2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl → 1-(2-methoxy-4-neopentylphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide

HRID 1473569Notes

Reaction equation

HRID 1473569 reaction equation
Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[I-].[CH2:60]([Zn+])[C:61]([CH3:64])([CH3:63])[CH3:62]>CO.CO.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:29][O:28][C:4]1[CH:3]=[C:2]([CH2:60][C:61]([CH3:64])([CH3:63])[CH3:62])[CH:7]=[CH:6][C:5]=1[C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][N:23]=3)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1

Participants

7

Reactant 3

HCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 866874841-(4-chloro-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamideHCID 178445888HCID 178445888, compound

Product 1

HCID 866876311-(2-methoxy-4-neopentylphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamideYield 32.6%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 887MethanolSolventHCID 21226129Dichloromethane methanolSolvent

Conditions

Temperature
70 °C

Procedure

A vial was charged with 1-(4-chloro-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (EXAMPLE 160; 67 mg, 0.157 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (6.44 mg, 0.016 mmol), and Pd2(dba)3 (7.19 mg, 7.85 mmol). The vial was flushed with Ar (g), then neopentylzinc(II) iodide (0.5 M in THF) (1570 μl, 0.785 mmol) was added. The mixture was sonicated for 30 s to give a suspension. The sealed vial was heated to 70° C. for 2 h then 90° C. overnight. The mixture was diluted with MeOH, filtered through Celite, and concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-7.5% MeOH/DCM) to give a yellow foam. The material was dissolved in MeOH/DCM and loaded onto a 2-g SCX-2 ion exchange column. The filtrate was concentrated, and the residue was purified by chromatography on silica gel (25-g Interchim 15 micron column, 3.5% MeOH/DCM) to give 1-(2-methoxy-4-neopentylphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (23.65 mg, 0.051 mmol, 32.6% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=13.07 (br. s, 1H), 8.70-8.61 (m, 2H), 8.57 (s, 1H), 8.24 (br. s., 1H), 8.06 (d, J=5.8 Hz, 1H), 7.94 (dd, J=1.7, 8.9 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.03 (br. s., 1H), 6.96 (s, 1H), 6.89 (d, J=7.6 Hz, 1H), 3.62 (s, 3H), 2.60 (s, 2H), 0.97 (s, 9H). m/z (ESI) 463.2 (M+H)+.

Workup

  1. customThe vial was flushed with Ar (g)
  2. customThe mixture was sonicated for 30 s
  3. customto give a suspension
  4. custom90° C. overnight
  5. filtrationfiltered through Celite
  6. concentrationconcentrated
  7. customThe residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-7.5% MeOH/DCM)
  8. customto give a yellow foam
  9. concentrationThe filtrate was concentrated
  10. customthe residue was purified by chromatography on silica gel (25-g Interchim 15 micron column, 3.5% MeOH/DCM)

Sources & evidence

ORD record
ord-84bc4e79b7d44acf95ecc5be3788fa89
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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