Lithium Hexamethyldisilazide → 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide

HRID 1473379Notes

Reaction equation

HRID 1473379 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)[CH:32]=[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)[CH:32]=[CH:31][N:30]=1

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 49931979N-(2,4-dimethoxybenzyl)thiazol-2-amineHCID 86687382Perfluorophenyl 1-chloroisoquinoline-6-sulfonate

Product 1

HCID 866873781-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of N-(2,4-dimethoxybenzyl)thiazol-2-amine (0.642 g, 2.56 mmol) in tetrahydrofuran (9.39 ml) was cooled in a dry ice-acetone bath for 5 min. Lithium bis(trimethylsilyl)amide (1M in THF) (2.68 ml, 2.68 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-chloroisoquinoline-6-sulfonate (see Example 73, Step 1; 1.0 g, 2.441 mmol) in THF (5 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 an 80-g with 0 to 50% EtOAc/Heptane to afford 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (INTERMEDIATE OOO) as a white solid. (ESI) 498.2 (M+Na)+.

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 an 80-g with 0 to 50% EtOAc/Heptane

Sources & evidence

ORD record
ord-f8d349b252934db09075cd9efa5fef2c
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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