4-(2-methoxyethoxy)phenol

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

Procedure: A solution of 4-(2-methoxyethoxy)phenol in toluene (350 ml) was added to a solution of magnesium methoxide in methanol (8% by weight solution, 331 mls), under an atmosphere of argon. The reaction mixture was heated at reflux for 2 hours. Toluene (350 mls) was added and the reaction mixture distilled at atmospheric pressure until the internal temperature reached 92° C. A mixture of paraformaldehyde in toluene (300 ml) was added to the reaction mixture and the reaction mixture was heated at reflux for 3.5 hours. The mixture was cooled to ambient temperature and then stirred at ambient temperature for 18 hours. The reaction mixture was diluted with toluene (400 ml), washed with 2M aqueous hydrochloric acid (2×150 ml) and water (to pH 1). The residue was distilled under vacuum to give 2-hydroxy-5-(2-methoxyethoxy)benzaldehyde as an oil (35 g), bp 104-130° C. [0.01 mm Hg]; NMR(CDCl3): 3.45(3H,s), 3.75(2H,m), 4.12(2H,m), 6.92(1H,d), 7.05(1H,d), 7.2(1H,dd), 9.84(1H,s) and 10.63(1H,s); m/z 197(M+H). The reaction mixture was heated at reflux for 2 hours the reaction mixture distilled at atmospheric pressure until the internal temperature reached 92° C A mixture of paraformaldehyde in toluene (300 ml) was added to the reaction mixture the reaction mixture was heated at reflux for 3.5 hours The reaction mixture was diluted with toluene (400 ml) washed with 2M aqueous hydrochloric acid (2×150 ml) and water (to pH 1) The residue was distilled under vacuum

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

Procedure: A solution of 4-(2-methoxyethoxy)phenol in toluene (350 ml) was added to a solution of magnesium methoxide in methanol (8% by weight solution, 331 mls), under an atmosphere of argon. The reaction mixture was heated at reflux for 2 hours. Toluene (350 mls) was added and the reaction mixture distilled at atmospheric pressure until the internal temperature reached 92° C. A mixture of paraformaldehyde in toluene (300 ml) was added to the reaction mixture and the reaction mixture was heated at reflux for 3.5 hours. The mixture was cooled to ambient temperature and then stirred at ambient temperature for 18 hours. The reaction mixture was diluted with toluene (400 ml), washed with 2M aqueous hydrochloric acid (2×150 ml) and water (to pH 1). The residue was distilled under vacuum to give 2-hydroxy-5-(2-methoxyethoxy)benzaldehyde as an oil (35 g), bp 104-130° C. [0.01 mm Hg]; NMR(CDCl3): 3.45(3H,s), 3.75(2H,m), 4.12(2H,m), 6.92(1H,d), 7.05(1H,d), 7.2(1H,dd), 9.84(1H,s) and 10.63(1H,s); m/z 197(M+H). The reaction mixture was heated at reflux for 2 hours the reaction mixture distilled at atmospheric pressure until the internal temperature reached 92° C A mixture of paraformaldehyde in toluene (300 ml) was added to the reaction mixture the reaction mixture was heated at reflux for 3.5 hours The reaction mixture was diluted with toluene (400 ml) washed with 2M aqueous hydrochloric acid (2×150 ml) and water (to pH 1) The residue was distilled under vacuum

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

Procedure: A mixture of 1-(benzyloxy)-4-(2-methoxyethoxy)benzene (180 g), ethanol (2000 ml) and palladium on carbon catalyst (20 g) was stirred under an atmosphere of hydrogen, at room temperature and atmospheric pressure. After the theoretical quantity of hydrogen had been consumed, the reaction mixture was filtered. The filtrate was evaporated to give a solid which was crystallised from a mixture of ethyl acetate and n-hexane to give 4-(2-methoxyethoxy)phenol as a solid (94.7 g) m.p. 97.9° C.; microanalysis, found: C, 64.3%; H, 7.4%; C9H12O3 requires: C, 64.3%; H, 7.2%; NMR: 3.35(3H,s), 3.6(2H,m), 3.95(2H,m), 6.7(4H,m) and 8.9(1H,s); m/z 169(M+H). After the theoretical quantity of hydrogen had been consumed the reaction mixture was filtered The filtrate was evaporated to give a solid which was crystallised from a mixture of ethyl acetate and n-hexane

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

Procedure: 1.42 g (5 mmol) of the compound obtained in Step 1 was dissolved in 20 ml of acetonitrile, 1.38 g (10 mmol) of K2CO3 and 0.84 g (5 mmol) of 4-(2-methoxyethoxy)phenol were added thereto, which was refluxed for 15 hours. The reaction mixture was distilled under a reduced pressure to remove the solvent, and 20 ml of ethyl acetate was added thereto. The resulting mixture was washed twice with water, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The concentrate was subjected to column chromatography using 20% ethyl acetate/hexane to obtain 1.76 g (yield 95%) of 1-(2-bromo-5-chlorobenzyloxy)-4-(2-methoxyethoxy)benzene. which was refluxed for 15 hours The reaction mixture was distilled under a reduced pressure to remove the solvent, and 20 ml of ethyl acetate was added The resulting mixture was washed twice with water dried over anhydrous MgSO4 concentrated under a reduced pressure

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 60% sodium hydride (436 mg, 18.2 mmol) in DMF (2.0 mL) was added hydroquinone (1.0 g, 18.2 mmol) in DMF (10.0 mL) dropwisely. The solution was added with 2-methoxyethyl 4-methylbenzenesulfonate (12-2, 2.10 g, 21.8 mmol) dropwisely. The reaction was stirred at 65° C. for 16 h. The solution was cooled to room temperature, poured into icy H2O, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 4-(2-methoxyethoxy)phenol (12-3, 1.0 g), which was used directly for the next step without further purification. The solution was cooled to room temperature extracted with ethyl acetate The organic layer was washed with brine dried over anhydrous MgSO4(s) concentrated under reduced pressure

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

Procedure: 1.42 g (5 mmol) of the compound obtained in Step 1 was dissolved in 20 ml of acetonitrile, 1.38 g (10 mmol) of K2CO3 and 0.84 g (5 mmol) of 4-(2-methoxyethoxy)phenol were added thereto, which was refluxed for 15 hours. The reaction mixture was distilled under a reduced pressure to remove the solvent, and 20 ml of ethyl acetate was added thereto. The resulting mixture was washed twice with water, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The concentrate was subjected to column chromatography using 20% ethyl acetate/hexane to obtain 1.76 g (yield 95%) of 1-(2-bromo-5-chlorobenzyloxy)-4-(2-methoxyethoxy)benzene. which was refluxed for 15 hours The reaction mixture was distilled under a reduced pressure to remove the solvent, and 20 ml of ethyl acetate was added The resulting mixture was washed twice with water dried over anhydrous MgSO4 concentrated under a reduced pressure

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

Procedure: Bromine dissolved in chloroform is added at 0° to a solution of 4-(2-methoxyethoxy)phenol (M.P. 98°-99°) [prepared by reacting 4-benzyloxyphenol with 2-chloroethyl methyl ether and debenzylating the resultant 1-benzyloxy-4-(2-methoxyethoxy)benzene (M.P. 41°-43°) by hydrogenation with palladium on charcoal] in methanol and the mixture stirred for 2 hours. After chromatography over silicagel, the resultant 2-bromo-4-(2-methoxyethoxy)phenol (oil) is reacted for 60 hours with a mixture of potassium carbonate, acetone and benzyl bromide. After chromatography over silicagel, the resultant 1-benzyloxy-2-bromo-4-(2-methoxyethoxy)benzene (oil) is reacted in dimethylformamide for 5 hours with cuprous cyanide. After purification by partition between aqueous hydrochloric acid solution and ethyl acetate, the resultant 2-benzyloxy-5-(2-methoxyethoxy)benzonitrile (M.P. 50°-51° ) is debenzylated over 10% palladium on charcoal in methanol. The resultant 2-hydroxy-5-(2-methoxyethoxy)benzonitrile (oil) is reacted at 100° with epichlorhydrin and a catalytic amount of piperidine, and 2-(2,3-epoxypropoxy)-5-(2-methoxyethoxy)benzonitrile (oil) is obtained. prepared After purification by partition between aqueous hydrochloric acid solution and ethyl acetate The resultant 2-hydroxy-5-(2-methoxyethoxy)benzonitrile (oil) is reacted at 100° with epichlorhydrin

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

Procedure: A solution of 4-(2-methoxyethoxy)phenol in toluene (350 ml) was added to a solution of magnesium methoxide in methanol (8% by weight solution, 331 mls), under an atmosphere of argon. The reaction mixture was heated at reflux for 2 hours. Toluene (350 mls) was added and the reaction mixture distilled at atmospheric pressure until the internal temperature reached 92° C. A mixture of paraformaldehyde in toluene (300 ml) was added to the reaction mixture and the reaction mixture was heated at reflux for 3.5 hours. The mixture was cooled to ambient temperature and then stirred at ambient temperature for 18 hours. The reaction mixture was diluted with toluene (400 ml), washed with 2M aqueous hydrochloric acid (2×150 ml) and water (to pH 1). The residue was distilled under vacuum to give 2-hydroxy-5-(2-methoxyethoxy)benzaldehyde as an oil (35 g), bp 104-130° C. [0.01 mm Hg]; NMR(CDCl3): 3.45(3H,s), 3.75(2H,m), 4.12(2H,m), 6.92(1H,d), 7.05(1H,d), 7.2(1H,dd), 9.84(1H,s) and 10.63(1H,s); m/z 197(M+H). The reaction mixture was heated at reflux for 2 hours the reaction mixture distilled at atmospheric pressure until the internal temperature reached 92° C A mixture of paraformaldehyde in toluene (300 ml) was added to the reaction mixture the reaction mixture was heated at reflux for 3.5 hours The reaction mixture was diluted with toluene (400 ml) washed with 2M aqueous hydrochloric acid (2×150 ml) and water (to pH 1) The residue was distilled under vacuum

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

Procedure: A mixture of 1-(benzyloxy)-4-(2-methoxyethoxy)benzene (180 g), ethanol (2000 ml) and palladium on carbon catalyst (20 g) was stirred under an atmosphere of hydrogen, at room temperature and atmospheric pressure. After the theoretical quantity of hydrogen had been consumed, the reaction mixture was filtered. The filtrate was evaporated to give a solid which was crystallised from a mixture of ethyl acetate and n-hexane to give 4-(2-methoxyethoxy)phenol as a solid (94.7 g) m.p. 97.9° C.; microanalysis, found: C, 64.3%; H, 7.4%; C9H12O3 requires: C, 64.3%; H, 7.2%; NMR: 3.35(3H,s), 3.6(2H,m), 3.95(2H,m), 6.7(4H,m) and 8.9(1H,s); m/z 169(M+H). After the theoretical quantity of hydrogen had been consumed the reaction mixture was filtered The filtrate was evaporated to give a solid which was crystallised from a mixture of ethyl acetate and n-hexane