Acetonitrile → (R)-N-(2-((1-benzylpyrrolidin-3-yl)amino)-2-oxoethyl)-3-(trifluoromethyl)benzamide

To a solution of (3-Trifluoromethyl-benzoylamino)acetic acid (4.2 g, 17 mmol) and NMM (2.8 mL, 25.5 mmol) in dry THF (30 mL) at −10 to −15° C. under N2, was slowly added isobutylchloroforinate (2.4 mL, 17.85 mmol) via syringe. The reaction mixture gradually became pink. 15 min later, a solution of (3R)-1-benzylpyrrolidin-3-amine (3.0 g, 17 mmol) in THF (15 mL) was dropwise added to the above mixed anhydride over 20 min, maintaining reaction temperature <−10° C. The reaction mixture became a dark red color. 1 h later, the reaction mixture was allowed to warm to rt, and quenched with water (25 mL), extracted with EtOAc×3, dried, filtered and concentrated to give an orange solid. MeCN was added and concentrated to remove EtOAc. Then MeCN (15-20 mL) was added to afford a slurry, which was chilled in ice bath and stirred for 30 min. After filtration, the solid product was rinsed with cold MeCN (10-15 mL) until the filtrate was colorless After dried under high vacuum overnight, a pale yellow solid product: 5.0 g (73%) was afforded. MS (M+H+)=406.2; 1H NMR (CDCl3) δ 8.16 (s, 1 H), 8.00 (dd, 1H), 7.78 (dd, 1H), 7.57 (m, 1H), 7.25 (m, 6H), 7.06 (m, 1H), 6.39 (m, 1H), 4.48 (m, 1H), 4.04 (d, 2H), 3.62 (d, 2H), 2.86 (m, 1H), 2.63 (m, 1H), 2.57 (m, 1H), 2.36 (m, 2H).

1. temperaturemaintaining
2. customreaction temperature <−10° C
3. custom1 h
4. customquenched with water (25 mL)
5. extractionextracted with EtOAc×3
6. customdried
7. filtrationfiltered
8. concentrationconcentrated
9. customto give an orange solid
10. concentrationconcentrated
11. customto remove EtOAc
12. additionThen MeCN (15-20 mL) was added
13. customto afford a slurry, which
14. temperaturewas chilled in ice bath
15. filtrationAfter filtration
16. washthe solid product was rinsed with cold MeCN (10-15 mL) until the filtrate
17. customAfter dried under high vacuum overnight
18. customa pale yellow solid product: 5.0 g (73%) was afforded

ORD record

ord-18e05d409f4546cfa079f3b86a3811a2

Source dataset

uspto-grants-2014_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08729063B2