Potassium Phosphate, Tribasic → 4-((1-Benzhydrylpiperidin-4-yl)methoxy) 5-cyclopropyl-2-fluorobenzoic acid

HRID 1849885Notes

Reaction equation

HRID 1849885 reaction equation
[CH:1]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][O:21][C:22]2[C:30](Cl)=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([F:32])[CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1(B(O)O)[CH2:35][CH2:34]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][O:21][C:22]2[C:30]([CH:33]3[CH2:35][CH2:34]3)=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([F:32])[CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 2760897Cyclopropylboronic acidHCID 20066521Tri(cyclohexyl)phosphine tetrafluoroborateHCID 867037644-((1-Benzhydrylpiperidin-4-yl)methoxy)-5-chloro-2-fluorobenzoic acid

Product 1

HCID 867037654-((1-Benzhydrylpiperidin-4-yl)methoxy) 5-cyclopropyl-2-fluorobenzoic acid

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 4-((1-benzhydrylpiperidin-4-yl)methoxy)-5-chloro-2-fluorobenzoic acid (480 mg, 0.94 mmol), cyclopropylboronic acid (162 mg, 1.88 mmol), potassium phosphate (797 mg, 3.67 mmol), palladium acetate (21 mg, 0.047 mmol) and tricyclohexylphosphine tetrafluoroborate (36 mg, 0.094 mmol) in toluene (10 mL) and water (0.5 mL) was stirred under a nitrogen atmosphere at 100° C. for 18 h. The reaction mixture was cooled down, quenched with water (50 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford product (320 mg, 46%, crude) as oil which was used in the next step without further purification. LCMS (ESI) m/z: 458.1 [M+H]+.

Workup

  1. temperatureThe reaction mixture was cooled down
  2. customquenched with water (50 mL)
  3. extractionextracted with ethyl acetate (20 mL×3)
  4. washThe combined organic layers were washed with brine (20 mL)
  5. dry with materialdried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto afford product (320 mg, 46%, crude) as oil which
  9. customwas used in the next step without further purification

Sources & evidence

ORD record
ord-7554cdfe36ff4f6ebcab8d8c3332aa14
Source dataset
uspto-grants-2015_02
Patent number
US08952169B2

Reaction notes

Loading…