(1R,2S)-2-(3,4-二氟苯基)环丙胺

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: R-(−)-Mandelic acid (2.26 kg) was added to a solution containing trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2.6 kg, 91.8% enantiomeric excess), stirring at 17° C. in ethyl acetate (45.3 L). The mixture was stirred at 25° C. for 3 hours and 8 minutes, then filtered and washed twice with ethyl acetate (13.8 kg total). The crystalline product was dried at 40° C. under reduced pressure for 23 hours, affording trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropanaminium (2R)-2-hydroxy-2-phenylethanoate (4.45 kg). filtered washed twice with ethyl acetate (13.8 kg total) The crystalline product was dried at 40° C. under reduced pressure for 23 hours

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: R-(−)-Mandelic acid (2.26 kg) was added to a solution containing trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2.6 kg, 91.8% enantiomeric excess), stirring at 17° C. in ethyl acetate (45.3 L). The mixture was stirred at 25° C. for 3 hours and 8 minutes, then filtered and washed twice with ethyl acetate (13.8 kg total). The crystalline product was dried at 40° C. under reduced pressure for 23 hours, affording trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropanaminium (2R)-2-hydroxy-2-phenylethanoate (4.45 kg). filtered washed twice with ethyl acetate (13.8 kg total) The crystalline product was dried at 40° C. under reduced pressure for 23 hours

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Acetic anhydride (0.31 ml) was added to a suspension of (1R-trans)-2-(3,4-difluorophenyl)cyclopropanamine, (R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1) (prepared as described in International Patent Application WO 9905143) (700 mg) and potassium carbonate (1.0 g) in tetrahydrofuran (20 ml) and stirred for 20 h. Saturated ammonium chloride solution was added and the mixture was extracted with ether and the organic layers were dried (MgSO4) and evaporated to afford the sub-title compound (470 mg). the mixture was extracted with ether the organic layers were dried (MgSO4) evaporated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Acetic anhydride (0.31 ml) was added to a suspension of (1R-trans)-2-(3,4-difluorophenyl)cyclopropanamine, (R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1) (prepared as described in International Patent Application WO 9905143) (700 mg) and potassium carbonate (1.0 g) in tetrahydrofuran (20 ml) and stirred for 20 h. Saturated ammonium chloride solution was added and the mixture was extracted with ether and the organic layers were dried (MgSO4) and evaporated to afford the sub-title compound (470 mg). the mixture was extracted with ether the organic layers were dried (MgSO4) evaporated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Prepared using the product from Example 13 step b) (0.15 g) and (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine, (2R,3R)-2,3-dihydroxybutanedioate (1:1) (0.20 g) (prepared as described in WO 9905143) by the method of Example 13, step c). Purified by chromatography (SiO2, ethyl acetate:dichloromethane 1:9 as eluant) to afford the title (0.12 g). Prepared Purified by chromatography (SiO2, ethyl acetate:dichloromethane 1:9 as eluant) to afford the title (0.12 g)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 2-((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol (370 mg, 0.86 mmol, 1.00 equiv) (15 mL), (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (145.6 mg, 0.86 mmol, 1.00 equiv.) and N,N-diisopropylethylamine (155.7 mg, 1.21 mmol, 1.20 equiv.) in dichloromethane was stirred at ambient temperature for about 16 hours, and then water (10 mL) was added. Standard extractive workup with dichloromethane (3×10 mL) gave the title product as a yellow oil (450 mg; yield=93%). m/z=563 (MH)+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of (1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid (8.0 g, 40.40 mmol, 1.00 equiv.), diphenylphosphoryl azide (11.2 g, 40.73 mmol, 1.00 equiv.), triethylamine (6.2 g, 61.39 mmol, 1.50 equiv.) in toluene (60 mL) was heated at reflux for about 1 hour and then refluxing 6N hydrogen chloride was added. The mixture was kept at reflux for 16 hours, and then cooled to ambient temperature. The resulting mixture was concentrated in vacuo, and the resulting residue was dissolved in water/ether (1:1) 200 mL). Following standard extractive workup with ether (3×100 mL), the resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (1:4˜1:0)) to give the title product as a light-brown solid (6.2 g; yield=91%). 1H NMR (300 MHz, CDCl3) δ: 6.98-7.07 (m, 1H), 6.72-6.81 (m, 2H), 2.40 (m, 1H), 1.82-1.87 (m, 1H), 1.05-1.11 (m, 1H), 0.85-0.96 (m, 1H). at reflux for about 1 hour was added at reflux for 16 hours The resulting mixture was concentrated in vacuo the resulting residue was dissolved in water/ether (1:1) 200 mL) the resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (1:4˜1:0))

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: R-(−)-Mandelic acid (2.26 kg) was added to a solution containing trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2.6 kg, 91.8% enantiomeric excess), stirring at 17° C. in ethyl acetate (45.3 L). The mixture was stirred at 25° C. for 3 hours and 8 minutes, then filtered and washed twice with ethyl acetate (13.8 kg total). The crystalline product was dried at 40° C. under reduced pressure for 23 hours, affording trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropanaminium (2R)-2-hydroxy-2-phenylethanoate (4.45 kg). filtered washed twice with ethyl acetate (13.8 kg total) The crystalline product was dried at 40° C. under reduced pressure for 23 hours

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 2-((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol (370 mg, 0.86 mmol, 1.00 equiv) (15 mL), (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (145.6 mg, 0.86 mmol, 1.00 equiv.) and N,N-diisopropylethylamine (155.7 mg, 1.21 mmol, 1.20 equiv.) in dichloromethane was stirred at ambient temperature for about 16 hours, and then water (10 mL) was added. Standard extractive workup with dichloromethane (3×10 mL) gave the title product as a yellow oil (450 mg; yield=93%). m/z=563 (MH)+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of (1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid (8.0 g, 40.40 mmol, 1.00 equiv.), diphenylphosphoryl azide (11.2 g, 40.73 mmol, 1.00 equiv.), triethylamine (6.2 g, 61.39 mmol, 1.50 equiv.) in toluene (60 mL) was heated at reflux for about 1 hour and then refluxing 6N hydrogen chloride was added. The mixture was kept at reflux for 16 hours, and then cooled to ambient temperature. The resulting mixture was concentrated in vacuo, and the resulting residue was dissolved in water/ether (1:1) 200 mL). Following standard extractive workup with ether (3×100 mL), the resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (1:4˜1:0)) to give the title product as a light-brown solid (6.2 g; yield=91%). 1H NMR (300 MHz, CDCl3) δ: 6.98-7.07 (m, 1H), 6.72-6.81 (m, 2H), 2.40 (m, 1H), 1.82-1.87 (m, 1H), 1.05-1.11 (m, 1H), 0.85-0.96 (m, 1H). at reflux for about 1 hour was added at reflux for 16 hours The resulting mixture was concentrated in vacuo the resulting residue was dissolved in water/ether (1:1) 200 mL) the resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (1:4˜1:0))

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: R-(−)-Mandelic acid (2.26 kg) was added to a solution containing trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2.6 kg, 91.8% enantiomeric excess), stirring at 17° C. in ethyl acetate (45.3 L). The mixture was stirred at 25° C. for 3 hours and 8 minutes, then filtered and washed twice with ethyl acetate (13.8 kg total). The crystalline product was dried at 40° C. under reduced pressure for 23 hours, affording trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropanaminium (2R)-2-hydroxy-2-phenylethanoate (4.45 kg). filtered washed twice with ethyl acetate (13.8 kg total) The crystalline product was dried at 40° C. under reduced pressure for 23 hours

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: R-(−)-Mandelic acid (2.26 kg) was added to a solution containing trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2.6 kg, 91.8% enantiomeric excess), stirring at 17° C. in ethyl acetate (45.3 L). The mixture was stirred at 25° C. for 3 hours and 8 minutes, then filtered and washed twice with ethyl acetate (13.8 kg total). The crystalline product was dried at 40° C. under reduced pressure for 23 hours, affording trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropanaminium (2R)-2-hydroxy-2-phenylethanoate (4.45 kg). filtered washed twice with ethyl acetate (13.8 kg total) The crystalline product was dried at 40° C. under reduced pressure for 23 hours