Trifluoroacetic acid → HCID 74221332, compound

Trifluoroacetic acid (0.511 mL, 6.67 mmol) was added dropwise by syringe to an ice-cooled, stirring solution of tert-butyl 3-((4-chloro-2-ethyl-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(hydroxy)(1-methyl-1H-1,2,3-triazol-5-yl)methyl)azetidine-1-carboxylate (0.411 g, 0.667 mmol, Example 89) in dichloromethane (3.3 mL). After 20 min, the flask was removed from the cooling bath and allowed to warm to room temperature. After 18 h, dichloromethane (15 mL) and saturated aqueous sodium bicarbonate solution (10 mL) were added in sequence. The biphasic mixture was stirred for 10 min. The mixture was partitioned between water (10 mL) and dichloromethane (10 mL). The layers were separated. The organic layer was dried with sodium sulfate. The dried solution was filtered and the filtrate was concentrated to afford an off-white solid. The solid was dissolved in dry dichloromethane (6.1 mL). The resulting solution was cooled in an ice-water bath. Triethylamine (0.257 mL, 1.85 mmol) and methanesulfonyl chloride (0.072 mL, 0.924 mmol) were added in sequence. After 25 min, dichloromethane (50 mL) and water (25 mL) were added. The layers were separated. The aqueous layer was extracted with dichloromethane (15 mL). The organic layers were combined and the combined solution was dried with sodium sulfate. The dried solution was filtered. Celite (5 g) was added to the filtrate and the solvents were removed by rotary evaporation to provide a free-flowing powder. The powder was loaded onto a silica gel column. Elution with dichloromethane initially, grading to 7% methanol-dichloromethane provided the title compound as a white solid, which was not pure. Additional purification by rp-HPLC(H2O/acetonitrile/TFA) followed by partitioning between dichloromethane and saturated aqueous sodium bicarbonate solution to neutralize any ammonium salts provided the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.38 (d, J=2.0 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.54 (d, J=8.1 Hz, 2H), 7.49 (s, 1H), 7.44-7.40 (m, 1H), 7.21 (d, J=8.0 Hz, 2H), 5.25 (s, 1H), 4.51 (s, 2H), 4.27-4.08 (m, 3H), 3.72 (s, 3H), 3.63-3.51 (m, 2H), 2.99-2.87 (m, 5H), 1.35-1.27 (m, 3H); MS (ESI): mass calcd. for C27H27ClF3N5O3S, 593.1; m/z found, 594.0 [M+H]+.

1. temperaturecooled
2. customthe flask was removed from the cooling bath
3. waitAfter 18 h
4. additiondichloromethane (15 mL) and saturated aqueous sodium bicarbonate solution (10 mL) were added in sequence
5. customThe mixture was partitioned between water (10 mL) and dichloromethane (10 mL)
6. customThe layers were separated
7. dry with materialThe organic layer was dried with sodium sulfate
8. filtrationThe dried solution was filtered
9. concentrationthe filtrate was concentrated
10. customto afford an off-white solid
11. temperatureThe resulting solution was cooled in an ice-water bath
12. waitAfter 25 min
13. customThe layers were separated
14. extractionThe aqueous layer was extracted with dichloromethane (15 mL)
15. dry with materialthe combined solution was dried with sodium sulfate
16. filtrationThe dried solution was filtered
17. additionCelite (5 g) was added to the filtrate
18. customthe solvents were removed by rotary evaporation
19. customto provide a free-flowing powder
20. washElution with dichloromethane initially

ORD record

ord-6538991652d74866bd34687a5dedaee6

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09290476B2