Cesium carbonate → 1-Methyl-4-(2-methyl-4-methylsulfonyl-phenyl)-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine

HRID 1748735Notes

Reaction equation

HRID 1748735 reaction equation
C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.Br[C:44]1[CH:49]=[CH:48][C:47]([CH:50]2[S:56][CH2:55][CH2:54][NH:53][C:52]3[N:57]([CH3:66])[N:58]=[C:59]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][N:61]=4)[C:51]2=3)=[C:46]([CH3:67])[CH:45]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:74][S:75]([O-:77])=[O:76].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:66][N:57]1[C:52]2[NH:53][CH2:54][CH2:55][S:56][CH:50]([C:47]3[CH:48]=[CH:49][C:44]([S:75]([CH3:74])(=[O:77])=[O:76])=[CH:45][C:46]=3[CH3:67])[C:51]=2[C:59]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][N:61]=2)=[N:58]1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 2733271Sodium methanesulfinateHCID 1363484254-(4-Bromo-2-methyl-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine

Product 1

HCID 1362162871-Methyl-4-(2-methyl-4-methylsulfonyl-phenyl)-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepineYield 3.8%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
120 °C

Procedure

To a degassed solution of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.057 g, 0.1 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.045 g, 0.025 mmol) in toluene (6 mL) was added 4-(4-bromo-2-methyl-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.400 g, 0.96 mmol, Example #4 step D), cesium carbonate (0.470 g, 1.5 mmol) and sodium methanesulfinate (0.118 g, 1.2 mmol). The resulting mixture was heated at about 120° C. overnight. After cooling to rt, the mixture was diluted with ethyl acetate (50 mL), washed with water (20 mL) and brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, DCM/methanol 1:1) followed by prep-HPLC (Table 2, Method b) to give 1-methyl-4-(2-methyl-4-methylsulfonyl-phenyl)-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.015 g, 0.036 mmol, 3%) as an off white solid: LC-MS (Table 1, Method a) Rt=2.98 min; m/z 415 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.65-2.73 (1H, m) 2.70 (3H, s) 2.81 (1H, ddd, J=15.0, 9.3, 2.4 Hz) 3.01 (3H, s) 3.23-3.32 (1H, m) 3.61-3.71 (1H, m) 3.84 (3H, s) 3.86 (1H, br s) 6.79 (1H, s) 7.09 (1H, ddd, J=7.4, 5.1, 1.0 Hz) 7.40 (1H, d, J=8.1 Hz) 7.58-7.64 (2H, m) 7.73 (1H, d, J=1.6 Hz) 7.86 (1H, d, J=8.0 Hz) 8.44 (1H, d, J=4.8 Hz).

Workup

  1. temperatureAfter cooling to rt
  2. washwashed with water (20 mL) and brine (20 mL)
  3. dry with materialdried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by column chromatography (SiO2, DCM/methanol 1:1)

Sources & evidence

ORD record
ord-e3ee9fc77c1c4301a0c30f6262bcc2f5
Source dataset
uspto-grants-2015_10
Patent number
US09150592B2

Reaction notes

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