反应详情

温度

105 °C

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).

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