1,4-Dioxane → HCID 86687691, compound

HRID 1473622Notes

Reaction equation

HRID 1473622 reaction equation
[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([S:28]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][N:33]=4)(=[O:30])=[O:29])=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)=[C:14]([O:38][CH3:39])[CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH3:39][O:38][C:14]1[CH:13]=[C:12]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:17]=[CH:16][C:15]=1[C:18]1[C:27]2[C:22](=[CH:23][C:24]([S:28]([NH:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][N:33]=3)(=[O:30])=[O:29])=[CH:25][CH:26]=2)[CH:21]=[CH:20][N:19]=1

Participants

6

Reactant 4

HCID 312751,4-DioxaneHCID 62657Potassium Phosphate, TribasicHCID 27332672-Methylphenyl boronic acidHCID 866874841-(4-chloro-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide

Product 1

HCID 86687691HCID 86687691, compoundYield 32.6%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
150 °C

Procedure

A microwave vial charged with 2-methylphenylboronic acid (0.022 g, 0.158 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1′1′-biphenyl (4.33 mg, 10.54 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (7.99 mg, 10.54 μmol), 1-(4-chloro-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (From Example 160; 45 mg, 0.105 mmol), potassium phosphate (90 mg, 0.422 mmol), 1 mL dioxane and 0.25 mL water was heated to 150° C. in the microwave for 30 minutes. LC/MS showed mostly product, so the aqueous layer was removed. The reaction mixture was acidified with 4N HCl in dioxane then was concentrated. The crude product was purified by reverse phase column chromatography [PREP LC/MS-2 System Column: XBridge 19×100 mm 12230326114 03 Mobile phase: 0.1% NH4OH in water/acetonitrile Flow rate: 40 ml/min Inj: 2200 uL. Gradient: 10 min 10-40%_LV_NH3] yielding 1-(3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.017 g, 0.034 mmol, 32.6% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 2.36 (s, 3H) 3.68 (s, 3H) 6.95 (br. s., 1H) 7.08 (d, J=7.27 Hz, 1H) 7.14 (s, 1H) 7.27 (br. s., 1H) 7.29-7.44 (m, 5H) 7.78 (d, J=8.82 Hz, 1H) 7.97 (d, J=8.71 Hz, 1H) 8.08 (d, J=5.96 Hz, 1H) 8.18 (br. s., 1H) 8.52 (br. s., 1H) 8.62 (br. s., 1H) 8.68 (d, J=5.56 Hz, 1H); (M+H)+=483.0.

Workup

  1. customso the aqueous layer was removed
  2. concentrationthen was concentrated
  3. customThe crude product was purified by reverse phase column chromatography [PREP LC/MS-2 System Column: XBridge 19×100 mm 12230326114 03 Mobile phase: 0.1% NH4OH in water/acetonitrile Flow rate: 40 ml/min Inj: 2200 uL. Gradient: 10 min 10-40%_LV_NH3]

Sources & evidence

ORD record
ord-23b2a928a76646338cd86d9d10f984fe
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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