Trifluoroacetic acid → HCID 74221333, compound

Trifluoroacetic acid (0.442 mL, 5.78 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 (0.356 g, 0.578 mmol, Example 89) in dichloromethane (2.9 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 oily residue. The residue was dissolved in dichloromethane (5.8 mL). Triethylamine (0.401 mL, 2.89 mmol) and acetic anhydride (0.218 mL, 2.31 mmol) were added in sequence and the solution was heated to 46° C. After 2 h, the reaction was cooled to room temperature. Dichloromethane (50 mL) and saturated aqueous sodium bicarbonate solution were added in sequence. The biphasic mixture was stirred for 10 min. The layers were separated. The organic layer was dried over sodium sulfate and the dried solution was filtered. Celite (4 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 10% methanol-dichloromethane provided the title compound as a white solid. 1H NMR (500 MHz, CDCl3, 3:1 mixture of amide rotamers, * denotes minor rotamer isomer) δ ppm 8.44 (d, J=2.0 Hz, 1H), 8.39* (d, J=2.1 Hz, 1H), 8.03-7.97 (m, 1H), 7.57-7.50 (m, 3H), 7.48-7.42 (m, 1H), 7.24-7.18 (m, 2H), 6.42 (s, 1H), 5.48* (s, 1H), 4.56-4.46 (m, 2H), 4.43-4.36* (m, 1H), 4.36-4.31* (m, 1H), 4.26-4.19 (m, 1H), 4.19-4.13 (m, 1H), 4.07-3.99 (m, 1H), 3.81-3.62 (m, 4H), 3.61-3.46 (m, 1H), 2.97-2.90 (m, 2H), 1.81* (s, 3H), 1.58 (s, 3H), 1.35-1.26 (m, 3H); MS (ESI): mass calcd. for C28H27ClF3N5O2, 557.2; m/z found, 558.0 [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 oily residue
11. temperaturethe solution was heated to 46° C
12. waitAfter 2 h
13. temperaturethe reaction was cooled to room temperature
14. stirringThe biphasic mixture was stirred for 10 min
15. customThe layers were separated
16. dry with materialThe organic layer was dried over sodium sulfate
17. filtrationthe dried solution was filtered
18. additionCelite (4 g) was added to the filtrate
19. customthe solvents were removed by rotary evaporation
20. customto provide a free-flowing powder
21. washElution with dichloromethane initially

ORD record

ord-6b88a0a44152449ca609c19e9a7b7cf0

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09290476B2