Lithium Hexamethyldisilazide → 1-(4-chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide

HRID 1473581Notes

Reaction equation

HRID 1473581 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:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:44]3[C:39](=[CH:40][C:41]([S:45](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:47])=[O:46])=[CH:42][CH:43]=3)[CH:38]=[CH:37][N:36]=2)=[C:31]([O:60][CH3:61])[CH:30]=1>C1COCC1.[Cl-].[NH4+].O>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:44]3[C:39](=[CH:40][C:41]([S:45]([N:6]([CH2:5][C:4]4[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=4[O:2][CH3:1])[C:7]4[S:11][N:10]=[CH:9][N:8]=4)(=[O:47])=[O:46])=[CH:42][CH:43]=3)[CH:38]=[CH:37][N:36]=2)=[C:31]([O:60][CH3:61])[CH:30]=1

Participants

7

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 57732216N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amineHCID 86687421Perfluorophenyl 1-(4-chloro-2-methoxyphenyl)isoquinoline-6-sulfonate

Product 1

HCID 866876421-(4-chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamideYield 96%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 25517Ammonium ChlorideSolvent

Procedure

A round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (117 mg, 0.466 mmol) and THF (1944 μl) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (466 μl, 0.466 mmol) was added drop wise. The flask was removed from the cooling bath for 3 min, then recooled in the bath. A solution of perfluorophenyl 1-(4-chloro-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE NNN, 200.53 mg, 0.389 mmol) in THF (1 mL with a 0.5 mL-flask wash) was added drop wise. After another minute, the flask was transferred to an ice-water bath. After 10 min, the mixture was diluted with saturated aq ammonium chloride and water, then extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g Interchim 25-micron column, 25-75% EtOAc/Heptane) to give 1-(4-chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (217 mg, 0.372 mmol, 96% yield) as a white foam. m/z (ESI) 583.0 (M+H)+.

Workup

  1. customto give a clear solution
  2. temperatureThe flask was cooled in a dry ice-acetone bath for 5 min
  3. customThe flask was removed from the cooling bath for 3 min
  4. additionwas added drop wise
  5. customAfter another minute, the flask was transferred to an ice-water bath
  6. extractionextracted 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 (25-g Interchim 25-micron column, 25-75% EtOAc/Heptane)

Sources & evidence

ORD record
ord-5868d218f4f648e3af9b622861949dae
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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