反应详情

温度

25 °C

To a 22 L three neck round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel, and nitrogen inlet, were added 3.84 L of tetrahydrofuran, 91.6 grams (0.17 moles) of bis(diphenylphosphino)ethanenickel (II) chloride, and 96 grams (0.39 moles) of 2-chloro-3-(2-methoxybenzylamino)pyridine. The orange slurry was stirred at 25° C. for about 30 minutes. Phenylmagnesium bromide (3M in ether, 231.6 mL, 0.69 moles) was added over a 4 hour period and the resulting black slurry was stirred for 22 hours at 25° C. During this time, the reaction was monitored by thin layer chromatography assay, and a total of 86 mL (0.26 moles) of additional phenylmagnesium bromide solution was added to the system. The reaction mixture was cooled to 10° C. and the reaction was quenched with 3.84 L of 20% aqueous HCl over 30 minutes. Ethyl acetate (3.84 L) was added and the reaction mixture was stirred an additional 10 minutes. The layers were separated and the organic layer was washed with 4 L of 25% aqueous HCl. The pH of the aqueous layer was, adjusted from 0.98 to 11.6 with 1.6 L of 50% aqueous sodium hydroxide. Diatomaceous earth (Celite®) (1 kg) and 7 L of ethyl acetate were added. The mixture was stirred for 15 minutes, filtered through diatomaceous earth (Celite®) and the cake was washed with about 1 L of ethyl acetate. The layers were separated, the aqueous layer washed twice with 2 L of ethyl acetate, and the organic layers were combined and dried with sodium sulfate. The drying agent was removed by filtration, the cake was washed with ethyl acetate, and the filtrate was vacuum concentrated to about 2 L volume. This solution was treated with 510 g of silica gel for 30 minutes at 20°-25° C., filtered, and the silica gel was washed twice with 2 L of ethyl acetate. The filtrate was vacuum concentrated to a yellow slurry and displaced with 1 L of isopropanol to a final volume of about 275 mL. The slurry was granulated at 0°-5° C. for 30 minutes, filtered, washed with cold isopropanol, and dried giving 83.8 g (74.8%) of crude material (Mp 122°-125° C). A portion (48.3 g) of this material was purified by chromatography to give 38.6 g of the title compound as a yellow solid. Mp 124°-128° C. Spectral data for this compound are identical to the data reported in step 1 of Example 4.

1. additionthermometer, addition funnel, and nitrogen inlet
2. stirringthe resulting black slurry was stirred for 22 hours at 25° C
3. temperatureThe reaction mixture was cooled to 10° C.
4. customthe reaction was quenched with 3.84 L of 20% aqueous HCl over 30 minutes
5. additionEthyl acetate (3.84 L) was added
6. stirringthe reaction mixture was stirred an additional 10 minutes
7. customThe layers were separated
8. washthe organic layer was washed with 4 L of 25% aqueous HCl
9. additionDiatomaceous earth (Celite®) (1 kg) and 7 L of ethyl acetate were added
10. stirringThe mixture was stirred for 15 minutes
11. filtrationfiltered through diatomaceous earth (Celite®)
12. washthe cake was washed with about 1 L of ethyl acetate
13. customThe layers were separated
14. washthe aqueous layer washed twice with 2 L of ethyl acetate
15. dry with materialdried with sodium sulfate
16. customThe drying agent was removed by filtration
17. washthe cake was washed with ethyl acetate
18. concentrationconcentrated to about 2 L volume
19. additionThis solution was treated with 510 g of silica gel for 30 minutes at 20°-25° C.
20. filtrationfiltered
21. washthe silica gel was washed twice with 2 L of ethyl acetate
22. concentrationconcentrated to a yellow slurry
23. waitThe slurry was granulated at 0°-5° C. for 30 minutes
24. filtrationfiltered
25. washwashed with cold isopropanol
26. customdried
27. customgiving 83.8 g (74.8%) of crude material (Mp 122°-125° C)
28. customA portion (48.3 g) of this material was purified by chromatography