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

HRID 1473580Notes

Reaction equation

HRID 1473580 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+].[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]([O:48]C4C(F)=C(F)C(F)=C(F)C=4F)(=O)=[O:46])=[CH:42][CH:43]=3)[CH:38]=[CH:37][N:36]=2)=[C:31]([O:60][CH3:61])[CH:30]=1>C1COCC1.CCOC(C)=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]([NH:6][C:7]4[S:11][N:10]=[CH:9][N:8]=4)(=[O:48])=[O:46])=[CH:42][CH:43]=3)[CH:38]=[CH:37][N:36]=2)=[C:31]([O:60][CH3:61])[CH:30]=1

Participants

6

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 866876411-(4-chloro-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamideYield 41%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (33.3 mg, 0.172 mmol) and THF (718 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) (172 μl, 0.172 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, 74.12 mg, 0.144 mmol) in THF (0.6 mL with a 0.4 mL-flask wash) was added drop wise. After another minute, the flask was transferred to an ice-water bath. After 10 min of stirring, the mixture was concentrated, and the residue was taken up in DCM (1 mL) and TFA (0.5 mL). The mixture was stirred for 30 min, then diluted with MeOH and concentrated. The residue was purified by chromatography on silica gel (25-g Interchim column, 25-75% EtOAc/Heptane) to give white solid. The solid was taken up in EtOAc, filtered, washed with EtOAc (3×), dried under a stream of N2 (g), then dried under vacuum to give 1-(4-chloro-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (25.5 mg, 0.059 mmol, 41.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.69 (d, J=5.7 Hz, 1H), 8.57 (d, J=1.9 Hz, 1H), 8.48 (s, 1H), 8.13 (d, J=5.6 Hz, 1H), 7.89-7.89 (m, 0H), 7.91-7.81 (m, 1H), 7.75 (d, J=8.9 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.32 (d, J=1.9 Hz, 1H), 7.20 (dd, J=1.9, 8.1 Hz, 1H), 3.68 (s, 3H). m/z (ESI) 433.0 (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. concentrationthe mixture was concentrated
  7. stirringThe mixture was stirred for 30 min
  8. additiondiluted with MeOH
  9. concentrationconcentrated
  10. customThe residue was purified by chromatography on silica gel (25-g Interchim column, 25-75% EtOAc/Heptane)
  11. customto give white solid
  12. filtrationfiltered
  13. washwashed with EtOAc (3×)
  14. dry with materialdried under a stream of N2 (g)
  15. customdried under vacuum

Sources & evidence

ORD record
ord-ce7ad0efc87d410a975e56eeb380f1e9
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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