Potassium Carbonate → 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]pyridine-3-carbaldehyde

HRID 1517625Notes

Reaction equation

HRID 1517625 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.[C:25](=[O:28])([O-])[O-].[K+].[K+].CN[C@@H]1C[CH2:37][CH2:36][CH2:35][C@H:34]1[NH:39][CH3:40]>C1(C)C=CC=CC=1.[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:34]2[C:35]([CH:25]=[O:28])=[CH:36][CH:37]=[CH:40][N:39]=2)[CH:18]=1)[CH2:9][CH2:8]3

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamineHCID 178434546HCID 178434546, compound

Product 1

HCID 582685962-[4-[(2-Chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]pyridine-3-carbaldehydeYield 240.6%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 1140TolueneSolvent

Conditions

Temperature
105 °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] (168.4 g, 451 mmol), CuI (12.9 g, 67.7 mmol) and potassium carbonate (131 g, 947 mmol) in anhydrous toluene (340 mL) is degassed at room temperature for 30 min. 2-Bromo-pyridine-3-carbaxaldehyde (125 g, 677 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (21.3 mL, 135.4 mmol) are added sequentially. The contents are degassed 30 min. before heating at 105° C. while stirring for 18 hr. LC/MS analysis of the reaction mixture reveals complete consumption of 2-chloro-4,4-difluoro-1′-[(3-methyl-1H-pyrazol-4-yl)methyl]spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]. The reaction mixture is cooled to room temperature, diluted with ethyl acetate (1.5 L), stirred and filtered through a pad of celite. The mother liquid is washed sequentially with 10% ammonium hydroxide (5×100 mL), water (3×100 mL), and brine. It is then dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue is purified on silica gel using 50% ethyl acetate in hexane containing 1% triethylamine to afford 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]pyridine-3-carbaldehyde as a solid (156 g, 72% yield). MS (m/z): 479 (M+1).

Workup

  1. customis degassed at room temperature for 30 min
  2. customThe contents are degassed 30 min.
  3. customconsumption of 2-chloro-4,4-difluoro-1′-[(3-methyl-1H-pyrazol-4-yl)methyl]spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]
  4. temperatureThe reaction mixture is cooled to room temperature
  5. additiondiluted with ethyl acetate (1.5 L)
  6. stirringstirred
  7. filtrationfiltered through a pad of celite
  8. washThe mother liquid is washed sequentially with 10% ammonium hydroxide (5×100 mL), water (3×100 mL), and brine
  9. dry with materialIt is then dried (sodium sulfate)
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customThe residue is purified on silica gel using 50% ethyl acetate in hexane containing 1% triethylamine

Sources & evidence

ORD record
ord-b77851377d1244deb4fabbf1d301ee58
Source dataset
uspto-grants-2012_07
Patent number
US08232289B2

Reaction notes

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