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

HRID 1524435Notes

Reaction equation

HRID 1524435 reaction equation
[Br:1][C:2]1[N:6]=[C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([S:37](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:39])=[O:38])[CH:35]=2)[C:30]([C:52]2[CH:57]=[CH:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][C:53]=2[C:62]2[N:66]([CH3:67])[N:65]=[CH:64][CH:63]=2)=[CH:29]1>C1COCC1.CCOC(C)=O.CCCCCCC>[Br:1][C:2]1[N:6]=[C:5]([N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:37]([C:34]2[CH:35]=[C:36]3[C:31]([C:30]([C:52]4[CH:57]=[CH:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][C:53]=4[C:62]4[N:66]([CH3:67])[N:65]=[CH:64][CH:63]=4)=[CH:29][N:28]3[CH3:27])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[S:4][N:3]=1

Participants

6

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 712593363-bromo-N-(4-methoxybenzyl)-1,2,4-thiadiazol-5-amine2×HCID 89407674perfluorophenyl 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonate2×

Product 1

HCID 71259358N-(3-bromo-1,2,4-thiadiazol-5-yl)-N-(4-methoxybenzyl)-1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonamideYield 73.2%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 21899848Ethylacetate heptaneSolvent

Procedure

A 25-mL round-bottom flask was charged with 3-bromo-N-(4-methoxybenzyl)-1,2,4-thiadiazol-5-amine (INTERMEDIATE K) (157 mg, 0.522 mmol) and THF (2.6 mL) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (653 μl, 0.653 mmol) was added dropwise. The resulting clear solution was stirred for 20 min, then a solution perfluorophenyl 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonate (INTERMEDIATE E) (157 mg, 0.261 mmol) in THF (1 mL with a 0.5 mL vial/syringe wash) was added dropwise over 1 min. The resulting solution was stirred for 10 min, then the flask was lowered into an ice bath for 2.5 h. The reaction mixture was quenched with saturated aq ammonium chloride solution, diluted with water, and extracted with EtOAc (2×). The combined organic extracts were concentrated, and the crude product was purified by chromatography on silica gel (0 to 60% EtOAc/Heptane) N-(3-bromo-1,2,4-thiadiazol-5-yl)-N-(4-methoxybenzyl)-1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonamide (136.87 mg, 0.191 mmol, 73.1% yield) as a white foam. 1H NMR (400 MHz, DMSO-d6) δ=8.09 (d, J=1.8 Hz, 1 H), 7.96-7.83 (m, 2 H), 7.79 (d, J=1.4 Hz, 1 H), 7.66-7.49 (m, 2 H), 7.39 (d, J=1.9 Hz, 1 H), 7.31 (s, 1 H), 7.26 (d, J=8.8 Hz, 2 H), 6.86-6.79 (m, 2 H), 6.33 (d, J=1.9 Hz, 1 H), 5.08 (s, 2 H), 3.83 (s, 3 H), 3.68 (s, 3 H), 3.24 (s, 3H). m/z (ESI) 717.2 (M+H)+.

Workup

  1. customto give a clear solution
  2. temperatureThe flask was cooled in a dry ice-acetone bath for 10 min
  3. stirringThe resulting solution was stirred for 10 min
  4. waitthe flask was lowered into an ice bath for 2.5 h
  5. customThe reaction mixture was quenched with saturated aq ammonium chloride solution
  6. additiondiluted with water
  7. extractionextracted with EtOAc (2×)
  8. concentrationThe combined organic extracts were concentrated

Sources & evidence

ORD record
ord-7c206e0aa8e74e22af062abec48d6c00
Source dataset
uspto-grants-2015_07
Patent number
US09079902B2

Reaction notes

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