Cesium carbonate → HCID 68379859, compound

Temperature

60 °C

Cesium carbonate (28.6 g, 87.8 mmol) was added to a solution of crude 4-fluoro-2-(1,1,1-trifluoropropan-2-yl)phenol (C44) (6.00 g, 28.8 mmol) in N,N-dimethylformamide (60 mL). After addition of (2S)-2-[(tert-butoxycarbonyl)amino]propyl methanesulfonate (P12) (7.5 g, 29.6 mmol), the reaction mixture was heated in a 60° C. oil bath for 30 minutes, then treated with additional P12 (7.5 g, 29.6 mmol) and heated for 18 hours. At this point, the reaction mixture was allowed to cool to room temperature, diluted with water (500 mL), and extracted with diethyl ether (3×150 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting material (11.23 g) was dissolved in dichloromethane (200 mL); trifluoroacetic acid (40 mL) was added, and the reaction mixture was stirred for 1 hour. After removal of solvents in vacuo, the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification using silica gel chromatography (Eluents: 75% ethyl acetate in heptane, then ethyl acetate, then 10% methanol in ethyl acetate) afforded the product as a roughly 1:1 mixture of two diastereomers, as assessed by 1H NMR. Yield: 5.44 g, 20.5 mmol, 71%. LCMS m/z 266.1 (M+1). 1H NMR (400 MHz, CDCl3) δ [1.31 (d, J=6.6 Hz) and 1.32 (d, J=6.6 Hz), total 3H], 1.41 (d, J=7.2 Hz, 3H), 3.50-3.59 (m, 1H), 3.82-4.22 (m, 3H), 6.79-6.84 (m, 1H), 6.92-6.98 (m, 1H), 7.05-7.11 (m, 1H). Also obtained was material enriched in the higher Rf diastereomer (1.10 g, 4.15 mmol, 14%) and material enriched in the lower Rf diastereomer (324 mg, 1.22 mmol, 4%).

1. additiontreated with additional P12 (7.5 g, 29.6 mmol)
2. temperatureheated for 18 hours
3. temperatureto cool to room temperature
4. extractionextracted with diethyl ether (3×150 mL)
5. dry with materialThe combined organic layers were dried over magnesium sulfate
6. filtrationfiltered
7. concentrationconcentrated under reduced pressure
8. dissolutionThe resulting material (11.23 g) was dissolved in dichloromethane (200 mL)
9. additiontrifluoroacetic acid (40 mL) was added
10. customAfter removal of solvents in vacuo
11. dissolutionthe residue was dissolved in ethyl acetate
12. washwashed with saturated aqueous sodium bicarbonate solution and with saturated aqueous sodium chloride solution
13. dry with materialdried over magnesium sulfate
14. filtrationfiltered
15. concentrationconcentrated in vacuo
16. customPurification
17. custom75% ethyl acetate in heptane, then ethyl acetate, then 10% methanol in ethyl acetate) afforded the product
18. additionas a roughly 1:1 mixture of two diastereomers
19. customAlso obtained

ORD record

ord-415683923f124b2f8cb81ddd21dc9032

Source dataset

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09067934B2