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

HRID 531268Notes

Reaction equation

HRID 531268 reaction equation
[F:1][C:2]([F:34])([F:33])[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]([N:27]4[CH2:30][CH:29]([F:31])[CH2:28]4)[N:21]=3)[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:35]([C:38]1[CH:39]=[C:40](B(O)O)[C:41]([O:44][CH3:45])=[N:42][CH:43]=1)([CH3:37])[CH3:36].C([O-])([O-])=O.[K+].[K+]>[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:34])([F:33])[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:40]4[C:41]([O:44][CH3:45])=[N:42][CH:43]=[C:38]([CH:35]([CH3:37])[CH3:36])[CH:39]=4)=[CH:24][N:23]=[C:22]([N:27]4[CH2:30][CH:29]([F:31])[CH2:28]4)[N:21]=3)[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 90009107(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one2×HCID 900091535-Isopropyl-2-methoxypyridin-3-ylboronic acid

Product 1

HCID 118021390(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[2-(3-fluoroazetidin-1-yl)-5-(5-isopropyl-2-methoxypyridin-3-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Reagents, catalysts & solvents 1

HCID 178454861HCID 178454861, compoundCatalyst

Conditions

Temperature
50 °C

Procedure

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 14, 1.2 g, 2.153 mmol), 5-isopropyl-2-methoxypyridin-3-ylboronic acid (0.716 g, 2.58 mmol), 1,1′-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (211 mg, 0.323 mmol) and K2CO3 (893 mg, 6.46 mmol) were added to a reaction vial that was evacuated and charged with nitrogen three times. The solid reactants were then mixed with THF (15 mL) and water (3 mL), degassed and refilled with nitrogen, capped and heated for 1 hour at 50° C. in a BIOTAGE microwave reactor, after which LCMS showed complete conversion to product. The reaction was diluted with 50 mL ethyl acetate and poured into 100 mL sat′d NH4Cl soln. The ethyl acetate layer was washed with brine (100 mL) filtered through a 20 g plug of sodium sulfate, eluting with 50 mL ethyl acetate. The filtrate was concentrated prior to RP Prep purification on a X-Bridge 30×300 mm RP column. After loading the column was eluted with a 10-100% acetonitrile/water (0.1% NH4OH) linear gradient over 20 minutes. The product of interest eluted in 80% portion of above gradient. Pure fractions were concentrated and lyophilized to give a white solid. LCMS (M+H)+: 628.5 1H NMR (CDCl3, 500 MHz): δ 8.16 (s, 1H), 8.11 (d, J=2.2 Hz, 1H), 7.91 (s, 1H), 7.76 (s, 2H), 7.36 (d, J=2.2 Hz, 1H), 5.68 (d, J=8.6 Hz, 1H), 5.54 (m, 0.5H) 5.43 (m, 0.5H), 4.70 (d, J=17.2 Hz, 1H), 4.51 (m, 2H), 4.33 (m, 2H), 4.02 (d, J=17.4 Hz, 1H), 3.94 (s, 3H), 2.96 (m, 1H), 1.30 (d, J=6.9 Hz, 6H), 0.74 (d, J=6.7 Hz, 3H). SPA IC50: 11 nM.

Workup

  1. customthat was evacuated
  2. additioncharged with nitrogen three times
  3. additionThe solid reactants were then mixed with THF (15 mL) and water (3 mL)
  4. customdegassed
  5. additionrefilled with nitrogen
  6. customcapped
  7. additionThe reaction was diluted with 50 mL ethyl acetate
  8. additionpoured into 100 mL
  9. washThe ethyl acetate layer was washed with brine (100 mL)
  10. filtrationfiltered through a 20 g plug of sodium sulfate
  11. washeluting with 50 mL ethyl acetate
  12. concentrationThe filtrate was concentrated
  13. customto RP Prep purification on a X-Bridge 30×300 mm RP column
  14. washwas eluted with a 10-100% acetonitrile/water (0.1% NH4OH) linear gradient over 20 minutes
  15. washThe product of interest eluted in 80% portion of above gradient
  16. concentrationPure fractions were concentrated
  17. customto give a white solid

Sources & evidence

ORD record
ord-b28e8e250a2343ac89bc60a006fd2282
Source dataset
uspto-grants-2016_05
Patent number
US09353101B2

Reaction notes

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