反应详情

温度

25 °C

In dimethylformamide [DMF] (242 kg) was dissolved methyl 2-carboxy-3-nitrobenzoate [MNA] (164 kg) obtained in Reference Example 1. To the solution was dropped diphenylphosphorylazide [DPPA] (204 kg) at room temperature and then triethylamine (87 kg) at the temperature ranging 20-35° C. After the solution was stirred at 20-30° C. for about 3 hours, t-butylalcohol (930 kg) was added to the reaction solution. The solution was heated for 3-5 hours to 85-90° C. and then stirred for 1-2 hours under reflux (85-90° C.). The reaction solution was cooled, concentrated and dissolved in ethyl acetate(1400 L). The solution was washed with a mixture of 15% hydrochloric acid (160 L) and water (1890 L), water (660 L), 5% solution of sodium bicarbonate (1100 kg), and water (660 L), in this order and the organic layer was concentrated under reduced pressure. To the concentrate was added methanol (300 kg) and then were added crystal seeds (15 kg) and methanol (450 kg). The solution was heated to 50-60° C. to dissolve insoluble materials. The solution was cooled to 5° C. and precipitated crystals were separated. The crystals were washed with cooled methanol (100 L) and dried to give methyl 2-t-butoxycarbonylamino-3-nitrobenzoate [BAN] (187.0 kg, 86.7%). Mother liquor and the methanol solution used for washing the crystals was concentrated under reduced pressure and cooled. The precipitated crystals were centrifuged, washed with cooled methanol and dried to obtain the second crystals of BAN.

1. customobtained in Reference Example 1
2. customranging 20-35° C
3. temperatureThe solution was heated for 3-5 hours to 85-90° C.
4. stirringstirred for 1-2 hours
5. temperatureunder reflux (85-90° C.)
6. temperatureThe reaction solution was cooled
7. concentrationconcentrated
8. dissolutiondissolved in ethyl acetate(1400 L)
9. washThe solution was washed with a mixture of 15% hydrochloric acid (160 L) and water (1890 L), water (660 L), 5% solution of sodium bicarbonate (1100 kg), and water (660 L), in this order
10. concentrationthe organic layer was concentrated under reduced pressure
11. additionTo the concentrate was added methanol (300 kg)
12. additionwere added crystal seeds (15 kg) and methanol (450 kg)
13. temperatureThe solution was heated to 50-60° C.
14. dissolutionto dissolve insoluble materials
15. temperatureThe solution was cooled to 5° C.
16. customprecipitated crystals
17. customwere separated
18. washThe crystals were washed with cooled methanol (100 L)
19. customdried