1,4-Dioxane → tert-Butyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(3-fluoroazetidin-1-yl)pyrimidin-5-yl]-6-methylpyridin-3-yl}-3-methylbenzoate

HRID 531314Notes

Reaction equation

HRID 531314 reaction equation
[F:1][C:2]([F:42])([F:41])[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](B4OC(C)(C)C(C)(C)O4)=[CH:24][N:23]=[C:22]([N:35]4[CH2:38][CH:37]([F:39])[CH2:36]4)[N:21]=3)[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[C:44]1[CH:45]=[C:46]([C:51]2[CH:63]=[CH:62][C:54]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])=[CH:53][C:52]=2[CH3:64])[CH:47]=[N:48][C:49]=1[CH3:50].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>[Pd](Cl)Cl.O>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:44]4[CH:45]=[C:46]([C:51]5[CH:63]=[CH:62][C:54]([C:55]([O:57][C:58]([CH3:60])([CH3:61])[CH3:59])=[O:56])=[CH:53][C:52]=5[CH3:64])[CH:47]=[N:48][C:49]=4[CH3:50])=[CH:24][N:23]=[C:22]([N:35]4[CH2:36][CH:37]([F:39])[CH2:38]4)[N:21]=3)[C@H:14]2[CH3:40])[CH:4]=[C:3]([C:2]([F:42])([F:41])[F:1])[CH:8]=1

Participants

7

Reactant 4

HCID 312751,4-DioxaneHCID 62657Potassium Phosphate, TribasicHCID 90009119HCID 90009119, compound2×HCID 118021442tert-Butyl 4-(5-chloro-6-methylpyridin-3-yl)-3-methylbenzoate2×

Product 1

HCID 118021378tert-Butyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(3-fluoroazetidin-1-yl)pyrimidin-5-yl]-6-methylpyridin-3-yl}-3-methylbenzoateYield 46%

Reagents, catalysts & solvents 2

HCID 24290Palladium ChlorideCatalystHCID 962WaterSolvent

Conditions

Temperature
180 °C

Procedure

To a 10 mL microwave tube was added (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2-(3-fluoroazetidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 22, 86 mg, 0.142 mmol), tert-butyl 4-(5-chloro-6-methylpyridin-3-yl)-3-methylbenzoate (INTERMEDIATE 39, 41 mg, 0.129 mmol), potassium phosphate (41 mg, 0.194 mmol), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride (XPHOS Biphenyl Precatalyst) (20.3 mg, 0.026 mmol), followed by dioxane (2 mL) and water (0.1 mL). The tube was sealed and stirred at 180° C. in the microwave reactor for 10 minutes. After cooling down, the solvent was evaporated. The residue was purified by silica gel chromatography (0 to 100% Ethyl acetate/hexane) and afforded the title compound as a white solid in 46% yield. LCMS (M+H)+: 760.2.

Workup

  1. customThe tube was sealed
  2. temperatureAfter cooling down
  3. customthe solvent was evaporated
  4. customThe residue was purified by silica gel chromatography (0 to 100% Ethyl acetate/hexane)

Sources & evidence

ORD record
ord-fc6b071523ae457aa68170efaa280ed8
Source dataset
uspto-grants-2016_05
Patent number
US09353101B2

Reaction notes

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