Sodium Fluoride → (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one

온도

27 °C

A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (5 g, 26.7 mmol) in DMF (50 mL) was cooled to −5° C. under N2 atmosphere. Internal temperature was monitored and maintained at ca. −5° C. during the portionwise addition of 60% NaH (1.28 g, 32 mmol) over 5 mins (no appreciable exotherm seen, but effervescence observed and cloudy suspension resulted). Added 2,4,5-trifluoropyrimidine (3.76 g, 28 mmol) dropwise whilst still maintaining the temperature at ca. −5° C. After complete addition the reaction mixture was stirred at this temperature for 15 mins before removing the cooling bath and allowing the rm to warm to room temperature (ca. 27° C. internal temp). Left stirring at room temperature for 6 h. Sampled reaction mixture and quenched with water, extracted into EtOAc; TLC and LCMS show significant product but remaining oxazolidinone sm. Cooled reaction mixture to 0° C. and added an additional portion of trifluoropyrimidine (1.2 g, 8.95 mmol), warmed to room temperature and left stirring for 3 h at rt. Still faint residual sm seen by TLC of sample, but quenched reaction mixture at this point. Workup: [Safety Note: NaF salt present. Do not acidify workup] Quenched the reaction mixture with water (100 mL) which resulted in considerable effervescence. Added EtOAc (75 mL) and separated, extracted the aqueous with EtOAc (2×75 mL), combined the organics, washed with water (100 mL), brine (50 mL), dried (MgSO4) and concentrated to dryness to give crude product as a pale yellow oil. Crude was purified by silica gel chromatography (initial neat DCM, then ramp to 20% EtOAc/DCM). Pure product fractions were combined and concentrated to dryness to give a colourless oil which was placed under high vacuum. Upon standing the oil converted into a white solid. 1H NMR (400 MHz, CDCl3) δ 8.47 (dd, J=3, 1 Hz, 1H); 4.73-4.68 (m, 1H); 4.62-4.52 (m, 2H); 4.34-4.28 (m, 1H); 1.20 (s, 9H); 1.11 (d, 3H). MS m/z 302.1 (M+H)+.

1. customcloudy suspension resulted)
2. additionAfter complete addition the reaction mixture
3. custombefore removing the cooling bath
4. waitLeft
5. stirringstirring at room temperature for 6 h
6. aliquotSampled
7. customreaction mixture
8. customquenched with water
9. extractionextracted into EtOAc
10. temperatureCooled
11. customreaction mixture to 0° C.
12. temperaturewarmed to room temperature
13. waitleft
14. stirringstirring for 3 h at rt
15. customquenched
16. customreaction mixture at this point
17. customQuenched the reaction mixture with water (100 mL) which
18. customresulted in considerable effervescence
19. customAdded EtOAc (75 mL) and separated
20. extractionextracted the aqueous with EtOAc (2×75 mL)
21. washwashed with water (100 mL), brine (50 mL)
22. dry with materialdried (MgSO4)
23. concentrationconcentrated to dryness
24. customto give crude product as a pale yellow oil
25. customCrude was purified by silica gel chromatography (initial neat DCM
26. concentrationconcentrated to dryness
27. customto give a colourless oil which

ORD 기록

ord-ff827a08ae1046a585c9070ea8ca1f5d

출처 데이터셋

uspto-grants-2016_09

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US09434719B2