Lithium Hexamethyldisilazide → 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(5-methyl-4-(trifluoromethyl)thiazol-2-yl)-1H-indole-6-sulfonamide

HRID 1524414Notes

Reaction equation

HRID 1524414 reaction equation
[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([O:14]C3C(F)=C(F)C(F)=C(F)C=3F)(=O)=[O:12])[CH:9]=2)[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=2[C:36]2[N:40]([CH3:41])[N:39]=[CH:38][CH:37]=2)=[CH:3]1.[CH3:42][C:43]1[S:47][C:46]([NH2:48])=[N:45][C:44]=1[C:49]([F:52])([F:51])[F:50].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([NH:48][C:46]3[S:47][C:43]([CH3:42])=[C:44]([C:49]([F:52])([F:50])[F:51])[N:45]=3)(=[O:12])=[O:14])[CH:9]=2)[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:35])[F:34])=[CH:28][C:27]=2[C:36]2[N:40]([CH3:41])[N:39]=[CH:38][CH:37]=2)=[CH:3]1

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 534185345-Methyl-4-(trifluoromethyl)-1,3-thiazol-2-amineHCID 89407674perfluorophenyl 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonate2×

Product 1

HCID 716079281-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(5-methyl-4-(trifluoromethyl)thiazol-2-yl)-1H-indole-6-sulfonamideYield 27.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A flask was charged with perfluorophenyl 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)-phenyl)-1H-indole-6-sulfonate (INTERMEDIATE E) (44.48 mg, 0.074 mmol), 5-methyl-4-(trifluoromethyl)thiazol-2-amine (17.51 mg, 0.096 mmol) and THF (0.5 mL). The flask was cooled in an ice bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (185 μl, 0.185 mmol) was added dropwise to give an orange solution. The mixture was stirred for 1 h, then an additional portion of the base solution (0.08 mL) was added. After 20 min, the cooling bath was removed. The mixture was stirred for an additional 20 min, then an additional portion of 5-methyl-4-(trifluoromethyl)thiazol-2-amine (10 mg) was added. The mixture was stirred for 20 min, then was quenched with AcOH (0.1 mL) and concentrated from MeOH/DCM. The crude product was purified by chromatography on silica gel (0 to 5% MeOH/DCM) to give 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(5-methyl-4-(trifluoromethyl)thiazol-2-yl)-1H-indole-6-sulfonamide (12.27 mg, 0.020 mmol, 27.7% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ=8.01 (d, J=1.5 Hz, 1 H), 7.94-7.82 (m, 2 H), 7.77 (d, J=0.9 Hz, 1 H), 7.61 (d, J=8.5 Hz, 1 H), 7.50 (dd, J=1.7, 8.5 Hz, 1 H), 7.37 (d, J=1.9 Hz, 1 H), 7.24 (s, 1 H), 6.34 (d, J=1.9 Hz, 1 H), 3.82 (s, 3 H), 3.24 (s, 3 H), 2.40-2.35 (m, 3 H). m/z (ESI) 600.2 (M+H)+.

Workup

  1. temperatureThe flask was cooled in an ice bath for 5 min
  2. customto give an orange solution
  3. waitAfter 20 min
  4. customthe cooling bath was removed
  5. stirringThe mixture was stirred for an additional 20 min
  6. additionan additional portion of 5-methyl-4-(trifluoromethyl)thiazol-2-amine (10 mg) was added
  7. stirringThe mixture was stirred for 20 min
  8. customwas quenched with AcOH (0.1 mL)
  9. concentrationconcentrated from MeOH/DCM
  10. customThe crude product was purified by chromatography on silica gel (0 to 5% MeOH/DCM)

Sources & evidence

ORD record
ord-7654c97242d340cc8f4c59b90ca10477
Source dataset
uspto-grants-2015_07
Patent number
US09079902B2

Reaction notes

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