ethyl 3,4-dihydroxybenzoate

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

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

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

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

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of Cs2CO3 (270 g, 1.49 mol) in DMF (1000 mL) were added 3,4-dihydroxybenzoic acid ethyl ester (54.6 g, 0.3 mol) and 1,2-dibromoethane (54.3 g, 0.29 mol) at room temperature. The resulting mixture was stirred at 80° C. overnight and then poured into ice-water. The mixture was extracted with EtOAc (200 mL×3). The combined organic layers were washed with water (200 mL×3) and brine (100 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified by column (Petroleum Ether/Ethyl Acetate 50:1) on silica gel to obtain 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid ethyl ester (18 g, 29%). 1H NMR (300 MHz, CDCl3) δ 7.53 (dd, J=1.8, 7.2 Hz, 2H), 6.84-6.87 (m, 1H), 4.22-4.34 (m, 6H), 1.35 (t, J=7.2 Hz, 3H). The mixture was extracted with EtOAc (200 mL×3) The combined organic layers were washed with water (200 mL×3) and brine (100 mL) dried over Na2SO4 concentrated to dryness The residue was purified by column (Petroleum Ether/Ethyl Acetate 50:1) on silica gel

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

Procedure: Ethyl 3,4-dihydroxybenzoate (910.9 mg, 5 mmol) was combined with 2,2-dimethoxypropane (1.23 mL, 10 mmol) and a catalytic amount of p-toluene sulfonic acid in toluene. The mixture was heated to reflux using a Dean-Stark trap for 20 hours. After solvent removal under reduced pressure, the crude was dissolved in ethyl acetate and washed successively with a saturated aqueous solution of sodium bicarbonate, water, and brine. The organic layer was dried over anhydrous sodium sulfate. Purification by chromatography on silica gel using a gradient hexane:ethyl acetate, 90:10 to 75:25, afforded a white powder (539.1 mg, 49%). 1H NMR (CDCl3): δ 1.36 (t, 3H, J=7.2 Hz), 1.69 (s, 6H), 4.32 (q, 2H, J=7.1 Hz, J=14.2 Hz), 6.74 (d, 1H, d, J=8.2 Hz), 7.38 (d, 1 h, J=1.7 Hz), 7.61 (dd, 1H, J=1.8 Hz, J=8.3 Hz). The mixture was heated to reflux for 20 hours After solvent removal under reduced pressure the crude was dissolved in ethyl acetate washed successively with a saturated aqueous solution of sodium bicarbonate, water, and brine The organic layer was dried over anhydrous sodium sulfate Purification by chromatography on silica gel using a gradient hexane

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: Triethylamine (2.211 g, 21.86 mM) was added to a solution of1.989 g (10.93 mM) of ethyl 3,4-dihydroxybenzoate in 30 ml of ether. The mixture was cooled to -30° C. to -20° C. and a solution of 1.627 g (10.93 mM) of methyl dichlorophosphate in 10 ml of ether was added thereto dropwise with stirring over 10 minutes. The reaction mixture was stirred at the same temperature for 5 minutes, the bath was then removed and the temperature was allowed to rise to 20° C. Filtration and washing were carried out by the procedure of Reference Example 1, and the filtrate and washings were concentrated at room temperature (20°~25° C.) under reduced pressure. There was obtained 2.387 g (84.6% yield) of 5-ethoxycarbonyl-2-methoxy-2-oxo-1,3,2-benzo-dioxaphosphole as a viscous oil. The mixture was cooled to -30° C. to -20° C. The reaction mixture was stirred at the same temperature for 5 minutes the bath was then removed to rise to 20° C Filtration washing the filtrate and washings were concentrated at room temperature (20°~25° C.) under reduced pressure

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

Procedure: 3,4-Dihydroxy-benzoic acid ethyl ester (compound A′) (2.0 g) was dissolved in acetone (20 ml). Potassium carbonate (4.3 g) and 1-bromo-2-methoxy-ethane (compound D) (5 ml) were added to the solution at room temperature, and the mixture was then stirred at 70° C. for 24 hr. After the completion of the reaction, the reaction solution was allowed to stand for cooling at room temperature, and the reaction system was concentrated under the reduced pressure. Distilled water was added to the residue, and the mixture was then subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography using a hexane-acetone system to give 3,4-bis-(2-methoxy-ethoxy)-benzoic acid ethyl ester (3.06 g, yield 93%). After the completion of the reaction for cooling at room temperature the reaction system was concentrated under the reduced pressure Distilled water was added to the residue the mixture was then subjected to separatory extraction with chloroform The organic layer was washed with saturated brine was dried over sodium sulfate was then concentrated under the reduced pressure The residue was purified by column chromatography

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

Procedure: 3,4-Dihydroxy-benzoic acid ethyl ester (compound A′) (2.0 g) was dissolved in acetone (20 ml). Potassium carbonate (4.3 g) and 1-bromo-2-methoxy-ethane (compound D) (5 ml) were added to the solution at room temperature, and the mixture was then stirred at 70° C. for 24 hr. After the completion of the reaction, the reaction solution was allowed to stand for cooling at room temperature, and the reaction system was concentrated under the reduced pressure. Distilled water was added to the residue, and the mixture was then subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography using a hexane-acetone system to give 3,4-bis-(2-methoxy-ethoxy)-benzoic acid ethyl ester (3.06 g, yield 93%). After the completion of the reaction for cooling at room temperature the reaction system was concentrated under the reduced pressure Distilled water was added to the residue the mixture was then subjected to separatory extraction with chloroform The organic layer was washed with saturated brine was dried over sodium sulfate was then concentrated under the reduced pressure The residue was purified by column chromatography