反应详情

To a solution of ((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (62.8 g, 74.1 mmol; Preparation 3) and N,N-diisopropylethylamine (20.1 mL, 115.2 mmol) in DCM (750 mL) was slowly added 1 M methylaminoformyl chloride in DMA (68.4 mL) over 10 min at 10-15° C. After 50 min, 1 M methylaminoformyl chloride in DMA (3.6 mL) was added and the reaction mixture was stirred overnight. To the reaction mixture was added water (750 mL) and 1 N HCl (40 mL). The organic layer was washed with water, dried over Na2SO4, and evaporated. Methanol (300 mL) and 2 N LiOH (10 mL) were added to the crude product and the reaction mixture was stirred for 30 min. Water (110 mL) was added slowly to the reaction mixture. Seeds of crystalline title product were added after 50 mL of water. The reaction mixture was stirred for 2 days and then methanol (60 mL) and water (24 mL) were added. After 30 min, the mixture was filtered. The solid was washed with 2:1 methanol:water (120 mL), and dried under vacuum at 35° C. overnight to provide the title compound (54 g).

1. customover 10 min
2. customat 10-15° C
3. washThe organic layer was washed with water
4. dry with materialdried over Na2SO4
5. customevaporated
6. additionMethanol (300 mL) and 2 N LiOH (10 mL) were added to the crude product
7. stirringthe reaction mixture was stirred for 30 min
8. additionWater (110 mL) was added slowly to the reaction mixture
9. additionSeeds of crystalline title product were added after 50 mL of water
10. stirringThe reaction mixture was stirred for 2 days
11. additionmethanol (60 mL) and water (24 mL) were added
12. waitAfter 30 min
13. filtrationthe mixture was filtered
14. washThe solid was washed with 2:1 methanol
15. dry with materialwater (120 mL), and dried under vacuum at 35° C. overnight