Lithium Hexamethyldisilazide → HCID 86687426, compound

HRID 1473384Notes

Reaction equation

HRID 1473384 reaction equation
[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][C:35]([S:39](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:41])=[O:40])=[CH:36][CH:37]=2)[C:32]([F:54])=[CH:31][N:30]=1>O1CCCC1>[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][C:35]([S:39]([N:6]([CH2:5][C:4]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=3[O:2][CH3:1])[C:7]3[S:8][CH:9]=[CH:10][N:11]=3)(=[O:41])=[O:40])=[CH:36][CH:37]=2)[C:32]([F:54])=[CH:31][N:30]=1

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 49931979N-(2,4-dimethoxybenzyl)thiazol-2-amineHCID 86687425HCID 86687425, compound

Product 1

HCID 86687426HCID 86687426, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of N-(2,4-dimethoxybenzyl)thiazol-2-amine (0.031 g, 0.123 mmol) in tetrahydrofuran (0.450 ml) was cooled in a dry ice-acetone bath for 5 min. Lithium bis(trimethylsilyl)amide (1M in THF) (0.129 ml, 0.129 mmol) was added drop wise, then the flask was removed from the cooling bath for 5 min. The flask was again cooled into a dry ice-acetone bath for 20 min, resulting in the formation of a thick slurry. A solution of perfluorophenyl 1-chloro-4-fluoroisoquinoline-6-sulfonate (0.050 g, 0.117 mmol) in THF (0.25 mL) was added drop wise, and the reaction was stirred for 30 minutes. The reaction was warmed to room temperature and quenched with saturated ammonium chloride solution, diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The filtrate was purified by chromatography on a 12-g column with 0 to 100% EtOAc/Heptane to afford 1-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (INTERMEDIATE PPP) as an oily solid. (ESI) 516.2 (M+H)+.

Workup

  1. customthe flask was removed from the cooling bath for 5 min
  2. temperatureThe flask was again cooled into a dry ice-acetone bath for 20 min
  3. customresulting in the formation of a thick slurry
  4. customquenched with saturated ammonium chloride solution
  5. additiondiluted with ethyl acetate
  6. washwashed with water
  7. extractionThe aqueous layer was extracted with ethyl acetate
  8. dry with materialthe combined organic layers were dried with sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe filtrate was purified by chromatography on a 12-g column with 0 to 100% EtOAc/Heptane

Sources & evidence

ORD record
ord-4888343019d9457bb7448eb2905ea86d
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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