The acylation of (VII) with phenyl chloroformate (VIII) in toluene affords the carbamate (IX), which is finally cyclized by means of NaOH in ethanol.
| 【1】 Turconi, M.; et al.; Azabicycloalkyl benzimidazolone derivatives: A novel class of 5-HT3 receptor antagonists. 199th ACS Natl Meet (April 22 1990, Boston) 1990, Abst MEDI 103. |
| 【2】 Turconi, M.; et al.; Synthesis of a new class of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid derivatives as highly potent 5-HT3 receptor antagonists. J Med Chem 1990, 33, 8, 2101. |
| 【3】 Turconi, M.; Schiantarelli, P.; Borsini, F.; Rizzi, C.A.; Ladinsky, H.; Donetti, A.; Azabicycloalkyl benzimidazolones: Interaction with serotonergic 5-HT3 and 5-HT4 receptors and potential therapeutic implications. Drugs Fut 1991, 16, 11, 1011. |
| 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) | 19105 | (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylamine; (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine | C8H16N2 | 详情 | 详情 | |
| (V) | 32271 | iodomethyl (5R)-3,3-dimethyl-4,4,7-trioxo-4lambda(6)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C9H12INO5S | 详情 | 详情 | |
| (VI) | 42927 | N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-N'-(2-nitrophenyl)urea | C15H20N4O3 | 详情 | 详情 | |
| (VII) | 42928 | N-(2-aminophenyl)-N'-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]urea | C15H22N4O | 详情 | 详情 | |
| (VIII) | 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 |
| (IX) | 42929 | phenyl 2-[([[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino]carbonyl)amino]phenylcarbamate | C22H26N4O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)This compound has been obtained by two different ways: 1. The reaction of 2,3-dihydro-1H-benzimidazol-2-one (I) with trichloromethyl chloroformate (II) in THF gives 2-oxo-2,3-dihydro-1H-benzimidazol-2-ylcarbonyl chloride (III), which is condensed with endo-8-methyl-8-azabicyclo[3,2,1]octan-3-amine (IV) in THF, yielding the corresponding amide (V). Finally, this compound is alkylated with ethyl chloride (VI) and NaH in DMF. 2. The condensation of 2-nitrophenyl isocyanate (VII) with endo-8-methyl-8-azabicyclo[3,2,1]octan-3-amine (IV) in THF/cyclohexane gives the corresponding 2-nitrophenylurea (VIII), which is reduced with H2 over Pd/C in ethanol to yield the 2-aminophenylurea (IX). The acylation of (IX) with phenyl chloroformate (X) in toluene affords the carbamate (XI), which is cyclized by means of NaOH in ethanol to afford the amide (V). Finally, this compound is alkylated with ethyl chloride (VI) and NaH in DMF.
| 【1】 Turconi, M.; Schiantarelli, P.; Borsini, F.; Rizzi, C.A.; Ladinsky, H.; Donetti, A.; Azabicycloalkyl benzimidazolones: Interaction with serotonergic 5-HT3 and 5-HT4 receptors and potential therapeutic implications. Drugs Fut 1991, 16, 11, 1011. |
| 【2】 Turconi, M.; et al.; Azabicycloalkyl benzimidazolone derivatives: A novel class of 5-HT3 receptor antagonists. 199th ACS Natl Meet (April 22 1990, Boston) 1990, Abst MEDI 103. |
| 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) | 42923 | 1,3-dihydro-2H-benzimidazol-2-one | 615-16-7 | C7H6N2O | 详情 | 详情 |
| (II) | 42918 | Chloroformic acid trichloromethyl ester; di-Phosgene; Chloroformic Acid, Trichloromethyl Ester; Trichloromethyl chloroformate; Diphosgene | 503-38-8 | C2Cl4O2 | 详情 | 详情 |
| (III) | 42924 | 2-oxo-2,3-dihydro-1H-benzimidazole-1-carbonyl chloride | C8H5ClN2O2 | 详情 | 详情 | |
| (IV) | 19105 | (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylamine; (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine | C8H16N2 | 详情 | 详情 | |
| (V) | 42925 | N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide | C16H20N4O2 | 详情 | 详情 | |
| (VI) | 42926 | 1-chloroethane | 75-00-3 | C2H5Cl | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)The condensation of 2-nitrophenyl isocyanate (VII) with endo-8-methyl-8-azabicyclo[3,2,1]octan-3-amine (IV) in THF/cyclohexane gives the corresponding 2-nitrophenylurea (VIII), which is reduced with H2 over Pd/C in ethanol to yield the 2-aminophenylurea (IX). The acylation of (IX) with phenyl chloroformate (X) in toluene affords the carbamate (XI), which is cyclized by means of NaOH in ethanol to afford the amide (V). Finally, this compound is alkylated with ethyl chloride (VI) and NaH in DMF.
| 【1】 Turconi, M.; et al.; Synthesis of a new class of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid derivatives as highly potent 5-HT3 receptor antagonists. J Med Chem 1990, 33, 8, 2101. |
| 【2】 Turconi, M.; et al.; Azabicycloalkyl benzimidazolone derivatives: A novel class of 5-HT3 receptor antagonists. 199th ACS Natl Meet (April 22 1990, Boston) 1990, Abst MEDI 103. |
| 【3】 Turconi, M.; Schiantarelli, P.; Borsini, F.; Rizzi, C.A.; Ladinsky, H.; Donetti, A.; Azabicycloalkyl benzimidazolones: Interaction with serotonergic 5-HT3 and 5-HT4 receptors and potential therapeutic implications. Drugs Fut 1991, 16, 11, 1011. |
| 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) | 19105 | (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylamine; (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine | C8H16N2 | 详情 | 详情 | |
| (V) | 42925 | N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide | C16H20N4O2 | 详情 | 详情 | |
| (VI) | 42926 | 1-chloroethane | 75-00-3 | C2H5Cl | 详情 | 详情 |
| (VII) | 32771 | 1-isocyanato-2-nitrobenzene; 2-nitrophenyl isocyanate | 3320-86-3 | C7H4N2O3 | 详情 | 详情 |
| (VIII) | 42927 | N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-N'-(2-nitrophenyl)urea | C15H20N4O3 | 详情 | 详情 | |
| (IX) | 42928 | N-(2-aminophenyl)-N'-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]urea | C15H22N4O | 详情 | 详情 | |
| (X) | 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 |
| (XI) | 42929 | phenyl 2-[([[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino]carbonyl)amino]phenylcarbamate | C22H26N4O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)The reaction of 2,3-dihydro-1H-benzimidazol-2-one (I) with trichloromethyl chloroformate (II) in THF gives 2-oxo-2,3-dihydro-1H-benzimidazol-2-ylcarbonyl chloride (III), which is condensed with endo-8-methyl-8-azabicyclo[3,2,1]octan-3-amine (IV) in THF, yielding the corresponding amide (V). Finally, this compound is alkylated with isopropyl bromide (VI) and NaH in DMF.
| 【1】 Turconi, M.; et al.; Azabicycloalkyl benzimidazolone derivatives: A novel class of 5-HT3 receptor antagonists. 199th ACS Natl Meet (April 22 1990, Boston) 1990, Abst MEDI 103. |
| 【2】 Turconi, M.; Schiantarelli, P.; Borsini, F.; Rizzi, C.A.; Ladinsky, H.; Donetti, A.; Azabicycloalkyl benzimidazolones: Interaction with serotonergic 5-HT3 and 5-HT4 receptors and potential therapeutic implications. Drugs Fut 1991, 16, 11, 1011. |
| 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) | 42923 | 1,3-dihydro-2H-benzimidazol-2-one | 615-16-7 | C7H6N2O | 详情 | 详情 |
| (II) | 42918 | Chloroformic acid trichloromethyl ester; di-Phosgene; Chloroformic Acid, Trichloromethyl Ester; Trichloromethyl chloroformate; Diphosgene | 503-38-8 | C2Cl4O2 | 详情 | 详情 |
| (III) | 42924 | 2-oxo-2,3-dihydro-1H-benzimidazole-1-carbonyl chloride | C8H5ClN2O2 | 详情 | 详情 | |
| (IV) | 19105 | (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylamine; (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine | C8H16N2 | 详情 | 详情 | |
| (V) | 42925 | N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide | C16H20N4O2 | 详情 | 详情 | |
| (VI) | 29984 | 2-chloropropane | 75-29-6 | C3H7Cl | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)The condensation of 2-nitrophenyl isocyanate (VII) with endo-8-methyl-8-azabicyclo[3,2,1]octan-3-amine (IV) in THF/cyclohexane gives the corresponding 2-nitrophenylurea (VIII), which is reduced with H2 over Pd/C in ethanol to yield the 2-aminophenylurea (IX). The acylation of (IX) with phenyl chloroformate (X) in toluene affords the carbamate (XI), which is cyclized by means of NaOH in ethanol to afford the amide (V). Finally, this compound is alkylated with isopropyl bromide (VI) and NaH in DMF.
| 【1】 Turconi, M.; et al.; Synthesis of a new class of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid derivatives as highly potent 5-HT3 receptor antagonists. J Med Chem 1990, 33, 8, 2101. |
| 【2】 Turconi, M.; Schiantarelli, P.; Borsini, F.; Rizzi, C.A.; Ladinsky, H.; Donetti, A.; Azabicycloalkyl benzimidazolones: Interaction with serotonergic 5-HT3 and 5-HT4 receptors and potential therapeutic implications. Drugs Fut 1991, 16, 11, 1011. |
| 【3】 Turconi, M.; et al.; Azabicycloalkyl benzimidazolone derivatives: A novel class of 5-HT3 receptor antagonists. 199th ACS Natl Meet (April 22 1990, Boston) 1990, Abst MEDI 103. |
| 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) | 19105 | (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylamine; (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine | C8H16N2 | 详情 | 详情 | |
| (V) | 42925 | N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide | C16H20N4O2 | 详情 | 详情 | |
| (VI) | 29984 | 2-chloropropane | 75-29-6 | C3H7Cl | 详情 | 详情 |
| (VII) | 32771 | 1-isocyanato-2-nitrobenzene; 2-nitrophenyl isocyanate | 3320-86-3 | C7H4N2O3 | 详情 | 详情 |
| (VIII) | 42927 | N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-N'-(2-nitrophenyl)urea | C15H20N4O3 | 详情 | 详情 | |
| (IX) | 42928 | N-(2-aminophenyl)-N'-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]urea | C15H22N4O | 详情 | 详情 | |
| (X) | 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 |
| (XI) | 42929 | phenyl 2-[([[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino]carbonyl)amino]phenylcarbamate | C22H26N4O3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XVIII)Bromination of methyl methoxyacetate (XIII) with NBS in the presence of benzoyl peroxide in refluxing CCl4 gave (XIV), which was treated with triphenylphosphine to produce the phosphonium salt (XV). Then, phosphonium salt (XV) was condensed with aldehyde (XII) in the presence of DBU in THF to afford indolylpentadienoate (XVI). Finally, ester (XVI) was hydrolyzed to acid (XVII) and then condensed with amine (XVIII) to provide the title amide.
| 【1】 Consolandi, E.; Nadler, G.; Gagliardi, S.; et al.; 5-(5,6-Dichloro-2-indolyl)-2-methoxy-2, 4-pentadienamides: Novel and selective inhibitors of the vacuolar H+-ATPase of osteoclasts with bone antiresorptive activity. J Med Chem 1998, 41, 10, 1568. |
| 【2】 Farina, C.; Gagliardi, S.; Parini, C.; Pinza, M.; Nadler, G.M.M.G.; Morvan, M.J.-M. (SmithKline Beecham SpA); Indole derivs. useful in the treatment of osteoporosis. JP 1998512251; WO 9621644 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 19099 | (E)-3-(5,6-dichloro-1H-indol-2-yl)-2-propenal | C11H7Cl2NO | 详情 | 详情 | |
| (XIII) | 19100 | methyl 2-methoxyacetate | 6290-49-9 | C4H8O3 | 详情 | 详情 |
| (XIV) | 19101 | methyl 2-bromo-2-methoxyacetate | C4H7BrO3 | 详情 | 详情 | |
| (XV) | 19102 | (1,2-dimethoxy-2-oxoethyl)(triphenyl)phosphonium bromide | C22H22BrO3P | 详情 | 详情 | |
| (XVI) | 19103 | methyl (2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoate | C15H13Cl2NO3 | 详情 | 详情 | |
| (XVII) | 19104 | (2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoic acid | C14H11Cl2NO3 | 详情 | 详情 | |
| (XVIII) | 19105 | (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylamine; (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine | C8H16N2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(III)The reaction of 8-methyl-8-azabicyclo[3.2.1]octan-3-one (I) with hydroxylamine and pyridine in refluxing ethanol gives the oxime (II), which is reduced with LiAlH4 in refluxing 10% H2SO4 yielding endo-methyl-8-azabicyclo[3.2.1]octan-3-amine (III). Finally, this compound is condensed with 1-isopropylbenzimidazole-2-carboxylic acid isopropyl ester (IV) by means of Al(CH3)3 in refluxing toluene. The intermediate 1-isopropylbenzimidazole-2-carboxylic acid isopropyl ester (IV) has been obtained as follows: The cyclization of o-phenylenediamine (V) with 2-hydroxyacetic acid (VI) in refluxing 4N HCl gives 1H-benzyldazole-2-ylmethanol (VII), which is oxidized with KMnO4 to the corresponding carboxylic acid (VIII). Finally, this compound is alkylated and esterified with isopropyl chloride and NaH in DMF.
| 【1】 Labeaga, L.; Alonso-Cires, L.; Tapia, I.; Mosquera, R.; Orjales, A.; Lopez-Tudanca, P.; Benzimidazole-2-carboxylic acid amides and esters: A new structural class of 5-HT3 ligands. Eur J Med Chem 1999, 34, 5, 415. |
| 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) | 38416 | Tropinone; 3-Tropanone; Tropionone; 8-methyl-8-azabicyclo[3.2.1]octan-3-one | 532-24-1 | C8H13NO | 详情 | 详情 |
| (II) | 38412 | 8-methyl-8-azabicyclo[3.2.1]octan-3-one oxime | C8H14N2O | 详情 | 详情 | |
| (III) | 19105 | (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylamine; (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine | C8H16N2 | 详情 | 详情 | |
| (IV) | 38413 | isopropyl 1-isopropyl-1H-benzimidazole-2-carboxylate | C14H18N2O2 | 详情 | 详情 | |
| (V) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
| (VI) | 29856 | 2-hydroxyacetic acid;glycolic acid | 79-14-1 | C2H4O3 | 详情 | 详情 |
| (VII) | 38414 | 1H-benzimidazol-2-ylmethanol | 4856-97-7 | C8H8N2O | 详情 | 详情 |
| (VIII) | 38415 | 1H-benzimidazole-2-carboxylic acid | C8H6N2O2 | 详情 | 详情 |