2-Chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine

4-(4-fluorophenyl)-5, 6, 7, 8, 9, 10-hexahydrocyclooctadiene[b]pyridine-2(1H)one 80.0 g was charged with 520 ml dimethylformamide, Cooling the temperature to 5 °C and introduced into a 36.84 g phosphorus pentachloride in 10 times. After raising the temperature to 15 ° C and it reacted for 3 hours. Injecting the purified water to 520 ml and stirred for 1 hour at 10 ° C. Filtering the precipitated crystals from the reaction solution by nuche filter (Buchner funnel, Coors) and the residue was washed with purified water 300 ml. To the crystals were dried at 70 ° C as an off-white 2-chloro-4-(4-fluorophenyl)-5, 6, 7, 8, 9, 10-hexahydrocyclooctadiene[b]pyridine 80.0 g (to give the yield 93.6percent).4-(4-fluorophenyl)-5, 6, 7, 8, 9, 10-hexahydrocycloocta[b]pyridin-2(1H)-one (120g) and phenylphosphonic dichloride (187 ml) was added into a 350 ml sealed tube. At 150 °C (external temperature), heat for 4h. After the reaction was complete, is distilled under reduced pressure to obtain black benzene phosphine acid radical two chlorine viscous liquid, the liquid is poured into 2L in the ice water mixture, by adding ammonia water to adjust pH to 9, stir vigorously 3-6h, a gray solid precipitated, or similar light filter or centrifugal obtained white solid. Then add ethanol (1.8L), heating and stirring to dissolve, then adding active carbon (50g), at this temperature to continue stirring 30 min, hot filtering, using 400 ml of hot ethanol washing the filter cake, natural crystallization filtrate, to obtain white needle-like crystal (111.2g), to yield 87.2percent. HPLC purity 99.8percent.To a mixture of phenylphosphine dichloride and 73 g of 3 was heated to 155-160 °Cfor 4 h and TLC monitored complete the reaction and cool thereaction mass at ambient temperature then dichloromethane700 mL and water 30 mL was added, adjusted pH 8.5 with liqammonia then organic layer separated, washed the organiclayer with water distilled under vacuum solid obtained andpurified with acetone to get pure compound. Yield: 66 g;85 percent.4- (4-fluorophenyl) -5, 6, 7, 8, 9, 10-hexahydrocycloocta [b] pyridin-2 (1 H) -one (20 kg), Dichloromethane (100 L), phenylphosphonic dichloride(28.7 kg) were charged to the reactor.The solvent dichloromethane was removed by distillation under atmospheric pressure.The temperature was gradually increased from T = 140 to 148 ° C. and maintained for 8 to 9 hours.The reaction mixture was cooled to T = 105 to 108 ° C., Toluene (100 L) was slowly added while maintaining T = 80 - 110 ° C.The mixture was cooled to T = 50-55 ° C. and water (40 L) was slowly added while maintaining the temperature of T = 50-85 ° C. The temperature was adjusted to T = 70 to 75 ° C., The layers were separated and the lower aqueous layer was removed. Saline solution (36 L) was added, The pH of the aqueous layer was adjusted to> 8 by adding 5percent NaOH. The layers separated and the lower aqueous layer was removed. The organic layer was filtered through a cartridge, The solvent was then removed by vacuum distillation to a small volume. IsopropanolStripping was carried out with water (40 L) to remove residual toluene.Isopropanol (90 L) was added and the suspension was heated to T = 80-85 ° C. Dissolution occurred and the mixture was cooled to T = 20-25 ° C.The product was isolated by filtration and washed with isopropanol.Drying the moist product under vacuum at T = 45 to 50 ° C. gives 2-chloro-4 (4-fluorophenyl) -5, 6, 7, 8, 9, 10-hexahydrocycloocta [B] pyridine was obtained with purity of 99.95percent Apercent HPLC (method 2) (16.4 kg, molar yield 78percent).1180 ml of phenylphosphonic dichloride was charged to the reactor, Cooled to below 25 , 900 g of compound (III) was added in portions to the reactor at 40 ° C, After feeding, The system is heated to an internal temperature of 165 ~ 170 , Continue to heat the reaction, After the reaction of raw materials is completed, System cooling to about 40 ~ 45 , The reaction solution was slowly added to 13.5 L of dichloromethane, Stirring, The reaction system was slowly added to 13.5L of ice water, Keep the temperature below 5 , Slowly dropping 10percent NaOH solution to adjust the pH to 9 to 10, Add diatomaceous earth, filter, Liquid separation, The combined organic phase, dry, Dichloromethane was removed, About 933 g of a dark brown solid was obtained, Add 465ml ethanol refining, 631 g of a khaki-colored solid product were obtained, Ie, compounds of formula (II)Purity greater than 98.3percent.

Molecular Weight:289.8
XLogP3:5.9
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:289.1033554
Monoisotopic Mass:289.1033554
Topological Polar Surface Area:12.9
Heavy Atom Count:20
Complexity:303
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes