1,4-difluorobenzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,4-Difluorobenzene (22 ml, 210 mmol) was mixed with □-valerolactone (4 ml, 42 mmol) and AlCl3 (28 g, 210 mmol) was added by portions to the stirred reaction mixture. The reaction mixture was then refluxed at stirring for 16 h (oil bath 110° C.). The reaction mixture was cooled down (ice/brine bath) and ice/conc. HCl was added and stirred until homogeneous mixture was obtained. The reaction mixture was then extracted into methylene chloride, washed with water (4×10 ml) and sodium bicarbonate solution (3×100 ml). The organic extract was dried over Na2SO4. Concentration by rotary evaporation gave 6.7 g of product as yellow powder. Yield 81%. was added by portions to the stirred reaction mixture The reaction mixture was then refluxed stirred until homogeneous mixture was obtained The reaction mixture was then extracted into methylene chloride washed with water (4×10 ml) and sodium bicarbonate solution (3×100 ml) The organic extract was dried over Na2SO4 Concentration by rotary evaporation

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 100 g of 1-acetyl-4-piperidine carboxylic acid chloride in 500 ml of 1,4-difluorobenzene was added in aliquots, 211 g of anhydrous aluminum chloride. The mixture was stirred at reflux under nitrogen for 3 hrs and allowed to cool to room temperature. The mixture was poured into ice and extracted twice with ethyl acetate. The extracts were washed with saturated sodium bicarbonate solution and dried over anhydrous potassium carbonate. Filtration followed by evaporation of the solvent provided an oil which crystallized on standing. The solid was washed with cyclohexane and dried to provide 73.3 g (52.1%) of 1-acetyl-4-(2,5-difluorobenzoyl)piperidine: mp 82°-87° C. Recrystallization from a mixture of isopropyl alcohol, diisopropyl ether and hexane provided product with mp 93°-95° C. at reflux under nitrogen for 3 hrs The mixture was poured into ice extracted twice with ethyl acetate The extracts were washed with saturated sodium bicarbonate solution dried over anhydrous potassium carbonate Filtration followed by evaporation of the solvent provided an oil which crystallized The solid was washed with cyclohexane dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 0.80 g, 20 mmol) in anhydrous DMF (10 ml) under nitrogen was added dropwise a solution of 1-benzhydryl-azetidin-3-ol (3.5 g, 15 mmol) in DMF (10 ml)—Care: hydrogen gas evolution! The mixture was stirred 30 min after gas evolution had ceased then 1,4-difluorobenzene (1.8 mL, 18 mmol) was added dropwise. The mixture was heated to 100 C and stirred for 12 h, then cooled to room temperature and poured into aq sodium hydrogencarbonate solution (50 ml) and extracted twice with EtOAc (2×50 ml). The combined organic layers were washed with water, concentrated under vacuum and purified by flash column chromatography (25 g silica gel; heptane-EtOAc: 1:0-9:1). The product-containing fractions were combined, concentrated under vacuum, washed with heptane and dried under vacuum to give the title compound (3.256 g, 67%). Method B HPLC-MS: MH+ requires m/z=334 Found: m/z=334, Rt=1.69 min (89%). 1H NMR (250 MHz, CDCl3) δ ppm 7.48-7.39 (4H, m), 7.39-7.12 (6H, m), 6.94 (2H, t), 6.71 (2H, dd), 4.75 (1H, m), 4.46 (1H, s), 3.78-3.65 (2H, m), and 3.20-3.07 (2H, m). The mixture was heated to 100 C stirred for 12 h extracted twice with EtOAc (2×50 ml) The combined organic layers were washed with water concentrated under vacuum purified by flash column chromatography (25 g silica gel; heptane-EtOAc: 1:0-9:1) concentrated under vacuum washed with heptane dried under vacuum

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Butyl lithium (70 ml of 2.22M solution, 155 mmole) was added to a solution of pentamethyldiethylenetriamine (23.3 ml, 155 mmole) in THF (250 ml) at -70° C. The solution was stirred for 5 min and 1,4-difluorobenzene (17.7 g, 155 mmole) in THF was added at -70° C. The solution was stirred for 2 hr during which time it was cooled to -75° C. and 4-cyanopyridine (15.6 g, 150 mmole) in THF was added at -75° C. The mixture was allowed to warm to 25° C. slowly and then quenched with ammonium chloride solution. The mixture was diluted with ether and the organic layer was separated. The organic layer was washed with water and 3N hydrochloric acid. The acid washes were stirred for 2 hr and basified with sodium hydroxide. The basic mixture was extracted with ether and the ether solution concentrated in vacuo. The crude product was purified by chromatography on silica eluting with ethyl acetate-hexane (20:1) to give 4-(2,5-difluorobenzoyl)pyridine (16.9 g, 51.5%). The solution was stirred for 2 hr during which time it to warm to 25° C. slowly quenched with ammonium chloride solution The mixture was diluted with ether the organic layer was separated The organic layer was washed with water and 3N hydrochloric acid The acid washes were stirred for 2 hr and basified with sodium hydroxide The basic mixture was extracted with ether the ether solution concentrated in vacuo The crude product was purified by chromatography on silica eluting with ethyl acetate-hexane (20:1)

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Butyl lithium (70 ml of 2.22M solution, 155 mmole) was added to a solution of pentamethyldiethylenetriamine (23.3 ml, 155 mmole) in THF (250 ml) at -70° C. The solution was stirred for 5 min and 1,4-difluorobenzene (17.7 g, 155 mmole) in THF was added at -70° C. The solution was stirred for 2 hr during which time it was cooled to -75° C. and 4-cyanopyridine (15.6 g, 150 mmole) in THF was added at -75° C. The mixture was allowed to warm to 25° C. slowly and then quenched with ammonium chloride solution. The mixture was diluted with ether and the organic layer was separated. The organic layer was washed with water and 3N hydrochloric acid. The acid washes were stirred for 2 hr and basified with sodium hydroxide. The basic mixture was extracted with ether and the ether solution concentrated in vacuo. The crude product was purified by chromatography on silica eluting with ethyl acetate-hexane (20:1) to give 4-(2,5-difluorobenzoyl)pyridine (16.9 g, 51.5%). The solution was stirred for 2 hr during which time it to warm to 25° C. slowly quenched with ammonium chloride solution The mixture was diluted with ether the organic layer was separated The organic layer was washed with water and 3N hydrochloric acid The acid washes were stirred for 2 hr and basified with sodium hydroxide The basic mixture was extracted with ether the ether solution concentrated in vacuo The crude product was purified by chromatography on silica eluting with ethyl acetate-hexane (20:1)

Conditions: temp:-80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sec-butyllithium (1.32 M in cyclohexane; 1.25 mL) is added dropwise via syringe over 0.25 h to a stirred solution of 1,4-difluorobenzene (0.162 g) in tetrahydrofuran (THF) (5 mL) at -84° C. under a nitrogen atmosphere. The yellow mixture is stirred for an additional 45 min at -80° C. and then added via a canula over 5 min to a stirred solution of pyridazine 4,5-dicarboxylic acid anhydride (0.22 g; prepared according to J.Het Chem. 14, 1099, (1977)) in THF at -80° C. by nitrogen pressure. The mixture is warmed to room temperature overnight and neutralized with amonium chloride. After removal of THF at reduced pressure the resultant tan solid is treated with an aqueous sodium bicarbonate solution (10 mL) and washed with diethyl ether (10 mL). The aqueous phase is acidified with aqueous hydrochloric acid. The precipitate is collected by filtration, washed with cold water (3×10 mL) and dried to give 4-(2',5'-difluorobenzoyl)pyridazine-5-carboxylic acid (0.23 g) as an off-white solid, m.p. 202°-205° C. After removal of THF at reduced pressure the resultant tan solid is treated with an aqueous sodium bicarbonate solution (10 mL) washed with diethyl ether (10 mL) The precipitate is collected by filtration washed with cold water (3×10 mL) dried

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 0.6 g of sodium hydride, 3.83 g of sodium hydride, 3.83 g of trans-1-methyl-3-phenyl-4-piperidinol of Example 1 and 30 ml of anhydrous DMF is heated to 90° C. for 1.5 hours, then cooled to room temperature. A solution of 2.85 g of p-difluorobenzene in 20 ml of DMF is added all at once; the mixture is stirred at 70°-80° C. under nitrogen for 48 hours. The mixture is cooled and partitioned between ether and saturated aqueous NaCl solution. The aqueous phase is extracted with ether, and the combined ether extracts are washed with water and saturated aqueous NaCl solution and then concentrated in vacuo to an oil. This material is dissolved in 200 ml of dichloromethane, and the solution is extracted with 2 N HCl solution. The dichloromethane phase is successively washed with 10% aqueous NaOH solution, water, saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated in vacuo to afford an oil which crystallizes upon standing. This material is chromatographed on silica gel, using acetone and then 25% methanol/acetone as solvent to obtain trans-4-(4-fluorophenoxy)-1-methyl-3-phenylpiperidine, m.p. s 67°, 69.5°-71.5° C. cooled to room temperature The mixture is cooled partitioned between ether and saturated aqueous NaCl solution The aqueous phase is extracted with ether the combined ether extracts are washed with water and saturated aqueous NaCl solution concentrated in vacuo to an oil This material is dissolved in 200 ml of dichloromethane the solution is extracted with 2 N HCl solution The dichloromethane phase is successively washed with 10% aqueous NaOH solution, water, saturated aqueous NaCl solution dried over anhydrous Na2SO4 concentrated in vacuo to afford an oil which crystallizes This material is chromatographed on silica gel

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 0.6 g of sodium hydride, 3.83 g of sodium hydride, 3.83 g of trans-1-methyl-3-phenyl-4-piperidinol of Example 1 and 30 ml of anhydrous DMF is heated to 90° C. for 1.5 hours, then cooled to room temperature. A solution of 2.85 g of p-difluorobenzene in 20 ml of DMF is added all at once; the mixture is stirred at 70°-80° C. under nitrogen for 48 hours. The mixture is cooled and partitioned between ether and saturated aqueous NaCl solution. The aqueous phase is extracted with ether, and the combined ether extracts are washed with water and saturated aqueous NaCl solution and then concentrated in vacuo to an oil. This material is dissolved in 200 ml of dichloromethane, and the solution is extracted with 2 N HCl solution. The dichloromethane phase is successively washed with 10% aqueous NaOH solution, water, saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated in vacuo to afford an oil which crystallizes upon standing. This material is chromatographed on silica gel, using acetone and then 25% methanol/acetone as solvent to obtain trans-4-(4-fluorophenoxy)-1-methyl-3-phenylpiperidine, m.p. s 67°, 69.5°-71.5° C. cooled to room temperature The mixture is cooled partitioned between ether and saturated aqueous NaCl solution The aqueous phase is extracted with ether the combined ether extracts are washed with water and saturated aqueous NaCl solution concentrated in vacuo to an oil This material is dissolved in 200 ml of dichloromethane the solution is extracted with 2 N HCl solution The dichloromethane phase is successively washed with 10% aqueous NaOH solution, water, saturated aqueous NaCl solution dried over anhydrous Na2SO4 concentrated in vacuo to afford an oil which crystallizes This material is chromatographed on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1,4-difluorobenzene (10 g, 87.6 mmol, 1 wt) in THF (175 mL, 17.5 vol) was stirred under nitrogen and cooled to −75 to −78° C. n-Butyllithium (82 mL of 1.6 M solution in hexanes, 131.4 mmol, 1.5 eq) was added to the reaction mixture over approximately 20 minutes while maintaining the temperature at <−65° C. After a further hour, DMF (10.16 mL, 131.4 mmol, 1.5 eq) was added over approximately 10 minutes while maintaining the temperature <−65° C. The reaction mixture was quenched after 10 minutes by the addition of acetic acid (17.5 mL, 1.75 mL) directly followed by water (440 mL, 36.4 vol). This caused the reaction to exotherm to 5° C. The cold bath was then removed, TBME (220 mL, 22 vol) added and the reaction stirred for 5 minutes. The phases were separated and the aqueous phase extracted with TBME (2×220 mL, 22 vol). The organic phases were combined, washed with 0.2 M HCl (220 mL, 22 vol), 2 M Na2CO3 (220 mL, 22 vol) then saturated brine (220 mL, 22 vol), dried over magnesium sulphate (50 g, 5 wt) and concentrated on a rotary evaporator to afford the crude product (11.07 g). Purification by Kugelrohr distillation gave the product as a clear, colourless oil (7.52 g, 60%) was added to the reaction mixture over approximately 20 minutes while maintaining the temperature at <−65° C After a further hour while maintaining the temperature <−65° C The reaction mixture was quenched after 10 minutes by the addition of acetic acid (17.5 mL, 1.75 mL) the reaction to exotherm to 5° C The cold bath was then removed TBME (220 mL, 22 vol) added The phases were separated the aqueous phase extracted with TBME (2×220 mL, 22 vol) washed with 0.2 M HCl (220 mL, 22 vol), 2 M Na2CO3 (220 mL, 22 vol) saturated brine (220 mL, 22 vol), dried over magnesium sulphate (50 g, 5 wt) concentrated on a rotary evaporator to afford the crude product (11.07 g) Purification by Kugelrohr distillation