(S)-1-(2-Chloroacetyl)pyrrolidine-2-carboxaMide

反応条件: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 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). The suspension was stirred for 1 h at RT filtered with suction The filter cake was washed with 20 mL of methylenechloride the filtrate was treated with 100 mL of water The layers were separated the aqueous phase was twice washed with a total of 68 mL of methylenechloride 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 inoculated at 30° C The suspension was cooled to −22° C. within 4 h stirred over night at this temperature 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)) dried to constant weight (50° C., 50 mbar, 3 h)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: This example was run in an analogous manner as example 1 but starting from 20.0 g (175.2 mmol) of L-Prolinamide (1), 20.5 g (201 mmol) of triethylamine, 23.2 g (203 mmol) of chloroactylchloride and totally 112 mL of methylenechloride. The resulting (S)-1-(2-Chloro-acetyl)-pyrrolidine-2-carboxylic acid amide was dehydrated while adding a solution of the Vilsmeier-Reagent at RT that was prepared from 33.8 mL (438 mmol) of DMF, 20 mL of methylenechloride and 25.3 g (201 mmol) of thionylchloride. The resulting mixture was stirred for 90 min, then quenched with water and extracted in an analogous manner as example 1. Crystallization from Isopropanol/n-heptane and drying afforded 24.7 g of (S)-1-(2-Chloroacetyl)-pyrrolidine-2-carbonitrile. (Yield: 82%, assay: 99.9% (m/m) based on HPLC). while adding a solution of the Vilsmeier-Reagent at RT that quenched with water extracted in an analogous manner as example 1 Crystallization from Isopropanol/n-heptane drying

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: This example was run in an analogous manner as example 1 but starting from 20.0 g (175.2 mmol) of L-Prolinamide (1), 20.5 g (201 mmol) of triethylamine, 23.2 g (203 mmol) of chloroactylchloride and totally 112 mL of methylenechloride. The resulting (S)-1-(2-Chloro-acetyl)-pyrrolidine-2-carboxylic acid amide was dehydrated while adding a solution of the Vilsmeier-Reagent at RT that was prepared from 33.8 mL (438 mmol) of DMF, 20 mL of methylenechloride and 25.3 g (201 mmol) of thionylchloride. The resulting mixture was stirred for 90 min, then quenched with water and extracted in an analogous manner as example 1. Crystallization from Isopropanol/n-heptane and drying afforded 24.7 g of (S)-1-(2-Chloroacetyl)-pyrrolidine-2-carbonitrile. (Yield: 82%, assay: 99.9% (m/m) based on HPLC). while adding a solution of the Vilsmeier-Reagent at RT that quenched with water extracted in an analogous manner as example 1 Crystallization from Isopropanol/n-heptane drying

反応条件: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 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). The suspension was stirred for 1 h at RT filtered with suction The filter cake was washed with 20 mL of methylenechloride the filtrate was treated with 100 mL of water The layers were separated the aqueous phase was twice washed with a total of 68 mL of methylenechloride 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 inoculated at 30° C The suspension was cooled to −22° C. within 4 h stirred over night at this temperature 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)) dried to constant weight (50° C., 50 mbar, 3 h)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: This example was run in an analogous manner as example 1 but starting from 20.0 g (175.2 mmol) of L-Prolinamide (1), 20.5 g (201 mmol) of triethylamine, 23.2 g (203 mmol) of chloroactylchloride and totally 112 mL of methylenechloride. The resulting (S)-1-(2-Chloro-acetyl)-pyrrolidine-2-carboxylic acid amide was dehydrated while adding a solution of the Vilsmeier-Reagent at RT that was prepared from 33.8 mL (438 mmol) of DMF, 20 mL of methylenechloride and 25.3 g (201 mmol) of thionylchloride. The resulting mixture was stirred for 90 min, then quenched with water and extracted in an analogous manner as example 1. Crystallization from Isopropanol/n-heptane and drying afforded 24.7 g of (S)-1-(2-Chloroacetyl)-pyrrolidine-2-carbonitrile. (Yield: 82%, assay: 99.9% (m/m) based on HPLC). while adding a solution of the Vilsmeier-Reagent at RT that quenched with water extracted in an analogous manner as example 1 Crystallization from Isopropanol/n-heptane drying