Potassium Phosphate, Tribasic → 1-{2,5-difluoro-4-[(phenylmethyl)oxy]phenyl}-4-[(phenylmethyl)oxy]-1H-indole

HRID 2421248Notes

Reaction equation

HRID 2421248 reaction equation
[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1([CH2:24][O:25][C:26]2[CH:31]=[C:30]([F:32])[C:29](Br)=[CH:28][C:27]=2[F:34])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C>[F:32][C:30]1[CH:31]=[C:26]([O:25][CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:27]([F:34])=[CH:28][C:29]=1[N:13]1[C:14]2[C:10](=[C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1

Participants

6

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 884654-(phenylmethoxy)-1H-indoleHCID 145742L-ProlineHCID 580861601-Benzyloxy-4-bromo-2,5-difluorobenzene

Product 1

HCID 596279201-{2,5-difluoro-4-[(phenylmethyl)oxy]phenyl}-4-[(phenylmethyl)oxy]-1H-indole

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
140 °C

Procedure

In two microwave vials were placed 4-[(phenylmethyl)oxy]-1H-indole (500 mg, 2.24 mmoL), 4-bromo-2,5-difluorophenyl phenylmethyl ether (prepared as described in part a), 559 mg, 1.87 mmoL), K3PO4 (990 mg, 4.67 mmoL), L-Proline (43 mg, 0.373 mmoL) and DMF (5 mL) and the mixture was degassed by sonication under a flow of argon. To each vial was added CuI (71 mg, 0.373 mmoL) and the solutions were heated to 140° C. in the microwave reactor. After 4 hours a second portion of L-Proline (43 mg, 0.373 mmoL) was added and heated for an additional hour. The two mixtures were partitioned between ethyl acetate (100 mL)/water (100 mL), the phases were separated and the aqueous phase re-extracted with ethyl acetate (100 mL). The combined organic phases were washed with sat. NH4Cl (2×100 mL), water (100 mL) and brine (2×100 mL) and finally dried over MgSO4. The combined crude materials were purified by flash chromatography (Biotage SP4, 40+M Cartridge) eluting with a gradient of 0 to 30% Et2O in hexane to give the title compound (D22), (258 mg).

Workup

  1. customprepared
  2. customthe mixture was degassed by sonication under a flow of argon
  3. additionTo each vial was added CuI (71 mg, 0.373 mmoL)
  4. additionAfter 4 hours a second portion of L-Proline (43 mg, 0.373 mmoL) was added
  5. temperatureheated for an additional hour
  6. customThe two mixtures were partitioned between ethyl acetate (100 mL)/water (100 mL)
  7. customthe phases were separated
  8. extractionthe aqueous phase re-extracted with ethyl acetate (100 mL)
  9. washThe combined organic phases were washed with sat. NH4Cl (2×100 mL), water (100 mL) and brine (2×100 mL)
  10. dry with materialfinally dried over MgSO4
  11. customwere purified by flash chromatography (Biotage SP4, 40+M Cartridge)
  12. washeluting with a gradient of 0 to 30% Et2O in hexane

Sources & evidence

ORD record
ord-0884957bb4434337b2df5a8095eda973
Source dataset
uspto-grants-2011_06
Patent number
US07956083B2

Reaction notes

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