反応 #85615

反応方程式

trifluoropyrimidine

(R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one

NaH

NaF

2,4,5-trifluoropyrimidine

→

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

溶媒

DMF

反応条件

後処理

1. 1
   その他cloudy suspension resulted)
2. 2
   workup.ADDITIONAfter complete addition the reaction mixture
3. 3
   その他before removing the cooling bath
4. 4
   workup.WAITLeft
5. 5
   workup.STIRRINGstirring at room temperature for 6 h
6. 6
   workup.ALIQUOTSampled
7. 7
   その他reaction mixture
8. 8
   その他quenched with water
9. 9
   抽出extracted into EtOAc
10. 10
    温度Cooled
11. 11
    その他reaction mixture to 0° C.
12. 12
    温度warmed to room temperature
13. 13
    workup.WAITleft
14. 14
    workup.STIRRINGstirring for 3 h at rt
15. 15
    その他quenched
16. 16
    その他reaction mixture at this point
17. 17
    その他Quenched the reaction mixture with water (100 mL) which
18. 18
    その他resulted in considerable effervescence
19. 19
    その他Added EtOAc (75 mL) and separated
20. 20
    抽出extracted the aqueous with EtOAc (2×75 mL)
21. 21
    洗浄washed with water (100 mL), brine (50 mL)
22. 22
    乾燥dried (MgSO4)
23. 23
    濃縮concentrated to dryness
24. 24
    その他to give crude product as a pale yellow oil
25. 25
    その他Crude was purified by silica gel chromatography (initial neat DCM
26. 26
    濃縮concentrated to dryness
27. 27
    その他to give a colourless oil which

実験手順

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)+.

出典