3-Pyridinecarboxaldehyde → HCID 22660272, compound

Temperature

24 °C

A mixture of 5-amino-2-methylphenol 1 (1.23 g, 10 mmol), 3-pyridinecarboxaldehyde 2 (1.18 g, 11 mmol) and sodium triactoxyborohydride (3.18 g, 15 mmol) in 1% AcOH in ClCH2CH2Cl (25 mL) was stirred for 18 h at 24° C. and evaporated under reduced pressure. To the solid residue was added water-ice (50 g) and the mixture was stirred for 0.5 h. The resulting precipitate was collected, washed and dried in vacuo to give 2-methyl-5-[(pyridin-3-ylmethyl)amino]-phenol 3 (1.8 g, 84% yield): 1HNMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.52 (s, 1H), 8.40 (d, 1H, J=3.7 Hz), 7.69 (d, 1H, J=7.6 Hz), 7.32 (dd, 1H, J=2.3, 4.9 Hz), 6.68 (d, 1H, J=7.9 Hz), 6.05 (s, 1H), 5.94 (m, 2H), 4.36 (s, 2H), 1.91 (s, 3H); 13CNMR (400 MHz, DMSO-d6) δ 156.1, 149.1, 148.1, 147.8, 136.3, 135.3, 131.0, 123.8, 111.8, 104.0, 100.0, 44.6, 15.5. A mixture of the compound 3 (0.21 g, 1.0 mmol) and di-tert-butyl dicarbonate (Boc2O)(0.55 g, 2.5 mmol) in anhydrous THF (5 mL) was stirred at room temperature for 18 h and evaporated. To the residue were added ethyl acetate (10 mL) and water (10 mL). The organic layer was separated, washed with water and brine, dried over MgSO4, filtered and evaporated to afford compound 4 as an orange oil (0.35 g, 85% yield): 1HNMR (400 MHz, DMSO-d6) δ 8.42 (d, J=4.0 Hz, 1H), 8.37 (s, 1H), 7.58 (d, 1H, J=7.8 Hz), 7.32 (dd, 1H, J=4.9, 7.7 Hz), 7.19 (d, 1H, J=8.1 Hz), 7.02 (m, 2H), 4.84 (s, 2H), 2.05 (s, 3H), 1.46 (s, 9H), 1.36 (s, 9H); 13CNMR (400 MHz, DMSO-d6) δ 154.0, 151.1, 149.1, 148.9, 148.7, 140.8, 135.3, 134.0, 131.1, 127.6, 124.2, 123.9, 120.2, 83.6, 80.7, 31.7, 28.2, 27.5, 15.4. To a solution of the compound 4 (0.30 g, 0.75 mmol) in anhydrous DMF (3 mL) was added iodomethane 5 (R=Me, 1.5 mmol). The reaction mixture was stirred at room temperature for 18 h and ethyl ether was added. The precipitate was collected, washed with ethyl ether and dried under vacuum to to give compound 6 (R=Me) as a dark yellow solid (0.39 g, 94% yield): 1HNMR (400 MHz, DMSO-d6) δ 8.85 (m, 2H), 8.38 (d, 1H, J=8.0 Hz), 8.06 (t, 1H, J=6.8 Hz), 7.24 (d, 1H, J=8.2 Hz), 7.15 (m, 2H), 4.99 (s, 2H), 4.31 (s, 3H), 2.08 (s, 3H), 1.47 (s, 9H), 1.36 (s, 9H); 13CNMR (400 MHz, DMSO-d6) δ 154.0, 151.2, 149.2, 144.7, 144.2, 143.7, 140.5, 139.2, 131.3, 128.2, 127.8, 124.4, 120.8, 83.7, 81.3, 50.2, 48.4, 28.2, 27.5, 15.4. To compound 6 (R═Me)(379 mg, 0.68 mmol) was added 4M HCl in dioxane (1.7 mL, 6.8 mmol). The reaction mixture was stirred at room temperature for 18 h. Et2O (25 mL) was added and then decanted and dried under vacuum to leave 3-[(3-hydroxy-4-methyl-phenylamino)-methyl]-1-methyl-pyridinium chloride 7 (R=Me, 0.18 g, 72% yield): 13CNMR (400 MHz, DMSO-d6) δ 155.7, 145.6, 144.1, 143.9, 143.8, 143.7, 141.4, 131.4, 127.6, 114.0, 100.7, 48.3, 44.3, 15.3.

1. customevaporated under reduced pressure
2. additionTo the solid residue was added water-ice (50 g)
3. stirringthe mixture was stirred for 0.5 h
4. customThe resulting precipitate was collected
5. washwashed
6. customdried in vacuo

ORD record

ord-ef2edf3642e54711bb9137d750e170a5

Source dataset

uspto-grants-2003_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06572665B2