(2-Aminopyridin-3-yl)methanol

Light yellow Cryst

In a three-necked flask, 5 g of ethyl 2-aminonicotinate (0.0302 mol) and 80 mL of tetrahydrofuran were added, and the mixture was stirred13g sodium borohydride (0.2416mol) powder, stirring was continued at 65 ° C for 15min, was added dropwise 65mL of methanol, the reaction was refluxedThe reaction was complete by TLC (trichloromethane: methanol = 4: 1) and concentrated in vacuo while still hot. 40 mL of the mixture was distilled off and 1 gNaOH, hydrolyzed at 70-80 for 7-8h, the organic phase was separated, dried over anhydrous sodium sulfate and concentrated to give 2-amino-3-picolinateAlcohol (Intermediate A) Light yellow solid powder 2.7 g, m.p. 67.5-68 ° C, 75percent yield.To a solution of 2-aminonicotinic acid (20. 5g, 148mmol) in tetrahydrofuran (300mL) at room temperature was added lithium aluminum hydride (1. OM in tetrahydrofuran, 300mL, 300mmol) dropwise over 45 minutes. The resulting solution was heated to reflux for 18hrs. The mixture was cooled to room temperature and quenched by the sequential dropwise addition of water (11. 5mL), 15percent aqueous sodium hydroxide (11. 5mL), and water (34. 5mL). The mixture was stirred for 15min., then filtered through Celite 545. The filter pad was washed thoroughly with tetrahydrofuran (500mL) and 5percent methanol in chloroform (500mL). The combined filtrate and washings were evaporated to give 17.7g (96percent) of the title compound as a yellow waxy solid. MS (LC/MS/pos): 125.0 (M+H) +. 1H NMR (CDC13) 5 4.13 (br. s, 1H), 4.59 (s, 2H), 6.56 (m, 1H), 7.29 (d, 1H), 7.90 (d, 1H).To a suspension of 2-aminonicotinic acid (25.0 g, 0.18 mol) in THF (500 mL) was added L1AIH4 (13.7 g, 0.36 mol) portion-wise at 0 °C. The mixture was heated to reflux and stirred further for 18 hours, then cooled to rt, and quenched by the sequential drop wise addition of water (16 mL), NaOH aqueous solution (16 mL, 15percent), and water (50 mL). The resulted mixture was stirred at rt for 20 minutes, then filtered through a CELITEThe compound 2 - amino-nicotinic acid (25.0 g, 0 . 18 µM) suspended in THF (500 ml) in, cooling to 0 °C, then added to the reaction solution in the LiAlH in batchesa) Step 1: 2-Amino-3-(hydroxymethyl)pyridineLithium aluminum hydride (12.4 g, 326.7 mmol) was portionwisely added to a suspension of 2-amino-3-carboxypyridine (30.0 g, 217.2 mmol) in THF (350 mL) at 0°C. Once the addition was completed, the reaction mixture was stirred at room temperature for 15 minutes and then at reflux overnight. The mixture was then cooled to 0°C and hydrolyzed by the successive addition of water (18 mL), a solution of sodium hydroxyde (18 mL) and water (30 mL) again. The resulting white suspension was filtered on Clarcela) a To a suspension of 2-aminonicotinic acid (5-Si, 1.58 g, 11.45 mmol) in THF (80 mL), LAH (1M in ether, 22.9 mL, 22.9 mmol) was added slowly at 0 °C under argon with stirring. After completion of the addition, the ice bath was removed and the mixture was stirred at room temperature. Additional LAH (1M in ether, 11.4 mL) was added after 48 hours and the reaction was again cooled with an ice bath before saturated NH4C1 aqueous solution (20 mL) was added with stirring to form slurry. The organic layer was separated by decantation and the slurry was washed with EtOAc. The combined organic layer was washed with iN NaOH aqueous solution, brine, and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure to afford (2-aminopyridin-3-yl)methanol (5-S2, 0.74 g) as an off-white solid.Preparation Example J-3. A mixture solution of N-(3-formylpyridin-2-yl)-2, 2-dimethylpropionamide described in Preparation Example J-2 (500mg, 2.4mmol) and an aqueous solution of 5N sodium hydroxide (7mL) was refluxed for 90 minutes. After cooling, ethyl acetate and tetrahydrofuran were added for extraction, the organic layer was washed with brine, then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (methanol : ethyl acetate = 1 : 5), and the title compound (160mg, 1.2mmol, 53percent) was obtained as a pale yellow solid. Step 2: 2-Amino-5-bromo-3-(hydroxymethyl)pyridineBromine (8.4 mL, 189.4 mmol) was added dropwise over 1 hour to a solution of 2- amino-3-(hydroxymethyl)pyridine (19.6 g, 157.8 mmol; which may be prepared as described in Dl, Step 1) in acetic acid (350 mL) at room temperature. The reaction mixture was then stirred overnight. After concentration to dryness, the residue was partitioned between a saturated solution of potassium carbonate (300 mL) and ethyl acetate (200 ml_). The aqueous layer was separated and extracted with ethyl acetate (2 x 200 ml_). The combined organic phases were washed with a saturated solution of sodium chloride (200 ml_), dried over sodium sulfate, filtered and concentrated to dryness. After trituration of the residue in pentane, the title product was obtained as a yellow solid (27.0 g, 84%).*H NMR (DMSO-c/6, 400 MHz) : delta (ppm) : 7.90 (d, J = 2.8 Hz, 1H), 7.53 (d, J = 2 Hz, 1H), 5.93 (br s, NH2), 5.29 (br s, OH), 4.31 (s, 2H).b) 2-Amino-5-bromo-3-(hydroxymethyl)pyridine To a solution of b 2-Amino-5-bromo-3-(hydroxymethyl)pyridine To a solution of S1. Acetic acid (456 g) was added to a 1 L three-necked flask at room temperature, and In a three-necked flask, 5 g of ethyl 2-aminonicotinate (0.0302 mol) and 80 mL of tetrahydrofuran were added, and the mixture was stirred13g sodium borohydride (0.2416mol) powder, stirring was continued at 65 C for 15min, was added dropwise 65mL of methanol, the reaction was refluxedThe reaction was complete by TLC (trichloromethane: methanol = 4: 1) and concentrated in vacuo while still hot. 40 mL of the mixture was distilled off and 1 gNaOH, hydrolyzed at 70-80 for 7-8h, the organic phase was separated, dried over anhydrous sodium sulfate and concentrated to give 2-amino-3-picolinateAlcohol (Intermediate A) Light yellow solid powder 2.7 g, m.p. 67.5-68 C, 75% yield.Preparation 19 Into a 100 mL round-bottom flask, was placed (2-aminopyri din-3 -yl)methanol (1.90 g, 15.6 mmol, 1 eq), TBDPSC1 (5.58 g, 20.3 mmol, 1.3 eq), imidazole (5.30 g, 78 mmol, 5 eq), DMF (15 mL). The mixture was stirred for 1.5 h at 25C. The reaction mixture was quenched with water and this was extracted with ethyl acetate. The organic layers combined and (1117) concentrated. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether. This resulted in 5.4 g (96%) of 3-[[(tert- butyldiphenylsilyl)oxy]methyl]pyridin-2-amine as off-white solid. LCMS: m/z = 363 [M+H]+.

Molecular Weight:124.14
XLogP3:0.2
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:124.063662883
Monoisotopic Mass:124.063662883
Topological Polar Surface Area:59.1
Heavy Atom Count:9
Complexity:87.1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes