p-Toluenesulfonic acid → 4-(4-Chloro-2-methyl-phenyl)-1,7-dimethyl-3-(2-pyridyl)-4,6-dihydropyrazolo[3,4-e][1,4]thiazepine

HRID 1748800Notes

Reaction equation

HRID 1748800 reaction equation
[CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:3]1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([CH3:23])[CH:16]=1.[SH:24][CH2:25][C:26](=O)[CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]2[S:24][CH2:25][C:26]([CH3:27])=[N:7][C:6]3[N:2]([CH3:1])[N:3]=[C:4]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[C:5]2=3)=[C:17]([CH3:23])[CH:16]=1

Participants

6

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 5201441-Mercapto-2-propanoneHCID 27576584-Chloro-2-methylbenzaldehydeHCID 133248371-Methyl-3-Pyridin-2-Yl-1H-Pyrazol-5-Amine

Product 1

HCID 867241284-(4-Chloro-2-methyl-phenyl)-1,7-dimethyl-3-(2-pyridyl)-4,6-dihydropyrazolo[3,4-e][1,4]thiazepineYield 76.4%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
150 °C

Procedure

A mixture of 1-methyl-3-(2-pyridyl)pyrazol-5-amine (0.215 g, 1.23 mmol), 4-chloro-2-methyl-benzaldehyde (0.1906 g, 1.23 mmol, Fluorochem), 1-sulfanylpropan-2-one (0.45 g, 4.93 mmol, Enamine), and p-toluenesulfonic acid (0.070 g, 0.37 mmol) in acetonitrile (3 mL) was heated, in a sealed microwave vessel, for about 30 min, at about 150° C., in a microwave. After cooling to rt the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (70 mL) and methanol (10 mL), and washed with 5% aqueous sodium bicarbonate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with water (40 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate/hexanes 1:4) to afford 4-(4-chloro-2-methyl-phenyl)-1,7-dimethyl-3-(2-pyridyl)-4,6-dihydropyrazolo[3,4-e][1,4]thiazepine (0.36 g, 0.94 mmol, 76%), as a yellow oil: LC-MS (Table 1, Method a) Rt=5.41 min, m/z 383 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.36 (3H, s) 2.60 (3H, s) 3.16 (1H, d, J=16.3 Hz) 3.29 (1H, dd, J=16.3, 1.5 Hz) 4.03 (3H, s) 6.50 (1H, d, J=8.2 Hz) 6.60 (1H, d, J=1.5 Hz) 6.88 (1H, dd, J=8.2, 2.1 Hz) 7.01 (1H, ddd, J=7.4, 4.9, 1.1 Hz) 7.16 (1H, d, J=2.1 Hz) 7.56 (1H, td, J=7.8, 1.7 Hz) 7.86 (1H, dt, J=8.1, 1.0 Hz) 8.35 (1H, ddd, J=4.8, 1.8, 0.8 Hz).

Workup

  1. temperatureAfter cooling to rt the mixture
  2. concentrationwas concentrated under reduced pressure
  3. dissolutionThe residue was dissolved in ethyl acetate (70 mL)
  4. washmethanol (10 mL), and washed with 5% aqueous sodium bicarbonate (20 mL)
  5. extractionThe aqueous layer was extracted with ethyl acetate (20 mL)
  6. washThe combined organic layers were washed with water (40 mL)
  7. dry with materialdried (MgSO4)
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified by column chromatography (SiO2, ethyl acetate/hexanes 1:4)

Sources & evidence

ORD record
ord-61164e3bd8d241508b8c724eaa0e1b7d
Source dataset
uspto-grants-2015_10
Patent number
US09150592B2

Reaction notes

Loading…