Lithium Hexamethyldisilazide → 1-chloro-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide

HRID 1473559Notes

Reaction equation

HRID 1473559 reaction equation
[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([S:38](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:40])=[O:39])=[CH:35][CH:36]=2)[CH:31]=[CH:30][N:29]=1>C1COCC1>[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([S:38]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=3)[C:9]3[CH:14]=[CH:13][N:12]=[CH:11][N:10]=3)(=[O:40])=[O:39])=[CH:35][CH:36]=2)[CH:31]=[CH:30][N:29]=1

Participants

5

Reactant 3

HCID 2733832Lithium Hexamethyldisilazide2×HCID 13230138N-(4-methoxybenzyl)pyrimidin-4-amineHCID 86687382Perfluorophenyl 1-chloroisoquinoline-6-sulfonate

Product 1

HCID 866876191-chloro-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamideYield 39.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A 100-mL round-bottom flask was charged with N-(4-methoxybenzyl)pyrimidin-4-amine (Intermediate OO; 0.796 g, 3.70 mmol) and THF (16.08 ml). The flask was cooled in a dry ice-acetone bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (3.70 ml, 3.70 mmol) was added drop wise. The flask was removed from the cooling bath for 5 min, then recooled for 5 min. A solution of perfluorophenyl 1-chloroisoquinoline-6-sulfonate (see EXAMPLE 73, STEP 1, 1.515 g, 3.70 mmol) in THF (4 mL with a 1-mL flask wash) was added drop wise. After 20 min, the flask was switched to an ice-water bath. The mixture was stirred for 20 min, then an additional portion of LHMDS solution (1 mL) was added drop wise. The mixture was warmed to room temperature and quenched by the addition of saturated aq. ammonium chloride. The mixture was extracted with EtOAc (2×), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 25-g silica gel loading column, 0-50% EtOAc/Heptante) to give 1-chloro-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (648 mg, 1.470 mmol, 39.7% yield) as a tan foam. m/z (ESI) 441.2 (M+H)+.

Workup

  1. temperatureThe flask was cooled in a dry ice-acetone bath for 10 min
  2. customThe flask was removed from the cooling bath for 5 min
  3. waitAfter 20 min
  4. customthe flask was switched to an ice-water bath
  5. customquenched by the addition of saturated aq. ammonium chloride
  6. extractionThe mixture was extracted with EtOAc (2×)
  7. dry with materialthe combined organic extracts were dried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 25-g silica gel loading column, 0-50% EtOAc/Heptante)

Sources & evidence

ORD record
ord-49e79ca1db2d4bb08895ec8a638df2b5
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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