Methanol → 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(benzo[c]furazan-5-yl)piperidine

Temperature

50 °C

A mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4, 5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 5-(bromomethyl)benzo[c]furazan (0.75 mmol), (piperidinomethyl)polystyrene (2.6-2.8 mmol/g, 60 mg, 0.15 mmol), methanol (0.2 mL), acetonitrile (1.0 mL), and chloroform (0.50 mL) was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. To the resulting material were added chloroform (1.5 mL) and phenyl isocyanate (0.075 mL) and the solution was stirred at room temperature for 1 h, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. The residue was dissolved in methanol (1 mL) and 4 N HCl in dioxane (0.50 mL) was added. The solution was stirred at room temperature overnight and concentrated. The residue was dissolved in methanol, loaded onto Varian™ SCX column, washed with CH3OH (5 mL×2), and eluted off using 2 N NH3 in CH3OH (5 mL). Concentration and preparative TLC (SiO2, ethyl acetate/MeOH=5/1) afforded 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(benzo[c]furazan-5-yl)piperidine (Compound No. 2130) (3.6 mg, 16%): The purity was determined by RPLC/MS (87%); ESI/MS m/e 459.3 (M++H, C22H24F2N6O3).

1. temperatureThe mixture was cooled to room temperature
2. washwashed with CH3OH (5 mL×2)
3. washProduct was eluted off
4. concentrationconcentrated
5. additionTo the resulting material were added chloroform (1.5 mL) and phenyl isocyanate (0.075 mL)
6. stirringthe solution was stirred at room temperature for 1 h
7. washwashed with CH3OH (5 mL×2)
8. washProduct was eluted off
9. concentrationconcentrated
10. dissolutionThe residue was dissolved in methanol (1 mL)
11. addition4 N HCl in dioxane (0.50 mL) was added
12. stirringThe solution was stirred at room temperature overnight
13. concentrationconcentrated
14. dissolutionThe residue was dissolved in methanol
15. washwashed with CH3OH (5 mL×2)
16. washeluted off
17. concentrationConcentration and preparative TLC (SiO2, ethyl acetate/MeOH=5/1)

ORD record

ord-472e39f9e7e44251bdb3e58ffb5c4e8b

Source dataset

uspto-grants-2002_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06362177B1