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

HRID 1473553Notes

Reaction equation

HRID 1473553 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]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=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[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:37]1[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=1)#[N:9]

Participants

6

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 27343883-(Trifluoromethyl)phenylboronic 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 866876111-(2-cyano-5-methoxy-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

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, 69.8 mg, 0.152 mmol) (3-(trifluoromethyl)phenyl)boronic acid (57.9 mg, 0.305 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (3.13 mg, 7.62 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (11.55 mg, 0.015 mmol) and potassium phosphate (162 mg, 0.762 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (693 μl) and water (69.3 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, MeOH-EtOAc, and MeOH-DCM. The combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-7.5% MeOH/DCM) to give an off-white solid. The solid was taken up in DCM and filtered. The collected solid was washed with DCM (2×), dried under a stream of N2 (g), and dried under vacuum to give 1-(2-cyano-5-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.80 (s, 1H), 8.73 (d, J=5.7 Hz, 1H), 8.62-8.55 (m, 1H), 8.17 (d, J=5.6 Hz, 1H), 8.11-8.04 (m, 2H), 7.98 (s, 1H), 7.96-7.78 (m, 3H), 7.51 (s, 1H), 7.19 (br. s., 1H), 3.83 (s, 3H). m/z (ESI) 567.9 (M+H)+.

Workup

  1. customThe vial was flushed with Ar (g)
  2. addition1,4-dioxane (693 μl) and water (69.3 μl) were added
  3. customThe vial was sealed
  4. extractionThe mixture was extracted with EtOAc, MeOH-EtOAc, and MeOH-DCM
  5. concentrationThe combined organic extracts were concentrated
  6. customThe residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-7.5% MeOH/DCM)
  7. customto give an off-white solid
  8. filtrationfiltered
  9. washThe collected solid was washed with DCM (2×)
  10. dry with materialdried under a stream of N2 (g)
  11. customdried under vacuum

Sources & evidence

ORD record
ord-0fe387caf84943a4ab5147663db839bd
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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