反应详情

温度

160 °C

The mixture of 50.7 g (0.35 mol) 1,2-diamino-4,5-difluorobenzene, 55.1 g (0.35 mol) 4-chlorobenzoic acid and 507 g polyphosphoric acid was heated to 160° C. and stirred at this temperature for 90 min. After cooling to 55° C., 1000 mL water and 500 mL ethyl acetate were added. Under ice cooling ca 1000 mL 32% aqueous sodium hydroxide solution was added (pH ca 9). The suspension was filtered over dicalite and the filter cake was washed with 1.5 L ethyl acetate. The phases were separated and the aqueous phase was washed with 0.5 L ethyl acetate. The organic phases were washed with 1M aqueous sodium hydroxide solution and brine, dried over magnesium sulfate and filtered. To the solution, silica gel was added and the solvent evaporated. The crude adsorbed product was purified by column chromatography over silica gel using a gradient of n-heptane:ethyl acetate (4:1 to 1:1, v/v) as eluant. The fractions containing the product in pure form were pooled and evaporated. The remaining fractions were dissolved in ethyl acetate, washed twice with 1M aqueous sodium hydroxide solution and brine, the combined aqueous layers extracted once with ethyl acetate and the combined organic layers dried over magnesium sulfate and filtered. Chromatography over silica gel afforded a second batch of compound. Total yield: 75 g (80%) light yellow solid. MS (Turbo Spray): m/z=264.9 [M+H].

1. temperatureAfter cooling to 55° C.
2. additionUnder ice cooling ca 1000 mL 32% aqueous sodium hydroxide solution was added (pH ca 9)
3. filtrationThe suspension was filtered over dicalite
4. washthe filter cake was washed with 1.5 L ethyl acetate
5. customThe phases were separated
6. washthe aqueous phase was washed with 0.5 L ethyl acetate
7. washThe organic phases were washed with 1M aqueous sodium hydroxide solution and brine
8. dry with materialdried over magnesium sulfate
9. filtrationfiltered
10. additionTo the solution, silica gel was added
11. customthe solvent evaporated
12. customwas purified by column chromatography over silica gel using a gradient of n-heptane:ethyl acetate (4:1 to 1:1
13. additionThe fractions containing the product in pure form
14. customevaporated
15. dissolutionThe remaining fractions were dissolved in ethyl acetate
16. washwashed twice with 1M aqueous sodium hydroxide solution and brine
17. extractionthe combined aqueous layers extracted once with ethyl acetate
18. dry with materialthe combined organic layers dried over magnesium sulfate
19. filtrationfiltered
20. customChromatography over silica gel afforded a second batch of compound