反应详情

Acetic anhydride (14.0 mL, 148 mmol), sodium formate (15.1 g, 222 mmol) and Hunig's base (25.8 mL, 148 mmol) were suspended in anhydrous DMF (50 mL) in a 1000 mL screw-top glass pressure-vessel. This was sealed with the screw cap and allowed to stir for 45 min at room temperature. To this mixture was added a solution of 4-[(R)-1-(3,5-dichloro-4-fluoro-phenyl)-5-iodo-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[1,2-a]imidazol-3-ylmethyl]-benzonitrile (40.0 g, 73.9 mmol) in anhydrous DMF (200 mL) followed by Pd(OAc)2 (830 mg, 3.70 mmol) and anhydrous LiCl (9.40 g, 221 mmol). The vessel was capped tightly and allowed to stir at 80° C. for 20 h. In a well ventilated fume hood, the reaction was cooled to room temperature and the screw cap was slowly removed allowing for gas release. The reaction was transferred to a seperatory funnel containing a solution of aqueous HCl (2N, 1 L) using EtOAc (1 L). The layers were separated and the organic phase was washed with aqueous 2N HCl (1 L). The combined aqueous phase was extracted with EtOAc (2×1 L). The combined organic phase was dried with MgSO4 and concentrated in vacuo. Toluene was added to the dark colored residue causing precipitation of a solid. The solid was filtered and washed with 1:1 toluene:hexanes followed by hexanes. The filtrate was concentrated and re-processed in a similar manner to give additional solids. A total of 29.4 g of the title compound was obtained as an off-white solid, m/z. 459.4 [M+H]+.

1. customThis was sealed with the screw
2. customcap
3. customThe vessel was capped tightly
4. stirringto stir at 80° C. for 20 h
5. temperatureIn a well ventilated fume hood, the reaction was cooled to room temperature
6. customthe screw cap
7. customwas slowly removed
8. customThe reaction was transferred to a seperatory funnel
9. additioncontaining a solution of aqueous HCl (2N, 1 L)
10. customThe layers were separated
11. washthe organic phase was washed with aqueous 2N HCl (1 L)
12. extractionThe combined aqueous phase was extracted with EtOAc (2×1 L)
13. dry with materialThe combined organic phase was dried with MgSO4
14. concentrationconcentrated in vacuo
15. additionToluene was added to the dark colored residue
16. customprecipitation of a solid
17. filtrationThe solid was filtered
18. washwashed with 1:1 toluene
19. concentrationThe filtrate was concentrated and re-processed in a similar manner
20. customto give additional solids