Benzimidazole → 3-(1H-1,3-benzodiazol-2-yl)propan-1-amine

Temperature

80 °C

Benzimidazole (2.4 g, 20 mmol) in dry THF (40 ml) was treated at room temperature with 60% NaH in oil (0.96 g). After hydrogen evolution ceased, 3-bromopropylphthalimide (5.36 g, 20 mmol) was added and the mixture heated at 80° C. overnight. The reaction was cooled, diluted with dichloromethane and water and then extracted twice with 5% aqueous potassium carbonate solution. The organic layer was dried over sodium sulfate and concentrated in vacuo to give a beige solid, 4.1 g. The solid was dissolved in methanol (60 ml) and treated with anhydrous hydrazine (4.0 ml), followed by refluxing for 4 hours. The mixture was then cooled to 4° C. for several hours, then filtered. The filtrate was concentrated in vacuo. The residue was partitioned between dichloromethane and 2.5 M aqueous sodium hydroxide. The organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to give 3-benzimidazolylpropyl amine as a pale pink oil, 1.1 g. This amine (1.03 g, 6 mmol) was reacted with benzotriazole carboxamidinium 4-methylbenzenesulfonate (2.0 g, 6 mmol) and DIEA (1.39 ml) in acetonitrile (8 ml) overnight at room temperature to give amino(3-benzimidazolylpropyl)carboxamidinium 4-methylbenzenesulfonate which was obtained as a beige solid after repeated trituration with ether. The guanidine (100 mg) was reacted) (65 hours, 105° C.) with 100 mg of resin in accordance with the method described in Example 10 (i.e., Resin Method C) to give the title compound.

1. temperatureThe reaction was cooled
2. extractionextracted twice with 5% aqueous potassium carbonate solution
3. dry with materialThe organic layer was dried over sodium sulfate
4. concentrationconcentrated in vacuo
5. customto give a beige solid, 4.1 g
6. temperatureby refluxing for 4 hours
7. temperatureThe mixture was then cooled to 4° C. for several hours
8. filtrationfiltered
9. concentrationThe filtrate was concentrated in vacuo
10. customThe residue was partitioned between dichloromethane and 2.5 M aqueous sodium hydroxide
11. washThe organic layer was washed with saturated sodium chloride solution
12. dry with materialdried over sodium sulfate
13. concentrationconcentrated in vacuo

ORD record

ord-e53637b441c44a62a99c9dce6933568f

Source dataset

uspto-grants-2002_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06489344B1