反应详情

To a clean, dry, nitrogen-purged 500 ml reactor were charged methyl-(4-methyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (25.0 g, 0.102 mol) and methylene chloride (250 ml). The mixture was stirred at room temperature for a minimum of 2.5 hours. To a clean, dry, nitrogen-purged 1 L reactor were charged cyanoacetic acid (18.2 g, 0.214 mol), methylene chloride (375 ml), and triethyl amine (30.1 ml, 0.214 mol). The mixture was cooled to −15.0-5.0° C. over one hour and trimethylacetyl chloride (25.6 ml, 0.204 mol) was added at a rate to maintain the temperature below 0° C. The reaction was held for a minimum of 2.5 hours, then the solution of the amine was added at a rate that maintained the temperature below 0° C. After stirring for 1 hour, the mixture was warmed to room temperature and 1M sodium hydroxide (125 ml) was added. The organic layer was washed with water (125 ml) The methylene chloride solution was displaced with acetone until a volume of 500 ml and a temperature of 55-65° C. had been achieved. Water (75 ml) was charged to the mixture while maintaining the temperature at 55-65° C. A solution of citric acid (20.76 g, 0.107 mol) in water (25.0) was charged and the mixture was cooled to room temperature. The reactor was stirred for a minimum of 5 hours and then the resulting solids were isolated by filtration and washed with acetone (2×75 ml), which was sent to the filter. The salt was charged into a clean, dry, nitrogen-purged 1 L reactor with 2B ethanol (190 ml) and water (190 ml). The slurry was heated to 75-85° C. for a minimum of 4 hours. The mixture was cooled to 20-30° C. and stirred for an additional 4 hours. The solids were isolated by filtration and washed with 2B ethanol (190 ml). After drying in a vacuum oven at 50° C. with a slight nitrogen bleed, 34.6 g (67.3%) of the title compound were isolated.

1. customTo a clean, dry
2. customnitrogen-purged 500 ml reactor
3. customTo a clean, dry
4. customnitrogen-purged 1 L reactor
5. temperatureThe mixture was cooled to −15.0-5.0° C. over one hour
6. temperatureto maintain the temperature below 0° C
7. customwas held for a minimum of 2.5 hours
8. temperaturemaintained the temperature below 0° C
9. stirringAfter stirring for 1 hour
10. temperaturethe mixture was warmed to room temperature
11. washThe organic layer was washed with water (125 ml) The methylene chloride solution
12. customa temperature of 55-65° C.
13. additionWater (75 ml) was charged to the mixture
14. temperaturewhile maintaining the temperature at 55-65° C
15. temperaturethe mixture was cooled to room temperature
16. stirringThe reactor was stirred for a minimum of 5 hours
17. customthe resulting solids were isolated by filtration
18. washwashed with acetone (2×75 ml), which
19. additionThe salt was charged into a clean,
20. customdry
21. customnitrogen-purged 1 L reactor with 2B ethanol (190 ml) and water (190 ml)
22. temperatureThe slurry was heated to 75-85° C. for a minimum of 4 hours
23. temperatureThe mixture was cooled to 20-30° C.
24. stirringstirred for an additional 4 hours
25. customThe solids were isolated by filtration
26. washwashed with 2B ethanol (190 ml)
27. customAfter drying in a vacuum oven at 50° C. with a slight nitrogen