반응 #85615

반응 방정식

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

용매

DMF

반응 조건

후처리

1. 1
   기타cloudy suspension resulted)
2. 2
   workup.ADDITIONAfter complete addition the reaction mixture
3. 3
   기타before removing the cooling bath
4. 4
   workup.WAITLeft
5. 5
   workup.STIRRINGstirring at room temperature for 6 h
6. 6
   workup.ALIQUOTSampled
7. 7
   기타reaction mixture
8. 8
   기타quenched with water
9. 9
   추출extracted into EtOAc
10. 10
    온도Cooled
11. 11
    기타reaction mixture to 0° C.
12. 12
    온도warmed to room temperature
13. 13
    workup.WAITleft
14. 14
    workup.STIRRINGstirring for 3 h at rt
15. 15
    기타quenched
16. 16
    기타reaction mixture at this point
17. 17
    기타Quenched the reaction mixture with water (100 mL) which
18. 18
    기타resulted in considerable effervescence
19. 19
    기타Added EtOAc (75 mL) and separated
20. 20
    추출extracted the aqueous with EtOAc (2×75 mL)
21. 21
    세척washed with water (100 mL), brine (50 mL)
22. 22
    건조dried (MgSO4)
23. 23
    농축concentrated to dryness
24. 24
    기타to give crude product as a pale yellow oil
25. 25
    기타Crude was purified by silica gel chromatography (initial neat DCM
26. 26
    농축concentrated to dryness
27. 27
    기타to give a colourless oil which

실험 절차

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)+.

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