N-[chloro(dimethylamino)phosphoryl]-N-methylmethanamine

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: A solution of 2-cyano-4-(2,4-dichlorophenyl)imidazole (1.0 g) in tetrahydrofuran (30 ml) was treated with sodium hydride (0.16 g of 80% dispersion in oil) at 0°. A solution of tetramethylphosphorodiamidic chloride (0.89 g) in tetrahydrofuran (10 ml) was added dropwise and the mixture stirred for 11/2 hours under nitrogen. It was then poured into water, stirred, and the precipitate filtered, dried and recrystalllsed from toluene/hexane to give 1-[bis(dimethylamino)phosphinyl]-2-cyano-4-(2,4-dichlorophenyl)imidazole, m.p. 140.5°-1°. (Compound 6). stirred the precipitate filtered dried

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

実験手順: A solution of 2-cyano-4-(2,4-dichlorophenyl)imidazole (1.0 g) in tetrahydrofuran (30 ml) was treated with sodium hydride (0.16 g of 80% dispersion in oil) at 0°. A solution of tetramethylphosphorodiamidic chloride (0.89 g) in tetrahydrofuran (10 ml) was added dropwise and the mixture stirred for 11/2 hours under nitrogen. It was then poured into water, stirred, and the precipitate filtered, dried and recrystalllsed from toluene/hexane to give 1-[bis(dimethylamino)phosphinyl]-2-cyano-4-(2,4-dichlorophenyl)imidazole, m.p. 140.5°-1°. (Compound 6). stirred the precipitate filtered dried

反応条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of 4-bromo-2-hydroxymethyl-N-(2,2,2-trifluoro-ethyl)-benzamide (3.37 g, 10.8 mmol) in anhydrous tetrahydrofuran (50 ml), N-methyl-2-pyrrolinone (20 mL), cooled to 5° C. under a nitrogen atmosphere was added a solution of 2M isopropyl magnesium chloride in anhydrous THF (25 ml) at a rate to keep the temperature of the reaction mixture under 10° C., After complete addition, approximately 45 minutes the reaction was stirred at this temperature for an additional 60 minutes, and then at room temperature for 60 minutes. After that time the reaction mixture was re-cooled to 5° C. and a solution of bis(dimethyl amino)phosphoryl chloride (1.85 g, 14.1 mmol) was added dropwise. No exotherm was observed and the reaction was heated at reflux for 72 hours once the addition was completed. After this time no starting material was observed by both TLC and LCMS and the reaction mixture was carefully quenched with water, and acidified with 1M aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3×100 ml) and the organic layers were combined and dried over Magnesium sulfate powder, filtered and concentrated under reduced pressure. Purification by column chromatography eluting with 25% ethyl acetate 75% petroleum ether gave product as a white powder 2.81 g (88% yield). NMR (DMSO 400 MHz) 4.36-4.43 (2H, m, alk), 4.62 (2H, s, alk), 7.68-7.74 (2H, m, ar) and 7.93 (H, s, ar). F19 NMR (DMSO 400 Mhz) −69.03. ES+ 296 under 10° C. After complete addition, approximately 45 minutes the reaction at room temperature for 60 minutes the reaction was heated at reflux for 72 hours once the addition the reaction mixture was carefully quenched with water The aqueous layer was extracted with ethyl acetate (3×100 ml) dried over Magnesium sulfate powder filtered concentrated under reduced pressure Purification by column chromatography eluting with 25% ethyl acetate 75% petroleum ether

反応条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of 4-bromo-2-hydroxymethyl-N-(2,2,2-trifluoro-ethyl)-benzamide (3.37 g, 10.8 mmol) in anhydrous tetrahydrofuran (50 ml), N-methyl-2-pyrrolinone (20 mL), cooled to 5° C. under a nitrogen atmosphere was added a solution of 2M isopropyl magnesium chloride in anhydrous THF (25 ml) at a rate to keep the temperature of the reaction mixture under 10° C., After complete addition, approximately 45 minutes the reaction was stirred at this temperature for an additional 60 minutes, and then at room temperature for 60 minutes. After that time the reaction mixture was re-cooled to 5° C. and a solution of bis(dimethyl amino)phosphoryl chloride (1.85 g, 14.1 mmol) was added dropwise. No exotherm was observed and the reaction was heated at reflux for 72 hours once the addition was completed. After this time no starting material was observed by both TLC and LCMS and the reaction mixture was carefully quenched with water, and acidified with 1M aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3×100 ml) and the organic layers were combined and dried over Magnesium sulfate powder, filtered and concentrated under reduced pressure. Purification by column chromatography eluting with 25% ethyl acetate 75% petroleum ether gave product as a white powder 2.81 g (88% yield). NMR (DMSO 400 MHz) 4.36-4.43 (2H, m, alk), 4.62 (2H, s, alk), 7.68-7.74 (2H, m, ar) and 7.93 (H, s, ar). F19 NMR (DMSO 400 Mhz) −69.03. ES+ 296 under 10° C. After complete addition, approximately 45 minutes the reaction at room temperature for 60 minutes the reaction was heated at reflux for 72 hours once the addition the reaction mixture was carefully quenched with water The aqueous layer was extracted with ethyl acetate (3×100 ml) dried over Magnesium sulfate powder filtered concentrated under reduced pressure Purification by column chromatography eluting with 25% ethyl acetate 75% petroleum ether

反応条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of 4-bromo-2-hydroxymethyl-N-(2,2,2-trifluoro-ethyl)-benzamide (3.37 g, 10.8 mmol) in anhydrous tetrahydrofuran (50 ml), N-methyl-2-pyrrolinone (20 mL), cooled to 5° C. under a nitrogen atmosphere was added a solution of 2M isopropyl magnesium chloride in anhydrous THF (25 ml) at a rate to keep the temperature of the reaction mixture under 10° C., After complete addition, approximately 45 minutes the reaction was stirred at this temperature for an additional 60 minutes, and then at room temperature for 60 minutes. After that time the reaction mixture was re-cooled to 5° C. and a solution of bis(dimethyl amino)phosphoryl chloride (1.85 g, 14.1 mmol) was added dropwise. No exotherm was observed and the reaction was heated at reflux for 72 hours once the addition was completed. After this time no starting material was observed by both TLC and LCMS and the reaction mixture was carefully quenched with water, and acidified with 1M aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3×100 ml) and the organic layers were combined and dried over Magnesium sulfate powder, filtered and concentrated under reduced pressure. Purification by column chromatography eluting with 25% ethyl acetate 75% petroleum ether gave product as a white powder 2.81 g (88% yield). NMR (DMSO 400 MHz) 4.36-4.43 (2H, m, alk), 4.62 (2H, s, alk), 7.68-7.74 (2H, m, ar) and 7.93 (H, s, ar). F19 NMR (DMSO 400 Mhz) −69.03. ES+296 under 10° C. After complete addition, approximately 45 minutes the reaction at room temperature for 60 minutes the reaction was heated at reflux for 72 hours once the addition the reaction mixture was carefully quenched with water The aqueous layer was extracted with ethyl acetate (3×100 ml) dried over Magnesium sulfate powder filtered concentrated under reduced pressure Purification by column chromatography eluting with 25% ethyl acetate 75% petroleum ether

反応条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of 4-bromo-2-hydroxymethyl-N-(2,2,2-trifluoro-ethyl)-benzamide (3.37 g, 10.8 mmol) in anhydrous tetrahydrofuran (50 ml), N-methyl-2-pyrrolinone (20 mL), cooled to 5° C. under a nitrogen atmosphere was added a solution of 2M isopropyl magnesium chloride in anhydrous THF (25 ml) at a rate to keep the temperature of the reaction mixture under 10° C., After complete addition, approximately 45 minutes the reaction was stirred at this temperature for an additional 60 minutes, and then at room temperature for 60 minutes. After that time the reaction mixture was re-cooled to 5° C. and a solution of bis(dimethyl amino)phosphoryl chloride (1.85 g, 14.1 mmol) was added dropwise. No exotherm was observed and the reaction was heated at reflux for 72 hours once the addition was completed. After this time no starting material was observed by both TLC and LCMS and the reaction mixture was carefully quenched with water, and acidified with 1M aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3×100 ml) and the organic layers were combined and dried over Magnesium sulfate powder, filtered and concentrated under reduced pressure. Purification by column chromatography eluting with 25% ethyl acetate 75% petroleum ether gave product as a white powder 2.81 g (88% yield). NMR (DMSO 400 MHz) 4.36-4.43 (2H, m, alk), 4.62 (2H, s, alk), 7.68-7.74 (2H, m, ar) and 7.93 (H, s, ar). F19 NMR (DMSO 400 Mhz) −69.03. ES+296 under 10° C. After complete addition, approximately 45 minutes the reaction at room temperature for 60 minutes the reaction was heated at reflux for 72 hours once the addition the reaction mixture was carefully quenched with water The aqueous layer was extracted with ethyl acetate (3×100 ml) dried over Magnesium sulfate powder filtered concentrated under reduced pressure Purification by column chromatography eluting with 25% ethyl acetate 75% petroleum ether

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of 4-bromo-2-(hydroxymethyl)-N-(2,2,2-trifluoroethyl)benzamide (3.37 g, 10.8 mmol) in anhydrous tetrahydrofuran (50 ml), N-methyl-2-pyrrolinone (20 mL), cooled to 5° C. under a nitrogen atmosphere was added a solution of 2M isopropyl magnesium chloride in anhydrous THF (25 ml) at such a rate to keep the temperature of the reaction mixture under 10° C. After complete addition, approximately 45 minutes, the reaction mixture was stirred at this temperature for an additional 60 minutes, and then at room temperature for 60 minutes. After that time, the reaction mixture was cooled down to 5° C. and a solution of bis(dimethylamino)phosphoryl chloride (1.85 g, 14.1 mmol) was added dropwise. No exotherm was observed and the reaction was heated at reflux for 72 hours once the addition was complete. After this time no starting material was observed by both TLC and LCMS and the reaction mixture was carefully quenched with water, and acidified with 1M aqueous hydrochloric acid. The aqueous was extracted with ethyl acetate (3×100 ml) and the organic layers were combined and dried over magnesium sulfate, filtered and concentrated under reduced pressure to leave a mobile oil which was purified by column chromatography eluting with 20% ethyl acetate/petroleum ether to afford the title compound as a white solid (2.81 g, 88% yield). 1H NMR (DMSO D6, 400 MHz) 4.36-4.43 (2H, m), 4.62 (2H, s), 7.68-7.74 (2H, m) and 7.93 (1H, s); MS (ES+) 296, (ES−) 292. under 10° C After complete addition, approximately 45 minutes at room temperature for 60 minutes the reaction was heated at reflux for 72 hours once the addition the reaction mixture was carefully quenched with water The aqueous was extracted with ethyl acetate (3×100 ml) dried over magnesium sulfate filtered concentrated under reduced pressure to leave a mobile oil which was purified by column chromatography eluting with 20% ethyl acetate/petroleum ether

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

実験手順: A solution of 2-cyano-4-(2,4-dichlorophenyl)imidazole (1.0 g) in tetrahydrofuran (30 ml) was treated with sodium hydride (0.16 g of 80% dispersion in oil) at 0°. A solution of tetramethylphosphorodiamidic chloride (0.89 g) in tetrahydrofuran (10 ml) was added dropwise and the mixture stirred for 11/2 hours under nitrogen. It was then poured into water, stirred, and the precipitate filtered, dried and recrystalllsed from toluene/hexane to give 1-[bis(dimethylamino)phosphinyl]-2-cyano-4-(2,4-dichlorophenyl)imidazole, m.p. 140.5°-1°. (Compound 6). stirred the precipitate filtered dried

反応条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of 4-bromo-2-hydroxymethyl-N-(2,2,2-trifluoro-ethyl)-benzamide (3.37 g, 10.8 mmol) in anhydrous tetrahydrofuran (50 ml), N-methyl-2-pyrrolinone (20 mL), cooled to 5° C. under a nitrogen atmosphere was added a solution of 2M isopropyl magnesium chloride in anhydrous THF (25 ml) at a rate to keep the temperature of the reaction mixture under 10° C., After complete addition, approximately 45 minutes the reaction was stirred at this temperature for an additional 60 minutes, and then at room temperature for 60 minutes. After that time the reaction mixture was re-cooled to 5° C. and a solution of bis(dimethyl amino)phosphoryl chloride (1.85 g, 14.1 mmol) was added dropwise. No exotherm was observed and the reaction was heated at reflux for 72 hours once the addition was completed. After this time no starting material was observed by both TLC and LCMS and the reaction mixture was carefully quenched with water, and acidified with 1M aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3×100 ml) and the organic layers were combined and dried over Magnesium sulfate powder, filtered and concentrated under reduced pressure. Purification by column chromatography eluting with 25% ethyl acetate 75% petroleum ether gave product as a white powder 2.81 g (88% yield). NMR (DMSO 400 MHz) 4.36-4.43 (2H, m, alk), 4.62 (2H, s, alk), 7.68-7.74 (2H, m, ar) and 7.93 (H, s, ar). F19 NMR (DMSO 400 Mhz) −69.03. ES+ 296 under 10° C. After complete addition, approximately 45 minutes the reaction at room temperature for 60 minutes the reaction was heated at reflux for 72 hours once the addition the reaction mixture was carefully quenched with water The aqueous layer was extracted with ethyl acetate (3×100 ml) dried over Magnesium sulfate powder filtered concentrated under reduced pressure Purification by column chromatography eluting with 25% ethyl acetate 75% petroleum ether

反応条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of 4-bromo-2-hydroxymethyl-N-(2,2,2-trifluoro-ethyl)-benzamide (3.37 g, 10.8 mmol) in anhydrous tetrahydrofuran (50 ml), N-methyl-2-pyrrolinone (20 mL), cooled to 5° C. under a nitrogen atmosphere was added a solution of 2M isopropyl magnesium chloride in anhydrous THF (25 ml) at a rate to keep the temperature of the reaction mixture under 10° C., After complete addition, approximately 45 minutes the reaction was stirred at this temperature for an additional 60 minutes, and then at room temperature for 60 minutes. After that time the reaction mixture was re-cooled to 5° C. and a solution of bis(dimethyl amino)phosphoryl chloride (1.85 g, 14.1 mmol) was added dropwise. No exotherm was observed and the reaction was heated at reflux for 72 hours once the addition was completed. After this time no starting material was observed by both TLC and LCMS and the reaction mixture was carefully quenched with water, and acidified with 1M aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3×100 ml) and the organic layers were combined and dried over Magnesium sulfate powder, filtered and concentrated under reduced pressure. Purification by column chromatography eluting with 25% ethyl acetate 75% petroleum ether gave product as a white powder 2.81 g (88% yield). NMR (DMSO 400 MHz) 4.36-4.43 (2H, m, alk), 4.62 (2H, s, alk), 7.68-7.74 (2H, m, ar) and 7.93 (H, s, ar). F19 NMR (DMSO 400 Mhz) −69.03. ES+296 under 10° C. After complete addition, approximately 45 minutes the reaction at room temperature for 60 minutes the reaction was heated at reflux for 72 hours once the addition the reaction mixture was carefully quenched with water The aqueous layer was extracted with ethyl acetate (3×100 ml) dried over Magnesium sulfate powder filtered concentrated under reduced pressure Purification by column chromatography eluting with 25% ethyl acetate 75% petroleum ether