Pyrazole → 2-(Methylsulfanyl)-7-(1H-pyrazol-1-yl)pyrrolo[2,1-f][1,2,4]triazine

HRID 1262339Notes

Reaction equation

HRID 1262339 reaction equation
Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I.CN(C=O)C>[CH3:12][S:11][C:8]1[N:7]=[CH:6][C:5]2=[CH:4][CH:3]=[C:2]([N:13]3[CH:17]=[CH:16][CH:15]=[N:14]3)[N:10]2[N:9]=1

Participants

6

Reactant 3

HCID 1048PyrazoleHCID 10796Cesium carbonateHCID 574161287-Bromo-2-(methylsulfanyl)pyrrolo[2,1-f][1,2,4]triazine

Product 1

HCID 574161022-(Methylsulfanyl)-7-(1H-pyrazol-1-yl)pyrrolo[2,1-f][1,2,4]triazine

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
110 °C

Procedure

To a RB flask under argon were introduced 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (300 mg, 1 mmol), 1H-Pyrazole (88.5 mg, 1.30 mmol), Cesium carbonate (801 mg, 2.46 mmol), Copper(I) iodide (50 mg, 0.3 mmol) and DMF (5 mL). The mixture was degassed for few minutes and heated at 110° C. overnight under argon. Solvent was removed and the mixture was taken in EtOAc and was passed through a pad of celite. Solvent evaporation gave the crude product which was purified by flash chromatography (ISCO, hexane :EtOAc 3:1). 2-Methylsulfanyl-7-pyrazol-1-yl-pyrrolo[2,1-f][1,2,4]triazine was isolated as a yellow syrup (23, 8%). LCMS (E/I+) 232 (M+H). 2-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-phenylamine (47.1 mg, 0.162 mmol), 2-Methanesulfinyl-7-pyrazol-1-yl-pyrrolo[2,1-f][1,2,4]triazine (20 mg, 0.08 mmol), N,N-Diisopropylethylamine (30 uL, 0.2 mmol) and 1-Methoxy-2-propanol (200 uL,) were combined in a microwave vial. The reaction was microwaved at 200° C. for 2.5 hours, taken up in DMSO, purified by Gilson RP-HPLC. The product, [2-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-(7-pyrazol-1-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine was isolated as a tan solid (8 mg, 21%). LCMS (E/I+) 475 (M+H). NMR 1H (DMSO-d6)-9.75 (br s, 1H), 8.94 (s, 1H), 8.58 (d, 1H, J=2.09 Hz), 7.94 (s, 1H), 7.83 (s, 1H), 7.67 (d, 1H, J=8.72 Hz), 6.94 (s, 2H), 6.70 (s, 1H), 6.60 (s, 1H), 6.52 (d, 1H, J=8.74 Hz), 4.04-3.13 (series of m, s along with the water peak, 14H), 2.71 (m, 2H), 2.15 (d, 2H, J=11.30 Hz), 1.72 (m, 2H).

Workup

  1. customThe mixture was degassed for few minutes
  2. customSolvent was removed
  3. customSolvent evaporation
  4. customgave the crude product which
  5. customwas purified by flash chromatography (ISCO, hexane :EtOAc 3:1)

Sources & evidence

ORD record
ord-a4902d445ee748e29a438758b35f4a16
Source dataset
uspto-grants-2013_06
Patent number
US08471005B2

Reaction notes

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