(4-Chloropyridin-2-yl)methanol

To a cooled (0 °C) solution of 24 (4.0 g, 23.3 mmol) and CaClCompound 6 was prepared according to a modified procedure (Comba, P., et al. inorg. Chem. 52, 6481-6501 (2013)). To a mixture of methanol (24 ml) and tetrahydrofurane (14 ml) were added 5 (4.1 g, 23.87 mmol) and calcium chloride (10.5 g, 95.48 mmol). The reaction mixture was cooled to 0 °C. Then, sodium borohydride (1.8 g, 47.74 mmol) was added portionwise. The resulting mixture was stirred at room temperature for 24 h. Then, the same amounts of methanol, tetrahydrofurane, calcium chloride, and sodium borohydride were added following the same procedure, and the reaction mixture was stirred for 24 h. After this time, water (80 ml) was added to the reaction mixture, which was stirred for 2 h. The product was extracted with EtOAc (3 4-Chloro-2-(hydroxymethyl)pyridine : A solution of 4-CHLOROPYRIDINE ASOXIDE (5 G, 38.6 MMOL) and TRIMETHYLOXONIUM TETRAFLUOROBORATE (5.94 G, 40.1 MMOI) in CH2CL2 (115 mL) was stirred for two hours at ambient temperature. The solvent was evaporated and the residue taken up in MeOH (115 mL) and heated to near boiling. Ammonium persulfate (1.76 G, 7.72 MMOL) dissolved in H2O (7.7 mL) was added and the mixture was heated to reflux for 30 min. A second portion of ammonium persulfate (0.88 G) in H2O (3.9 mL) was added and the mixture was refluxed for another 30 min. The solvent was evaporated and the residue was partitioned between CHZCTZ and aqueous Na2CO3 (10percent w/v). The organic layer was washed with H2O, dried over MgSO4 and evaporated leaving 2.4 G (43percent) of the title compound. 1H NMR (CDC13) 8 8.20 (d, 1H, J=5. 0 Hz, H-6); 7.31 (s, 1H, H-3); 7.04 (d, 1H, J=5. 0 Hz, H-5); 5.46 (s, LH, OH); 4.61 (s, 2H, CH2).Manufacturing Example 51-1-1 (4-Chloro-pyridin-2-yl)-methanol; To a mixture of 4-chloro-2-picoline (1.0 g, 7.84 mmol) and dichloromethane (20 mL), was added m-chloroperbenzoic acid (3.5 g, 13.2 mmol) on an ice bath, which was stirred for 1.5 hours at room temperature. Water and sodium hydrogencarbonate were added to the reaction, followed by extraction with dichloromethane. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. Acetic anhydride (20 mL) was added to the residue obtained by concentrating the filtrate under a reduced pressure, and this was stirred for 1 hour at 100° C. The reaction mixture was cooled to room temperature and concentrated under a reduced pressure. A 5 N aqueous sodium hydroxide solution (1.57 mL, 7.87 mmol) was added to a mixture of the resulting residue and methanol (20 mL) on an ice bath, which was stirred for 1.5 hours at room temperature. Water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=6:1) to obtain the title compound (200 mg, 18percent).Concentrated sulfuric acid (0.25 mL) was added to a solution of 4-chloropyridine hydrochloride (3.00 g) in methanol (25 mL), followed by refluxing for 0.5 hours. An aqueous solution (25 mL) of ammonium persulfate (12.2 g) was added to the reaction mixture, followed by refluxing for 2.5 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. A sodium carbonate aqueous solution was added to the obtained residues, and the resultant product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residues were purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1), whereby (4-chloro pyridin-2-yl)methanol (1.90 g) was obtainedTo a mixture of 4-chloro-2-picoline (1.0 g, 7.84 mmol) and dichloromethane (20 mL), was added m-chloroperbenzoic acid (3.5 g, 13.2 mmol) on an ice bath, which was stirred for 1.5 hours at room temperature. Water and sodium hydrogencarbonate were added to the reaction, followed by extraction with dichloromethane. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. Acetic anhydride (20 mL) was added to the residue obtained by concentrating the filtrate under a reduced pressure, and this was stirred for 1 hour at 100 C. The reaction mixture was cooled to room temperature and concentrated under a reduced pressure. A 5 N aqueous sodium hydroxide solution (1.57 mL, 7.87 mmol) was added to a mixture of the resulting residue and methanol (20 mL) on an ice bath, which was stirred for 1.5 hours at room temperature. Water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=6:1) to obtain the title compound (200 mg, 18%). 1H-NMR Spectrum (CDCl3) delta (ppm): 4.76 (2H, s), 7.23-7.25 (1H, m), 7.32-7.33 (1H, m), 8.46 (1H, d, J=5.6 Hz).To a cooled (0 C) solution of 24 (4.0 g, 23.3 mmol) and CaCl2 (10.3 g, 93.2 mmol) in dry MeOH-THF (2 : 1, 30 mL) was added portionwise NaBH4 (1.8 g, 46.6 mmol). After cooling to 0 C, water was added to quench the reaction. The solvent were removed by evaporation and the residue was dissolved in water and extracted with CHCl3. The extracts was dried over MgSO4 and concentrated by evaporation to give 25 (3.3 g, 98 %) as a white solid.Compound 6 was prepared according to a modified procedure (Comba, P., et al. inorg. Chem. 52, 6481-6501 (2013)). To a mixture of methanol (24 ml) and tetrahydrofurane (14 ml) were added 5 (4.1 g, 23.87 mmol) and calcium chloride (10.5 g, 95.48 mmol). The reaction mixture was cooled to 0 C. Then, sodium borohydride (1.8 g, 47.74 mmol) was added portionwise. The resulting mixture was stirred at room temperature for 24 h. Then, the same amounts of methanol, tetrahydrofurane, calcium chloride, and sodium borohydride were added following the same procedure, and the reaction mixture was stirred for 24 h. After this time, water (80 ml) was added to the reaction mixture, which was stirred for 2 h. The product was extracted with EtOAc (3 chi 180 ml). The combined organic layer was washed with brine (100 ml), dried over MgS04 and concentrated to dryness under reduced pressure to afford 6 (3.0 g, 87%) as a pale white solid. XH N MR (300 MHz, CDCI3): delta 8.38 (d, J = 5.5 Hz, 1H), 7.34 (s, 1H), 7.18 (dd, J = 5.5, 2.0 Hz, 1H), 4.71 (s, 2H), 4.19 (br s, 1H).13C N MR (75 M Hz, CDCIs): delta 161.6, 149.5, 145.0, 122.8, 121.1, 64.2. H RMS (ESI-TOF) calcd. for C6H6CIN NaO+ [M+Na]+ 166.0036, found: 166.0028.[0180] To a solution of DIBAL in toluene (1 M, 12.3 mL, 12.3 mmol) and THF (1:1) in an ice-salt bath, was added a solution of the above ester (700 mg, 4.10 mmol) in 10 mL of THF. After addition, the reaction mixture was allowed to warm up to room temperature and stir for 3 h. The mixture was then poured into crushed ice with 5 mL of 4M NaOH, extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to give 450 mg of the desired alcohol, which was used in next step without purification.Preparation of 2-Chloromethyl-4-chloropyridine To a slurry of lithium aluminum hydride (0.45 g, 11.9 mmol) in anhydrous diethyl ether (40 mL) at 0 C., a solution of methyl 4-chloro-pyridine-2-carboxylate (2.0 g, 11.7 mmol) in diethyl ether (30 mL) was added. The resulting mixture was stirred at room temp. overnight, and quenched with successive addition of water (0.45 mL), 15% aqueous NaOH (0.45 mL), and water (1.35 mL). The resultant slurry was stirred at room temp. for 30 min., and filtered through a small plug of Celite. The filtrate was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide General procedure: At a temperature of less than 40 C, Dissolve 1300 g of Cpd 2 in 7 L of ethanol.Add 400g of sodium borohydride in batches, Stir at room temperature overnight;2N hydrochloric acid was added dropwise at a temperature of less than 20 C to adjust the pH to weakly alkaline, Rotate most of the ethanol, add water, Adjusted to strong alkaline with potassium carbonate, Extracted with ethyl acetate (EA), Wash the product to the aqueous phase with 1N hydrochloric acid.Extracted with EA, The aqueous phase is added with potassium carbonate to adjust to strong alkalinity, EA extraction, sodium chloride washing, Dry over anhydrous sodium sulfate and spin dry.Through the column, 4-bromopyridine-2-methanol (Cpd 3) 650 g was obtained. The yield was 62%.To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2 -amine (Intermediate E, 50mg, O.l9mmol),

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