Potassium Phosphate, Tribasic → HCID 86687638, compound

HRID 1473577Notes

Reaction equation

HRID 1473577 reaction equation
Cl[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[S:24][CH:25]=[N:26][N:27]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[C:35]([F:37])[CH:36]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CO.C(Cl)Cl>[S:24]1[CH:25]=[N:26][N:27]=[C:23]1[NH:22][S:19]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[C:9]([C:5]1[C:4]([O:28][CH3:29])=[CH:3][C:2]([C:33]3[CH:32]=[C:31]([F:30])[CH:36]=[C:35]([F:37])[CH:34]=3)=[C:7]([F:8])[CH:6]=1)=[N:10][CH:11]=[CH:12]2)(=[O:20])=[O:21]

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 2734338(3,5-Difluorophenyl)boronic acidHCID 86687637HCID 86687637, compound

Product 1

HCID 86687638HCID 86687638, compoundYield 30.5%

Reagents, catalysts & solvents 2

HCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylCatalystHCID 21226129Dichloromethane methanolSolvent

Conditions

Temperature
120 °C

Procedure

A vial was charged with 1-(4-chloro-5-fluoro-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (INTERMEDIATE HHHHH; 88.75 mg, 0.197 mmol). (3,5-difluorophenyl)boronic acid (62.2 mg, 0.394 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (2.020 mg, 4.92 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (7.46 mg, 9.84 μmol), and potassium phosphate (125 mg, 0.590 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (895 μl) and water (89 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 (4×). The combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-4% MeOH/DCM, then with 4-10% MeOH/DCM) to give N-(1,3,4-thiadiazol-2-yl)-1-(2,3′,5′-trifluoro-5-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonamide (31.54 mg, 0.060 mmol, 30.3% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=14.50 (br. s., 1H), 8.78 (s, 1H), 8.71 (d, J=5.7 Hz, 1H), 8.57 (d, J=1.6 Hz, 1H), 8.14 (d, J=5.5 Hz, 1H), 7.90 (dd, J=1.8, 8.9 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.49 (d, J=7.6 Hz, 2H), 7.43-7.34 (m, 3H), 3.73 (s, 3H). m/z (ESI) 528.9 (M+H)+.

Workup

  1. customThe vial was flushed with Ar (g)
  2. addition1,4-dioxane (895 μl) and water (89 μl) were added
  3. customThe vial was sealed
  4. extractionThe mixture was extracted with EtOAc (4×)
  5. concentrationThe combined organic extracts were concentrated
  6. customThe residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-4% MeOH/DCM

Sources & evidence

ORD record
ord-a4430c3b6d5049afae54ef4b277aefda
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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