Potassium Phosphate, Tribasic → HCID 59458802, compound

HRID 1874242Notes

Reaction equation

HRID 1874242 reaction equation
Br[C:2]1[CH:3]=[C:4]([C@@:9]([NH:31][C:32](=[O:44])[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[C:35]([C:40]([F:43])([F:42])[F:41])[CH:34]=2)([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:45]1(B(O)O)[CH2:47][CH2:46]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:45]1([C:2]2[CH:3]=[C:4]([C@@:9]([NH:31][C:32](=[O:44])[C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([C:40]([F:42])([F:41])[F:43])[CH:34]=3)([C:17]3[CH:22]=[C:21]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:20]=[C:19]([F:30])[CH:18]=3)[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[CH:6][C:7]=2[F:8])[CH2:47][CH2:46]1

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 2760897Cyclopropylboronic acidHCID 59459328HCID 59459328, compound

Product 1

HCID 59458802HCID 59458802, compoundYield 30%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

To a mixture of (S)—N-(1-(3-bromo-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide, prepared as described in Procedures 3, 62, 5, 6 and 7, (50 mg, 0.07 mmol), (50 mg, 0.07 mmol), cyclopropylboronic acid (6 mg, 0.07 mmol), palladium (II) acetate (1 mg, 0.004 mmol) and tricyclohexylphosphine (2 mg, 0.007 mmol) in toluene (2 mL) was added K3PO4 (0.072 mL, 0.22 mmol). The reaction mixture was heated at 100° C. under microwave irradiation for 15 min. The reaction mixture was filtered, concentrated and the resulting residue was purified by preparative HPLC (Sunfire-S5-C18 18×50 mm column, eluting with 10-90% MeOH/H2O gradient over 8 min, with flow rate 20 mL/min and UV detection at 220 nm) to yield (R)—N-(1-(3-cyclopropyl-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide (Example 309, 14 mg, 30% yield). LCMS: RT=4.37 min [M+H] 656.38 (Waters Sunfire-S5-C18 4.6×50 mm, eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). 1H NMR (500 MHz, CDCl3) δ ppm 7.90 (1H, dd, J=6.60, 1.92 Hz), 7.81-7.84 (1H, m), 7.22-7.30 (5H, m), 7.16 (2H, t, J=7.56 Hz), 6.93-7.00 (4H, m), 6.77-6.81 (1H, m), 6.68 (2H, d, J=7.42 Hz), 6.62 (1H, s), 6.54 (1H, dd, J=6.87, 2.47 Hz), 5.88 (1H, t, J=52.73 Hz), 4.08 (1H, d, J=13.20 Hz), 3.66 (1H, d, J=13.20 Hz), 2.03 (1H, ddd, J=13.75, 8.52, 5.22 Hz), 0.92-0.96 (2H, m), 0.52-0.56 (1H, m), 0.43-0.47 (1H, m).

Workup

  1. customprepared
  2. filtrationThe reaction mixture was filtered
  3. concentrationconcentrated
  4. customthe resulting residue was purified by preparative HPLC (Sunfire-S5-C18 18×50 mm column, eluting with 10-90% MeOH/H2O gradient over 8 min, with flow rate 20 mL/min and UV detection at 220 nm)

Sources & evidence

ORD record
ord-a1c5ac79ec1b46dd92a47abe8974a67e
Source dataset
uspto-grants-2012_11
Patent number
US08304403B2

Reaction notes

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