反应详情

An oven dried three-necked 250 mL 14/20 standard taper round bottom flask was equipped with a magnetic stir bar and a rubber septum, a glass stopper, and a reflux condenser in each of the three necks. A piece of vacuum tubing from a Firestone valve was connected to a tubing adapter placed at the top of the condenser. The flask was then charged with a suspension of 10.473 g (30.7 mmol) of 6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (prepared in similar fashion to Step B Example 1) in 35 mL toluene, the atmosphere in the reaction vessel was replaced with nitrogen by cycling the Firestone valve, and finally hexamethyldisilazane (6.40 mL, 30.7 mmol) was added via syringe. The reaction mixture was stirred and gently refluxed for 2.5 h, then cooled and stirred at −40° C. using an external dry ice-acetone bath and diisobutylaluminum hydride (31.0 mL, 46.0 mmol) was then slowly added by syringe. The reaction mixture was stirred at −40° to −30° C. for 3 h at which point LC/MS analysis of an acid-quenched aliquot indicated that the reduction was complete. The cooling bath was removed and the reaction was quenched by dropwise addition of 40 mL of 2 N HCl. After gas evolution had ceased, the reaction mixture was transferred to a 1 L Erlenmeyer flask using 100 mL THF to rinse the solids. Additional 2 N HCl was added (200 mL), and the two phase mixture was stirred and heated for 30 min on a hot plate to ensure complete hydrolysis of the intermediate imine. EtOAc (200 mL) was added and the reaction mixture was stirred and heated until the solids had dissolved. The organic layer was separated, evaporated to dryness, then redissolved in EtOAc. The aq layer was adjusted to pH=7 with 6 N sodium hydroxide solution, then added back to organic layer. The layers were again heated and magnetically stirred to dissolve all the solids, then separated. The aq layer was washed with additional hot EtOAc, the organic layers were combined and then washed with water, brine, then dried (MgSO4), filtered and slowly evaporated. The product was crystallized from the EtOAc solution during the evaporation process and collected by vacuum filtration. The yellow crystalline solid was dried in vacuo to afford the title compound. HPLC/MS: 344.1 (M+1), 346.1 (M+3); Rt=3.17 min.

1. customA piece of vacuum tubing from a Firestone valve was connected to a tubing adapter
2. additionwas added via syringe
3. temperaturegently refluxed for 2.5 h
4. temperaturecooled
5. stirringstirred at −40° C.
6. stirringThe reaction mixture was stirred at −40° to −30° C. for 3 h at which point LC/MS analysis of
7. customan acid-quenched aliquot
8. customThe cooling bath was removed
9. customthe reaction was quenched by dropwise addition of 40 mL of 2 N HCl
10. washto rinse the solids
11. additionAdditional 2 N HCl was added (200 mL)
12. stirringthe two phase mixture was stirred
13. temperatureheated for 30 min on a hot plate
14. customhydrolysis of the intermediate imine
15. stirringthe reaction mixture was stirred
16. temperatureheated until the solids
17. dissolutionhad dissolved
18. customThe organic layer was separated
19. customevaporated to dryness
20. dissolutionredissolved in EtOAc
21. additionadded back to organic layer
22. temperatureThe layers were again heated
23. stirringmagnetically stirred
24. dissolutionto dissolve all the solids
25. customseparated
26. washThe aq layer was washed with additional hot EtOAc
27. washwashed with water, brine
28. dry with materialdried (MgSO4)
29. filtrationfiltered
30. customslowly evaporated
31. customThe product was crystallized from the EtOAc solution during the evaporation process
32. filtrationcollected by vacuum filtration
33. customThe yellow crystalline solid was dried in vacuo