Water → HCID 68288764, compound

HRID 1853097Notes

Reaction equation

HRID 1853097 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:23])=[N:10][CH:11]=[C:12](B3OC(C)(C)C(C)(C)O3)[N:13]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:31]1[C:32]([F:44])=[C:33]([CH:41]=[CH:42][CH:43]=1)[O:34][CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([NH2:23])=[N:10][CH:11]=[C:12]([C:31]3[CH:43]=[CH:42][CH:41]=[C:33]([O:34][CH:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[C:32]=3[F:44])[N:13]=2)=[CH:6][CH:7]=1

Participants

7

Reactant 4

HCID 962WaterHCID 10340Sodium CarbonateHCID 68288570HCID 68288570, compoundHCID 68288979HCID 68288979, compound

Product 1

HCID 68288764HCID 68288764, compoundYield 29.5%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
150 °C

Procedure

To a 80 mL microwave vessel containing the compound prepared in Example 15 (263.9 mg) was added Na2CO3 (181.7 mg) and Pd(PPh3)4 (48.8 mg). The 4-(3-bromo-2-fluorophenoxy)tetrahydro-2H-pyran (253.6 mg) was added by dissolving in 3:1 1,4-dioxane:H2O then adding via pipet and using the remainder of the solvent to wash over any remaining material (total volume: 8.5 mL). The mixture was stirred and sparged with argon for 5 minutes. The vial was placed in the microwave then heated to 150° C. After 15 minutes at 150° C., the mixture was allowed to cool. The dark brown mixture was diluted with EtOAc and washed with H2O two times. The aqueous layers were back extracted with EtOAc. The combined organic layers were washed with brine then dried over Na2SO4, filtered and solvent was removed in vacuo. The material was absorbed onto silica and purified on the Isolera (50 g silica column; 0-15% MeOH in EtOAc) followed by purification via reverse phase on the Isolera (60 g C18 column; 5-95% ACN with 0.1% trifluoroacetic acid (TFA) in H2O with 0.1% TFA). Fractions containing product were combined and solvent was removed in vacuo. The material was taken up in MeOH and desalted by passing through a StratoSphere 200 mg PL-HCO3 MP SPE cartridge. Resin was washed with MeOH and 20% MeOH in DCM. Solvent was removed in vacuo to give the title compound (94.9 mg) having the following data as a dark amber solid/film solid.

Workup

  1. washto wash over any remaining material (total volume: 8.5 mL)
  2. customsparged with argon for 5 minutes
  3. temperatureto cool
  4. additionThe dark brown mixture was diluted with EtOAc
  5. washwashed with H2O two times
  6. extractionThe aqueous layers were back extracted with EtOAc
  7. washThe combined organic layers were washed with brine
  8. dry with materialthen dried over Na2SO4
  9. filtrationfiltered
  10. customsolvent was removed in vacuo
  11. customThe material was absorbed onto silica
  12. custompurified on the Isolera (50 g silica column; 0-15% MeOH in EtOAc)
  13. customfollowed by purification via reverse phase on the Isolera (60 g C18 column; 5-95% ACN with 0.1% trifluoroacetic acid (TFA) in H2O with 0.1% TFA)
  14. additionFractions containing product
  15. customsolvent was removed in vacuo
  16. washResin was washed with MeOH and 20% MeOH in DCM
  17. customSolvent was removed in vacuo

Sources & evidence

ORD record
ord-1c94ef3c091d4c38b6291aec8b6a8e3c
Source dataset
uspto-grants-2015_02
Patent number
US08962623B2

Reaction notes

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