Lithium Hexamethyldisilazide → 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide

HRID 1473436Notes

Reaction equation

HRID 1473436 reaction equation
COC1C=C(OC)C=CC=1C[NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:28][O:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=1[C:40]1[C:49]2[C:44](=[CH:45][C:46]([S:50](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:52])=[O:51])=[CH:47][CH:48]=2)[CH:43]=[CH:42][N:41]=1>C1COCC1.[Cl-].[NH4+].C(Cl)Cl.C(O)(C(F)(F)F)=O.CO>[CH3:28][O:29][C:30]1[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:32][C:31]=1[C:40]1[C:49]2[C:44](=[CH:45][C:46]([S:50]([NH:6][C:7]3[S:11][N:10]=[CH:9][N:8]=3)(=[O:51])=[O:52])=[CH:47][CH:48]=2)[CH:43]=[CH:42][N:41]=1

Participants

9

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 57732216N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amineHCID 86687478Perfluorophenyl 1-(2-methoxy-4-(trifluoromethyl)phenyl)isoquinoline-6-sulfonate

Product 1

HCID 866874811-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamideYield 67%

Reagents, catalysts & solvents 5

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 6422Trifluoroacetic acidSolventHCID 8028TetrahydrofuranSolvent2×HCID 25517Ammonium ChlorideSolvent

Procedure

A round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (50.3 mg, 0.200 mmol) and THF (1 mL) to give a clear, light-orange solution. The flask was cooled in a dry ice-acetone bath for 5 min to give a suspension. Lithium bis(trimethylsilyl)amide (1M in THF) (200 μl, 0.200 mmol) was added dropwise. After about 5 min, a solution of perfluorophenyl 1-(2-methoxy-4-(trifluoromethyl)phenyl)isoquinoline-6-sulfonate (INTERMEDIATE LLL; 100 mg, 0.182 mmol) in THF (0.5 mL with a 0.25 mL syringe/vial wash) was added drop wise. After another 2 min, the flask was placed in an ice-water bath. The mixture was stirred for another 20 min, then diluted with saturated aq ammonium chloride and 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 (12-g column, 10 to 50% EtOAc/Heptane). The desired product was collected with some of the excess amine to give a white foam. The solid was taken up in DCM (1 mL) and TFA (0.5 mL). After 2 h, the mixture was diluted with methanol and concentrated. The crude product was purified by chromatography on silica gel (12-g column, 0 to 10% MeOH/DCM) to give 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (56.9 mg, 0.122 mmol, 67.0% yield) as a white powder: 1H NMR (400 MHz, DMSO-d6) δ ppm=8.73 (d, J=5.7 Hz, 1H), 8.61 (d, J=1.9 Hz, 1H), 8.51 (s, 1H), 8.18 (d, J=5.3 Hz, 1H), 7.89 (dd, J=1.9, 8.9 Hz, 1H), 7.74 (d, J=8.9 Hz, 1H), 7.61-7.43 (m, 3H), 3.75 (s, 3H). m/z (ESI) 467.2 (M+H)+.

Workup

  1. customto give a clear, light-orange solution
  2. temperatureThe flask was cooled in a dry ice-acetone bath for 5 min
  3. customto give a suspension
  4. additionwas added drop wise
  5. waitAfter another 2 min
  6. customthe flask was placed in an ice-water bath
  7. extractionextracted with EtOAc (2×)
  8. dry with materialThe combined organic extracts were dried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe residue was purified by chromatography on silica gel (12-g column, 10 to 50% EtOAc/Heptane)
  12. customThe desired product was collected with some of the excess amine
  13. customto give a white foam
  14. waitAfter 2 h
  15. concentrationconcentrated
  16. customThe crude product was purified by chromatography on silica gel (12-g column, 0 to 10% MeOH/DCM)

Sources & evidence

ORD record
ord-1c6673a72f1246139a5f6e927f14b072
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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