Potassium Carbonate → 4-(2-Chloro-4-methyl-phenyl)-1-methyl-3-(2 pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine

HRID 1748744Notes

Reaction equation

HRID 1748744 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH2:12][NH:11][C:10]3[N:15]([CH3:24])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[C:9]2=3)=[C:4]([Cl:25])[CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:4]1[CH:3]=[C:2]([CH3:26])[CH:7]=[CH:6][C:5]=1[CH:8]1[S:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]([CH3:24])[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:9]1=2

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 574072TrimethylboroxineHCID 1363484284-(4-Bromo-2-chloro-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine

Product 1

HCID 1363484294-(2-Chloro-4-methyl-phenyl)-1-methyl-3-(2 pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepineYield 60%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a degassed solution of 4-(4-bromo-2-chloro-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.4 g, 0.92 mmol, see Ex. #3 step D) in 1,4-dioxane (10 mL) was added potassium carbonate (0.4 g, 2.9 mmol), trimethylboroxine (0.200 g, 1.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.2 g, 0.18 mmol). The resulting mixture was heated, in a sealed microwave vessel, for about 1 h at about 100° C. in a microwave. After cooling to rt, the mixture was concentrated in vacuo. The residue was treated with water (25 mL) and ethyl acetate (150 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were washed with water (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, ethyl acetate/hexanes 1:1) to give 4-(2-chloro-4-methyl-phenyl)-1-methyl-3-(2 pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.055 g, 0.15 mmol, 60%) as an off white solid: LC-MS (Table 1, Method e) Rt=8.02 min; m/z 371 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.27 (3 H, s) 2.72 (1 H, ddd, J=15.0, 6.0, 2.5 Hz) 2.86 (1 H, ddd, J=15.0, 9.0, 2.5 Hz) 3.22-3.29 (1 H, m) 3.54-3.63 (1 H, m) 3.80 (1 H, br s) 3.84 (3 H, s) 6.75 (1 H, s) 6.89 (1 H, br.d, J=7.5 Hz) 7.07 (1 H, ddd, J=7.5, 5.0, 1.0 Hz) 7.16 (1 H, d, J=8.0 Hz) 7.22 (1 H, br.d, J=1.0 Hz) 7.58 (1H, td, J=7.5, 2.0 Hz) 7.70 (1 H, dt, J=8.0, 1.0 Hz) 8.53 (1 H, ddd, J=5.0, 2.0, 1.0 Hz).

Workup

  1. temperatureAfter cooling to rt
  2. concentrationthe mixture was concentrated in vacuo
  3. additionThe residue was treated with water (25 mL) and ethyl acetate (150 mL)
  4. customThe layers were separated
  5. extractionthe aqueous layer was extracted with ethyl acetate (50 mL)
  6. washThe combined organic layers were washed with water (50 mL)
  7. dry with materialdried (MgSO4)
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe resulting residue was purified by column chromatography (SiO2, ethyl acetate/hexanes 1:1)

Sources & evidence

ORD record
ord-a8f2fa9cb0ba4a3d8ea79d980fb64d17
Source dataset
uspto-grants-2015_10
Patent number
US09150592B2

Reaction notes

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