Cesium carbonate → 4-[[2-[4-[(2-Chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methyl]morpholin-3-one

HRID 1517621Notes

Reaction equation

HRID 1517621 reaction equation
[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:20][CH2:21][C:22]([F:24])([F:23])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:19])=[N:16][NH:17][CH:18]=1)[CH2:9][CH2:8]3.Br[C:26]1[C:31]([CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][C:34]2=[O:39])=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>CN(C)C=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:20][CH2:21][C:22]([F:23])([F:24])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:19])=[N:16][N:17]([C:26]2[C:31]([CH2:32][N:33]4[CH2:38][CH2:37][O:36][CH2:35][C:34]4=[O:39])=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:18]=1)[CH2:9][CH2:8]3

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamineHCID 582686224-((2-Bromopyridin-3-yl)methyl)morpholin-3-oneHCID 178434546HCID 178434546, compound

Product 1

HCID 582686364-[[2-[4-[(2-Chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methyl]morpholin-3-oneYield 30.1%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
130 °C

Procedure

A mixture of 2-chloro-4,4-difluoro-1′-[(3-methyl-1H-pyrazol-4-yl)methyl]spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine] (0.20 g, 0.53 mmol), 4-[(2-bromo-3-pyridyl)methyl]morpholin-3-one (0.21 g, 0.77 mmol), copper(I) iodide (0.015 g, 0.078 mmol) and cesium carbonate (0.36 g, 1.10 mmol) in dimethylformamide (5 mL) is degassed by bubbling argon for 15 minutes. (1R,2R)—N,N′-dimethylcyclohexane-1,2-diamine (0.02 g, 0.14 mmol) is added while degassing for 15 minutes and then the mixture is heated to 130° C. for 16 hours. After completion, the reaction mixture is allowed to cool to room temperature and filtered through celite. The residue is washed with ethyl acetate (2×25 mL) and the filtrate is washed with water (30 mL). The aqueous layer was extracted with ethyl acetate (2×25 mL) and the combined organic extracts are dried over sodium sulfate and concentrated in vacuo. The crude mixture is purified by column chromatography over silica gel eluting with dichloromethane/methanol (96:4) to yield 0.09 g (30%) of the title compound. MS (m/z): 564 (M+1).

Workup

  1. customis degassed
  2. customby bubbling argon for 15 minutes
  3. customwhile degassing for 15 minutes
  4. temperatureto cool to room temperature
  5. filtrationfiltered through celite
  6. washThe residue is washed with ethyl acetate (2×25 mL)
  7. washthe filtrate is washed with water (30 mL)
  8. extractionThe aqueous layer was extracted with ethyl acetate (2×25 mL)
  9. dry with materialthe combined organic extracts are dried over sodium sulfate
  10. concentrationconcentrated in vacuo
  11. customThe crude mixture is purified by column chromatography over silica gel eluting with dichloromethane/methanol (96:4)

Sources & evidence

ORD record
ord-e307071acee34867a0a616ab9e2653f7
Source dataset
uspto-grants-2012_07
Patent number
US08232289B2

Reaction notes

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