Dimethylformamide → 1-(4-isobutoxy-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide

HRID 1473571Notes

Reaction equation

HRID 1473571 reaction equation
[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21](CC4C=CC(OC)=CC=4)[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:37][CH3:38])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.I[CH2:51][CH:52]([CH3:54])[CH3:53]>O.CO.C(Cl)Cl>[CH2:51]([O:1][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:19])=[O:20])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:37][CH3:38])[CH:3]=1)[CH:52]([CH3:54])[CH3:53]

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 10556Isobutyl iodide2×HCID 10796Cesium carbonate2×HCID 1364090681-(4-hydroxy-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide

Product 1

HCID 896136251-(4-isobutoxy-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamideYield 88%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 21226129Dichloromethane methanolSolvent

Procedure

A vial was charged with 1-(4-hydroxy-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (38.07 mg, 0.072 mmol), cesium carbonate (70.4 mg, 0.216 mmol), and DMF (360 μl). Within a few minutes, a deep red solution formed. 1-iodo-2-methylpropane (16.58 μl, 0.144 mmol) was added. The vial was sealed and lowered into a 50° C. heating bath. After 2 h, additional portions of cesium carbonate (70.4 mg, 0.216 mmol) and 1-iodo-2-methylpropane (16.58 μl, 0.144 mmol) were added. The mixture was heated for another 1 h, then it was cooled, diluted with water, and extracted with EtOAc (3×). The combined organic extracts were concentrated. The residue was taken up in DCM (1 mL). The mixture was cooled in an ice-bath for 5 min, then TFA (0.4 mL) was added drop wise. The ice-bath was then removed and an additional portion of TFA (0.4 mL) was added. The mixture was stirred overnight, then was diluted with MeOH and concentrated. The residue was dissolved in DCM and saturated aq. sodium bicarbonate solution was added. The layers were separated, and the aq. layer was extracted with DCM (2×). 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, 50-100% EtOAc, then 10% MeOH/DCM) to give 1-(4-isobutoxy-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (29.3 mg, 0.063 mmol, 88% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=13.02 (br. s., 1H), 8.69-8.51 (m, 3H), 8.25 (br. s., 1H), 8.04 (s, 1H), 7.95-7.87 (m, 1H), 7.75 (d, J=8.9 Hz, 1H), 7.23 (d, J=8.3 Hz, 1H), 7.04 (br. s., 1H), 6.74 (d, J=2.2 Hz, 1H), 6.69 (dd, J=2.2, 8.3 Hz, 1H), 3.86 (d, J=6.7 Hz, 2H), 3.63 (s, 3H), 2.08 (quind, J=6.6, 13.2 Hz, 1H), 1.03 (d, J=6.7 Hz, 6H). m/z (ESI) 465.2 (M+H)+.

Workup

  1. waitWithin a few minutes
  2. customa deep red solution formed
  3. customThe vial was sealed
  4. customlowered into a 50° C.
  5. temperatureheating bath
  6. temperatureThe mixture was heated for another 1 h
  7. temperatureit was cooled
  8. extractionextracted with EtOAc (3×)
  9. concentrationThe combined organic extracts were concentrated
  10. temperatureThe mixture was cooled in an ice-bath for 5 min
  11. additionTFA (0.4 mL) was added drop wise
  12. customThe ice-bath was then removed
  13. additionan additional portion of TFA (0.4 mL) was added
  14. additionwas diluted with MeOH
  15. concentrationconcentrated
  16. dissolutionThe residue was dissolved in DCM
  17. additionsaturated aq. sodium bicarbonate solution was added
  18. customThe layers were separated
  19. extractionthe aq. layer was extracted with DCM (2×)
  20. dry with materialThe combined organic extracts were dried over sodium sulfate
  21. filtrationfiltered
  22. concentrationconcentrated
  23. customThe residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 50-100% EtOAc

Sources & evidence

ORD record
ord-354acb11ddac49c7af4392b75cbb2fd8
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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