2,4-dichloro-1-fluorobenzene

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 229.6 g of 1,3-dichloro-4-fluorobenzene and 205.34 g of aluminum chloride was heated at 80° C. A 56 g portion of acetic anhydride was added dropwise over 2 hours, then the reaction ws heated at 100° C. for 8 hours, poured onto a mixture of concentrated hydrochloric acid and ice and extracted several times with ether. The ether extracts were combined, washed with water, dried and the solvents evaporated. The solid was purified by vacuum distillation, giving 156.63 g of 6-acetyl-1,3-dichloro-4-fluorobenzene. the reaction ws heated at 100° C. for 8 hours extracted several times with ether washed with water dried the solvents evaporated The solid was purified by vacuum distillation

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 229.6 g of 1,3-dichloro-4-fluorobenzene and 205.34 g of aluminum chloride was heated at 80° C. A 56 g portion of acetic anhydride was added dropwise over 2 hours, then the reaction ws heated at 100° C. for 8 hours, poured onto a mixture of concentrated hydrochloric acid and ice and extracted several times with ether. The ether extracts were combined, washed with water, dried and the solvents evaporated. The solid was purified by vacuum distillation, giving 156.63 g of 6-acetyl-1,3-dichloro-4-fluorobenzene. the reaction ws heated at 100° C. for 8 hours extracted several times with ether washed with water dried the solvents evaporated The solid was purified by vacuum distillation

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

実験手順: A mixture of 1,3-dichloro-4-fluorobenzene )Aldrich; 4.21 g), piperazine (Aldrich; 11.0 g), and N,N-dimethylacetamide (Aldrich; 15 mL) is heated at 165° C. for 6.5 h. After cooling, the mixture is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated under reduced pressure to give 4.48 g of 1-(2,4-dichlorophenyl)piperazine. 1H NMR (CDCl3) δ 3.00, 3.06, 6.96, 7.19, 7.36. After cooling the mixture is partitioned between dichloromethane and aq. sodium bicarbonate The organic layers are dried over sodium sulfate concentrated under reduced pressure

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

実験手順: (S)-3-((R)-1-Hydroxy-2-isopropoxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (25.0 mg, 91.4 μmol) was dissolved in DMF (190 μL). NaH (2.6 mg, 109.7 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 2,4-Dichloro-1-fluorobenzene (21.4 μL, 182.9 mmol) was added and the mixture was stirred at 70° C. for 3 hours. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (949 μL, 1.1 mmol) and stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt oil (29.5 mg, 97% purity). MS m/z: [M+H]+ calcd for C15H21Cl2NO2, 318.10. found 318.0. the mixture was stirred at 70° C. for 3 hours The mixture was concentrated stirred overnight The product was concentrated purified by preparative HPLC

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

実験手順: (S)-3-((R)-1-Hydroxy-2-isopropoxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (25.0 mg, 91.4 μmol) was dissolved in DMF (190 μL). NaH (2.6 mg, 109.7 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 2,4-Dichloro-1-fluorobenzene (21.4 μL, 182.9 mmol) was added and the mixture was stirred at 70° C. for 3 hours. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (949 μL, 1.1 mmol) and stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt oil (29.5 mg, 97% purity). MS m/z: [M+H]+ calcd for C15H21Cl2NO2, 318.10. found 318.0. the mixture was stirred at 70° C. for 3 hours The mixture was concentrated stirred overnight The product was concentrated purified by preparative HPLC

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

実験手順: (S)-3-((R)-2-Ethoxy-1-hydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (25.0 mg, 96.4 μmol) was dissolved in DMF (200 μL). NaH (2776 μg, 115.7 mmol) was added and the mixture was stirred at room temperature for 15 minutes. 2,4-Dichloro-1-fluorobenzene (22.6 μL, 192.8 μmol) was added and the mixture was stirred at 70° C. for 3 hours. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (1.0 mL, 1.2 mmol) and stirred overnight. The product was concentrated and purified by preparative HPLC (10-40%, 60 min, BDS) to yield the title compound as a mono-TFA salt oil (24.4 mg, 100% purity). MS m/z: [M+H]+ calcd for C14H19Cl2NO2, 304.08. found 304.0. the mixture was stirred at 70° C. for 3 hours The mixture was concentrated stirred overnight The product was concentrated purified by preparative HPLC (10-40%, 60 min, BDS)

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

実験手順: (S)-3-((R)-2-Ethoxy-1-hydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (25.0 mg, 96.4 μmol) was dissolved in DMF (200 μL). NaH (2776 μg, 115.7 mmol) was added and the mixture was stirred at room temperature for 15 minutes. 2,4-Dichloro-1-fluorobenzene (22.6 μL, 192.8 μmol) was added and the mixture was stirred at 70° C. for 3 hours. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (1.0 mL, 1.2 mmol) and stirred overnight. The product was concentrated and purified by preparative HPLC (10-40%, 60 min, BDS) to yield the title compound as a mono-TFA salt oil (24.4 mg, 100% purity). MS m/z: [M+H]+ calcd for C14H19Cl2NO2, 304.08. found 304.0. the mixture was stirred at 70° C. for 3 hours The mixture was concentrated stirred overnight The product was concentrated purified by preparative HPLC (10-40%, 60 min, BDS)

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

実験手順: (S)-3-((R)-1-Hydroxy-2-methoxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10.0 mg, 40.8 μmol) was dissolved in DMF (0.1 mL). NaH (1.5 mg, 61.1 μmol) was slowly added and the mixture was stirred at room temperature for 15 minutes. Then, 2,4-dichloro-1-fluorobenzene (20.2 mg, 122 μmol) was added. The mixture was stirred at 100° C. for 1 hour, then cooled to room temperature. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (1.0 mL, 1.2 mmol) and stirred overnight at room temperature. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (12.8 mg, 99% purity). MS m/z: [M+H] calcd for C13H17Cl2NO2, 290.06. found 290.0. The mixture was stirred at 100° C. for 1 hour cooled to room temperature The mixture was concentrated stirred overnight at room temperature The product was concentrated purified by preparative HPLC

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

実験手順: (S)-3-((R)-1-Hydroxy-2-methoxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10.0 mg, 40.8 μmol) was dissolved in DMF (0.1 mL). NaH (1.5 mg, 61.1 μmol) was slowly added and the mixture was stirred at room temperature for 15 minutes. Then, 2,4-dichloro-1-fluorobenzene (20.2 mg, 122 μmol) was added. The mixture was stirred at 100° C. for 1 hour, then cooled to room temperature. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (1.0 mL, 1.2 mmol) and stirred overnight at room temperature. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (12.8 mg, 99% purity). MS m/z: [M+H] calcd for C13H17Cl2NO2, 290.06. found 290.0. The mixture was stirred at 100° C. for 1 hour cooled to room temperature The mixture was concentrated stirred overnight at room temperature The product was concentrated purified by preparative HPLC

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

実験手順: Process for the preparation of 2,4-dichlorofluorobenzene in high yield and purity without intermediate separation of the isomers formed,(1) by nitrating 1 mol of fluorobenzene to give nitrofluorobenzene using a mixture comprising 35 to 65 parts by weight of 50 to 90% strength sulfuric acid and 35 to 65 parts by weight of a nitrating acid comprising 35 to 55 parts by weight of 95 to 98% strength sulfuric acid and 45 to 65 parts by weight of 96 to 98% strength nitric acid, with the proviso that 0.8 to 2.0 equivalents of the nitrating agent NO2+ are used per mol of fluorobenzene, at 20° to 90° C., (2) allowing 25 g to 150 g of chlorine, in the presence of a ring chlorinating catalyst, to act on each 100 g of the crude nitrofluorobenzene mixture obtained, at 20° to 100° C., and (3) allowing about 18 g to about 203 g of chlorine or equivalent amounts of a chlorine releasing agent to act on each 100 g of the crude chlorofluoronitrobenzene mixture obtained, after removal of the ring chlorinating catalyst, at 110° to 220° C., and isolating the 2,4-dichlorofluorobenzene. obtained, at 20° to 100° C. obtained after removal of the ring chlorinating catalyst