methyl 3-formyl-2-hydroxybenzoate

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3.0 g of methyl 3-formyl-2-hydroxybenzoate, 3.31 g of t-butyl chloroacetate, 12.0 g of potassium carbonate and 40 ml of dimethylformamide is heated at 70° C. for 2.5 hours. After cooling, the reaction mixture is poured into water and the aqueous mixture is extracted with ethyl acetate. The extract is washed with an aqueous saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is dissolved in trifluoroacetic acid and the solution is stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure and the residue is treated with ether to give 2.09 g of (2-methoxycarbonyl-6-formylphenoxy)acetic acid as pale yellow powder. After cooling the aqueous mixture is extracted with ethyl acetate The extract is washed with an aqueous saturated sodium chloride solution dried evaporated to remove solvent The residue is dissolved in trifluoroacetic acid The reaction mixture is concentrated under reduced pressure the residue is treated with ether

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

Procedure: A mixture of 1.90 g of methyl 3-formyl-2-hydroxybenzoate, 3.0 g of nitroethane, 0.15 ml of piperidine and 30 ml of toluene is refluxed overnight while removing water. The reaction mixture is poured into ice-water and the aqueous mixture is extracted with ethyl acetate. The extract is washed successively with 10% hydrochloric acid and an aqueous saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is recrystallized from methanol to give 2.05 g of methyl 2-hydroxy-3-(2-nitro-1-propenyl)benzoate. is refluxed overnight while removing water The reaction mixture is poured into ice-water the aqueous mixture is extracted with ethyl acetate The extract is washed successively with 10% hydrochloric acid an aqueous saturated sodium chloride solution, dried evaporated to remove solvent The residue is recrystallized from methanol

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

Procedure: A mixture of 5.0 g of methyl 3-formyl-2-hydroxybenzoate, 11.7 g of 4-nitrobenzyl bromide, 11.7 g of potassium carbonate and 70 ml of dimethylformamide is stirred at room temperature for 1 hour. The reaction mixture is poured into water and the aqueous mixture is extracted with ethyl acetate. The extract is dried and evaporated to remove solvent to give 8.70 g of methyl 3-formyl-2-(4-nitrobenzyloxy)benzoate as colorless powder. the aqueous mixture is extracted with ethyl acetate The extract is dried evaporated to remove solvent

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2.0 g of methyl 3-formyl-2-hydroxybenzoate, 3.51 g of methyl α-bromo-p-chlorophenylacetate, 5.55 g of potassium carbonate and 60 ml of dimethylformamide is heated at 70°-80° C. for 15 minutes and further heated at 100° C. for 10 minutes. The reaction mixture is filtered and washed with ethyl acetate. The washings and the filtrate are combined and water is added to the mixture. The mixture is acidified with 10% hydrochloric acid. The organic layer is collected and the aqueous layer is extracted with ethyl acetate. The organic layer and the extract are combined, washed with water, dried and evaporated to remove solvent. The residue is dissolved in 30 ml of ethanol and 3.25 g of potassium hydroxide are added to the solution. The mixture is refluxed for 1 hour. The reaction mixture is evaporated to remove solvent, and water is added to the residue. The aqueous mixture is acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. 100 ml of xylene and 150 mg of p-toluenesulfonic acid are added to the residue and the mixture is refluxed for 1 hour. After cooling, ethyl acetate is added to the reaction mixture. The mixture is washed with water, dried and evaporated to remove solvent. The residue is recrystallized from ethyl acetate to give 1.84 g of 2-(4-chlorophenyl)benzofuran-7-carboxylic acid as colorless needles. is heated at 70°-80° C. for 15 minutes The reaction mixture is filtered washed with ethyl acetate water is added to the mixture The organic layer is collected the aqueous layer is extracted with ethyl acetate washed with water dried evaporated to remove solvent The residue is dissolved in 30 ml of ethanol 3.25 g of potassium hydroxide are added to the solution The mixture is refluxed for 1 hour The reaction mixture is evaporated to remove solvent, and water is added to the residue extracted with ethyl acetate The extract is washed with water dried evaporated to remove solvent 100 ml of xylene and 150 mg of p-toluenesulfonic acid are added to the residue the mixture is refluxed for 1 hour After cooling ethyl acetate is added to the reaction mixture The mixture is washed with water dried evaporated to remove solvent The residue is recrystallized from ethyl acetate

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

Procedure: 86 g of methyl 5-chloro-3-(1,3-dioxolan-2-yl)-2-hydroxybenzoate are dissolved in a mixture of 700 ml of methanol and 50 ml of tetrahydrofuran, and 70 ml of triethylamine and 7 g of 10% palladium-carbon are added to the solution. The mixture is subjected to catalytic hydrogenation under atmospheric pressure. The reaction mixture is filtered and the filtrate is evaporated to remove solvent. 10% hydrochloric acid is added to the residue and the mixture is concentrated. Water is added to the residue and the aqueous mixture is extracted with ethyl acetate. The extract is dried and evaporated to remove solvent. The resultant crystals are collected, washed with cold ethanol and dried to give 51.1 g of methyl 3-formyl-2-hydroxybenzoate as colorless needles. are added to the solution The reaction mixture is filtered the filtrate is evaporated to remove solvent 10% hydrochloric acid is added to the residue the mixture is concentrated Water is added to the residue the aqueous mixture is extracted with ethyl acetate The extract is dried evaporated to remove solvent The resultant crystals are collected washed with cold ethanol dried

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

Procedure: A slurry of methyl 3-formyl-2-hydroxybenzoate (640 mg, 3.56 mmol), K2CO3 (982 mg, 7.12 mmol) and benzyl bromide (0.63 mL, 5.34 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours and diluted with EtOAc (100 mL) and water (40 mL). The layers were separated and the organic phase dried over MgSO4. After filtration and concentration in vacuo, the residue was purified via silica gel chromatography, eluting with 0-15% EtOAc in isohexane, to give the title compound as a white solid (598 mg, 62%). The layers were separated the organic phase dried over MgSO4 After filtration and concentration in vacuo the residue was purified via silica gel chromatography eluting with 0-15% EtOAc in isohexane

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

Procedure: A slurry of methyl 3-formyl-2-hydroxybenzoate (640 mg, 3.56 mmol), K2CO3 (982 mg, 7.12 mmol), and benzyl bromide (0.63 mL, 5.34 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours and diluted with EtOAc (100 mL) and water (40 mL). The layers were separated and the organic phase dried over MgSO4. After filtration and concentration in vacuo, the residue was purified via silica gel chromatography, eluting with 0-15% EtOAc in isohexane, to give the title compound as a white solid (598 mg, 62%). The layers were separated the organic phase dried over MgSO4 After filtration and concentration in vacuo the residue was purified via silica gel chromatography eluting with 0-15% EtOAc in isohexane

Conditions: temp:22.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1.1 g (6 mmol) of the aldehyde of Example 2 in 30 ml of anhydrous methanol was reacted with 0.9 g (6 mmol) of p-toluenebenzohydrazide with acid catalysis (para-toluenesulfonic acid). After the reaction mixture had been stirred for approximately 14 hours at 20 to 25° C., it was freed from the solvent. 1.9 g of the title compound, which corresponded to 99% of theory, were obtained from the residue. (m.p. 134-137° C.)

Conditions: temp:22.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 63 ml of concentrated sulfuric acid were added dropwise at approximately 20 to 25° C. to a solution of 64 g (0.17 mol) of the dibromide of Example 1 in 500 ml of anhydrous methanol. The temperature of the reaction solution was kept at 30° C. by cooling. After the mixture had been stirred for 30 minutes at 20 to 25° C., it was heated for 3 hours to 50° C. The reaction mixture was stirred into approximately 3.5 l of water. The precipitate was filtered off and washed with water and then with a pentane/MTBE mixture (5:1). After drying, 25 g of the title compound were obtained, which corresponds to 81% of theory. (m.p. 82° C.) was kept at 30° C. by cooling it was heated for 3 hours to 50° C The precipitate was filtered off washed with water After drying