Potassium Carbonate → (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5-(5-isopropyl-2-methoxypyridin-3-yl)-2-(methylthio)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

HRID 531231Notes

Reaction equation

HRID 531231 reaction equation
[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:32]([C:35]1[CH:36]=[C:37](B(O)O)[C:38]([O:41][CH3:42])=[N:39][CH:40]=1)([CH3:34])[CH3:33].C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-]>C(OCC)(=O)C.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:37]4[C:38]([O:41][CH3:42])=[N:39][CH:40]=[C:35]([CH:32]([CH3:34])[CH3:33])[CH:36]=4)=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 25517Ammonium ChlorideHCID 57576287(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(methylthio)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one2×HCID 900091535-Isopropyl-2-methoxypyridin-3-ylboronic acid

Product 1

HCID 118021417(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5-(5-isopropyl-2-methoxypyridin-3-yl)-2-(methylthio)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Reagents, catalysts & solvents 2

HCID 178454861HCID 178454861, compoundCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(methylsulfanyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 8, 2.0 g, 3.77 mmol), 5-isopropyl-2-methoxypyridin-3-ylboronic acid (1.25 g, 4.53 mmol) and K2CO3 (1.56 g, 11.31 mmol) were added to a round bottom flask, which was then evacuated and charged with nitrogen 3 times. THF (15 mL) and water (3 mL) were then added. After evacuating and charging again with nitrogen, 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.369 g, 0.566 mmol) was added and the reaction heated for 60 minutes at 50° C., at which time LCMS showed complete conversion to product. The reaction was diluted with 50 mL ethyl acetate and poured into 100 mL saturated NH4Cl solution. The ethyl acetate layer was washed with brine (100 mL), then filtered through a 20 g plug of sodium sulfate, eluting with 50 mL ethyl acetate. The filtrate was concentrated prior to flash purification. The crude was purified by silica gel chromatography, eluting with a 0-20% ethyl acetate/hexanes gradient followed by isocratic elution at 20% ethyl acetate/hexanes. Pure fractions were concentrated to give product as colorless foam. LCMS (M+H)+: 601.4.

Workup

  1. customwhich was then evacuated
  2. additioncharged with nitrogen 3 times
  3. additionTHF (15 mL) and water (3 mL) were then added
  4. customAfter evacuating
  5. additionwas added
  6. washThe ethyl acetate layer was washed with brine (100 mL)
  7. filtrationfiltered through a 20 g plug of sodium sulfate
  8. washeluting with 50 mL ethyl acetate
  9. concentrationThe filtrate was concentrated
  10. customto flash purification
  11. customThe crude was purified by silica gel chromatography
  12. washeluting with a 0-20% ethyl acetate/hexanes gradient
  13. washfollowed by isocratic elution at 20% ethyl acetate/hexanes
  14. concentrationPure fractions were concentrated
  15. customto give product as colorless foam

Sources & evidence

ORD record
ord-71a518b2391f4fa4b2857081efdcb4d2
Source dataset
uspto-grants-2016_05
Patent number
US09353101B2

Reaction notes

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