Cesium carbonate → (R)-3-(5-fluoro-2-(((S)-1-(1-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one

HRID 57487Notes

Reaction equation

HRID 57487 reaction equation
C([O:5][C@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[C:19]([F:20])=[CH:18][N:17]=[C:16]([NH:21][C@H:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH3:23])[N:15]=1)[CH3:7])(C)(C)C.Br[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:37]([CH3:43])([CH3:42])[C:38]([F:41])([F:40])[F:39])[CH:32]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:20][C:19]1[C:14]([N:9]2[C@@H:8]([C@@H:6]([OH:5])[CH3:7])[CH2:12][O:11][C:10]2=[O:13])=[N:15][C:16]([NH:21][C@H:22]([CH:24]2[CH2:25][CH2:26][N:27]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([C:37]([CH3:43])([CH3:42])[C:38]([F:41])([F:40])[F:39])[CH:32]=3)[CH2:28][CH2:29]2)[CH3:23])=[N:17][CH:18]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 716828104-Bromo-2-(2,2,2-trifluoro-1,1-dimethylethyl)pyridineHCID 90417340(R)-4-((S)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2-(((S)-1-(piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

Product 1

HCID 90415196(R)-3-(5-fluoro-2-(((S)-1-(1-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-oneYield 18.1%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Procedure

A cloudy solution of (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2-(((S)-1-(piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (21 mg, 0.051 mmol), 4-bromo-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine (14 mg, 0.051 mmol), Pd(OAc)2 (1 mg, 5 umol), BINAP (3 mg, 5 umol), and Cs2CO3 (25 mg, 0.077 mmol) in 6 mL toluene was heated at 90° C. overnight. The mixture was cooled to room temperature, and filtered through Celite. The celite cake was rinsed with 5 mL EtOAc. The filtrate was poured into 5 mL water. Organic layer was separated, and the aqueous was further extracted with EtOAc (5 mL). The organic extracts were combined and concentrated by rotary evaporation. The resulting crude was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction solution was stirred for 2 hour at room temperature and was concentrated by rotary evaporation. The resulting residue was dissolved in DCM (2 mL) and water (2 mL) and the pH was adjusted to ˜9 with NH4OH. The DCM layer was separated and concentrated by rotary evaporation. The crude was dissolved in a mixture of MeOH (1 mL) and DMSO (1 mL) and purified by reverse phase HPLC. Selected fractions were collected and concentrated by rotary evaporation to afford the title product as a colorless oil (5 mg) (ratio of two peaks with same MS: 93/7% by LC-MS). (400 MHz, CD2Cl2) δ 8.16-8.08 (m, 2H), 6.79-6.75 (m, 1H), 6.57-6.52 (m, 1H), 4.97-4.86 (m, 1H), 4.47-4.39 (m, 2H), 4.33-4.25 (m, 1H), 4.11-4.02 (m, 1H), 3.89-3.75 (m, 3H), 2.97 (br s, 1H), 2.80-2.67 (m, 2H), 1.84-1.67 (m, 2H), 1.67-1.55 (m, 1H), 1.48 (s, 6H), 1.38-1.15 (m, 2H), 1.11 (d, J=5.91 Hz, 3H), 1.07 (d, J=5.91 Hz, 3H), HRMS(C) tR=3.59 min; MS m/z 541.2557 (M+H)+

Workup

  1. filtrationfiltered through Celite
  2. washThe celite cake was rinsed with 5 mL EtOAc
  3. additionThe filtrate was poured into 5 mL water
  4. customOrganic layer was separated
  5. extractionthe aqueous was further extracted with EtOAc (5 mL)
  6. concentrationconcentrated by rotary evaporation
  7. dissolutionThe resulting crude was dissolved in DCM (1 mL)
  8. additionTFA (1 mL) was added
  9. concentrationwas concentrated by rotary evaporation
  10. dissolutionThe resulting residue was dissolved in DCM (2 mL)
  11. customThe DCM layer was separated
  12. concentrationconcentrated by rotary evaporation
  13. dissolutionThe crude was dissolved in a mixture of MeOH (1 mL) and DMSO (1 mL)
  14. custompurified by reverse phase HPLC
  15. customSelected fractions were collected
  16. concentrationconcentrated by rotary evaporation

Sources & evidence

ORD record
ord-1ba8345eefa6411089b5f27a9156a4a9
Source dataset
uspto-grants-2016_09
Patent number
US09434719B2

Reaction notes

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