تفاعل #85615

معادلة التفاعل

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

المذيبات

DMF

ظروف التفاعل

المعالجة

1. 1
   أخرىcloudy suspension resulted)
2. 2
   workup.ADDITIONAfter complete addition the reaction mixture
3. 3
   أخرىbefore removing the cooling bath
4. 4
   workup.WAITLeft
5. 5
   workup.STIRRINGstirring at room temperature for 6 h
6. 6
   workup.ALIQUOTSampled
7. 7
   أخرىreaction mixture
8. 8
   أخرىquenched with water
9. 9
   استخلاصextracted into EtOAc
10. 10
    درجة الحرارةCooled
11. 11
    أخرىreaction mixture to 0° C.
12. 12
    درجة الحرارةwarmed to room temperature
13. 13
    workup.WAITleft
14. 14
    workup.STIRRINGstirring for 3 h at rt
15. 15
    أخرىquenched
16. 16
    أخرىreaction mixture at this point
17. 17
    أخرىQuenched the reaction mixture with water (100 mL) which
18. 18
    أخرىresulted in considerable effervescence
19. 19
    أخرىAdded EtOAc (75 mL) and separated
20. 20
    استخلاصextracted the aqueous with EtOAc (2×75 mL)
21. 21
    غسيلwashed with water (100 mL), brine (50 mL)
22. 22
    تجفيفdried (MgSO4)
23. 23
    تركيزconcentrated to dryness
24. 24
    أخرىto give crude product as a pale yellow oil
25. 25
    أخرىCrude was purified by silica gel chromatography (initial neat DCM
26. 26
    تركيزconcentrated to dryness
27. 27
    أخرىto give a colourless oil which

الإجراء التجريبي

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)+.

المصدر