N-[(4-methoxyphenyl)methyl]-1,3-thiazol-2-amine → HCID 86687555, compound

HRID 1473499Notes

Reaction equation

HRID 1473499 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+].[CH3:26][O:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[C:38]1[C:47]2[C:42](=[CH:43][C:44]([S:48](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:50])=[O:49])=[CH:45][CH:46]=2)[C:41](=[O:63])[NH:40][N:39]=1>C1COCC1>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[CH:30][C:29]=1[C:38]1[C:47]2[C:42](=[CH:43][C:44]([S:48]([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:50])=[O:49])=[CH:45][CH:46]=2)[C:41](=[O:63])[NH:40][N:39]=1

Participants

5

Reactant 3

HCID 578640N-[(4-methoxyphenyl)methyl]-1,3-thiazol-2-amineHCID 2733832Lithium Hexamethyldisilazide2×HCID 86687556HCID 86687556, compound

Product 1

HCID 86687555HCID 86687555, compoundYield 38%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A round-bottom flask was charged with N-(4-methoxybenzyl)thiazol-2-amine (46.7 mg, 0.212 mmol) and THF (1.2 mL) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 5 min to give a suspension. Lithium bis(trimethylsilyl)amide (212 μl, 0.212 mmol, 1M in THF) was added drop wise to give a light yellow solution. The mixture was stirred for 15 min. Then, a solution of perfluorophenyl 1-(2-methoxy-4-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (100 mg, 0.177 mmol) in THF (1.2 mL) was added drop wise. After 1.5 h, more LHMDS (450 μL, 1M in THF) was added at −78° C. After 1 h, the reaction was quenched with saturated aqueous ammonium chloride at −78° C. The reaction was warmed to RT. The product was extracted with EtOAc and the organic extract was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g column, 20 to 50% EtOAc/Heptane) to give 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-4-oxo-N-(thiazol-2-yl)-3,4-dihydrophthalazine-6-sulfonamide (40 mg, 38% yield) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.68 (s, 3H), 3.80 (s, 3H), 5.06 (s, 2H), 6.81 (m, J=8.66 Hz, 2H), 7.21 (m, J=8.66 Hz, 2H), 7.45-7.54 (m, 4H), 7.62 (d, J=7.69 Hz, 1H), 8.13 (dd, J=8.60, 2.08 Hz, 1H), 8.53 (d, J=1.82 Hz, 1H), 13.24 (s, 1H). m/z (ESI) 603.0 (M+H)+.

Workup

  1. customto give a clear solution
  2. temperatureThe flask was cooled in a dry ice-acetone bath for 5 min
  3. customto give a suspension
  4. customto give a light yellow solution
  5. waitAfter 1.5 h
  6. waitAfter 1 h
  7. customthe reaction was quenched with saturated aqueous ammonium chloride at −78° C
  8. extractionThe product was extracted 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 (40-g column, 20 to 50% EtOAc/Heptane)

Sources & evidence

ORD record
ord-50d2a6fb431d4b4c95675342e5fec0f0
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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