Potassium Hydroxide → HCID 11548806, compound

HRID 1028658Notes

Reaction equation

HRID 1028658 reaction equation
[F:1][C:2]([F:30])([F:29])[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]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3Cl)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:31][C:32]1[C:37]([CH:38]([CH3:40])[CH3:39])=[CH:36][C:35](B(O)O)=[C:34]([O:44][CH3:45])[CH:33]=1.[OH-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCCC>[F:1][C:2]([F:30])([F:29])[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]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[C:35]3[CH:36]=[C:37]([CH:38]([CH3:40])[CH3:39])[C:32]([F:31])=[CH:33][C:34]=3[O:44][CH3:45])[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

Participants

8

Reactant 4

HCID 14797Potassium HydroxideHCID 83681Tris(1,1-dimethylethyl)phosphine2×HCID 53363739(4-Fluoro-5-isopropyl-2-methoxyphenyl)boronic acidHCID 59135125HCID 59135125, compound

Product 1

HCID 11548806HCID 11548806, compound

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalyst2×HCID 8058HexaneSolvent2×HCID 312751,4-DioxaneSolvent

Procedure

To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-chloro-6-fluorobenzyl)-4-methyl-1,3-oxazolidin-2-one (327 mg, 0.72 mmol) in 1,4-dioxane (4 mL) was added (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (228 mg, 1.08 mmol), Palladium(II) acetate (33 mg, 20 mol %), potassium hydroxide (588 μL, 3M, 2.5 eq.) and tri-tert-butylphosphine (44 mg, 0.22 mmol, 30 mol % as a 10% w/w hexane solution). The resulting reaction mixture was purged with nitrogen and sealed in a microwave vessel. The vessel was subject to microwave irradiation at 135° C. for 50 min. LC-MS indicated the starting material/product ratio was about 55:45. The reaction mixture was re-submitted to reaction conditions (μw at 135° C. for 50 min). The LC-MS trace indicated that no progress was made from the 2nd irradiation. More palladium(II) acetate (33 mg, 20 mol %) and tri-tert-butylphosphine (44 mg, 0.22 mmol, 30 mol % as a 10% w/w hexane solution) were added into reaction mixture. The mixture was resubmitted to reaction conditions (μw at 135° C., 1 hr). Again, the LC-MS indicated no significant progress. The reaction mixture was quenched with H2O. The volatiles were removed under reduced pressure. The resulting mixture was extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo to a yellow oil. The oil was dissolved in DMSO and purified twice by a reversed phase prep-HPLC (column: Kromasil, 100-5C18, 100×21.1 mm) eluted by 10% to 90% H2O (0.1% TFA, v/v)/MeCN (0.1% TFA, v/v). The resulting glassy material was then purified on a prep-TLC plate by 100% dichloromethane to afford the titled compound. LC-MS: 588.21 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 1:1 mixture of rotamers δ 7.83 (s, 1 H), 7.67 (s, 1 H) 7.65 (s, 1 H), 7.32-7.41 (m, 1H), 7.09-7.16 (m, 1H), 6.96-7.06 (m, 1H), 6.64-6.70 (m, 1H), 5.47 (d, J=8.0 Hz, 0.5 H), 5.19 (d, J=7.8 Hz, 0.5 H), 4.96 (d, J=14.9 Hz, 0.5 H), 4.80 (d, J=15.1 Hz, 0.5 H), 4.31 (d, J=15.1 Hz, 0.5 H), 3.91 (d, J=15.1 Hz, 0.5 H), 3.78 (s, 1.5 H), 3.75 (s, 1.5 H), 3.62-3.69 (m, 1 H), 3.15-3.26 (m, 1 H), 1.14-1.25 (m, 6 H), 0.54 (d, J=6.6 Hz, 1.5 H), 0.33 (d, J=6.4 Hz, 1.5 H).

Workup

  1. customThe resulting reaction mixture
  2. customwas purged with nitrogen
  3. customsealed in a microwave vessel
  4. customirradiation at 135° C. for 50 min
  5. customThe reaction mixture was re-submitted to reaction conditions (μw at 135° C. for 50 min)
  6. customwas made from the 2nd irradiation
  7. customThe mixture was resubmitted to reaction conditions (μw at 135° C., 1 hr)
  8. customThe reaction mixture was quenched with H2O
  9. customThe volatiles were removed under reduced pressure
  10. extractionThe resulting mixture was extracted with EtOAc
  11. dry with materialThe combined extracts were dried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo to a yellow oil
  14. dissolutionThe oil was dissolved in DMSO
  15. custompurified twice by a reversed phase prep-HPLC (column: Kromasil, 100-5C18, 100×21.1 mm)
  16. washeluted by 10% to 90% H2O (0.1% TFA, v/v)/MeCN (0.1% TFA, v/v)
  17. customThe resulting glassy material was then purified on a prep-TLC plate by 100% dichloromethane

Sources & evidence

ORD record
ord-9a169bb976b04dba940b9f66e5c14381
Source dataset
uspto-grants-2014_05
Patent number
US08735435B2

Reaction notes

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