Acetic Acid → Benzamide, 2-amino-N-[2-[[(3R)-1-[(4-bromo-2-fluorophenyl)methyl]-3-pyrrolidinyl]amino]-2-oxoethyl]-5-(trifluoromethyl)-

Temperature

50 °C

To a mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (0.050 mmol), 4-bromo-2-fluorobenzaldehyde (0.15 mmol), methanol (1.5 mL), and acetic acid (0.016 mL) was added NaBH3CN (0.25 mmol) in methanol (0.50 mL). The reaction mixture 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. The residue was dissolved in methanol (0.25 mL) and 4 N HCl in dioxane (0.50 mL) was added. The solution was stirred at room temperature for 5 h and concentrated. The residue was dissolved in methanol, 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 resulting material was dissolved into ethyl acetate (0.5 mL), loaded onto Varian™ Si column, eluted off using ethyl acetate/methanol=5:1 (6 mL), and concentrated to afford (R)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4-bromo-2-fluorobenzyl)pyrrolidine (Compound No. 2120) (16.0 mg, 31%): The purity was determined by RPLC/MS (99%); ESI/MS m/e 517.0 (M++H, C21H21BrF4N4O2).

1. temperatureThe mixture was cooled to room temperature
2. washwashed with CH3OH (5 mL×2)
3. washProduct was eluted off
4. concentrationconcentrated
5. dissolutionThe residue was dissolved in methanol (0.25 mL)
6. addition4 N HCl in dioxane (0.50 mL) was added
7. stirringThe solution was stirred at room temperature for 5 h
8. concentrationconcentrated
9. dissolutionThe residue was dissolved in methanol
10. washwashed with CH3OH (5 mL×2)
11. washProduct was eluted off
12. concentrationconcentrated
13. dissolutionThe resulting material was dissolved into ethyl acetate (0.5 mL)
14. washeluted off
15. concentrationconcentrated

ORD record

ord-c18e19cc0176438890aceb8a947a5349

Source dataset

uspto-grants-2002_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06362177B1