3,5-dimethyl-4-phenylmethoxyphenol

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

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

Procedure: A solution of 18.0 g (75 mmol) of 3,5-dimethyl-4-(phenylmethoxy)benzaldehyde (Example F) and 17.1 g of 85% meta-chloroperbenzoic acid (14.5 g contained; 1.2×75 mmol) in 600 mL of dichloromethane is stirred at reflux for 16 hours. The cooled solution is stirred with 2×150 mL saturated sodium bicarbonate solution, 150 mL of 10% sodium bisulfite solution, then dried (magnesium sulfate) and evaporated leaving 15.2 g of a turbid oil. A solution of the latter in 225 mL of methanol is stirred at ambient temperature with a solution of 12.6 g (3×75 mmol) of potassium hydroxide in 75 mL of water. After 18 hours the methanol is removed on a rotary evaporator and the residual aqueous solution is diluted with 200 mL of water, and back-extracted with 150 mL of diethyl ether. The aqueous solution is acidified with 50 mL of 6N hydrochloric acid solution and the product is isolated with diethyl ether. The diethyl ether solution is washed with brine, dried (magnesium sulfate) and evaporated leaving 8.1 g of a brown solid. The original diethyl ether extract is dried (magnesium sulfate) and evaporated leaving 10.7 g of a light yellow viscous oil. The two fractions are combined and the crude precipitate is chromatographed on a 4.5 cm column containing 250 g of silica gel prepared in toluene. Elution with 98% toluene:2% ethyl acetate affords 16.6 g of the product. Recrystallization from cyclohexane affords the title compound as off-white leaflets; mp 89°-91° C. at reflux for 16 hours dried (magnesium sulfate) evaporated leaving 15.2 g of a turbid oil After 18 hours the methanol is removed on a rotary evaporator the residual aqueous solution is diluted with 200 mL of water back-extracted with 150 mL of diethyl ether the product is isolated with diethyl ether The diethyl ether solution is washed with brine dried (magnesium sulfate) evaporated

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

Procedure: A mixture of 11.3 g (49.6 mmol) of 3,5-dimethyl-4-(phenylmethoxy)phenol (Example G), 13.3 g (1.2×49.6 mmol) of 5-bromo-2,2-dimethylvaleric acid, methyl ester (U.S. Pat. No. 4,665,226) and 8.2 g (1.2×49.6 mmol) of anhydrous potassium carbonate in 300 mL of acetonitrile is stirred at reflux for 18 hours. The reaction flask and inorganic residue are washed with fresh acetonitrile and the solvent is removed. A diethyl ether solution of the residual product is washed with 50 mL of 2N potassium hydroxide solution, brine, dried and evaporated leaving 20.6 g of the product as a pale yellow oil. Distillation through a short path apparatus affords 15.4 g of the title compound; bp 190°-194° C./0.1 mm (230°-240° C). at reflux for 18 hours The reaction flask and inorganic residue are washed with fresh acetonitrile the solvent is removed A diethyl ether solution of the residual product is washed with 50 mL of 2N potassium hydroxide solution, brine dried evaporated

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

Procedure: Using 4.22 g of the compound of Example 15, 2.7 ml of chloromethyloxirane, 2.42 g of anhydrous potassium carbonate and 100 ml of methyl ethyl ketone, reaction and workup carried out as in Example 1-A gave about 4.80 g of 1-(4-benzyloxy-3,5-dimethylphenoxy)-2,3-epoxypropane as yellow oil. Using the epoxy compound thus obtained, 4.04 g of 1-(2-methoxyphenyl)piperazine and 100 ml of dioxane, reaction and workup carried out as in Example 1-A followed by purification by column chromatography (silica gel, eluted with ethyl acetate:hexane=1:1) gave 5.96 g of white crystals, m.p. 93-94° C.

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

Procedure: Using 4.22 g of the compound of Example 15, 2.7 ml of chloromethyloxirane, 2.42 g of anhydrous potassium carbonate and 100 ml of methyl ethyl ketone, reaction and workup carried out as in Example 1-A gave about 4.80 g of 1-(4-benzyloxy-3,5-dimethylphenoxy)-2,3-epoxypropane as yellow oil. Using the epoxy compound thus obtained, 4.04 g of 1-(2-methoxyphenyl)piperazine and 100 ml of dioxane, reaction and workup carried out as in Example 1-A followed by purification by column chromatography (silica gel, eluted with ethyl acetate:hexane=1:1) gave 5.96 g of white crystals, m.p. 93-94° C.

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

Procedure: A solution of 18.0 g (75 mmol) of 3,5-dimethyl-4-(phenylmethoxy)benzaldehyde (Example F) and 17.1 g of 85% meta-chloroperbenzoic acid (14.5 g contained; 1.2×75 mmol) in 600 mL of dichloromethane is stirred at reflux for 16 hours. The cooled solution is stirred with 2×150 mL saturated sodium bicarbonate solution, 150 mL of 10% sodium bisulfite solution, then dried (magnesium sulfate) and evaporated leaving 15.2 g of a turbid oil. A solution of the latter in 225 mL of methanol is stirred at ambient temperature with a solution of 12.6 g (3×75 mmol) of potassium hydroxide in 75 mL of water. After 18 hours the methanol is removed on a rotary evaporator and the residual aqueous solution is diluted with 200 mL of water, and back-extracted with 150 mL of diethyl ether. The aqueous solution is acidified with 50 mL of 6N hydrochloric acid solution and the product is isolated with diethyl ether. The diethyl ether solution is washed with brine, dried (magnesium sulfate) and evaporated leaving 8.1 g of a brown solid. The original diethyl ether extract is dried (magnesium sulfate) and evaporated leaving 10.7 g of a light yellow viscous oil. The two fractions are combined and the crude precipitate is chromatographed on a 4.5 cm column containing 250 g of silica gel prepared in toluene. Elution with 98% toluene:2% ethyl acetate affords 16.6 g of the product. Recrystallization from cyclohexane affords the title compound as off-white leaflets; mp 89°-91° C. at reflux for 16 hours dried (magnesium sulfate) evaporated leaving 15.2 g of a turbid oil After 18 hours the methanol is removed on a rotary evaporator the residual aqueous solution is diluted with 200 mL of water back-extracted with 150 mL of diethyl ether the product is isolated with diethyl ether The diethyl ether solution is washed with brine dried (magnesium sulfate) evaporated

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

Procedure: A mixture of 11.3 g (49.6 mmol) of 3,5-dimethyl-4-(phenylmethoxy)phenol (Example G), 13.3 g (1.2×49.6 mmol) of 5-bromo-2,2-dimethylvaleric acid, methyl ester (U.S. Pat. No. 4,665,226) and 8.2 g (1.2×49.6 mmol) of anhydrous potassium carbonate in 300 mL of acetonitrile is stirred at reflux for 18 hours. The reaction flask and inorganic residue are washed with fresh acetonitrile and the solvent is removed. A diethyl ether solution of the residual product is washed with 50 mL of 2N potassium hydroxide solution, brine, dried and evaporated leaving 20.6 g of the product as a pale yellow oil. Distillation through a short path apparatus affords 15.4 g of the title compound; bp 190°-194° C./0.1 mm (230°-240° C). at reflux for 18 hours The reaction flask and inorganic residue are washed with fresh acetonitrile the solvent is removed A diethyl ether solution of the residual product is washed with 50 mL of 2N potassium hydroxide solution, brine dried evaporated

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

Procedure: Using 4.22 g of the compound of Example 15, 2.7 ml of chloromethyloxirane, 2.42 g of anhydrous potassium carbonate and 100 ml of methyl ethyl ketone, reaction and workup carried out as in Example 1-A gave about 4.80 g of 1-(4-benzyloxy-3,5-dimethylphenoxy)-2,3-epoxypropane as yellow oil. Using the epoxy compound thus obtained, 4.04 g of 1-(2-methoxyphenyl)piperazine and 100 ml of dioxane, reaction and workup carried out as in Example 1-A followed by purification by column chromatography (silica gel, eluted with ethyl acetate:hexane=1:1) gave 5.96 g of white crystals, m.p. 93-94° C.

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

Procedure: A solution of 18.0 g (75 mmol) of 3,5-dimethyl-4-(phenylmethoxy)benzaldehyde (Example F) and 17.1 g of 85% meta-chloroperbenzoic acid (14.5 g contained; 1.2×75 mmol) in 600 mL of dichloromethane is stirred at reflux for 16 hours. The cooled solution is stirred with 2×150 mL saturated sodium bicarbonate solution, 150 mL of 10% sodium bisulfite solution, then dried (magnesium sulfate) and evaporated leaving 15.2 g of a turbid oil. A solution of the latter in 225 mL of methanol is stirred at ambient temperature with a solution of 12.6 g (3×75 mmol) of potassium hydroxide in 75 mL of water. After 18 hours the methanol is removed on a rotary evaporator and the residual aqueous solution is diluted with 200 mL of water, and back-extracted with 150 mL of diethyl ether. The aqueous solution is acidified with 50 mL of 6N hydrochloric acid solution and the product is isolated with diethyl ether. The diethyl ether solution is washed with brine, dried (magnesium sulfate) and evaporated leaving 8.1 g of a brown solid. The original diethyl ether extract is dried (magnesium sulfate) and evaporated leaving 10.7 g of a light yellow viscous oil. The two fractions are combined and the crude precipitate is chromatographed on a 4.5 cm column containing 250 g of silica gel prepared in toluene. Elution with 98% toluene:2% ethyl acetate affords 16.6 g of the product. Recrystallization from cyclohexane affords the title compound as off-white leaflets; mp 89°-91° C. at reflux for 16 hours dried (magnesium sulfate) evaporated leaving 15.2 g of a turbid oil After 18 hours the methanol is removed on a rotary evaporator the residual aqueous solution is diluted with 200 mL of water back-extracted with 150 mL of diethyl ether the product is isolated with diethyl ether The diethyl ether solution is washed with brine dried (magnesium sulfate) evaporated

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

Procedure: A mixture of 11.3 g (49.6 mmol) of 3,5-dimethyl-4-(phenylmethoxy)phenol (Example G), 13.3 g (1.2×49.6 mmol) of 5-bromo-2,2-dimethylvaleric acid, methyl ester (U.S. Pat. No. 4,665,226) and 8.2 g (1.2×49.6 mmol) of anhydrous potassium carbonate in 300 mL of acetonitrile is stirred at reflux for 18 hours. The reaction flask and inorganic residue are washed with fresh acetonitrile and the solvent is removed. A diethyl ether solution of the residual product is washed with 50 mL of 2N potassium hydroxide solution, brine, dried and evaporated leaving 20.6 g of the product as a pale yellow oil. Distillation through a short path apparatus affords 15.4 g of the title compound; bp 190°-194° C./0.1 mm (230°-240° C). at reflux for 18 hours The reaction flask and inorganic residue are washed with fresh acetonitrile the solvent is removed A diethyl ether solution of the residual product is washed with 50 mL of 2N potassium hydroxide solution, brine dried evaporated

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

Procedure: Using 4.22 g of the compound of Example 15, 2.7 ml of chloromethyloxirane, 2.42 g of anhydrous potassium carbonate and 100 ml of methyl ethyl ketone, reaction and workup carried out as in Example 1-A gave about 4.80 g of 1-(4-benzyloxy-3,5-dimethylphenoxy)-2,3-epoxypropane as yellow oil. Using the epoxy compound thus obtained, 4.04 g of 1-(2-methoxyphenyl)piperazine and 100 ml of dioxane, reaction and workup carried out as in Example 1-A followed by purification by column chromatography (silica gel, eluted with ethyl acetate:hexane=1:1) gave 5.96 g of white crystals, m.p. 93-94° C.