Cdcl3

Example 4

This example is directed to a synthesis of (R)-1-(4-morpholinophenyl)ethanamine hydrochloride (intermediate 4). See FIG. 4.

This example is directed to a synthesis of (S)—N-(1-phenylethyl)imidazo[1,2-a]pyridine-2-carboxamide.

[Figure (not displayed)]

The mixture of imidazo[1,2-a]pyridine-2-carboxylic acid (100 mg, 0.62 mmol), HATU (258 mg, 0.68 mmol), and DIPEA (269 μL, 1.54 mmol) in DMF (3.0 mL) was stirred at room temperature for 1 hours. After (S)-1-phenylethanamine (79.0 μL, 0.62 mmol) was added, the reaction mixture was stirred at room temperature for overnight. The reaction mixture was partitioned between water and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO₂ (Hexane:EtOAc=1:4) to afford the (S)—N-(1-phenylethyl)imidazo[1,2-a]pyridine-2-carboxamide (120 mg, 73%) as a yellow solid. ¹H-NMR (CDCl₃, Varian, 400 MHz): δ 1.63 (3H, d, J=6.8 Hz), 5.31-5.39 (1H, m), 6.84 (1H, t, J=6.8 Hz), 7.22-7.27 (2H, m), 7.34 (2H, t, J=7.6 Hz), 7.42 (2H, d, J=7.6 Hz), 7.56 (1H, d, J=9.2 Hz), 7.62 (1H, d, J=6.8 Hz), 8.13-8.15 (2H, m). MS: 266.0 [MH⁺].

Example 21

This example is directed to a synthesis of N—((R)-1-(4-((2S,6R)-2,6-dimethylmorpholino)phenyl)ethyl)imidazo[1,2-a]pyridine-2-carboxamide.

[Figure (not displayed)]

To a solution of imidazo[1,2-a]pyridine-2-carboxylic acid (24.0 mg, 0.15 mmol) in DMF (2.0 mL) were added HATU (84.0 mg, 0.22 mmol) and DIPEA (77 μL, 0.44 mmol). The reaction mixture was stirred for 1 hour at room temperature. After addition of (R)-1-(4-((2S,6R)-2,6-dimethylmorpholino)phenyl)ehtylamine hydrochloride (intermediate 8, 60.0 mg, 0.22 mmol), the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was partitioned between water and EtOAc and the separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO₂ (Hexane:EtOAc=1:1 to 1:2) to afford the N—((R)-1-(4-((2S,6R)-2,6-dimethylmorpholino)phenyl)ethyl)imidazo[1,2-a]pyridine-2-carboxamide (32.0 mg, 57%) as a white solid. ¹H-NMR (CDCl₃, Varian, 400 MHz): δ 1.23 (6H, d, J=6.0 Hz), 1.59 (3H, d, J=7.2 Hz), 2.34-2.40 (2H, m), 3.40 (2H, d, J=10.8 Hz), 3.74-3.81 (2H, m), 5.23-5.29 (1H, m), 7.20-7.24 (1H, m), 7.32 (2H, d, J=8.8 Hz), 7.53 (1H, d, J=9.2 Hz), 7.59 (1H, d, J=8.0 Hz), 8.11-8.13 (2H, m). MS: 379.2 [MH⁺].

Example 23

This example is directed to a synthesis of (R)—N-(1-(4-(2,2-dimethylmorpholino)phenyl)ethyl)imidazo[1,2-a]pyridine-2-carboxamide.

[Figure (not displayed)]

To a solution of imidazo[1,2-a]pyridine-2-carboxylic acid (40.0 mg, 0.24 mmol) in DMF (3.0 mL) were added HATU (140 mg, 0.36 mmol) and DIPEA (130 μL, 0.73 mmol). The reaction mixture was stirred for 3 hours at room temperature. After addition of (R)-1-(4-(2,2-dimethylmorpholino)phenyl)ethanamine hydrochloride (intermediate 10, 100 mg, 0.36 mmol), the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was partitioned between water and EtOAc and the separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO₂ (Hexane:EtOAc=1:1 to 1:2) to afford the (R)—N-(1-(4-(2,2-dimethylmorpholino)phenyl)ethyl)imidazo[1,2-a]pyridine-2-carboxamide (60.0 mg, 64%) as a white solid. ¹H-NMR (CDCl₃, Varian, 400 MHz): δ 1.31 (6H, s), 1.60 (3H, d, J=6.8 Hz), 2.91 (2H, s), 3.86 (2H, t, J=4.8 Hz), 3.86 (2H, t, J=4.8 Hz), 5.26-5.30 (1H, m), 6.80-6.86 (3H, m), 7.20-7.24 (1H, m), 7.32 (2H, d, J=8.8 Hz), 7.53 (1H, d, J=9.2 Hz), 7.59 (1H, d, J=8.0 Hz), 8.11-8.13 (2H, m). MS: 379.2 [MH⁺].

Example 27

This example is directed to a synthesis of (R)—N-(1-phenylethyl)pyrazolo[1,5-a]pyridine-2-carboxamide.

[Figure (not displayed)]

The mixture of pyrazolo[1,5-a]pyridine-2-carboxylic acid (100 mg, 0.62 mmol), (R)-1-phenylethanamine (79.0 μL, 0.62 mmol), HATU (258 mg, 0.68 mmol), and DIPEA (269 μL, 1.54 mmol) in DMF (3.0 mL) was stirred overnight at room temperature. The reaction mixture was partitioned between water and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO₂ (Hexane:EtOAc=1:1) to afford the (R)—N-(1-phenylethyl)pyrazolo[1,5-a]pyridine-2-carboxamide (155 mg, 95%) as a yellow solid. ¹H-NMR (CDCl₃, Varian, 400 MHz): δ 1.64 (3H, d, J=6.8 Hz), 5.29-5.41 (1H, m), 6.84 (1H, t, J=6.8 Hz), 7.06 (1H, s), 7.11-7.15 (1H, m), 7.25-7.28 (1H, m), 7.35-7.37 (3H, m), 7.43 (2H, d, J=7.2 Hz), 7.57 (1H, d, J=9.2 Hz), 8.36 (1H, d, J=7.2). MS: 351.2 [MH⁺].

Example 2

This example is directed to an alternative synthesis of (R)-1-(4-((4-methylpiperazin-1-yl)methyl)phenyl)ethanamine (intermediate 2). See FIG. 2.

This example is directed to a synthesis of N-benzylimidazo[1,2-a]pyridine-2-carboxamide.

[Figure (not displayed)]

The mixture of imidazo[1,2-a]pyridine-2-carboxylic acid (100 mg, 0.62 mmol), HATU (258 mg, 0.68 mmol), and DIPEA (269 μL, 1.54 mmol) in DMF (3.0 mL) was stirred at room temperature for 1 hours. After phenylmethanamine (67.0 μL, 0.62 mmol) was added, the reaction mixture was stirred at room temperature for overnight. The reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO₂ (Hexane:EtOAc=1:4) to afford the N-benzylimidazo[1,2-a]pyridine-2-carboxamide (100 mg, 64%) as a yellow solid. ¹H-NMR (CDCl₃, Varian, 400 MHz): δ 4.67 (2H, d, J=6.4 Hz), 6.85 (1H, t, J=6.8 Hz), 7.22-7.29 (2H, m), 7.33-7.55 (4H, m), 7.53 (1H, d, J=9.2 Hz), 7.70 (1H, brs), 8.15 (1H, d, J=7.2 Hz), 8.17 (1H, s). MS: 252.1 [MH⁺].