2-Pyridinemethanol,5-chloro-(9CI)

(1) Ethyl S-chloro^-pyridinecarboxylate (104.0 mg, 0.560 mmol) was dissolved in THF (5.6 mL) and cooled to 0To a solution of 5-chloropicolinic acid (5 g, 31 .7 mmol) in tetrahydrofuran (50 mL) was added borane-dimethylsulfide complex (10 mL) at 0°C and resulting reaction mixture was maintained at rt for 16 h. Cooled the reaction mass to 0°C, excess borane-dimethylsulfide complex was quenched with methanol (15 mL), refluxed for 1 h, concentrated the reaction, diluted in ethyl acetate (150 mL), washed with water (2 x 50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated to afford 3 g (66.6percent yield) of (5-Chloropyridin-2-yl)methanol as a white solid.(5-Chloropyridin-2-yl)methyl 4-isopropyl-l, 4, 6, 7-tetrahydro-5H-imidazo[4, 5-c]- pyridine-5-carboxylate; 5-Chloropyridine-2-carboxylic acid (2.00 g, 12.7 mmol) was dissolved in THF (12 mL) at 0 To a cooled (0Intermediate 2: (5-chloro-2-pyridinyl)methanol To a cooled (0Intermediate 2: (5-chloro-2-pyridinyl)methanol To a cooled (0Intermediate 2: (5-chloro-2-pyridinyl)methanol To a cooled (0Intermediate 2: (5-chloro-2-pyridinyl)methanolTo a cooled (0II. (5-chloro-2-pyridinyl)methanol To a cooled (0°C) solution of methyl 5-chloro-2-pyridinecarboxylate (43 g, 251 mmol) in methanol (400 mL) was added NaB (28.7 g, 754 mmol) in small portions over approximately 30 min. After addition, the reaction mixture was stirred at room temperature for 2 h, at which time TLC analysis showed the completion of the reaction. The reaction mixture was then concentrated under reduced pressure, and the residue was adjusted to pH 1 by adding IN HC1. The resulting solution was extracted with EtOAc (3 X 300 mL). The combined organic layers were dried (Na5-chloro-2(chloromethyl)pyridine; [00372] To a 0 °C solution of 5-chloropicolinic acid (3.00 g, 19.0 mmol) indichloromethane (20 mL) was added sulfurous dichloride (2.78 mL, 38.1 mmol), after which the reaction was warmed to room temperature and stirred at that temperature for 4 hours. The reaction was then concentrated to dryness, then reconstituted in dichloromethane (5 mL). Methanol (10 mL) was added to the reaction mixture, and the reaction was allowed to stir at room temperature for 12 hours, after which it was then diluted with water, extracted with ethyl acetate (3 x 50 mL), washed with water, then washed with saturated sodium bicarbonate solution, dried (magnesium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography (ISCO 80g) using 0 to 80percent ethyl acetate in hexanes to afford methyl 5-chloropicolinate was as an off-white solid (2.75 g, 15.2 mmol, 80percent yield ).[00373] To a 0 °C solution of methyl 5-chloropicolinate (2.70 g, 15.7 mmol) in methanol (50 mL) was added sodium borohydride (1.79 g, 47.2 mmol), after which the reaction was warmed to room temperature and stirred at that temperature for 4 hours. The reaction mixture was then concentrated to a residue which was treated with 1M hydrochloric acid solution (15 mL), extracted with ethyl acetate (3 x 100 mL), washed with water, then washed with saturated sodium bicarbonate solution, dried (magnesium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography (ISCO 80g) using 0 to 60percent ethyl acetate in hexanes to afford (5-chloropyridin-2-yl)methanol was as an off-white solid (2.15 g, 14.9 mmol, 95percent yield).[00374] To a 0 °C solution of (5-chloropyridin-2-yl)methanol (2.10 g, 14.6 mmol) in dichloromethane (10 mL) was added sulfurous dichloride (1.60 mL, 21.9 mmol) followed by N, N-dimethylformamide (50 μ), after which the reaction was warmed to room temperature and stirred at that temperature for 4 hours. The reaction mixture was then concentrated to a residue which was reconstituted in water (15 mL), ethyl acetate (15 mL), and saturated sodium bicarbonate solution (15 mL). The organic layers were separated and washed with saturated sodium chloride solution, dried (magnesium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography (ISCO 40g) using 0 to 50percent ethyl acetate in hexanes to afford 5-chloro-2(chloromethyl)pyridine as an light brown oil (2.11 g, 13.0 mmol, 89percent yield).A solution of methyl 5-chloropicolinate (2 g, 1 1 .7 mmol) in MeOH (20 ml) and sodium borohydride (0.89 g, 23.3 mmol) was stirred at rt for 1 h. After reaction was completed, solvent was evaporated. Distilled water was added and the aqueous layer was extracted with dichloromethane (3 x 30 ml). The combined organic layer was washed with brine, dried over anhydrous NaD. (5-Chloropyridin-2-yl)methanol Sodium methoxide (IM in MeOH) (0.162 mL, 0.162 mmol) was added to a solution of (5-chloropyridin-2-yl)methyl benzoate Part C (200 mg, 0.808 mmol) in MeOH (47.5 mL) and stirred at RT for 2.0 h. The solvent was removed in vacuo and the crude product was subjected to flash chromatography (silica gel/DCM-MeOH 100:0 to 90: 10 gradient) to afford (5-chloropyridin-2-yl)methanol 16D (68 mg, 59 percent yield) as an off-white solid. LC-MS, [M + H]+ = 144. EXAMPLE 1.9. (3S, 4/?)-(5-chloropyridin-2-yl)methyl 4-(([l, 2, 4]triazolo[4, 3-o]pyrazin-8-ylamino)-methyl)- 3-fluoropiperidine-l-carboxylate (E1-Y1.3). [0211] To a stirred solution of

Molecular Weight:143.57
XLogP3:0.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:143.0137915
Monoisotopic Mass:143.0137915
Topological Polar Surface Area:33.1
Heavy Atom Count:9
Complexity:89.1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes