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

HRID 1748764Notes

Reaction equation

HRID 1748764 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][C:12](=O)[NH:11][C:10]3[N:16]([CH3:25])[N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:9]2=3)=[C:4]([CH3:26])[CH:3]=1.B.C1COCC1.Cl.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH2:12][NH:11][C:10]3[N:16]([CH3:25])[N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:9]2=3)=[C:4]([CH3:26])[CH:3]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 2723981Borane;tetrahydrofuranHCID 1362162894-(4-Chloro-2-methyl-phenyl)-1-methyl-3-(2-pyridyl)-4,8-dihydropyrazolo[3,4-e][1,4]thiazepin-7-one

Product 1

HCID 1362162514-(4-Chloro-2-methyl-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepineYield 48.1%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
4 °C

Procedure

To a solution of 4-(4-chloro-2-methyl-phenyl)-1-methyl-3-(2-pyridyl)-4,8-dihydropyrazolo[3,4-e][1,4]thiazepin-7-one (0.200 g, 0.52 mmol, prepared using C from example #2 step B with thioglycolic acid, and 4-chloro-2-methylbenzaldehyde (Fluorochem)) in THF (6 mL) was added a solution of borane THF complex (4 mL, 1M in THF, 4 mmol, Acros) at rt. Subsequently, the mixture was heated under reflux for about 3 h. After cooling to about 4° C., HCl (5 M aqueous 6 mL) was added dropwise and the mixture was stirred for about 2 h at about 4° C., then NaOH (1 M aqueous, 50 mL) and ethyl acetate (100 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were washed with water (2×25 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Table 2, Method a) to give 4-(4-chloro-2-methyl-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.0917 g, 0.25 mmol, 48%) as white solid: LC-MS (Table 1, Method a) Rt=4.23 min, m/z 371 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) 2.58 (3H, s) 2.68 (1H, ddd, J=15.0, 6.1, 2.5 Hz) 2.85 (1H, ddd, J=15.0., 9.6, 2.5 Hz) 3.21-3.29 (1 H, m) 3.56-3.65 (1 H, m) 3.79 (1 H, br s) 3.83 (3H, s) 6.66 (1H, s) 6.99 (1 H, dd J=8.3, 2.1 Hz) 7.07 (1 H, ddd J=8.0, 5.0, 1.0 Hz) 7.12 (1 H, d J=8.0 Hz) 7.15 (1 H, d, J=2.0 Hz) 7.59 (1 H, td, J=7.5, 2.0 Hz) 7.79 (1H, d, J=8.0 Hz) 8.46 (1H, d, J=4.5 Hz).

Workup

  1. temperatureSubsequently, the mixture was heated
  2. temperatureunder reflux for about 3 h
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted with ethyl acetate (50 mL)
  5. washThe combined organic layers were washed with water (2×25 mL)
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by preparative HPLC (Table 2, Method a)

Sources & evidence

ORD record
ord-2d155d99ba854b8bbc7dbfe638f01deb
Source dataset
uspto-grants-2015_10
Patent number
US09150592B2

Reaction notes

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