Acetyl chloride → 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide

HRID 1524407Notes

Reaction equation

HRID 1524407 reaction equation
Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14](CC3C=CC(OC)=CC=3OC)[C:15]3[S:19][N:18]=[CH:17][N:16]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH3:31])[CH:3]=1.[CH3:32][N:33]1[C:37]([C:38]2[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[CH:40][C:39]=2B(O)O)=[CH:36][CH:35]=[N:34]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(Cl)(=O)C>>[CH3:31][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([S:11]([NH:14][C:15]3[S:19][N:18]=[CH:17][N:16]=3)(=[O:12])=[O:13])[CH:6]=2)[C:2]([C:39]2[CH:40]=[CH:41][C:42]([C:44]([F:47])([F:45])[F:46])=[CH:43][C:38]=2[C:37]2[N:33]([CH3:32])[N:34]=[CH:35][CH:36]=2)=[CH:3]1

Participants

5

Reactant 4

HCID 6367Acetyl chlorideHCID 62657Potassium Phosphate, TribasicHCID 71258947(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid2×HCID 712592223-Bromo-N-(2,4-Dimethoxybenzyl)-1-Methyl-N-(1,2,4-Thiadiazol-5-yl)-1H-Indole-6-Sulfonamide2×

Product 1

HCID 712596211-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamideYield 74.1%

Conditions

Temperature
90 °C

Procedure

A microwave vial was charged with 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (Intermediate D) (48.17 mg, 0.092 mmol), (2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid (Intermediate G) (32.3 mg, 0.120 mmol), potassium phosphate (58.6 mg, 0.276 mmol), and Pd(AmPhos)2Cl2 (3.26 mg, 4.60 μmol). The vial was flushed with Ar, then 1,4-dioxane (0.4 mL) and water (0.125 mL) were added in sequence. The vial was sealed and heated in a microwave reactor at 90° C. for 20 min. The mixture was diluted with water, then extracted with EtOAc (3×). The combined organic extracts were concentrated. The residue was taken up in MeOH (1 mL), and cooled in an ice bath for 5 min. Acetyl chloride (65.4 μl, 0.920 mmol) was added dropwise, and the resulting mixture was stirred for 2 h. The mixture was concentrated under vacuum to remove excess HCl, and the residue was taken up in 2N ammonia in methanol. The resulting mixture was again concentrated under vacuum. The crude product was purified by chromatography on silica gel (0 to 10% MeOH/DCM) to give 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (35.38 mg, 0.068 mmol, 74.1% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.37 (s, 1 H), 7.97-7.83 (m, 3 H), 7.77 (d, J=1.9 Hz, 1 H), 7.60-7.53 (m, 1 H), 7.47-7.36 (m, 2 H), 7.17 (s, 1 H), 6.35 (d, J=1.9 Hz, 1 H), 3.81 (s, 3 H), 3.22 (s, 3 H). m/z (ESI) 519.2 (M+H)+.

Workup

  1. customThe vial was flushed with Ar
  2. addition1,4-dioxane (0.4 mL) and water (0.125 mL) were added in sequence
  3. customThe vial was sealed
  4. additionThe mixture was diluted with water
  5. extractionextracted with EtOAc (3×)
  6. concentrationThe combined organic extracts were concentrated
  7. temperaturecooled in an ice bath for 5 min
  8. concentrationThe mixture was concentrated under vacuum
  9. customto remove excess HCl
  10. concentrationThe resulting mixture was again concentrated under vacuum
  11. customThe crude product was purified by chromatography on silica gel (0 to 10% MeOH/DCM)

Sources & evidence

ORD record
ord-755347a6734e48bfbcdde4f36d204e19
Source dataset
uspto-grants-2015_07
Patent number
US09079902B2

Reaction notes

Loading…