(2-CHLORO-PYRIDIN-4-YL)-METHANOL

Reference Example 7 Methyl 2-chloropyridine-4-carboxylate (2.50 g, 14.60 mmol) was dissolved in anhydrous THF (50 mL) and this solution was cooled to -78 To a cooled solution of methyl 2-chloroisonicotinate (1.7 g, 0.009 mole) inTHF (30 mL) under N2, was added lithium borohydride (0.43 g, 0.019 mole) inportions. The reaction mixture was warmed to RT and stirred further for 3 hours. Thereaction mixture was concentrated under reduced pressure; residue was dissolved inice cold water (50 mL) and extracted with ethyl acetate (50 mL x 3). Organic layer was washed with brine solution (50 mL) and dried over Na2SO4. The organic phase was concentrated under vacuum to obtain the crude compound which was further purified by flash chromatography using ethyl acetate: n-hexane (40: 60) to afford (2-chloropyridin-4-yl)-methanol.Yield: 1.0 g (71 percent); ‘H - NMR (CDC13, 400MHz) ö ppm: 2.29 (bs, 1H), 4.75 (s, 2H), 7.20 - 7.21 (d, J = 4.9 Hz, 1H), 7.31 (s, 1H), 8.32 - 8.33 (d, J = 5.0 Hz, 1H); Mass(m/z): 144.0 (M+H), 145.9 (M+H).A sample of methyl 2-chloroisonicotinate (5.00 g, 29.14 mmol) was dissolved in 10 niL THF, treated with 10 drops of methanol, and cooled to 0 Intermediate T : Preparation of 2-chloro-4-(chloromethyl)pyridine; Step 1: Preparation of (2-chloropyridin-4-yl)methanol; A sample of methyl 2-chloroisonicotinate (5.00 g, 29.14 mmol) was dissolved in 10 mL THF, treated with 10 drops of methanol, and cooled to 0 °C. The solution was treated with lithium borohydride solution (21.86 mL of 1 M in THF, 43.71mmol) and then allowed to warm to room temp. After 4 h the solution was cooled to 0 °C and quenched with 1 N HC1 solution. The pH was adjusted to pH 10 with 1 N NaOH solution, and the reaction mixture was extracted with EtOAc. The organic extracts were washed with brine and concentrated in vacuo yielding 2.96 g (70.8percent) of product.'H NMR (300 MHz, CDPreparation of (2-chloropyridin-4-yl)methanolA sample of methyl 2-chloroisonicotinate (5.00 g, 29.14 mmol) was dissolved in 10 mL THF, treated with 10 drops of methanol, and cooled to 0 C. The solution was treated with lithium borohydride solution (21.86 mL of 1 M in THF, 43.71 mmol) and then allowed to warm to room temp. After 4 h the solution was cooled to 0 C and quenched with 1 N HCl solution. The pH was adjusted to pH 10 with 1 N NaOH solution, and the reaction mixture was extracted with EtOAc. The organic extracts were washed with brine and concentrated in vacuo yielding 2.96 g (70.8percent) of product.1H NMR (300 MHz, CD3CN) ' 8.32 (d, 1 H), 7.39 (s, 1 H), 7.29 (d, 1 H), 4.62 (s, 2 H) and 3.53 ppm (bs, 1 H).Carbonyldiimidazole (CDI, 7.88 g, 46.2 mmol, 1.5 equiv) is added at room temperature to a solution of 2-chloroisonicotinic acid (5.0 g, 30.8 mmol) in THF (70 ml). The reaction mixture is stirred at rt overnight, and then added dropwise to a cold (0 Borane-dimethyl sulfide complex (14.30 mL, 14.30 mmols) was added to tetrahydrofuran solution of 2-chloroisonicotinic acid (17.56 g, 11.5 mmols) under cooling with ice, and stirred at room temperature for 2.5 days, followed by further an hour's stirring at 50°C. Cooling the reaction liquid to room temperature, ethyl acetate was added, followed by washing with saturated aqueous ammonium chloride solution and saturated brine and drying over anhydrous sodium sulfate. Concentrating the solvent under reduced pressure, the title compound (15.0 g, 93percent) was obtained.Preparation B-11; A. 2-Chloro-4-(chloromethyl)pyridine; Boron trifluoride diethyl etherate (71 g, 0.5 mol) was added dropwise to a suspension of 2-chloroisonicotinic acid (20 g, 0.125 mol) and sodium borohydride (14.3 g, 0.376 mol) in THF (200 ml.) with stirring at -10-5 (2-Chloro-pyridin-4-yl)-methanol:; To a stirred solution of 2-chloroisonicotinic acid (3.15 g, 20 mmol) in anhydrous THF (40 ml) cooled in an ice bath, was added borane-methyl sulfide complex (6 mL, 60 mmol). After 1 hr, the mixture was stirred for 48 hr at room temperature. The mixture was cooled in an ice bath and conc. HCl (30 ml) was added and stirred for 30 min. The mixture was then basified by addition of 50percent aqueous NaOH (30 ml). The product was extracted with dichloromethane, dried with anhydrous potassium carbonate, filtered, and evaporated in vacuo. The crude product was purified by silica gel column chromatography (eluent, ether:hexane (5:1)) to afford 172 g (60percent) of 2-chloro-4-pyridinemethanol as a white solid. m.p. 77-79° C.; Synthesis of (2-(2-(l H-indazol-4-yl)pyridin-4-yl)-l -fluoroethane-1 , 1 - diyl)diphosphonic acidStep 4a: Synthesis of (2-chloropyridin-4-yl)methanol2-Chl oroi son icot inic acid (2.0 g; 12.7 mmol) is dissolved in 25 mL THF under anhydrous conditions and borane (1.0 M in THF; 25.4 ml; 25.4 mmol) is added drop wise via a syringe. The solution is stirred overnight at 50 °C. The mixture is cooled to R Γ and quenched with 5 mL MeOH, concentrated under reduced pressure and purified by column chromatography on silica gel using a solvent gradient of hexanes to EtOAc. The final product is isolated as a white powder (1.1 g, 60percent yield). NMR (300 MHz, CDC3/4): δ 8.34 (d, J = 5.1 Hz, 1H), 7.36 (dq, J = 1.6, 0.8 Hz, 1H), 7.22 - 7.19 (m, lH). 4.75 (s, 2H).To a solution of 2-chloropyridine-4-carbaldehyde (0.71 g, 5.06 mmol) in anhydrous THF (16 mL) was added a solution of lanthanum(III) chloride bis(lithium chloride) complex (0.6M in THF, 16.7 mL, 10.03 mmol) and the mixture was stirred at room temperature for 0.75 hours, then cooled to 0° C.

Molecular Weight:143.57
XLogP3:0.9
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