Potassium Phosphate, Tribasic → 1-(2-cyano-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide

HRID 1473554Notes

Reaction equation

HRID 1473554 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[S:28][N:27]=[CH: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.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[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[S:28][N:27]=[CH: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

5

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 27339863-Fluorophenylboronic acidHCID 866876091-(4-chloro-5-cyano-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide

Product 1

HCID 866876121-(2-cyano-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamideYield 76%

Reagents, catalysts & solvents 1

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

Conditions

Temperature
120 °C

Procedure

A vial was charged with 1-(4-chloro-5-cyano-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (Example 337, 68.14 mg, 0.149 mmol) (3-fluorophenyl)boronic acid (62.5 mg, 0.446 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (3.05 mg, 7.44 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (11.27 mg, 0.015 mmol), and potassium phosphate (158 mg, 0.744 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (676 μl) and water (67.6 μl) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 1 h at 120° C. LCMS showed >95% conversion to the desired product. The mixture was extracted with EtOAc (3×), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 7.5% MeOH/DCM). The resulting material was taken up in DCM, sonicated, filtered, 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-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (58.22 mg, 0.112 mmol, 76% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.72 (d, J=5.7 Hz, 1H), 8.58 (d, J=1.6 Hz, 1H), 8.39 (s, 1H), 8.17 (d, J=5.8 Hz, 1H), 7.96 (s, 1H), 7.91 (dd, J=1.9, 8.9 Hz, 1H), 7.79 (d, J=9.0 Hz, 1H), 7.69-7.58 (m, 3H), 7.45 (s, 1H), 7.41 (dt, J=1.6, 8.5 Hz, 1H), 3.82 (s, 3H). m/z (ESI) 518.2 (M+H)+.

Workup

  1. customThe vial was flushed with Ar (g)
  2. addition1,4-dioxane (676 μl) and water (67.6 μl) were added
  3. customThe vial was sealed
  4. extractionThe mixture was extracted with EtOAc (3×)
  5. dry with materialthe combined organic extracts were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 7.5% MeOH/DCM)
  9. customsonicated
  10. filtrationfiltered
  11. washwashed with DCM (2×)
  12. dry with materialdried under a stream of N2 (g)
  13. customdried under vacuum

Sources & evidence

ORD record
ord-88e8f46dffeb432e9d6cba859ba6f450
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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