[Synthesis]
Example 1; Preparation of diethyl [5-(3-fluorophenyl)-pyridin-2-ylmethyl]-phosphonate; To a reaction vessel was added diethyl (5-bromopyridin-2-yl)methylphosphonate (100 g, 0.29 mol), 5% Pd/C 50% wet (5.0 g), 3-fluorophenylboronic acid (61 g; 0.44 mol) and sodium carbonate (100 g; 0.94 mol). 600 ml of isobutyl acetate was added and the mixture was stirred. 400 ml of water was added and the stirred mixture was heated to 70-80°C for at least 3 hours, at which point HPLC analysis indicated complete reaction. Upon completion, the reaction mixture was cooled to 25°C and filtered to remove the Pd/C catalyst. The catalyst filter cake was washed with 200 ml of isobutyl acetate (combined with the filtrate/batch) and 100 ml of water (waste solution). The batch was adjusted to pH 11-13 using 25% sodium hydroxide solution.During the process, the reaction mixture was maintained at a temperature of 20 °C to 30 °C. The reaction was carried out on the catalyst. The organic layer was separated and washed with 500 ml of water under stirring. The pH of the batch was adjusted to pH 11 to pH 13 using a 25% sodium hydroxide solution. the temperature was maintained at a value of about 20°C to about 30°C throughout the process. After washing, the layers were separated and the organic layer was washed with 300 ml of 2% sodium chloride solution with agitation for 10-15 minutes. The layers were separated and the organic layer was analyzed by HPLC showing reduction of impurities to the desired level. Darco (10 g) was added to the organic layer. The resulting slurry was stirred for 1 hour and then filtered to remove the decolorant. The filter cake was washed with 200 ml of isobutyl acetate (combined with the filtrate/batch) and the batch was concentrated under reduced pressure to about 200 ml at 40°C to 50°C and then cooled to a temperature of 0°C to 50°C. Heptane (1000 ml) was added to the cold concentrate over a period of 2.5-3 hours, maintaining the temperature at about 15°C to 25°C. The mixture was cooled to 15°C to 25°C. From -15°C to -5°C over 3 hours and stirred at the same temperature for 1 hour. The crystalline solid was filtered, washed with 200 ml of heptane and dried under vacuum at a temperature of about 25°C to 35°C overnight to give 70.37 g (75%). Melting point 61-63°C.1H NMR (CDCl3) δ1.3 (t, J=7.05Hz, 6H), 3.47 (d, J=22.02Hz, 2H), 4.12 (q, J=7.08Hz, 4H), 7.10 (ddd, J=8.42,2.55,0.88, Hz, 1H), 7.28 (ddd, J=9.85 ,2.36,1.80 Hz, 1H), 7.36(dt, J=7.86,1.27, Hz, 1H), 7.46(m, 1H), 7.83(ddd, J=8.1,2.2,0.32 Hz, 1H), 8.76(d, J=2.38,1H). |