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

HRID 1473317Notes

Reaction equation

HRID 1473317 reaction equation
[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:13][N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37](Cl)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1>C1COCC1>[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:13][N:12]=[CH:11][N:10]=3)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 65271538N-(4-Methoxybenzyl)-1,2,4-thiadiazol-5-amineHCID 861938101-Chloroisoquinoline-6-sulfonyl chloride

Product 1

HCID 866873721-chloro-N-(4-methoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamideYield 25.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-70 °C

Procedure

To a solution of N-(4-methoxybenzyl)-1,2,4-thiadiazol-5-amine (1.40 g, 6.33 mmol) in THF (42.2 mL) at −70° C. under an argon atmosphere was added lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran (6.96 mL, 6.96 mmol) dropwise. The reaction mixture was removed from cooling and stirred for 45 min. The mixture was again cooled to −70° C. (internal temperature) to give a yellow suspension. Then solid 1-chloroisoquinoline-6-sulfonyl chloride (1.82 g, 6.96 mmol) was added in one portion. After 15 min, the mixture was warmed to room temperature and concentrated. The residue was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (80 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide 1-chloro-N-(4-methoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (0.73 g, 1.633 mmol) as an orange solid. MS (ESI): 447.0 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ ppm 3.65 (s, 3H), 5.24 (s, 2H), 6.77 (m, J=8.66 Hz, 2H), 7.28 (m, J=8.66 Hz, 2H), 8.10 (dd, J=5.9, 10.8 Hz, 1H), 8.15 (d, J=6.4 Hz, 1H), 8.42 (d, J=8.6 Hz, 1H), 8.45 (s, 1H), 8.50 (d, J=5.56 Hz, 1H), 8.77 (d, J=1.71 Hz, 1H).

Workup

  1. customThe reaction mixture was removed
  2. temperaturefrom cooling
  3. customto give a yellow suspension
  4. waitAfter 15 min
  5. temperaturethe mixture was warmed to room temperature
  6. concentrationconcentrated
  7. customThe residue was absorbed onto a plug of silica gel
  8. custompurified by chromatography through a silica gel column (80 g)
  9. washeluting with a gradient of 0% to 50% EtOAc in hexane

Sources & evidence

ORD record
ord-1913948711554629b8c3dcd3a6826d40
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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