Cesium carbonate → 1-(2-Cyclopropylpyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine

HRID 1662252Notes

Reaction equation

HRID 1662252 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH:25]4[CH2:27][CH2:26]4)[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.CCO.O.CCOC(C)=O.[Cl-].[Na+].O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH:25]1([C:21]2[CH:20]=[C:19]([C:8]3([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:32]5[CH:33]=[N:28][CH:29]=[N:30][CH:31]=5)[CH:3]=4)[C:16]4[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=4)[C:10]([NH2:18])=[N:9]3)[CH:24]=[CH:23][N:22]=2)[CH2:27][CH2:26]1

Participants

8

Reactant 3

HCID 10796Cesium carbonateHCID 2795193(Pyrimidin-5-yl)boronic acidHCID 593275531-(3-Bromophenyl)-1-(2-cyclopropylpyridin-4-yl)-4-fluoro-1H-isoindol-3-amine

Product 1

HCID 462020811-(2-Cyclopropylpyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amineYield 62%

Reagents, catalysts & solvents 4

HCID 53485975CID 53485975CatalystHCID 8857Ethyl AcetateSolventHCID 57417360Sodium chloride; waterSolventHCID 86587095Dimethoxyethane ethanol waterSolvent

Conditions

Temperature
150 °C

Procedure

To a solution of 1-(3-bromophenyl)-1-(2-cyclopropylpyridin-4-yl)-4-fluoro-1H-isoindol-3-amine (97 mg, 0.23 mmol) in DME:EtOH:water (6:3:1) (5 mL) was added pyrimidin-5-ylboronic acid (37.0 mg, 0.30 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]-palladium (II) dichloromethane adduct (9.38 mg, 0.01 mmol) and cesium carbonate (225 mg, 0.69 mmol). The vial was sealed and heated in a microwave reactor at 150° C. for 20 minutes. The reaction was diluted with EtOAc and brine, the layers were separated and the aqueous layer was extracted with EtOAc. The organics were combined, dried (Na2SO4), filtered and the solvent was removed under reduced pressure. The crude was purified by preparative HPLC, appropriate fractions combined and the MeOH removed by evaporation. The remaining aqueous phase was basified by addition of sat. aqueous NaHCO3 (pH˜9) and extracted with dichloromethane (×3). The organics were combined, washed once with sat. aqueous NaHCO3, dried (Na2SO4), filtered and evaporated to give 60 mg (62%) of the title compound.

Workup

  1. customThe vial was sealed
  2. customthe layers were separated
  3. extractionthe aqueous layer was extracted with EtOAc
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. customthe solvent was removed under reduced pressure
  7. customThe crude was purified by preparative HPLC, appropriate fractions
  8. customthe MeOH removed by evaporation
  9. additionThe remaining aqueous phase was basified by addition of sat. aqueous NaHCO3 (pH˜9)
  10. extractionextracted with dichloromethane (×3)
  11. washwashed once with sat. aqueous NaHCO3
  12. dry with materialdried (Na2SO4)
  13. filtrationfiltered
  14. customevaporated

Sources & evidence

ORD record
ord-e175f6894d734e34b52fa7bbad214535
Source dataset
uspto-grants-2011_10
Patent number
US08030500B2

Reaction notes

Loading…