Potassium Phosphate, Tribasic → HCID 86687614, compound

HRID 1473556Notes

Reaction equation

HRID 1473556 reaction equation
Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:23][C:24]4[CH:28]=[CH:27][O:26][N:25]=4)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)Cl>[C:8]([C:7]1[CH:6]=[C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:23][C:24]4[CH:28]=[CH:27][O:26][N:25]=4)(=[O:21])=[O:22])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)[C:4]([O:29][CH3:30])=[CH:3][C:2]=1[C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=1)#[N:9]

Participants

6

Reactant 4

HCID 62657Potassium Phosphate, Tribasic2×HCID 27339863-Fluorophenylboronic acid2×HCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 86687615HCID 86687615, compound

Product 1

HCID 86687614HCID 86687614, compoundYield 20.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
120 °C

Procedure

A vial was charged with 1-(4-chloro-5-cyano-2-methoxyphenyl)-N-(isoxazol-3-yl)isoquinoline-6-sulfonamide (INTERMEDIATE WWWW, 95.3 mg, 0.216 mmol), (3-fluorophenyl)boronic acid (60.5 mg, 0.432 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (2.219 mg, 5.40 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (8.19 mg, 10.81 μmol), and potassium phosphate (138 mg, 0.649 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (983 μl) and water (98 μl) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 2.5 h at 120° C. Additional portions of (3-fluorophenyl)boronic acid (60.5 mg, 0.432 mmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (8.19 mg, 10.81 μmol), and potassium phosphate (138 mg, 0.649 mmol) were added. The vial was heated for an additional 30 min at 150° C. The mixture organic layer was separated, and the aq. layer was diluted with 0.5 N aq. HCl and extracted with EtOAc (3×). The combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (25-g Interchim 15-micron column, 0-4% MeOH/DCM) to give a light-yellow solid. The material was taken up in DCM, sonicated, and filtered. The collected solid was washed with DCM (2×), dried under a stream of N2 (g), then dried under vacuum to give 1-(2-cyano-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)isoquinoline-6-sulfonamide (22.04 mg, 0.044 mmol, 20.37% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=11.93 (br. s., 1H), 8.82-8.64 (m, 3H), 8.19 (d, J=5.7 Hz, 1H), 8.01-7.83 (m, 3H), 7.71-7.55 (m, 3H), 7.49-7.33 (m, 2H), 6.50 (d, J=1.7 Hz, 1H), 3.81 (s, 3H). m/z (M+H) 501.0 (M+H)+.

Workup

  1. customThe vial was flushed with Ar (g)
  2. addition1,4-dioxane (983 μl) and water (98 μl) were added
  3. customThe vial was sealed
  4. temperatureThe vial was heated for an additional 30 min at 150° C
  5. customThe mixture organic layer was separated
  6. additionthe aq. layer was diluted with 0.5 N aq. HCl
  7. extractionextracted with EtOAc (3×)
  8. concentrationThe combined organic extracts were concentrated
  9. customThe residue was purified by chromatography on silica gel (25-g Interchim 15-micron column, 0-4% MeOH/DCM)
  10. customto give a light-yellow solid
  11. customsonicated
  12. filtrationfiltered
  13. washThe collected solid was washed with DCM (2×)
  14. dry with materialdried under a stream of N2 (g)
  15. customdried under vacuum

Sources & evidence

ORD record
ord-d4faed9e582948aeb2e09d59f5b37198
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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