N-[(4-methoxyphenyl)methyl]-1,3-thiazol-2-amine → 1-bromo-3-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide

HRID 1473388Notes

Reaction equation

HRID 1473388 reaction equation
[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH:30]=[C:29]([Cl:52])[N:28]=1>C1COCC1.[Cl-].[NH4+].O>[Br:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH:30]=[C:29]([Cl:52])[N:28]=1

Participants

7

Reactant 3

HCID 578640N-[(4-methoxyphenyl)methyl]-1,3-thiazol-2-amineHCID 2733832Lithium HexamethyldisilazideHCID 86687429Perfluorophenyl 1-bromo-3-chloroisoquinoline-6-sulfonate

Product 1

HCID 866874301-bromo-3-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamideYield 93.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 25517Ammonium ChlorideSolvent

Procedure

A round-bottom flask was charged with N-(4-methoxybenzyl)thiazol-2-amine (238 mg, 1.081 mmol) and THF (4912 μl) to give an opaque solution. The flask was cooled in a dry ice-acetone bath for 5 min to give a milky suspension, then lithium bis(trimethylsilyl)amide (1M in THF) (1081 μl, 1.081 mmol) was added. The flask was removed from the bath for 2 min to give a clear solution, then resubmerged. The mixture appeared to remain a solution. After 5 min, a solution of perfluorophenyl 1-bromo-3-chloroisoquinoline-6-sulfonate (480 mg, 0.982 mmol) in THF (3 mL with a 2 mL wash) was added drop wise. After 25 min, the mixture was diluted with saturated aq. ammonium chloride solution and warmed to room temperature. The mixture was diluted with water and extracted with EtOAc. The organic extract was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (0 to 40% EtOAc/Heptane) to give 1-bromo-3-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (481 mg, 0.916 mmol, 93% yield) as a white foam: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.32 (d, J=9.0 Hz, 1H), 8.04 (d, J=1.8 Hz, 1H), 7.83 (dd, J=1.9, 9.0 Hz, 1H), 7.67 (s, 1H), 7.44 (d, J=3.6 Hz, 1H), 7.30 (d, J=8.8 Hz, 2H), 7.07 (d, J=3.5 Hz, 1H), 6.75-6.71 (m, 2H), 5.12 (s, 2H), 3.74 (s, 3H). m/z (ESI) 546.0 (M+H)+.

Workup

  1. customto give an opaque solution
  2. temperatureThe flask was cooled in a dry ice-acetone bath for 5 min
  3. customto give a milky suspension
  4. customThe flask was removed from the bath for 2 min
  5. customto give a clear solution
  6. additionwas added drop wise
  7. waitAfter 25 min
  8. extractionextracted with EtOAc
  9. extractionThe organic extract
  10. dry with materialwas dried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customThe residue was purified by chromatography on silica gel (0 to 40% EtOAc/Heptane)

Sources & evidence

ORD record
ord-4831468b863846e18a0044a689f9744e
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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