N-[(2,3-dichlorophenyl)methyl]cyclopropanamine

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: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: To a stirred sol. of compound D8 (0.38 g, 0.594 mmol) in CH2Cl2 (3.0 mL) were added EDC.HCl (0.285 g, 1.49 mmol), HOBt (0.109 g, 0.713 mmol), DMAP (2.0 mg, 0.15 mmol) and DIPEA (0.467 mL, 2.67 mmol). After 15 min cyclopropyl-(2,3-dichloro-benzyl)amine (0.257 g, 1.19 mmol) was added and stirring was continued for 7 days. Every day cyclopropyl-(2,3-dichlorobenzyl)amine (prepared by reductive amination from 2,3-dichlorobenzaldehyde and cyclopropylamine, 0.128 g, 0.59 mmol) was added. The reaction mixture was partitioned between aq. 1M HCl and CH2Cl2, and the phases were separated, washed with aq. sat. NaHCO3, dried over MgSO4, filtered, and the solvents were removed in vacuo. Purification of the crude by FC (heptane/EtOAc 7/3→1/1) yielded the title product (60 mg, 12%) as a yellow oil. LC-MS: tR=1.28 min, ES+: 837.48. The reaction mixture was partitioned between aq. 1M HCl and CH2Cl2 the phases were separated washed with aq. sat. NaHCO3 dried over MgSO4 filtered the solvents were removed in vacuo Purification of the crude by FC (heptane/EtOAc 7/3→1/1)

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

実験手順: To a stirred sol. of compound D8 (0.38 g, 0.594 mmol) in CH2Cl2 (3.0 mL) were added EDC.HCl (0.285 g, 1.49 mmol), HOBt (0.109 g, 0.713 mmol), DMAP (2.0 mg, 0.15 mmol) and DIPEA (0.467 mL, 2.67 mmol). After 15 min cyclopropyl-(2,3-dichloro-benzyl)amine (0.257 g, 1.19 mmol) was added and stirring was continued for 7 days. Every day cyclopropyl-(2,3-dichlorobenzyl)amine (prepared by reductive amination from 2,3-dichlorobenzaldehyde and cyclopropylamine, 0.128 g, 0.59 mmol) was added. The reaction mixture was partitioned between aq. 1M HCl and CH2Cl2, and the phases were separated, washed with aq. sat. NaHCO3, dried over MgSO4, filtered, and the solvents were removed in vacuo. Purification of the crude by FC (heptane/EtOAc 7/3→1/1) yielded the title product (60 mg, 12%) as a yellow oil. LC-MS: tR=1.28 min, ES+: 837.48. The reaction mixture was partitioned between aq. 1M HCl and CH2Cl2 the phases were separated washed with aq. sat. NaHCO3 dried over MgSO4 filtered the solvents were removed in vacuo Purification of the crude by FC (heptane/EtOAc 7/3→1/1)

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

実験手順: To a sol. of compound D5 (10 g, 14.7 mmol) in CH2Cl2 (200 mL) was added cyclopropyl-(2,3-dichlorobenzyl)amine (prepared by reductive amination from 2,3-dichlorobenzaldehyde and cyclopropylamine, 7.95 g, 36.8 mmol), DIPEA (10.1 mL, 58.8 mmol), DMAP (449 mg, 3.68 mmol), HOBt (2.48 g, 18.4 mmol), and EDC.HCl (8.45 g, 44.1 mmol). This mixture was stirred at rt for 3 days. EDC.HCl (2.83 g, 14.7 mmol) and DIPEA (2.5 mL, 26 mmol) were added, and the reaction mixture was stirred at rt for 24 h. EDC.HCl (2.82 g, 14.7 mmol) and cyclopropyl-(2,3-dichlorobenzyl)amine (3.10 g, 14.7 mmol) were added, and the mixture and was stirred for 48 h. CH2Cl2 was added, and the organic layer was washed with aq. 1M HCl (3×), and with aq. sat. NaHCO3 (1×). The org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:5→2:3) yielded the title compound (7.72 g, 65%). LC-MS: tR=1.31 min; ES+: 802.52. the reaction mixture was stirred at rt for 24 h the mixture and was stirred for 48 h the organic layer was washed with aq. 1M HCl (3×) layer was dried over MgSO4 filtered concentrated under reduced pressure Purification of the residue by FC (EtOAc/heptane 1:5→2:3)

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

実験手順: To a sol. of compound D5 (10 g, 14.7 mmol) in CH2Cl2 (200 mL) was added cyclopropyl-(2,3-dichlorobenzyl)amine (prepared by reductive amination from 2,3-dichlorobenzaldehyde and cyclopropylamine, 7.95 g, 36.8 mmol), DIPEA (10.1 mL, 58.8 mmol), DMAP (449 mg, 3.68 mmol), HOBt (2.48 g, 18.4 mmol), and EDC.HCl (8.45 g, 44.1 mmol). This mixture was stirred at rt for 3 days. EDC.HCl (2.83 g, 14.7 mmol) and DIPEA (2.5 mL, 26 mmol) were added, and the reaction mixture was stirred at rt for 24 h. EDC.HCl (2.82 g, 14.7 mmol) and cyclopropyl-(2,3-dichlorobenzyl)amine (3.10 g, 14.7 mmol) were added, and the mixture and was stirred for 48 h. CH2Cl2 was added, and the organic layer was washed with aq. 1M HCl (3×), and with aq. sat. NaHCO3 (1×). The org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:5→2:3) yielded the title compound (7.72 g, 65%). LC-MS: tR=1.31 min; ES+: 802.52. the reaction mixture was stirred at rt for 24 h the mixture and was stirred for 48 h the organic layer was washed with aq. 1M HCl (3×) layer was dried over MgSO4 filtered concentrated under reduced pressure Purification of the residue by FC (EtOAc/heptane 1:5→2:3)

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

実験手順: A sol. of compound D4 (1.39 mmol, 0.87 g) in CH2Cl2 (11.2 mL) was treated with DMAP (0.35 mmol, 42 mg), HOBt (1.67 mmol, 0.23 g), EDC.HCl (3.47 mmol, 0.66 g), and DIPEA (5.55 mmol, 0.95 mL). After 30 min at rt, cyclopropyl-(2,3-dichlorobenzyl)-amine (prepared by reductive amination from 2,3-dichlorobenzaldeyhde and cyclopropylamine; 4.16 mmol, 0.90 g) was added and the mixture was stirred for 4 days at rt. The reaction was then diluted with CH2Cl2 (40 mL), washed with aq. 1M HCl (2×50 mL), dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 30:70) yielded the title compound (0.48 g, 42%). LC-MS: tR=1.29 min; ES+: 823.50. washed with aq. 1M HCl (2×50 mL) dried over MgSO4 filtered the solvents were removed under reduced pressure Purification of the residue by FC (EtOAc/heptane 30:70)

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

実験手順: A mixture of compound D3 (355 mg, 0.500 mmol), cyclopropyl-(2,3-dichlorobenzyl)-amine (prepared from 2,3-dichlorobenzaldehyde and cyclopropylamine by reductive amination, 324 mg, 1.50 mmol), DIPEA (0.342 mL, 2.00 mmol), DMAP (15.3 mg, 0.125 mmol), HOBt (101 mg, 0.75 mmol) and EDC.HCl (288 mg, 1.50 mmol) in CH2Cl2 (7 mL) was stirred at rt for 2 weeks. The mixture was diluted with more CH2Cl2, and washed with aq. 1M HCl (3×) and aq. sat. NaHCO3 (1×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:9→2:8 3:7→4:6→1:1) yielded the title compound (160 mg, 35%). LC-MS: tR=1.34 min, ES+: 909.35. washed with aq. 1M HCl (3×) and aq. sat. NaHCO3 (1×) extracts were dried over MgSO4 filtered the solvents were removed under reduced pressure Purification of the residue by FC (EtOAc/heptane 1:9→2:8 3:7→4:6→1:1)

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

実験手順: A mixture of compound D3 (355 mg, 0.500 mmol), cyclopropyl-(2,3-dichlorobenzyl)-amine (prepared from 2,3-dichlorobenzaldehyde and cyclopropylamine by reductive amination, 324 mg, 1.50 mmol), DIPEA (0.342 mL, 2.00 mmol), DMAP (15.3 mg, 0.125 mmol), HOBt (101 mg, 0.75 mmol) and EDC.HCl (288 mg, 1.50 mmol) in CH2Cl2 (7 mL) was stirred at rt for 2 weeks. The mixture was diluted with more CH2Cl2, and washed with aq. 1M HCl (3×) and aq. sat. NaHCO3 (1×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:9→2:8 3:7→4:6→1:1) yielded the title compound (160 mg, 35%). LC-MS: tR=1.34 min, ES+: 909.35. washed with aq. 1M HCl (3×) and aq. sat. NaHCO3 (1×) extracts were dried over MgSO4 filtered the solvents were removed under reduced pressure Purification of the residue by FC (EtOAc/heptane 1:9→2:8 3:7→4:6→1:1)

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

実験手順: A mixture of compound D2 (2.87 g, 4.60 mmol), cyclopropyl-(2,3-dichlorobenzyl)amine (prepared from 2,3-dichlorobenzaldehyde and cyclopropylamine by reductive amination, 2.49 g, 11.5 mmol), DIPEA (3.15 mL, 18.4 mmol), DMAP (140 mg, 1.15 mmol), HOBt (932 mg, 6.90 mmol) and EDC.HCl (2.65 g, 13.8 mmol) in CH2Cl2 (50 mL) was stirred at rt for 6 days. The mixture was diluted with more CH2Cl2, and washed with aq. 1M HCl (3×) and aq. sat. NaHCO3 (1×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:5→1:3→1:2→1:1→3:2) yielded the title compound (1.30 g, 34%). LC-MS: tR=1.33 min, ES+: 821.54. washed with aq. 1M HCl (3×) and aq. sat. NaHCO3 (1×) extracts were dried over MgSO4 filtered the solvents were removed under reduced pressure Purification of the residue by FC (EtOAc/heptane 1:5→1:3→1:2→1:1→3:2)

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Into a 100 mL round bottom flask fitted with a reflux condenser and a nitrogen inlet, N-(2,3-dichlorobenzyl)cyclopropanamine (30.3 g, 140.3 mmol) (Example 1A) and (S)-benzyl 5-oxotetrahydrofuran-3-ylcarbamate (22.0 g, 93.5 mmol) were added. The mixture was heated without solvent at 100° C. for 24 hours. Purification by column chromatography (5%->10% MeOH/dichloromethane) gave 22.0 g (52%) of 4A. ESI-MS:m/z 451.3 (M+H)+. Into a 100 mL round bottom flask fitted with a reflux condenser and a nitrogen inlet Purification by column chromatography (5%->10% MeOH/dichloromethane)