Potassium Carbonate → HCID 90009309, compound

HRID 531262Notes

Reaction equation

HRID 531262 reaction equation
Cl[C:2]1[CH:3]=[C:4]([C:10]2[C:11]([CH2:18][N:19]3[C@@H:23]([CH3:24])[C@@H:22]([C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([F:35])[CH:26]=4)[O:21][C:20]3=[O:36])=[N:12][C:13]([S:16][CH3:17])=[N:14][CH:15]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:61]1[C:70]([CH3:71])=[CH:69][C:64]([C:65]([O:67][CH3:68])=[O:66])=[CH:63][C:62]=1[CH3:72].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.[Pd](Cl)Cl.[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:35][C:27]1[CH:26]=[C:25]([C@H:22]2[O:21][C:20](=[O:36])[N:19]([CH2:18][C:11]3[C:10]([C:4]4[CH:3]=[C:2]([C:61]5[C:70]([CH3:71])=[CH:69][C:64]([C:65]([O:67][CH3:68])=[O:66])=[CH:63][C:62]=5[CH3:72])[CH:7]=[N:6][C:5]=4[O:8][CH3:9])=[CH:15][N:14]=[C:13]([S:16][CH3:17])[N:12]=3)[C@H:23]2[CH3:24])[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=1

Participants

9

Reactant 5

HCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 24820334Methyl 4-bromo-3,5-dimethylbenzoateHCID 90009140HCID 90009140, compound2×

Product 1

HCID 90009309HCID 90009309, compoundYield 60.7%

Reagents, catalysts & solvents 3

HCID 24290Palladium ChlorideCatalystHCID 178454861HCID 178454861, compoundCatalystHCID 31374DimethylacetamideSolvent

Conditions

Temperature
130 °C

Procedure

A mixture of (4S,5R)-3-{[5-(5-chloro-2-methoxypyridin-3-yl)-2-(methylsulfanyl)pyrimidin-4-yl]methyl}-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 18, 211 mg, 0.389 mmol), bis(pinacolato)diboron (296 mg, 1.17 mmol), and potassium acetate (114 mg, 1.17 mmol) in N,N-dimethylacetamide (2.0 mL) was degassed three times with nitrogen gas before the addition of (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride (XPHOS Biphenyl Precatalyst) (15.5 mg, 0.019 mmol). The system was degassed three times and was then heated to 130° C. for 24 hours. LC/MS analysis indicated complete conversion to the product, but almost exclusively as the boronic acid. For this reason the crude reaction mixture was taken directly into the next step. Accordingly, methyl 4-bromo-3,5-dimethylbenzoate (142 mg, 0.584 mmol), (1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (24.5 mg, 0.039 mmol), and aqueous potassium carbonate (0.389 mL, 2.0 M) were added. The mixture was degassed, flushed with nitrogen and heated to 100° C. for 45 minutes. The reaction was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography to afford methyl 4-{5-[4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfanyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoate (158 mg, 0.236 mmol). LCMS (M+H)+: 671.1

Workup

  1. customwas degassed three times with nitrogen gas
  2. customThe system was degassed three times
  3. customFor this reason the crude reaction mixture
  4. customThe mixture was degassed
  5. customflushed with nitrogen
  6. temperatureheated to 100° C. for 45 minutes
  7. additionThe reaction was diluted with ethyl acetate
  8. washwashed with water, brine
  9. dry with materialdried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customThe crude product was purified by column chromatography

Sources & evidence

ORD record
ord-be5e805b94de461ea6aec8ef7af213e8
Source dataset
uspto-grants-2016_05
Patent number
US09353101B2

Reaction notes

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