Chloroacetyl chloride → (2S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile

Temperatur

35 °C

This example was run in an analogous manner as example 1 but starting from 20.0 g (175.2 mmol) of L-Prolinamide (1), 17.6 g (173.5 mmol) of triethylamine, 22.7 g (199.4 mmol) of Chloroactylchloride and totally 152 mL of methylenechloride. The resulting (S)-1-(2-Chloro-acetyl)-pyrrolidine-2-carboxylic acid amide was treated with 20 mL of DMF and 12.7 g (67.5 mmol) of cyanurchloride at 20° C. The resulting mixture was heated to 35° C., stirred for 2 h at this temperature and treated with 2.6 mL of water. The suspension was stirred for 1 h at RT and filtered with suction. The filter cake was washed with 20 mL of methylenechloride and the filtrate was treated with 100 mL of water. The layers were separated and the aqueous phase was twice washed with a total of 68 mL of methylenechloride. The organic layers were unified and concentrated under vacuum at a jacket temperature of 40° C. (400 mbar to 28 mbar). The remaining oil was treated with 130 mL of Isopropanol and inoculated at 30° C. The suspension was cooled to −22° C. within 4 h, stirred over night at this temperature and treated with 34 mL of n-heptane. The precipitate was filtered with suction, the filter cake was washed with 112 mL of a cold (−10° C. to 20° C.) mixture of n-heptane/2-propanol (8:2 (v/v)) and dried to constant weight (50° C., 50 mbar, 3 h) to afford 24.0 g of (S)-1-(2-Chloroacetyl)-pyrrolidine-2-carbonitrile. (Yield: 80%, assay: 100% (m/m) based on HPLC).

1. stirringThe suspension was stirred for 1 h at RT
2. filtrationfiltered with suction
3. washThe filter cake was washed with 20 mL of methylenechloride
4. additionthe filtrate was treated with 100 mL of water
5. customThe layers were separated
6. washthe aqueous phase was twice washed with a total of 68 mL of methylenechloride
7. concentrationconcentrated under vacuum at a jacket temperature of 40° C. (400 mbar to 28 mbar)
8. additionThe remaining oil was treated with 130 mL of Isopropanol
9. custominoculated at 30° C
10. temperatureThe suspension was cooled to −22° C. within 4 h
11. stirringstirred over night at this temperature
12. additiontreated with 34 mL of n-heptane
13. filtrationThe precipitate was filtered with suction
14. washthe filter cake was washed with 112 mL of a cold (−10° C. to 20° C.) mixture of n-heptane/2-propanol (8:2 (v/v))
15. customdried to constant weight (50° C., 50 mbar, 3 h)

ORD-Eintrag

ord-f7da5ee0a4824083a11f2568aa0aa623

Quelldatensatz

uspto-grants-2010_08

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07772264B2