Potassium Phosphate, Tribasic → 1-(4'-fluoro-3-methoxy-[1,1'-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide

HRID 1473563Notes

Reaction equation

HRID 1473563 reaction equation
Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21](CC4C=CC(OC)=CC=4)[C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:37][CH3:38])[CH:3]=1.[F:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[F:39][C:40]1[CH:45]=[CH:44][C:43]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:17]4[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]5[CH:27]=[CH:26][N:25]=[CH:24][N:23]=5)(=[O:20])=[O:19])=[CH:15][CH:16]=4)[CH:11]=[CH:10][N:9]=3)=[C:4]([O:37][CH3:38])[CH:3]=2)=[CH:42][CH:41]=1

Participants

5

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 2856454-Fluorophenylboronic acidHCID 866876231-(4-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide

Product 1

HCID 866876241-(4'-fluoro-3-methoxy-[1,1'-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamideYield 75.6%

Reagents, catalysts & solvents 1

HCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylCatalyst

Procedure

A vial was charged with 1-(4-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (INTERMEDIATE BBBBB, 42.9 mg, 0.078 mmol), (4-fluorophenyl)boronic acid (21.95 mg, 0.157 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (1.610 mg, 3.92 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (2.97 mg, 3.92 μmol), and potassium phosphate (49.9 mg, 0.235 mmol). The vial was flushed with Ar (g), then THF (0.4 mL) and water (0.04 mL) were added in sequence. The vial was sealed and placed in a 110° C. heating bath overnight, then the mixture was cooled and extracted with EtOAc (3×). The combined organic extracts were concentrated. The residue was taken up in DCM (1 mL), TFA (0.5 mL), and triflic acid (0.05 mL) (8:40 am). After 45 min, the mixture was concentrated. The residue was taken up in EtOAc. The organic solution was washed with saturated aq. sodium bicarbonate solution (2×), dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g Interchim 15 micron column, 10% MeOH/DCM) to give 1-(4′-fluoro-3-methoxy-[1,1′-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (28.7 mg, 0.059 mmol, 75% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=13.04 (s, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.64 (d, J=1.5 Hz, 1H), 8.56 (s, 1H), 8.23 (d, J=6.2 Hz, 1H), 8.09 (d, J=5.4 Hz, 1H), 7.95 (dd, J=1.9, 8.9 Hz, 1H), 7.91-7.83 (m, 2H), 7.78 (d, J=8.9 Hz, 1H), 7.46-7.39 (m, 3H), 7.38-7.31 (m, 2H), 7.02 (d, J=6.4 Hz, 1H), 3.75 (s, 3H). m/z (ESI) 487.2 (M+H)+.

Workup

  1. customThe vial was flushed with Ar (g)
  2. additionTHF (0.4 mL) and water (0.04 mL) were added in sequence
  3. customThe vial was sealed
  4. customplaced in a 110° C.
  5. temperatureheating bath overnight
  6. temperaturethe mixture was cooled
  7. extractionextracted with EtOAc (3×)
  8. concentrationThe combined organic extracts were concentrated
  9. concentrationthe mixture was concentrated
  10. washThe organic solution was washed with saturated aq. sodium bicarbonate solution (2×)
  11. dry with materialdried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customThe residue was purified by chromatography on silica gel (25-g Interchim 15 micron column, 10% MeOH/DCM)

Sources & evidence

ORD record
ord-9b40be1555c748039647c0168b29e810
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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