反应详情

To a suspension of zinc powder (320 mg, 4.92 mmol) and Celpure P65 in anhydrous DMA (3 mL) was added a 7:5 (v:v) mixture of TMS-C1:1,2-dibromoethane (65 μL) drop wise. The reaction mixture was stirred at room temperature for 15 min. A solution of 4-iodopiperidine-1-carboxylic acid tert-butyl ester (1.22 g, 3.95 mmol) in anhydrous DMA (2 mL) was added dropwise to the mixture described above and the reaction mixture was stirred for 30 minutes at room temperature. The zincate mixture was quickly filtered through a grade-3 sintered funnel and added onto a mixture of 2-Chloro-8-iodo-9-methyl-6-morpholin-4-yl-9H-purine (1.0 g, 2.63 mmol), Pd(dppf)Cl2.DCM (107 mg, 0.13 mmol) and CuI (50 mg, 0.26 mmol). The vessel was then evacuated and back-filled with nitrogen. The resulting reaction mixture was stirred at 85° C. for 18 hours, after 3 hours additional Pd(dppf)Cl2.DCM and CuI was added. The mixture was cooled to room temperature and partitioned between EtOAc and sat. aqueous solution of ammonium chloride. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (cyclohexane:EtOAc, 20-70%) affording 4-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)-piperidine-1-carboxylic acid tert-butyl ester as a solid (375 mg, 33%). LCMS (Method H): RT 4.57 min, [M+H]+ 437.46 1H NMR (400 MHz, CDCl3): δ 4.40-4.15 (m, 6 H); 3.81 (t, J=12.1 Hz, 4 H); 3.71 (s, 3); 2.99-2.87 (m, 3 H); 1.94-1.85 (m, 4 H); 1.71-1.59 (m, 1 H); 1.48 (s, 9H).

1. additionwas added
2. additiona 7:5 (v:v) mixture of TMS-C1
3. stirringthe reaction mixture was stirred for 30 minutes at room temperature
4. filtrationThe zincate mixture was quickly filtered through a grade-3 sintered funnel
5. customThe vessel was then evacuated
6. additionback-filled with nitrogen
7. customThe resulting reaction mixture
8. temperatureThe mixture was cooled to room temperature
9. custompartitioned between EtOAc and sat. aqueous solution of ammonium chloride
10. washThe organic layer was washed with water, brine
11. dry with materialdried over Na2SO4
12. filtrationfiltered
13. concentrationconcentrated in vacuo
14. customThe residue was purified by column chromatography (cyclohexane:EtOAc, 20-70%)