Cesium carbonate → HCID 86665116, compound

HRID 1038866Notes

Reaction equation

HRID 1038866 reaction equation
C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:8]1[N:9]=[C:10]([NH:17][CH2:18][CH:19]([F:21])[F:20])[C:11]2[O:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[NH2:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([CH3:34])([CH3:33])[C:28](=[O:32])[NH:29]2)=[CH:25][CH:24]=1>CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:20][CH:19]([F:21])[CH2:18][NH:17][C:10]1[C:11]2[O:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:8]([NH:22][C:23]2[CH:31]=[C:30]3[C:26]([C:27]([CH3:34])([CH3:33])[C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)[N:9]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 135892296-Amino-3,3-dimethyl-1,3-dihydro-2H-indol-2-oneHCID 86665115HCID 86665115, compound

Product 1

HCID 86665116HCID 86665116, compoundYield 25%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 3283Diethyl EtherSolvent

Conditions

Temperature
65 °C

Procedure

To a vial was added Pd2dba3 (0.235 g, 0.257 mmol), Cs2CO3 (2.37 g, 7.28 mmol) and Ru-Phos (0.240 g, 0.514 mmol) in t-AmOH (8.00 mL). The mixture was evacuated and purged with N2. The mixture was stirred at about 65° C. for about 20 min. 2-Chloro-N-(2,2-difluoroethyl)furo[3,2-d]pyrimidin-4-amine (1.00 g, 4.28 mmol) and 6-amino-3,3-dimethylindolin-2-one (0.754 g, 4.28 mmol, Astatech) were added in one portion. Additional t-AmOH (12.00 mL) was added. The mixture was evacuated and purged with N2. The mixture was stirred at about 70° C. for about 5 h, stirred at about 60° C. for about 15 h and then stirred at about 75° C. for about 2 h. The mixture was cooled to rt and filtered. The precipitate was washed with DCM (20 mL) and MeOH (20 mL). The combined filtrate was concentrated and purified by column chromatography eluting with 25-65% EtOAc/heptane (40 g silica gel) to give a crude material. The material was suspended in Et2O (about 15 mL) and sonicated. The suspension was filtered and washed with Et2O (50 mL), then with DCM (about 30 mL). The precipitate was dissolved in DCM (50 mL), combined with filtrate, concentrated under reduced pressure, dissolved in MeOH (40 mL), and adsorbed onto silica gel (Mesh#200-400, 60A°; 3 g). The material was purified by column chromatography eluting with 0 to 28% of 10% MeOH/DCM and DCM (40 g silica gel) to give a solid. The solid was purified by mass-triggered HPLC (Table 2, Method x) purification to give 6-(4-(2,2-difluoroethylamino)furo[3,2-d]pyrimidin-2-ylamino)-3,3-dimethylindolin-2-one (0.397 g, 25%): LC/MS (Table 2, Method c) Rt=1.75 min.; MS m/z: 374 (M+H)+. Syk IC50=A

Workup

  1. customThe mixture was evacuated
  2. custompurged with N2
  3. customThe mixture was evacuated
  4. custompurged with N2
  5. stirringThe mixture was stirred at about 70° C. for about 5 h
  6. stirringstirred at about 60° C. for about 15 h
  7. stirringstirred at about 75° C. for about 2 h
  8. temperatureThe mixture was cooled to rt
  9. filtrationfiltered
  10. washThe precipitate was washed with DCM (20 mL) and MeOH (20 mL)
  11. concentrationThe combined filtrate was concentrated
  12. custompurified by column chromatography
  13. washeluting with 25-65% EtOAc/heptane (40 g silica gel)
  14. customto give a crude material
  15. customsonicated
  16. filtrationThe suspension was filtered
  17. washwashed with Et2O (50 mL)
  18. dissolutionThe precipitate was dissolved in DCM (50 mL)
  19. concentrationconcentrated under reduced pressure
  20. dissolutiondissolved in MeOH (40 mL)
  21. customThe material was purified by column chromatography
  22. washeluting with 0 to 28% of 10% MeOH/DCM and DCM (40 g silica gel)
  23. customto give a solid
  24. customThe solid was purified by mass-triggered HPLC (Table 2, Method x) purification

Sources & evidence

ORD record
ord-33a9bb079c7a4382847f087992a93aac
Source dataset
uspto-grants-2013_10
Patent number
US08551981B2

Reaction notes

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