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

HRID 531267

Reaction equation

HRID 531267 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.[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[C:39]([O:42][CH3:43])=[N:40][CH:41]=1.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:38]4[C:39]([O:42][CH3:43])=[N:40][CH:41]=[C:36]([Cl:35])[CH:37]=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 44754881(5-Chloro-2-methoxypyridin-3-yl)boronic acidHCID 90009107HCID 90009107, compound2×

Product 1

HCID 90009178(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5-(5-chloro-2-methoxypyridin-3-yl)-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Reagents, catalysts & solvents 1

HCID 178454861HCID 178454861, compoundCatalyst

Conditions

Temperature
125 °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, 425 mg, 0.763 mmol), 5-chloro-2-methoxypyridin-3-ylboronic acid (214 mg, 1.144 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (49.7 mg, 0.076 mmol) and K2CO3 (316 mg, 2.288 mmol) were added to a reaction vial that was evacuated and charged with nitrogen three times. The solid reactants were then mixed with THF (4 mL) and water (400 μl), degassed and refilled with nitrogen, capped and heated for 30 minutes at 125° C. in a BIOTAGE microwave reactor, after which LCMS showed complete conversion to product. The reaction was diluted with 5 mL acetonitrile and filtered through a 1 g RP C18 silica cartridge, eluting with 15 mL acetonitrile until filtrate was colorless. The filtrate was concentrated prior to RP Prep purification on a X-Bridge 30×300 mm RP column. The sample was loaded in 7:3:1 CH3CN/water/DMSO (5 mL) and 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 (rich cut; impure discarded) were concentrated and lyophilized to give a white solid. LCMS (M+H)+: 619.1. 1H NMR (CDCl3, 500 MHz): δ 8.24 (s, 1H) 8.16 (s, 1H) 7.93 (s, 1H) 7.77 (s, 2H) 7.53 (s, 1H) 5.73 (m, 1H) 5.57 (m, 0.5H) 5.46 (m, 0.5H), 4.70 (d, J=17.4 Hz, 1H), 4.48 (m, 4H), 4.06 (d, J=17.5 Hz, 1H), 3.97 (s, 3H), 0.78 (bs, 3H). Rotomers gave broad signals. SPA IC50: 38 nM.

Workup

  1. customthat was evacuated
  2. additioncharged with nitrogen three times
  3. additionThe solid reactants were then mixed with THF (4 mL) and water (400 μl)
  4. customdegassed
  5. additionrefilled with nitrogen
  6. customcapped
  7. additionThe reaction was diluted with 5 mL acetonitrile
  8. filtrationfiltered through a 1 g RP
  9. washsilica cartridge, eluting with 15 mL acetonitrile until filtrate
  10. concentrationThe filtrate was concentrated
  11. customto RP Prep purification on a X-Bridge 30×300 mm RP column
  12. washeluted with a 10-100% acetonitrile/water (0.1% NH4OH) linear gradient over 20 minutes
  13. washThe product of interest eluted in 80% portion of above gradient
  14. concentrationPure fractions (rich cut; impure discarded) were concentrated
  15. customto give a white solid
  16. customRotomers gave broad signals

Sources & evidence

ORD record
ord-ba6a7d5c369e4f2a81c6c4adb34bc317
Source dataset
uspto-grants-2016_05
Patent number
US09353101B2

Linked notes

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