Potassium Phosphate, Tribasic → HCID 90244308, compound

HRID 2207114Notes

Reaction equation

HRID 2207114 reaction equation
[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[S:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3Br)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O:46][C:47]([C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57](B(O)O)[CH:56]=2)=[C:51]([CH3:66])[CH:50]=1)=[O:48])(C)(C)C>CN(C)C(=O)C.CCOC(C)=O.CCCCCC.CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[S:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:57]3[CH:56]=[C:55]([C:52]4[CH:53]=[CH:54][C:49]([C:47]([OH:48])=[O:46])=[CH:50][C:51]=4[CH3:66])[CH:60]=[CH:59][C:58]=3[O:61][CH3:62])[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

Participants

8

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 118468052HCID 118468052, compoundHCID 131735878HCID 131735878, compound

Product 1

HCID 90244308HCID 90244308, compound

Reagents, catalysts & solvents 4

HCID 72376365[2-(2-Aminophenyl)phenyl]-chloro-palladium dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphaneCatalystHCID 8058HexaneSolventHCID 8857Ethyl AcetateSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
80 °C

Procedure

In a microwave vial was placed (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-(2-bromo-5-(trifluoromethyl)benzyl)-4-methylthiazolidin-2-one (20 mg, 0.035 mmol) in N,N-Dimethylacetamide (0.5 ml). The mixture was degassed with N2, then chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (2.78 mg, 3.53 μmol) was added, followed by potassium phosphate tribasic (0.035 ml, 0.071 mmol) and then (4′-(tert-butoxycarbonyl)-4-methoxy-2′-methyl-[1,1′-biphenyl]-3-yl)boronic acid (18.13 mg, 0.053 mmol) (synthesized according to the procedure reported in WO 2012/058187) under a N2 atmosphere. The resulting mixture was stirred at 80° C. for 1 hour. The reaction was diluted with 50% EtOAc in hexane, then was washed with satd. NH4Cl, then brine, and then the organic layer was dried over Na2SO4, filtered and concentrated. The residue was dissolved in 50% TFA in DCM and was stirred at r.t. for 45 min. The reagents were removed, the residue was dissolved in ACN:H2O (3:1) mixture, and was purified by a reverse phase purification system. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers): δ 8.02 (d, J=12.5 Hz, 1H, contains protons of two atropisomers), 7.95 (d, J=8.5 Hz, 1H, contains protons of two atropisomers), 7.84 (d, J=10.5 Hz, 1H, contains protons of two atropisomers), 7.75 (s, 1H), 7.65 (m, 3H), 7.44 (m, 2H), 7.36 (d, J=7.5 Hz, 0.5H), 7.32 (d, J=7.5 Hz, 0.5H), 7.11 (d, J=3.5 Hz, 0.5H), 7.10 (d, J=3.5 Hz, 0.5H), 5.18 (d, J=15.5 Hz, 0.5H), 5.04 (d, J=15.5 Hz, 0.5H), 4.95 (d, J=7.0 Hz, 0.5H), 4.84 (d, J=7.5 Hz, 0.5H), 4.16 (d, J=15.5 Hz, 0.5H), 3.92 (d, 0.5H, one of the doublet peaks merged with a methoxy peak), 3.90 (s, 3H), 3.86 (s, 3H), 3.79 (m, 1H), 2.42 (s, 3H), 2.35 (s, 3H), 2.35 (s, 3H), 0.70 (d, J=6.5 Hz, 3H), 0.63 (d, J=6.5 Hz, 3H). MS ESI calc'd. for C35H26F9NO4 [M+H]+ 727.14. found 728.0. RTA (95% HS): 62 nM.

Workup

  1. customThe mixture was degassed with N2
  2. washwas washed with satd
  3. dry with materialNH4Cl, then brine, and then the organic layer was dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. dissolutionThe residue was dissolved in 50% TFA in DCM
  7. stirringwas stirred at r.t. for 45 min
  8. customThe reagents were removed
  9. dissolutionthe residue was dissolved in ACN:H2O (3:1) mixture
  10. customwas purified by a reverse phase purification system

Sources & evidence

ORD record
ord-365965074fed43a09a0907028156ee7e
Source dataset
uspto-grants-2016_06
Patent number
US09376408B2

Reaction notes

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