反应详情

To a screw-cap test tube are added copper(I) oxide (11 mg, 0.08 mmol), 2-chloro-4,4-difluoro-1′-[(3-methyl-1H-pyrazol-4-yl)methyl]spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine] (300 mg, 0.8 mmol), cesium carbonate (523 mg, 1.6 mmol), dry dimethylformamide (1.6 mL) and a stir bar. The reaction mixture is bubbled with nitrogen for 20 minutes and then methyl 2-iodopyridine-3-carboxylate (511 mg, 1.9 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.24 mmol; 34 mg) are added. The reaction tube is quickly sealed (caution: build-up of pressure possible; use a safety shield) and immersed in a preheated oil bath at 110° C. for 16 hours with the aid of a magnetic stirrer. Then, the mixture is poured on SCX column (10 g) and eluted with methanol and then 2N solution of ammonia in methanol. The basic fraction is concentrated and the resulting residue is purified by silica gel using normal phase Isco chromatography eluting with hexane:ethanol (gradient from 2 to 15% in ethanol) to give 307 mg of 2-(4-((2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]-1-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-nicotinic acid methyl ester. MS (m/z): 309 (M+1).

1. customThe reaction mixture is bubbled with nitrogen for 20 minutes
2. customThe reaction tube is quickly sealed (caution
3. additionThen, the mixture is poured on SCX column (10 g)
4. washeluted with methanol
5. concentrationThe basic fraction is concentrated
6. customthe resulting residue is purified by silica gel using normal phase Isco chromatography
7. washeluting with hexane