methyl 4-(4-chlorophenyl)-4-oxobutanoate

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 179 g (0.79 mole) of methyl-3-(4-chlorobenzoyl)propionate in 175 mL of dichloromethane was cooled to 0° and treated dropwise with 69.8 mL (117.3 g; 0.86 mole, d=1.68) of sulfuryl chloride. After the addition was complete, the cold bath was removed, and the reaction mixture was allowed to warm to room temperature while stirring overnight. The mixture was treated with 100 mL of water and basified cautiously with 50% sodium hydroxide. The layers were separated, the dichloromethane layer dried over magnesium sulfate and evaporated under reduced pressure (245.3 g). The residue was purified by vacuum distillation (135° C./0.3 mm) to obtain three fractions for a total of 198.6 g (96%). After the addition the cold bath was removed The mixture was treated with 100 mL of water and basified cautiously with 50% sodium hydroxide The layers were separated the dichloromethane layer dried over magnesium sulfate evaporated under reduced pressure (245.3 g) The residue was purified by vacuum distillation (135° C./0.3 mm) to obtain three fractions for a total of 198.6 g (96%)

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

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

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

Procedure: By the procedure described for the preparation of methyl 3-(4-chlorobenzoyl)propanoate (see Example 1), 4-chlorobenzaldehyde (22.48 g), methyl pent-2-enoate (13.65 g), and sodium cyanide (3.92 g) in dry dimethylformamide (DMF: 250 ml), followed by column chromatography on silica gel using dichloromethane: 40°-60° petrol (1:2) as eluent, gave methyl 3-(4-chlorobenzoyl)pentanoate (6.5 g, 21%) as a yellow oil.

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-chlorobenzaldehyde (23.4 g) in dry dimethylformamide (DMF: 100 ml) was added over 10 minutes to a stirred mixture of sodium cyanide (4.0 g) and dry DMF (200 ml). After 5 minutes a solution of methyl acrylate (10.75 g) in dry DMF (100 ml) was added to the reaction mixture over 20 minutes. The temperature of the reaction mixture was maintained at 35° C. throughout both additions and then for a further 3 hours before it was poured into water and extracted with diethyl ether. The extracts were washed successively with water (several times), dilute sulphuric acid, aqueous sodium bicarbonate, and water, before drying over magnesium sulphate and concentration under reduced pressure to give methyl 3-(4-chlorobenzoyl)propanoate (24.4 g, 86%) as a yellow solid. extracted with diethyl ether The extracts were washed successively with water (several times), dilute sulphuric acid, aqueous sodium bicarbonate, and water before drying over magnesium sulphate and concentration under reduced pressure

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

Procedure: A solution of 179 g (0.79 mole) of methyl-3-(4-chlorobenzoyl)propionate in 175 mL of dichloromethane was cooled to 0° and treated dropwise with 69.8 mL (117.3 g; 0.86 mole, d=1.68) of sulfuryl chloride. After the addition was complete, the cold bath was removed, and the reaction mixture was allowed to warm to room temperature while stirring overnight. The mixture was treated with 100 mL of water and basified cautiously with 50% sodium hydroxide. The layers were separated, the dichloromethane layer dried over magnesium sulfate and evaporated under reduced pressure (245.3 g). The residue was purified by vacuum distillation (135° C./0.3 mm) to obtain three fractions for a total of 198.6 g (96%). After the addition the cold bath was removed The mixture was treated with 100 mL of water and basified cautiously with 50% sodium hydroxide The layers were separated the dichloromethane layer dried over magnesium sulfate evaporated under reduced pressure (245.3 g) The residue was purified by vacuum distillation (135° C./0.3 mm) to obtain three fractions for a total of 198.6 g (96%)

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

Procedure: A solution of 179 g (0.79 mole) of methyl-3-(4-chlorobenzoyl)propionate in 175 mL of dichloromethane was cooled to 0° and treated dropwise with 69.8 mL (117.3 g; 0.86 mole, d=1.68) of sulfuryl chloride. After the addition was complete, the cold bath was removed, and the reaction mixture was allowed to warm to room temperature while stirring overnight. The mixture was treated with 100 mL of water and basified cautiously with 50% sodium hydroxide. The layers were separated, the dichloromethane layer dried over magnesium sulfate and evaporated under reduced pressure (245.3 g). The residue was purified by vacuum distillation (135° C./0.3 mm) to obtain three fractions for a total of 198.6 g (96%). After the addition the cold bath was removed The mixture was treated with 100 mL of water and basified cautiously with 50% sodium hydroxide The layers were separated the dichloromethane layer dried over magnesium sulfate evaporated under reduced pressure (245.3 g) The residue was purified by vacuum distillation (135° C./0.3 mm) to obtain three fractions for a total of 198.6 g (96%)

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

Procedure: Sodium borohydride (1.3 g, 35 mmol) was added portionwise to a stirred solution of methyl 3-(4-chlorobenzoyl)propionate (5.3 g, 23 mmol) in methanol (50 ml) at 0° C. The mixture was allowed to warm up to room temperature, stirred for 4 h and partitioned between 1M aqueous hydrochloric acid (100 ml) and DCM (150 ml). The organic layer was separated and the aqueous layer extracted with DCM 2×100 ml). The combined extracts were dried over anhydrous sodium sulphate, filtered and concentrated to give crude methyl 4-(4-chlorophenyl)-4-hydroxybutanoate which was dissolved in methanol (40 ml). Sodium hydride (80% dispersion in oil: 100 mg, 3 mmol) was added, the mixture stirred for 1 h, and partitioned between aqueous 1M hydrochloric acid (50 ml) and ethyl acetate (100 ml). The organic layer was separated and the aqueous layer extracted with ethyl acetate (100 ml). The combined organics were dried over anhydrous potassium carbonate, filtered and concentrated to give 5-(4-chlorophenyl)-gamma-butyrolactone (3.85 g, 83%) as a colourless oil. partitioned between 1M aqueous hydrochloric acid (100 ml) and DCM (150 ml) The organic layer was separated the aqueous layer extracted with DCM 2×100 ml) The combined extracts were dried over anhydrous sodium sulphate filtered concentrated

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

Procedure: Thionyl chloride (2.4 ml, 33 mmol) was added dropwise to a stirred solution of 3-(4-chlorobenzoyl)propionic acid (5.0 g, 24 mmol) in dry methanol (50 ml) at 0° C. The mixture was heated at reflux for 2 h, cooled and the solvent removed under reduced pressure to give methyl 3-(4-chlorobenzoyl)propionate (5.3 g, 97%) as a colourless oil. deltaH (250 MHz, CDCl3) 7.93 (2H, d, J 8.5 Hz), 7.45 (2H, d, J 8.6 Hz), 3.72 (3H, s), 3.29 (2H, t, J 6.6 Hz), 2.78 (2H, t, J 6.6 Hz). The mixture was heated at reflux for 2 h cooled the solvent removed under reduced pressure

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

Procedure: Sodium borohydride (1.3 g, 35 mmol) was added portionwise to a stirred solution of methyl 3-(4-chlorobenzoyl)propionate (5.3 g, 23 mmol) in methanol (50 ml) at 0° C. The mixture was allowed to warm up to room temperature, stirred for 4 h and partitioned between 1M aqueous hydrochloric acid (100 ml) and DCM (150 ml). The organic layer was separated and the aqueous layer extracted with DCM 2×100 ml). The combined extracts were dried over anhydrous sodium sulphate, filtered and concentrated to give crude methyl 4-(4-chlorophenyl)-4-hydroxybutanoate which was dissolved in methanol (40 ml). Sodium hydride (80% dispersion in oil: 100 mg, 3 mmol) was added, the mixture stirred for 1 h, and partitioned between aqueous 1M hydrochloric acid (50 ml) and ethyl acetate (100 ml). The organic layer was separated and the aqueous layer extracted with ethyl acetate (100 ml). The combined organics were dried over anhydrous potassium carbonate, filtered and concentrated to give 5-(4-chlorophenyl)-gamma-butyrolactone (3.85 g, 83%) as a colourless oil. partitioned between 1M aqueous hydrochloric acid (100 ml) and DCM (150 ml) The organic layer was separated the aqueous layer extracted with DCM 2×100 ml) The combined extracts were dried over anhydrous sodium sulphate filtered concentrated

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

Procedure: Thionyl chloride (2.4 ml, 33 mmol) was added dropwise to a stirred solution of 3-(4-chlorobenzoyl)propionic acid (5.0 g, 24 mmol) in dry methanol (50 ml) at 0° C. The mixture was heated at reflux for 2 h, cooled and the solvent removed under reduced pressure to give methyl 3-(4-chlorobenzoyl)propionate (5.3 g, 97%) as a colourless oil. deltaH (250 MHz, CDCl3) 7.93 (2H, d, J 8.5 Hz), 7.45 (2H, d, J 8.6 Hz), 3.72 (3H, s), 3.29 (2H, t, J 6.6 Hz), 2.78 (2H, t, J 6.6 Hz). The mixture was heated at reflux for 2 h cooled the solvent removed under reduced pressure