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【结 构 式】

【分子编号】42925

【品名】N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

【CA登记号】

【 分 子 式 】C16H20N4O2

【 分 子 量 】300.36056

【元素组成】C 63.98% H 6.71% N 18.65% O 10.65%
与该中间体有关的原料药合成路线共 4 条
合成路线1合成路线2合成路线3合成路线4

合成路线1

该中间体在本合成路线中的序号：(V)

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.

参考文献 中间体
合成目标
【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2

该中间体在本合成路线中的序号：(V)

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.

参考文献 中间体
合成目标
【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3

该中间体在本合成路线中的序号：(V)

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.

参考文献 中间体
合成目标
【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4

该中间体在本合成路线中的序号：(V)

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.

参考文献 中间体
合成目标
【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
Extended Information