Sodium Carbonate → 3-(5-Fluoropyrimidin-4-yl)-3-methyl-6-(1H-pyrazol-4-yl)isoindolin-1-one

HRID 1749384Notes

Reaction equation

HRID 1749384 reaction equation
O1CCOCC1.Br[C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:29]3[C:34]([F:35])=[CH:33][N:32]=[CH:31][N:30]=3)([CH3:28])[N:13]([C@@H](C3C=CC(OC)=CC=3)C)[C:14]2=[O:17])=[CH:10][CH:9]=1.CC1(C)C(C)(C)OB([C:44]2[CH:45]=[N:46][N:47](C(OC(C)(C)C)=O)[CH:48]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.C(OCC)(=O)C.CC(C)([O-])C.[K+]>[F:35][C:34]1[C:29]([C:12]2([CH3:28])[C:11]3[C:15](=[CH:16][C:8]([C:44]4[CH:45]=[N:46][NH:47][CH:48]=4)=[CH:9][CH:10]=3)[C:14](=[O:17])[NH:13]2)=[N:30][CH:31]=[N:32][CH:33]=1

Participants

8

Reactant 4

HCID 10340Sodium CarbonateHCID 312751,4-Dioxane2×HCID 16217654tert-butyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylateHCID 904084426-Bromo-3-(5-fluoropyrimidin-4-yl)-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-isoindolin-1-one

Product 1

HCID 862700183-(5-Fluoropyrimidin-4-yl)-3-methyl-6-(1H-pyrazol-4-yl)isoindolin-1-oneYield 76%

Reagents, catalysts & solvents 3

HCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylCatalystHCID 23665647Potassium tert-butoxideCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
150 °C

Procedure

Combine RuPhos Palladium(II) phenethylamine chloride (60 μmol, 43 mg), dioxane (0.5 mL) and potassium tert-butoxide (1 M tetrahydrofuran, 60 μmol, 60 μL) under nitrogen, sonicate the mixture for 0.5 minute. Add the Ruphos catalyst mixture to a reaction vessel under nitrogen containing 6-bromo-3-(5-fluoropyrimidin-4-yl)-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-isoindolin-1-one (544 mg, 1.192 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (1.79 mmol, 526 mg), 1,4-dioxane (6 mL), sodium carbonate (3.6 mmol, 2.4 mL 1.5 M aqueous) and heat in a microwave at 150° C. for 30 minutes. Dilute the mixture with ethyl acetate, wash with aqueous 1.5 M sodium carbonate, wash with saturated aqueous sodium chloride, dry over magnesium sulfate, filter through diatomaceous earth, and evaporate to a light yellow residue. Dissolve the residue in anisole (1 mL) and trifluoroacetic acid (7 mL) and heat to 80° C. for 4 hours, then heat to 70° C. for 18 hours. Evaporate the mixture under reduced pressure, dissolve in methanol, load on a 10 g SCX column, wash with methanol (100 mL), elute with 2 M ammonia in methanol and evaporate. Purify on 40 g silica gel with a gradient of 1-8% methanol/dichloromethane to give the title compound as a white foam (279 mg, 76%). ES/MS m/z: 310 (M+H).

Workup

  1. washwash with aqueous 1.5 M sodium carbonate
  2. washwash with saturated aqueous sodium chloride
  3. dry with materialdry over magnesium sulfate
  4. filtrationfilter through diatomaceous earth
  5. customevaporate to a light yellow residue
  6. dissolutionDissolve the residue in anisole (1 mL)
  7. temperaturetrifluoroacetic acid (7 mL) and heat to 80° C. for 4 hours
  8. temperatureheat to 70° C. for 18 hours
  9. customEvaporate the mixture under reduced pressure
  10. dissolutiondissolve in methanol
  11. washload on a 10 g SCX column, wash with methanol (100 mL)
  12. washelute with 2 M ammonia in methanol
  13. customevaporate
  14. customPurify on 40 g silica gel with a gradient of 1-8% methanol/dichloromethane

Sources & evidence

ORD record
ord-f7d43119e49e4a87b8d94fa0d5c7b94c
Source dataset
uspto-grants-2015_10
Patent number
US09156824B2

Reaction notes

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