Trifluoroacetic acid → HCID 118006437, compound

Temperature

23 °C

A mixture containing tert-butyl 3-((4-chloro-2-methyl-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(hydroxy)(1-methyl-1H-1,2,3-triazol-5-yl)methyl)azetidine-1-carboxylate (250 mg, 0.42 mmol, Example 31) and trifluoroacetic acid (0.32 mL, 0.32 mmol) in dichloromethane (2 mL) was stirred at 23° C. After 18 hours, dichloromethane (50 mL) and saturated aqueous sodium bicarbonate solution (25 mL) were added. The biphasic mixture was stirred for 5 minutes. The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. The filtrate was concentrated to provide a residue. This residue was used in the next step without further purification. A mixture of the residue (174 mg), triethylamine (0.25 mL), and acetic anhydride (0.14 mL) in dichloromethane (3.5 mL) was stirred at 46° C. After 2 hours, the flask was cooled to 23° C. Dichloromethane (40 mL) and saturated aqueous sodium bicarbonate solution (25 mL) were added. The biphasic mixture was stirred for 10 minutes at 23° C. The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. Celite® (3 g) was added to the filtrate and the mixture was concentrated in vacuo. The dry solid was loaded onto a silica gel column for flash-column chromatography. Elution with 100% dichloromethane initially, grading to 5% methanol-dichloromethane provided the title compound as an off-white solid. 1H NMR (500 MHz, CDCl3, 3:1 mixture of amide rotamers, asterisk denotes minor rotamer) δ ppm 8.44 (d, J=2.0 Hz, 1H), 8.38* (d, J=2.1 Hz, 1H), 8.00-7.94 (m, 1H), 7.60-7.51 (m, 3H), 7.48-7.42 (m, 1H), 7.25-7.20 (m, 2H), 6.23 (s, 1H), 5.09* (s, 1H), 4.54-4.45 (m, 2H), 4.43-4.36* (m, 1H), 4.34-4.28* (m, 1H), 4.27-4.19 (m, 1H), 4.19-4.13 (m, 1H), 4.08-3.96 (m, 1H), 3.80-3.65 (m, 4H), 3.63-3.54* (m, 1H), 3.54-3.46 (m, 1H), 2.69-2.63 (m, 3H), 1.82* (s, 3H), 1.65-1.54 (m, overlap with water, 3H); MS (ESI): mass calcd. for C27H25ClF3N5O2, 543.2. m/z found, 544.1 [M+H]+.

1. stirringThe biphasic mixture was stirred for 5 minutes
2. customThe layers were separated
3. dry with materialThe organic layer was dried with sodium sulfate
4. filtrationthe dried solution was filtered
5. concentrationThe filtrate was concentrated
6. customto provide a residue
7. customThis residue was used in the next step without further purification
8. additionA mixture of the residue (174 mg), triethylamine (0.25 mL), and acetic anhydride (0.14 mL) in dichloromethane (3.5 mL)
9. stirringwas stirred at 46° C
10. waitAfter 2 hours
11. temperaturethe flask was cooled to 23° C
12. additionDichloromethane (40 mL) and saturated aqueous sodium bicarbonate solution (25 mL) were added
13. stirringThe biphasic mixture was stirred for 10 minutes at 23° C
14. customThe layers were separated
15. dry with materialThe organic layer was dried with sodium sulfate
16. filtrationthe dried solution was filtered
17. additionCelite® (3 g) was added to the filtrate
18. concentrationthe mixture was concentrated in vacuo
19. washElution with 100% dichloromethane initially

ORD record

ord-f97cc3b3b9ac4bdd96d428054d43ef3b

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09284308B2