反应详情

温度

30 °C

This example was run in an analogous manner as example 15 but starting from 30.0 g (100.6 mmol) of 2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylammonium mesylate in DMF. Thus a 1000 mL double jacketed glass reactor equipped with a mechanical stirrer, a Pt-100 thermometer, a reflux condenser, a dropping funnel and a nitrogen inlet was charged with 30 g (100.6 mmol) of 2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylammonium mesylate, 11.3 g (145.8 mmol) of calciumhydroxyde and 175 mL of DMF. The resulting suspension was heated to 30° C. and stirred for 30 min at this temperature. A solution of 13.4 g (77.6 mmol) of (S)-1-(2-chloroacetyl)-pyrrolidine-2-carbonitrile in 75 mL of DMF was added within 25 min and the dropping funnel was rinsed with 10 mL of DMF. The mixture was heated to 25° C. to 30° C. and stirred for 1 to 2 h at this temperature. The reaction mixture was cooled to 10° C. and treated with 175 mL of water at 10° C. to 30° C. The suspension was filtered over Speedex with suction and the filter cake was washed with 35 mL of water. The filtrate was extracted with 200 mL of methylenechloride. The layers were separated and the aqueous phase was extracted with 100 mL of methylenechloride. The organic layers were unified and twice washed with a total of 200 mL of aqueous NaCl 10% solution. The organic layer was treated with 8.3 g (85.5 mmol) of methanesulfonic acid. Methylenechloride was removed by distillation under normal pressure at a jacket temperature of max. 55° C. The resulting suspension was treated with 180 mL of methylenechloride, filtered with suction and the filter cake was twice washed with totally 30 mL of methylenechloride. The filtrate was concentrated under vacuum (550-35 mbar) at a jacket temperature of max. 50° C. The residue was treated with 175 mL of THF at 45° C. to 50° C., inoculated and again treated with 175 mL of 2-butanone. 65 mL of THF were distilled off under vacuum (340 mbar). The resulting suspension was cooled to 0° C. within 4 h and stirred at this temperature for at least 2 h. The precipitate was filtered with suction, the filter cake was washed with 50 mL of cold THF (0° C.) and dried under vacuum (50° C., 50 mbar) to afford 24.2 g (yield 73.9% starting from of (S)-1-(2-chloroacetyl)-pyrrolidine-2-carbonitrile, 95.7% (m/m) purity based on HPLC assay) of (S)-1-{[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile mesylate as a colorless solid.

1. customequipped with a mechanical stirrer
2. washthe dropping funnel was rinsed with 10 mL of DMF
3. temperatureThe mixture was heated to 25° C. to 30° C.
4. stirringstirred for 1 to 2 h at this temperature
5. temperatureThe reaction mixture was cooled to 10° C.
6. additiontreated with 175 mL of water at 10° C. to 30° C
7. filtrationThe suspension was filtered over Speedex with suction
8. washthe filter cake was washed with 35 mL of water
9. extractionThe filtrate was extracted with 200 mL of methylenechloride
10. customThe layers were separated
11. extractionthe aqueous phase was extracted with 100 mL of methylenechloride
12. washtwice washed with a total of 200 mL of aqueous NaCl 10% solution
13. customMethylenechloride was removed by distillation under normal pressure at a jacket temperature of max
14. custom55° C
15. additionThe resulting suspension was treated with 180 mL of methylenechloride
16. filtrationfiltered with suction
17. washthe filter cake was twice washed with totally 30 mL of methylenechloride
18. concentrationThe filtrate was concentrated under vacuum (550-35 mbar) at a jacket temperature of max
19. custom50° C
20. additionThe residue was treated with 175 mL of THF at 45° C. to 50° C.
21. additionagain treated with 175 mL of 2-butanone
22. distillation65 mL of THF were distilled off under vacuum (340 mbar)
23. temperatureThe resulting suspension was cooled to 0° C. within 4 h
24. stirringstirred at this temperature for at least 2 h
25. filtrationThe precipitate was filtered with suction
26. washthe filter cake was washed with 50 mL of cold THF (0° C.)
27. customdried under vacuum (50° C., 50 mbar)