反应详情

温度

45 °C

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 50.0 g (483 mmol) of L-Prolinamide and 230 mL of methylenechloride. The suspension was stirred and treated with 51.2 g (504 mmol) of triethylamine and cooled to −40° C. to −50° C. and a solution of 58.0 g (508 mmol) of chloroacetylchloride in 50 mL of methylenechloride was added within 60 to 90 min. The dropping funnel was rinsed with 5 mL of methylenechloride. The suspension was warmed up to −5° C. to 0° C. within 1 h. The resulting (S)-1-(2-Chloro-acetyl)-pyrrolidine-2-carboxylic acid amide was dehydrated while adding the solution of the Vilsmeier-Reagent from the first reaction within 1 to 15 min at −5° C. to 5° C. The dropping funnel was rinsed with 5 mL of methylenechloride and the resulting mixture was stirred for about 1 h at −5° C. to 5° C. The reaction mixture was then poured onto 175 mL of water within 10 to 30 min and at a temperature of 5° C. to 20° C. The reactor was rinsed with 5 mL of methylenechloride. The mixture was stirred at RT for at least 30 min. The phases were separated and the aqueous phase was twice extracted with a total of 170 mL of methylenechloride. The organic phases were unified and washed with 88 mL of water. The resulting organic phase was concentrated under vacuum (500 mbar to 50 mbar) at 20° C. to 50° C. The resulting oil was treated within 10 to 30 min with 325 mL of isopropanol and heated to 45° C. Subsequently, the solution was again cooled to 25° C. to 30° C. within 20 min and inoculated where after the product started to precipitate. The suspension was stirred for 1 h at this temperature and then cooled down to −15° C. to −20° C. within 4 h. The crystallization was completed by the addition of 85 ml of n-heptane and the mixture was kept stirring for another 2 h. The precipitate was filtered with suction, the filter cake was washed with cold (−10° C. to 20° C.) n-heptane (140 mL) and dried to constant weight (50° C., 50 mbar, 3 h) to afford 62.6 g of (S)-1-(2-chloroacetyl)-pyrrolidine-2-carbonitrile. (Yield: 83%, assay: 100% (m/m) based on HPLC). The HPLC analysis was performed with an external standard of pure (S)-1-(2-chloroacetyl)-pyrrolidine-2-carbonitrile. Conditions for HPLC: Column Atlantis™ dC18 Waters, 3.9×150 mm, 3 μm, UV detection 205 nm, solutions for gradient: water (A), acetonitrile (B), pH 4.9 buffer KH2PO4 (C); flow 1.2 mL/min, 40° C.

1. customA 1000 mL double jacketed glass reactor equipped with a mechanical stirrer
2. temperaturecooled to −40° C. to −50° C.
3. washThe dropping funnel was rinsed with 5 mL of methylenechloride
4. temperatureThe suspension was warmed up to −5° C. to 0° C. within 1 h
5. additionwhile adding the solution of the Vilsmeier-Reagent
6. customfrom the first reaction within 1 to 15 min at −5° C. to 5° C
7. washThe dropping funnel was rinsed with 5 mL of methylenechloride
8. stirringthe resulting mixture was stirred for about 1 h at −5° C. to 5° C
9. additionThe reaction mixture was then poured onto 175 mL of water within 10 to 30 min and at a temperature of 5° C. to 20° C
10. washThe reactor was rinsed with 5 mL of methylenechloride
11. stirringThe mixture was stirred at RT for at least 30 min
12. customThe phases were separated
13. extractionthe aqueous phase was twice extracted with a total of 170 mL of methylenechloride
14. washwashed with 88 mL of water
15. concentrationThe resulting organic phase was concentrated under vacuum (500 mbar to 50 mbar) at 20° C. to 50° C
16. additionThe resulting oil was treated within 10 to 30 min with 325 mL of isopropanol
17. temperatureSubsequently, the solution was again cooled to 25° C. to 30° C. within 20 min
18. customto precipitate
19. stirringThe suspension was stirred for 1 h at this temperature
20. temperaturecooled down to −15° C. to −20° C. within 4 h
21. customThe crystallization
22. additionwas completed by the addition of 85 ml of n-heptane
23. stirringthe mixture was kept stirring for another 2 h
24. filtrationThe precipitate was filtered with suction
25. washthe filter cake was washed with cold (−10° C. to 20° C.) n-heptane (140 mL)
26. customdried to constant weight (50° C., 50 mbar, 3 h)