反应详情

温度

75 °C

[3-(2-Amino-4-morpholin-4-ylmethyl-phenylcarbamoyl)-1H-pyrazol-4-yl]-carbamic acid tert-butyl ester (1.350 Kg, 3.24 mol, 1.0 wt) and ethanol (6.75 L, 5.0 vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. Conc. aq. hydrochloric acid (1.10 L, 13.2 mol, 0.80 vol) was added at 15 to 30° C. under nitrogen and the contents were then heated to 70 to 80° C. and maintained at this temperature for 16 to 24 hours. A second portion of hydrochloric acid (0.11 L, 1.32 mol, 0.080 vol) was added at 70 to 80° C. and the reaction was heated for a further 4 hours. Reaction completion was determined by HPLC analysis. The reaction mixture was cooled to 10 to 20° C. and potassium carbonate (1.355 Kg, 9.08 mol, 1.0 wt) was charged portionwise at this temperature. The suspension was stirred until gas evolution ceased and was then filtered. The filter-cake was washed with ethanol (1.35 L, 1.0 vol) and the filtrates retained. The filter-cake was slurried with ethanol (4.00 L, 3.0 vol) at 15 to 25° C. for 20 to 40 minutes and the mixture was filtered. The filter-cake was washed with ethanol (1.35 L, 1.0 vol) and the total combined filtrates were concentrated under vacuum at 35 to 45° C. Ethanol (4.00 L, 3.0 vol) was charged to the residue and removed under vacuum at 35 to 45° C. Tetrahydrofuran (5.90 L, 4.4 vol) was added to the residue and stirred for 10 to 20 minutes at 15 to 25° C. The resulting solution was filtered, the filter-cake was washed with tetrahydrofuran (1.35 L, 1.0 vol) and the combined filtrates were concentrated under vacuum at 35 to 45° C. Tetrahydrofuran (5.40 L, 4.0 vol) was charged to the concentrate and removed under vacuum at 35 to 45° C. Tetrahydrofuran (5.40 L, 4.0 vol) was charged to the concentrate and removed under vacuum at 35 to 45° C. to give the desired product, 3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine (0.924 Kg, 95.5%, 82.84% by HPLC area) as a purple foam.

1. customequipped with a mechanical stirrer, condenser
2. temperaturemaintained at this temperature for 16 to 24 hours
3. temperaturethe reaction was heated for a further 4 hours
4. customReaction completion
5. temperatureThe reaction mixture was cooled to 10 to 20° C.
6. filtrationwas then filtered
7. washThe filter-cake was washed with ethanol (1.35 L, 1.0 vol)
8. filtrationthe mixture was filtered
9. washThe filter-cake was washed with ethanol (1.35 L, 1.0 vol)
10. concentrationthe total combined filtrates were concentrated under vacuum at 35 to 45° C
11. additionEthanol (4.00 L, 3.0 vol) was charged to the residue
12. customremoved under vacuum at 35 to 45° C
13. additionTetrahydrofuran (5.90 L, 4.4 vol) was added to the residue
14. stirringstirred for 10 to 20 minutes at 15 to 25° C
15. filtrationThe resulting solution was filtered
16. washthe filter-cake was washed with tetrahydrofuran (1.35 L, 1.0 vol)
17. concentrationthe combined filtrates were concentrated under vacuum at 35 to 45° C
18. additionTetrahydrofuran (5.40 L, 4.0 vol) was charged to the
19. concentrationconcentrate
20. customremoved under vacuum at 35 to 45° C
21. additionTetrahydrofuran (5.40 L, 4.0 vol) was charged to the
22. concentrationconcentrate
23. customremoved under vacuum at 35 to 45° C.