反应详情

To a solution of 7.2 g (29.48 mmol) (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (Example 73, intermediate g) in 75 ml methanole, 2.48 g (35.37 mmol) cyclopropanecarbaldehyde (commercially available) were added. After stirring for 5 min. at room temperature the solution was treated with 4.62 g (29.5 mmol) 4-chlorobenzoic acid (commercially available), followed by an addition of 3.6 ml (29.47 mmol) benzylisocyanide (commercially available). The formed solution was stirred at room temperature for 23 h, then 36.85 ml (147 mmol) 4 M hydrochloric acid in dioxane were added dropwise over 5 min. The resulting suspension was stirred for 23 h, then poured onto 500 ml saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and evaporated. The residue was purified by silica gel column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:ethyl acetate (100:0 to 50:50). Light yellow solid (99%). MS (Turbo Spray): m/z=452.1 [M+H].

1. stirringThe formed solution was stirred at room temperature for 23 h
2. stirringThe resulting suspension was stirred for 23 h
3. extractionThe aqueous layer was extracted three times with ethyl acetate
4. washThe combined organic layers were washed with water and brine
5. dry with materialdried over magnesium sulfate
6. filtrationfiltered
7. customevaporated
8. customThe residue was purified by silica gel column chromatography
9. washeluting with a gradient of heptane:ethyl acetate (100:0 to 50:50)