5-AMINO-1-METHYLPYRIDIN-2(1H)-ONE

Reductive iron powder (129mg, 2.30mmol) and 2N HCl (0.07mL) were added to a stirred solution of 19b (113mg, 0.33mmol) in ethanol (3mL) at OTo a solution of 5-nitro-1-methyl-2(1H)-pyridinone (10 g, 64.9 mmol) in THF (130 mL) was added 10 percent Pd/C (1 g). The resulting suspension was shaken at RT for 7.5 hr under hydrogen atmosphere. The mixture was filtered through a pad of Celite. The pad was washed with THF and the resulting filtrate was concentrated under reduced pressure to afford the title product (8 g, 99 percent yield) as greenish product, which was directly used for further steps.Reductive iron powder (39.0g, 69.6mmol) and 2N HCl (20mL) were added to a stirred solution of lb (15.4g, lOOmmol) in ethanol (300mL) at 0°C. The resulting mixture was heated under reflux for 2h and filtrated. The brown solid was washed with ethanol for several times. The combined ethanol phase was evaporated and the residue was dissolved in ethyl acetate (400mL) and washed with 1.5N NaTo a solution of 5-amino-1 -methylpyridin-2(1 H)-one (0.194 g, 1 .56 mmol) in dry 1 , 4-dioxane (5 mL) was added dropwise trimethylaluminum (0.76 mL, 1 .52 mmol, 2 M in toluene) under argon. The mixture was stirred at room temperature for 1 h before a solution of 6-(3-chlorobenzyl)pyridazine-3-carboxylate (0.100 g, 0.38 mmol) in dry 1 , 4-dioxane (3 mL) was added dropwise. The mixture was stirred at 100 C for 5 h. Reaction mixture was cooled to room temperature and quenched with 0.5 N hydrochloric acid (25 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was washed with 0.5 N hydrochloric acid (25 mL x 2), brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/methanol = 20/1 ) and prep-HPLC (column: Sunfire prep C18 10 pm OBD 19*250 mm; mobile phase: [water (0.05% trifluoroacetic acid-acetonitrile]; B%: 60%-88%, 15 minutes) to give 6-(3-chlorobenzyl)-A/-(1 -methyl-6-oxo-1 , 6-dihydropyridin-3-yl)pyridazine-3-carboxamide (75 mg, 0.21 mmol, 55.8%) as a yellow solid. 1 H NMR (500 MHz, Dimethylsulfoxide-c/6) d 1 0.92 (s, 1 H), 8.36 (d, J = 2.7 Hz, 1 H), 8.20 (d, J = 8.6 Hz, 1 H), 7.87 (d, J = 8.6 Hz, 1 H), 7.80 (dd, J = 9.7, 2.8 Hz, 1 H), 7.46 (s, 1 H), 7.40 - 7.24 (m, 3H), 6.44 (d, J = 9.7 Hz, 1 H), 4.44 (s, 2H), 3.46 (s, 3H); LCMS (ESI) m/z: 355.1 [M+H]+.To a solution of 5-amino-1 -methylpyridin-2(1 H)-one (0.200 g, 1 .66 mmol) in anhydrous 1 , 4-dioxane (8 ml_) was added trimethylaluminum (0.81 ml_, 1 .62 mmol, 2 /W in toluene) under nitrogen. The reaction mixture was stirred at room tmperature for 1 h before methyl 5-(3-chlorobenzyl)picolinate (0.106 g, 0.404 mmol) in 1 , 4-dioxane (3.0 ml_) was added and stirred at 100 C for 16 h. The mixture was cooled to room temperature and quenched with water (100 ml_). The aqueous layer was extracted with ethyl acetate (50 ml_ c 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude sample was dissolved in minimal A/, A/-dimethylformamide and purified via prep-HPLC (Sunfire prep C18 10 pm OBD 19*250 mm; mobile phase: [water (0.05% trifluoroacetic acid)-acetonitrile] ; B%: 60%-88%, 1 5 minutes) to give (5-(3-chlorobenzyl)-A/-(1 -methyl-6-oxo-1 , 6-dihydropyridin-3-yl)picolinamide (0.101 g, 0.285 mmol, 70.5%) as a white solid. 1 H NMR (500 MHz, Dimethylsulfoxide-c/gJ d 1 0.47 (s, 1 H), 8.67 (s, 1 H), 8.34 (d, J = 2.5 Hz, 1 H), 8.04 (d, J = 8.5 Hz, 1 H), 7.90 (dd, J = 8.0, 2.0 Hz, 1 H), 7.77 (dd, J = 9.5, 3.0 Hz, 1 H), 7.40 (s, 1 H), 7.35 (t, J = 7.5 Hz, 1 H), 7.30-7.27 (m, 2H), 6.42 (d, J = 9.0 Hz, 1 H), 4.12 (s, 2H), 3.44 (s, 3H); LCMS (ESI) m/z: 354.1 [M+H]+.General procedure: To a suspension of chloride 5 (1.0 equiv.) and amine (1.0 equiv.) in 1, 4-dioxane (0.40M in amine) was added TsOH·H2O (0.20 equiv). The reaction mixture was heated at 150°C under microwave irradiation for 30min, cooled down, and concentrated under reduced pressure. The residue was purified by Biotage® FlashMaster Personal+ flash chromatography (silica gel, DCM ramping to DCM:CH3OH=95:5 unless otherwise stated) to give the desired secondary amine.

Molecular Weight:124.14
XLogP3:-0.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:124.063662883
Monoisotopic Mass:124.063662883
Topological Polar Surface Area:46.3
Heavy Atom Count:9
Complexity:193
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes