Potassium Phosphate, Tribasic → Ethyl 6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

HRID 1021559Notes

Reaction equation

HRID 1021559 reaction equation
Br[C:2]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:3]=1[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:31]=[CH:30][C:12]([O:13][C:14]2[CH:23]=[C:22]3[C:17]([CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:20][O:21]3)=[CH:16][C:15]=2[Cl:29])=[CH:11][CH:10]=1)=[O:8].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P([CH:58]2[CH2:63][CH2:62]CCC2)C2CCCCC2)CCCCC1.C1(B(O)O)CC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:29][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:14]=1[O:13][C:12]1[CH:30]=[CH:31][C:9]([C:7](=[O:8])[NH:6][CH2:5][CH2:4][C:3]3[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:2]=3[CH:62]3[CH2:63][CH2:58]3)=[CH:10][CH:11]=1)[O:21][CH2:20][CH2:19][CH:18]2[C:24]([O:26][CH2:27][CH3:28])=[O:25]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 2760897Cyclopropylboronic acidHCID 67080384Ethyl 7-(4-(2-bromo-4-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate

Product 1

HCID 67080987Ethyl 6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylateYield 172.1%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Procedure

To a stirred suspension of ethyl 7-(4-(2-bromo-4-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (129 mg; 0.22 mmol) in 2 mL toluene was added successively water (0.1 mL), potassium phosphate (138 mg; 0.65 mmol), tricyclohexylphosphine (24 mg; 0.087 mmol), and cyclopropylboronic acid (0.435 mmol) at ambient temperature with stirring. A balloon of nitrogen with a three-way purge valve was attached, and the flask was evacuated and refilled five times with nitrogen. Palladium (II) acetate (10 mg; 0.043 mmol) was added, and again the flask was evacuated and refilled five times with nitrogen. The mixture was stirred in an oil bath set to 100° C. under the nitrogen balloon. After 4 hours the mixture was cooled to ambient temperature. The mixture was diluted with 10 mL EtOAc and 5 mL water. The mixture was transferred to a separatory funnel and after shaking, the organic layer was separated, dried over sodium sulfate and evaporated to give a brown oil. This material was purified by silica gel chromatography on a Biotage 25S column, eluting with 75/25 hexane/EtOAc to provide 83 mg of ethyl 6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate as a colorless oil. MS (apci, pos) m/z=554.

Workup

  1. customA balloon of nitrogen with a three-way purge valve
  2. customthe flask was evacuated
  3. additionrefilled five times with nitrogen
  4. customagain the flask was evacuated
  5. additionrefilled five times with nitrogen
  6. stirringThe mixture was stirred in an oil bath
  7. customset to 100° C. under the nitrogen balloon
  8. additionThe mixture was diluted with 10 mL EtOAc and 5 mL water
  9. customThe mixture was transferred to a separatory funnel
  10. stirringafter shaking
  11. customthe organic layer was separated
  12. dry with materialdried over sodium sulfate
  13. customevaporated
  14. customto give a brown oil
  15. customThis material was purified by silica gel chromatography on a Biotage 25S column
  16. washeluting with 75/25 hexane/EtOAc

Sources & evidence

ORD record
ord-6ca7f216634e4fa793decc83e4b885c8
Source dataset
uspto-grants-2014_05
Patent number
US08716498B2

Reaction notes

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