反应详情

To a screw-cap test tube is added copper (I) iodide (1.15 g, 6.02 mmol), 2-chloro-4,4-difluoro-1′-[(3-methyl-1H-pyrazol-4-yl)methyl]spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine] (15 g, 40.12 mmol), potassium carbonate (11.76 g, 84.26 mmol), 15 mL of toluene (previously bubbled with nitrogen for 20 minutes) and a stir bar. The reaction mixture is bubbled with nitrogen for additional 10 min and then 2-bromo-3-methoxymethyl-pyridine (10.54 g, 52.16 mmol), and trans-N,N′-dimethylcyclohexane-1,2-diamine (1.90 mL, 12.04 mmol) are added. The reaction tube is quickly sealed (caution: build-up of pressure possible; use a safety shield), stirred at room temperature for 5 min and immersed in a preheated oil bath at 115° C. for 24 h. The sample is cooled down to room temperature, diluted with ethyl acetate and filtered through celite. The solvent is evaporated in vacuo. The residue is purified by normal phase Isco chromatography using hexane/ethyl acetate (30-70%). The desired fractions are collected and evaporated. Some impure fractions (<2 g) are repurified by normal phase Isco chromatography using hexane/ethyl acetate (20-60% in ethyl acetate) as eluent. All the fractions containing final compound are combined and evaporated to dryness in vacuo. The residue is dissolved in dichloromethane and washed with 10% aqueous solution of ammonium hydroxide to remove copper residues. The organic solvent is evaporated and the compound is dried overnight to yield 13 g of 2-chloro-4,4-difluoro-1′-[[1-[3-(methoxymethyl)-2-pyridyl]-3-methyl-pyrazol-4-yl]methyl]spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]. MS (m/z): 495 (M+1).

1. custompreviously bubbled with nitrogen for 20 minutes) and a stir bar
2. customThe reaction mixture is bubbled with nitrogen for additional 10 min
3. customThe reaction tube is quickly sealed (caution
4. waitimmersed in a preheated oil bath at 115° C. for 24 h
5. temperatureThe sample is cooled down to room temperature
6. filtrationfiltered through celite
7. customThe solvent is evaporated in vacuo
8. customThe residue is purified by normal phase Isco chromatography
9. customThe desired fractions are collected
10. customevaporated
11. customSome impure fractions (<2 g) are repurified by normal phase Isco chromatography
12. additionAll the fractions containing final compound
13. customevaporated to dryness in vacuo
14. dissolutionThe residue is dissolved in dichloromethane
15. washwashed with 10% aqueous solution of ammonium hydroxide
16. customto remove copper residues
17. customThe organic solvent is evaporated
18. customthe compound is dried overnight