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

HRID 1473555Notes

Reaction equation

HRID 1473555 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:25][CH:26]=[N:27][N:28]=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: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:25][CH:26]=[N:27][N:28]=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 4

HCID 62657Potassium Phosphate, TribasicHCID 27339863-Fluorophenylboronic acidHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 866876101-(4-chloro-5-cyano-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide

Product 1

HCID 866876131-(2-cyano-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamideYield 48.8%

Conditions

Temperature
120 °C

Procedure

A vial was charged with 1-(4-chloro-5-cyano-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (Example 337, 55.6 mg, 0.121 mmol) (3-fluorophenyl)boronic acid (34.0 mg, 0.243 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (2.492 mg, 6.07 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (9.20 mg, 0.012 mmol), and potassium phosphate (129 mg, 0.607 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (552 μl) and water (55.2 μl) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 1 h at 120° C. The mixture was extracted with EtOAc (2×) and 10% MeOH/EtOAc (2×) 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, 0-7.5% MeOH/DCM, a few colored fractions were discarded). The resulting tan solid was taken up in DCM 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-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (30.69 mg, 0.059 mmol, 48.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=14.49 (br. s., 1H), 8.79 (s, 1H), 8.73 (d, J=5.7 Hz, 1H), 8.59 (d, J=1.7 Hz, 1H), 8.17 (d, J=5.8 Hz, 1H), 7.96 (s, 1H), 7.90 (dd, J=1.9, 8.9 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.68-7.57 (m, 3H), 7.45 (s, 1H), 7.41 (dt, J=1.7, 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 (552 μl) and water (55.2 μl) were added
  3. customThe vial was sealed
  4. extractionThe mixture was extracted with EtOAc (2×) and 10% MeOH/EtOAc (2×)
  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, 0-7.5% MeOH/DCM
  9. filtrationfiltered
  10. washThe collected solid was washed with DCM (2×)
  11. dry with materialdried under a stream of N2 (g)
  12. customdried under vacuum

Sources & evidence

ORD record
ord-ff816687c488460880640584b4a96092
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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