1-(3-hydroxyphenyl)propan-1-one

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

Conditions: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-(3-hydroxy-phenyl)-propan-1-one (5 g, 0.03 mol), paraformaldehyde (1 g, 0.03 mol), dimethylamine hydrochloride (3 g, 0.04 mol), hydrochloric acid (3.4 ml, 30%) and isopropanol (15 ml) was refluxed for 16 hours. Isopropanol was distilled off from the reaction mixture and resulting reaction mass was cooled to 25-30° C. Water (15 ml) was added to the reaction mass and washed with isopropyl ether (2×15 ml). Layers were separated and aqueous layer was added to a stirred mixture of aqueous sodium hydroxide solution (1.2 g in 16 ml water) and methyl tert-butyl ether (25 ml). Layers were separated. Organic layer was washed with water (10 ml), dried and solvent was distilled to give 3.45 g of the title compound. was refluxed for 16 hours Isopropanol was distilled off from the reaction mixture resulting reaction mass washed with isopropyl ether (2×15 ml) Layers were separated aqueous layer was added to a stirred mixture of aqueous sodium hydroxide solution (1.2 g in 16 ml water) and methyl tert-butyl ether (25 ml) Layers were separated Organic layer was washed with water (10 ml) dried solvent was distilled

Conditions: temp:32.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 1-(3-hydroxy-phenyl)-propan-1-one (2 kg, 13.32 mol) and potassium carbonate (3.681 kg, 26.64 mol) in dichloromethane (20 L), p-toluenesulfonyl chloride (2.8 kg, 14.65 mol) was added at 30-35° C. The reaction mixture was stirred at 30-35° C. for 1 hour. Reaction mixture was diluted with dichloromethane (10 L) and washed with water (2×10 L). Dichloromethane layer separated, dried and solvent distilled off to give title compound. Cyclohexane (10 L) was added to the resulting product at 65-70° C. and stirred for 2 hours. Mixture was cooled to ambient temperature, filtered and dried to give 3.87 kg the title compound. was added at 30-35° C Reaction mixture washed with water (2×10 L) Dichloromethane layer separated dried solvent distilled off

Conditions: temp:32.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 1-(3-hydroxy-phenyl)-propan-1-one (2 kg, 13.32 mol) and potassium carbonate (3.681 kg, 26.64 mol) in dichloromethane (20 L), p-toluenesulfonyl chloride (2.8 kg, 14.65 mol) was added at 30-35° C. The reaction mixture was stirred at 30-35° C. for 1 hour. Reaction mixture was diluted with dichloromethane (10 L) and washed with water (2×10 L). Dichloromethane layer separated, dried and solvent distilled off to give title compound. Cyclohexane (10 L) was added to the resulting product at 65-70° C. and stirred for 2 hours. Mixture was cooled to ambient temperature, filtered and dried to give 3.87 kg the title compound. was added at 30-35° C Reaction mixture washed with water (2×10 L) Dichloromethane layer separated dried solvent distilled off

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

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

Procedure: For the preparation of the preferred aryl alkyl ketones a Friedel-Crafts reaction can be used, e.g., to effect reaction according to the following general format ##STR7## wherein R" is the residue of the desired aryl (Ar) group and R1 is the residue of the carboxylic acyl halide. For example, the 6-methoxy-2-naphthyl propiophenone can be prepared by reacting 6-methoxynaphthalene with propionyl chloride in the presence of aluminum chloride in methylene chloride. The resulting 6-methoxy-2-naphthyl ethyl ketone is converted to the ketal starting material for this process by reacting it with trimethyl orthoformate in the presence of acid. The 3-phenoxyphenyl ethyl ketone ketal can be prepared by reacting 3-hydroxyphenyl ethyl ketone with phenyl bromide in the presence of potassium carbonate to form 3-phenoxyphenyl ethyl ketone and then reacting this ketone with trimethylorthoformate to form the ketal. The ketal of 2-fluoro-4-biphenylyl ethyl ketone is formed by reacting 2-fluoro-4-biphenylyl ethyl ketone with trimethylorthoformate to form the ketal. The 2-fluoro-4-biphenylyl ethyl ketone can be prepared from 4-bromopropiophenone via 4'-bromo-3'-nitropropiophenone (see Chemical Abstracts, 61, p. 8232g), 4-propionyl-2-nitrobiphenyl (Ullman reaction), 4-propionyl-2-aminobiphenyl (reduction) and finally the Schiemann Reaction. See U.S. Pat. No. 3,793,457, Example 1 for a similar synthesis of 2-fluoro-4-biphenyl methyl ketone. The difluorobiphenyl ketone can be prepared by reacting 4-cyano-2,2'-difluorobiphenyl with ethyl magnesium bromide to form the di-fluoro biphenylyl ethyl ketone. See U.S. Pat. No. 3,755,427. This ketone can be converted to the ketal by the procedure described above. a Friedel-Crafts reaction reaction

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

Procedure: For the preparation of the preferred aryl alkyl ketones a Friedel-Crafts reaction can be used, e.g., to effect reaction according to the following general format ##STR7## wherein R" is the residue of the desired aryl (Ar) group and R1 is the residue of the carboxylic acyl halide. For example, the 6-methoxy-2-naphthyl propiophenone can be prepared by reacting 6-methoxynaphthalene with propionyl chloride in the presence of aluminum chloride in methylene chloride. The resulting 6-methoxy-2-naphthyl ethyl ketone is converted to the ketal starting material for this process by reacting it with trimethyl orthoformate in the presence of acid. The 3-phenoxyphenyl ethyl ketone ketal can be prepared by reacting 3-hydroxyphenyl ethyl ketone with phenyl bromide in the presence of potassium carbonate to form 3-phenoxyphenyl ethyl ketone and then reacting this ketone with trimethylorthoformate to form the ketal. The ketal of 2-fluoro-4-biphenylyl ethyl ketone is formed by reacting 2-fluoro-4-biphenylyl ethyl ketone with trimethylorthoformate to form the ketal. The 2-fluoro-4-biphenylyl ethyl ketone can be prepared from 4-bromopropiophenone via 4'-bromo-3'-nitropropiophenone (see Chemical Abstracts, 61, p. 8232g), 4-propionyl-2-nitrobiphenyl (Ullman reaction), 4-propionyl-2-aminobiphenyl (reduction) and finally the Schiemann Reaction. See U.S. Pat. No. 3,793,457, Example 1 for a similar synthesis of 2-fluoro-4-biphenyl methyl ketone. The difluorobiphenyl ketone can be prepared by reacting 4-cyano-2,2'-difluorobiphenyl with ethyl magnesium bromide to form the di-fluoro biphenylyl ethyl ketone. See U.S. Pat. No. 3,755,427. This ketone can be converted to the ketal by the procedure described above. a Friedel-Crafts reaction reaction

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

Procedure: For the preparation of the preferred aryl alkyl ketones a Friedel-Crafts reaction can be used, e.g., to effect reaction according to the following general format ##STR7## wherein R" is the residue of the desired aryl (Ar) group and R1 is the residue of the carboxylic acyl halide. For example, the 6-methoxy-2-naphthyl propiophenone can be prepared by reacting 6-methoxynaphthalene with propionyl chloride in the presence of aluminum chloride in methylene chloride. The resulting 6-methoxy-2-naphthyl ethyl ketone is converted to the ketal starting material for this process by reacting it with trimethyl orthoformate in the presence of acid. The 3-phenoxyphenyl ethyl ketone ketal can be prepared by reacting 3-hydroxyphenyl ethyl ketone with phenyl bromide in the presence of potassium carbonate to form 3-phenoxyphenyl ethyl ketone and then reacting this ketone with trimethylorthoformate to form the ketal. The ketal of 2-fluoro-4-biphenylyl ethyl ketone is formed by reacting 2-fluoro-4-biphenylyl ethyl ketone with trimethylorthoformate to form the ketal. The 2-fluoro-4-biphenylyl ethyl ketone can be prepared from 4-bromopropiophenone via 4'-bromo-3'-nitropropiophenone (see Chemical Abstracts, 61, p. 8232g), 4-propionyl-2-nitrobiphenyl (Ullman reaction), 4-propionyl-2-aminobiphenyl (reduction) and finally the Schiemann Reaction. See U.S. Pat. No. 3,793,457, Example 1 for a similar synthesis of 2-fluoro-4-biphenyl methyl ketone. The difluorobiphenyl ketone can be prepared by reacting 4-cyano-2,2'-difluorobiphenyl with ethyl magnesium bromide to form the di-fluoro biphenylyl ethyl ketone. See U.S. Pat. No. 3,755,427. This ketone can be converted to the ketal by the procedure described above. a Friedel-Crafts reaction reaction

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

Procedure: For the preparation of the preferred aryl alkyl ketones, a Friedel-Crafts reaction can be used, e.g., to effect reaction according to the following general format ##STR7## wherein R" is the residue of the desired aryl (Ar) group and R1 is the residue of the carboxylic acyl halide. For example, the 6-methoxy-2-naphthyl propiophenone can be prepared by reacting 6-methoxynaphthalene with propionyl chloride in the presence of aluminum chloride in methylene chloride. The resulting 6-methoxy-2-naphthyl ethyl ketone is converted to the methyl enol ether starting material for this process by reacting it with trimethyl orthoformate in the presence of acid and heating in vacuo. The 3-phenoxyphenyl ethyl ketone methyl enol ether can be prepared by reacting 3-hydroxyphenyl ethyl ketone with phenyl bromide in the presence of potassium carbonate to form 3-phenoxyphenyl ethyl ketone and then reacting this ketone with trimethylorthoformate to form the ketal followed by heating with acid. The enol ether of 2-fluoro-4-biphenylyl ethyl ketone is formed by reacting 2-fluoro-4-biphenylyl ethyl ketone with trimethylorthoformate to form the ketal, then heating with p-toluenesulfonic acid in vacuo. The 2-fluoro-4-biphenylyl ethyl ketone can be prepared from 4-bromopropiophenone via 4'-bromo-3'-nitropropiophenone (See Chemical Abstracts, 61, p. 8232g), 4-propionyl-2-nitrobiphenyl (Ullman reaction), 4-propionyl-2-aminobiphenyl (reduction) and finally the Schiemann Reaction. See U.S. Patent No. 3,793,457, Example 1, for a similar synthesis of 2-fluoro-4-biphenylyl methyl ketone. The difluorobiphenyl ketone can be prepared by reacting 4-cyano-2,2'-difluorobiphenyl with ethyl magnesium bromide to form the difluoro biphenylyl ethyl ketone. See U.S. Pat. No. 3,755,427. This ketone can be converted to the enol ether by the procedure described above. A preferred method for preparing the enol ether for preparing ibuprofen esters according to this invention is set forth in the detailed examples below. a Friedel-Crafts reaction reaction heating in vacuo

Conditions: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-(3-hydroxy-phenyl)-propan-1-one (5 g, 0.03 mol), paraformaldehyde (1 g, 0.03 mol), dimethylamine hydrochloride (3 g, 0.04 mol), hydrochloric acid (3.4 ml, 30%) and isopropanol (15 ml) was refluxed for 16 hours. Isopropanol was distilled off from the reaction mixture and resulting reaction mass was cooled to 25-30° C. Water (15 ml) was added to the reaction mass and washed with isopropyl ether (2×15 ml). Layers were separated and aqueous layer was added to a stirred mixture of aqueous sodium hydroxide solution (1.2 g in 16 ml water) and methyl tert-butyl ether (25 ml). Layers were separated. Organic layer was washed with water (10 ml), dried and solvent was distilled to give 3.45 g of the title compound. was refluxed for 16 hours Isopropanol was distilled off from the reaction mixture resulting reaction mass washed with isopropyl ether (2×15 ml) Layers were separated aqueous layer was added to a stirred mixture of aqueous sodium hydroxide solution (1.2 g in 16 ml water) and methyl tert-butyl ether (25 ml) Layers were separated Organic layer was washed with water (10 ml) dried solvent was distilled

Conditions: temp:32.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 1-(3-hydroxy-phenyl)-propan-1-one (2 kg, 13.32 mol) and potassium carbonate (3.681 kg, 26.64 mol) in dichloromethane (20 L), p-toluenesulfonyl chloride (2.8 kg, 14.65 mol) was added at 30-35° C. The reaction mixture was stirred at 30-35° C. for 1 hour. Reaction mixture was diluted with dichloromethane (10 L) and washed with water (2×10 L). Dichloromethane layer separated, dried and solvent distilled off to give title compound. Cyclohexane (10 L) was added to the resulting product at 65-70° C. and stirred for 2 hours. Mixture was cooled to ambient temperature, filtered and dried to give 3.87 kg the title compound. was added at 30-35° C Reaction mixture washed with water (2×10 L) Dichloromethane layer separated dried solvent distilled off

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