2-(chloromethyl)-4-fluoro-1-methoxybenzene

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

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

Procedure: Alternatively, the following method may be used. Magnesium turnings (21.6 g, 0.888 mole, 2 eq.) and diethyl ether (300 ml) were loaded in a reactor under N2. A solution of 5-fluoro-2-methoxybenzyl chloride (116 g, 0.664 mole, 1.5 eq.) in diethyl ether (200 ml) was loaded in an addition funnel. Iodine crystals and a small amount of the 5-fluoro-2-methoxybenzyl chloride solution were added and the reaction mixture was stirred to initiate the reaction. The remainder of the 5-fluoro-2 methoxybenzyl chloride solution was then added drop-wise maintaining the temperature of the reaction mixture below 28° C. The mixture was stirred for another 5 minutes at 19° C. after completion of the addition and a white suspension was formed. A solution of (4-Benzyl-morpholin-2-yl)-phenyl-methanone (125 g, 0.444 mole) in diethyl ether (1.8 L) was added drop-wise, maintaining the temperature of the reaction mixture below 25° C. The suspension obtained was stirred for 2 hours. The reaction mixture was quenched through the addition of a saturated aqueous NaHCO3 solution (625 ml) and water (500 ml), maintaining the temperature below 20° C. The mixture was stirred for 30 minutes and the solids were filtered, washed with water (125 ml) and diethyl ether (200 ml). The filtrates were loaded into a separation funnel and the layers were separated. The aqueous layer was extracted with diethyl ether (1 L). The organic layers were combined and dried over MgSO4, filtered and the filter cake was washed with diethyl ether (100 ml). The filtrates were concentrated under vacuum. The yield of title compound was 201 g as a yellow solid (107%). Title compound (200 g, 0.474 mole) was then suspended in isopropanol (400 ml) under N2. The suspension was heated under reflux until all solids were dissolved. The solution is allowed to cool to 20° C. over 4 hours under stirring. The solid is filtered, washed with isopropanol (100 ml) and dried at 40° C. under vacuum. The yield of pure title compound is 158 g (79%). 1H-NMR (CDCl3): 6.99-7.26 ppm, 10H, mp; 6.60-6.71 ppm, 1H, dt; 6.49-6.60 ppm, 1H, dd; 6.31-6.44 ppm, 1H, dd; 3.92-4.01 ppm, 1H, dt; 3.80-3.90 ppm, 1H, dd; 3.64-3.73 ppm, 1H, dd; 3.59-3.64 ppm, 1H, d; 3.52-3.59 ppm, 3+1 H, 2s; 3.37-3.45 ppm, 1H, d; 3.07-3.17 ppm, 1H, d; 2.84-2.92 ppm, 1H, d; 2.43-2.53 ppm, 1H, d; 2.20-2.28 ppm, 1H, d; 1.98-2.11 ppm, 2H, mp. the reaction maintaining the temperature of the reaction mixture below 28° C The mixture was stirred for another 5 minutes at 19° C. after completion of the addition a white suspension was formed maintaining the temperature of the reaction mixture below 25° C The suspension obtained was stirred for 2 hours The reaction mixture was quenched through the addition of a saturated aqueous NaHCO3 solution (625 ml) and water (500 ml) maintaining the temperature below 20° C The mixture was stirred for 30 minutes the solids were filtered washed with water (125 ml) and diethyl ether (200 ml) The filtrates were loaded into a separation funnel the layers were separated The aqueous layer was extracted with diethyl ether (1 L) dried over MgSO4 filtered the filter cake was washed with diethyl ether (100 ml) The filtrates were concentrated under vacuum

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

Procedure: The procedure for the synthesis of example 1a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, was followed using 2-chloromethyl-4-fluoro-1-methoxy-benzene (synthesized as described above) as starting material making non-critical variations, to yield the title compound which was taken without further purification in the next step. LCMS (6 minutes method) [M+H]+=422 @ Rt 2.85 min. major peak.

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

Procedure: The procedure for the synthesis of example 1a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, was followed using 2-chloromethyl-4-fluoro-1-methoxy-benzene (synthesized as described above) as starting material making non-critical variations, to yield the title compound which was taken without further purification in the next step. LCMS (6 minutes method) [M+H]+=422 @ Rt 2.85 min. major peak.

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Neat (5-Fluoro-2-methoxy-phenyl)-methanol (19.587 g, 1 equiv.) was added to neat SOCl2 (42.2 mL, 4.6 equiv.) at −78° C. under a nitrogen atmosphere and the solution was then allowed to warn to room temperature and stirred until evolution of gas had ceased. An equivalent volume of anhydrous toluene was added to the flask and the solution heated to 60° C. On cooling the reaction solution was poured onto ice water. The toluene layer was separated and dried (MgSO4) and the solvent removed under reduced pressure. The crude material was sublimed (60-80° C./0.05 mBarr) to give the title compound as a white solid (13.40 g, 61%). 1H NMR (300 MHz, CDCl3): δ 3.87 (s, 3H), 4.60 (s, 2H), 6.79-7.20 (m, 3H). to warn to room temperature On cooling the reaction solution was poured onto ice water The toluene layer was separated dried (MgSO4) the solvent removed under reduced pressure (60-80° C./0.05 mBarr)

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

Procedure: 0.870 g (5.00 mmol) of 2-chloromethyl-4-fluoro-1-methoxy-benzene [B. Maziére, N. Dat-Xuong, Chim. Ther. (3), 1-9(1968)] and 0.83 ml of 3-chloro-1-propanol were dissolved in 4.8 ml of N,N-dimethylformamide. 0.267 g (6.23 mmol) of sodium hydride (55% dispersion in mineral oil) was added in small portions over 2 hours keeping the temperature at 10-15° C. After 1 hour stirring at room temperature, 0.032 g (0.75 mmol) of sodium hydride dispersion was added and the mixture stirred another 3 hours. Thereupon, the reaction mixture was poured into 50 ml of ice-water and extracted three times with 100 ml of ether. The combined ether phases were subsequently washed with water, dried over magnesium sulphate and evaporated on a rotary evaporator at a maximum 40° C. The residue (1.5 g) which was thereby obtained was chromatographed on silica gel with dichloromethane/hexane (1:1). There was thus obtained 0.928 g (3.99 mmol), 80%, 2-(3-chloro-propoxymethyl)-4-fluoro-1-methoxy-benzene as a colorless oil: MS: 232, 234 (M)+. at 10-15° C the mixture stirred another 3 hours extracted three times with 100 ml of ether The combined ether phases were subsequently washed with water dried over magnesium sulphate evaporated on a rotary evaporator at a maximum 40° C

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

Procedure: 19.0 g (0.12 mol) of (5-fluoro-2-methoxyphenyl)methanol are dissolved in 105 ml of dichloromethane. One drop of DMF is added, and 26.6 ml (0.37 mol) of thionyl chloride are then added slowly. The solution is stirred at RT for 2 hours and evaporated under reduced pressure. The residue is taken up in ethyl acetate, the mixture is cooled and admixed with water and then washed with saturated sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated under reduced pressure. evaporated under reduced pressure the mixture is cooled washed with saturated sodium bicarbonate solution and water dried over magnesium sulphate evaporated under reduced pressure

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

Procedure: 19.0 g (0.12 mol) of (5-fluoro-2-methoxyphenyl)methanol are dissolved in 105 ml of dichloromethane. One drop of DMF is added, and 26.6 ml (0.37 mol) of thionyl chloride are then added slowly. The solution is stirred at RT for 2 hours and evaporated under reduced pressure. The residue is taken up in ethyl acetate, the mixture is cooled and admixed with water and then washed with saturated sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated under reduced pressure. evaporated under reduced pressure the mixture is cooled washed with saturated sodium bicarbonate solution and water dried over magnesium sulphate evaporated under reduced pressure

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

Procedure: Neat (5-Fluoro-2-methoxy-phenyl)-methanol (19.587 g, 1 equiv.) is added to neat SOCl2 (42.2 mL, 4.6 equiv.) at −78° C. under a nitrogen atmosphere and the solution is then allowed to warm to room temperature and stirred until evolution of gas ceases. An equivalent volume of anhydrous toluene is added to the flask and the solution heated to 60° C. On cooling, the reaction solution is poured onto ice water. The toluene layer is separated and dried (MgSO4) and the solvent removed under reduced pressure. The crude material is sublimed (60-80° C./0.05 mBarr) to give the title compound as a white solid (13.40 g, 61%). MW 174.60; C8H8ClFO; 1H NMR (CDCl3): 3.87 (s, 3H), 4.60 (s, 2H), 6.79-7.20 (m, 3H). the solution heated to 60° C On cooling the reaction solution is poured onto ice water The toluene layer is separated dried (MgSO4) the solvent removed under reduced pressure (60-80° C./0.05 mBarr)

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

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

Procedure: Neat (5-Fluoro-2-methoxy-phenyl)-methanol (19.587 g, 1 equiv.) is added to neat SOCl2 (42.2 mL, 4.6 equiv.) at −78° C. under a nitrogen atmosphere and the solution is then allowed to warm to room temperature and stirred until evolution of gas ceases. An equivalent volume of anhydrous toluene is added to the flask and the solution heated to 60° C. On cooling, the reaction solution is poured onto ice water. The toluene layer is separated and dried (MgSO4) and the solvent removed under reduced pressure. The crude material is sublimed (60-80° C./0.05 mBarr) to give the title compound as a white solid (13.40 g, 61%). MW 174.60; C8H8ClFO; 1H NMR (CDCl3): 3.87 (s, 3H), 4.60 (s, 2H), 6.79-7.20 (m, 3H). the solution heated to 60° C On cooling the reaction solution is poured onto ice water The toluene layer is separated dried (MgSO4) the solvent removed under reduced pressure (60-80° C./0.05 mBarr)

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

Procedure: 19.0 g (0.12 mol) of (5-fluoro-2-methoxyphenyl)methanol are dissolved in 105 ml of dichloromethane. One drop of DMF is added, and 26.6 ml (0.37 mol) of thionyl chloride are then added slowly. The solution is stirred at RT for 2 hours and evaporated under reduced pressure. The residue is taken up in ethyl acetate, the mixture is cooled and admixed with water and then washed with saturated sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated under reduced pressure. evaporated under reduced pressure the mixture is cooled washed with saturated sodium bicarbonate solution and water dried over magnesium sulphate evaporated under reduced pressure