3,4-bis(methoxymethoxy)benzaldehyde

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

Procedure: Chloromethyl methyl ether (1.2 ml, 15.8 mmol) was added dropwise to a stirred solution containing 3,4-dihydroxybenzaldehyde (1 g, 7.25 mmol) and triethylamine (2 ml) in dimethylformamide (100 ml). After stirring at room temperature for 2 days, water (100 ml) was added to destroy any excess chloromethyl methyl ether. The reaction mixture was extracted with ethyl acetate (2×250 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a brown syrup. The crude mixture was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexanes (1:4) to give first 3,4-bismethoxymethoxybenzaldehyde (0.4 g) as a light yellow syrup, and then the monomethoxymethylated derivatives of 3,4-dihydroxybenzaldehyde. to destroy any excess chloromethyl methyl ether The reaction mixture was extracted with ethyl acetate (2×250 ml) The combined organic extracts were washed with brine dried over magnesium sulfate filtered concentrated in vacuo to give a brown syrup The crude mixture was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexanes (1:4)

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

Procedure: In 260 ml of ethanol were dissolved 33.37 g of the 2'-hydroxy-4',6'-bis(methoxymethoxy)acetophenone obtained in Production Example 11 and 32.20 g of the 3,4-bis(methoxymethoxy)benzaldehyde obtained in Production Example 24, and 300 ml of a saturated solution of potassium hydroxide in ethanol was added to the solution and the mixture was stirred for 24 hours to effect a reaction. After the reaction, the pH value of the reaction liquid was adjusted to about 6 by 6N hydrochloric acid, and the formed precipitate was recovered by filtration, washed with water and dried to obtain 53.17 g (yield=87.9%) of 2'-hydroxy-3,4,4',6'-tetrakis(methoxymethoxy)chalcone.

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 200 ml of dimethylformamide was dissolved 32.66 g of 3,4-dihydroxybenzaldehyde, and the solution was cooled to -5° C. and 200 ml of N,N-diisopropylethylamine was added to the solution. Then, 70 ml of chloromethyl methyl ether was gradually added to the mixture, and the mixture was stirred overnight to effect reaction. After the reaction, the reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate three times. The organic layer was washed with water three times and shaken with a saturated aqueous solution of sodium chloride, and the organic layer was dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation, and the obtained residue was recrystallized from ethyl acetate to obtain 41.20 g (yield=86.37%) of 3,4-bis(methoxymethoxy)benzaldehyde. reaction After the reaction the mixture was extracted with ethyl acetate three times The organic layer was washed with water three times shaken with a saturated aqueous solution of sodium chloride the organic layer was dried with anhydrous sodium sulfate filtered The solvent was removed from the filtrate by distillation the obtained residue was recrystallized from ethyl acetate

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

Procedure: 3,4-Dihydroxybenzaldehyde (10 g, 67 mmol) was dissolved in DMF (50 mL), and potassium carbonate (20 g, 134 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. Chloromethyl methyl ether (0.96 mL, 13 mmol) was added thereto, and the mixture was further stirred at room temperature for 20 hours. The reaction solution was poured into water and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with chloroform) to obtain 3,4-bis(methoxymethoxy)benzaldehyde (6.4 g; yield: 42%). the mixture was further stirred at room temperature for 20 hours the mixture was extracted with chloroform The organic layer was washed with a saturated aqueous solution of sodium chloride dried over sodium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (eluted with chloroform)

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

Procedure: 3,4-Dihydroxybenzaldehyde (10 g, 67 mmol) was dissolved in DMF (50 mL), and potassium carbonate (20 g, 134 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. Chloromethyl methyl ether (0.96 mL, 13 mmol) was added thereto, and the mixture was further stirred at room temperature for 20 hours. The reaction solution was poured into water and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with chloroform) to obtain 3,4-bis(methoxymethoxy)benzaldehyde (6.4 g; yield: 42%). the mixture was further stirred at room temperature for 20 hours the mixture was extracted with chloroform The organic layer was washed with a saturated aqueous solution of sodium chloride dried over sodium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (eluted with chloroform)

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

Procedure: Chloromethyl methyl ether (1.2 ml, 15.8 mmol) was added dropwise to a stirred solution containing 3,4-dihydroxybenzaldehyde (1 g, 7.25 mmol) and triethylamine (2 ml) in dimethylformamide (100 ml). After stirring at room temperature for 2 days, water (100 ml) was added to destroy any excess chloromethyl methyl ether. The reaction mixture was extracted with ethyl acetate (2×250 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a brown syrup. The crude mixture was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexanes (1:4) to give first 3,4-bismethoxymethoxybenzaldehyde (0.4 g) as a light yellow syrup, and then the monomethoxymethylated derivatives of 3,4-dihydroxybenzaldehyde. to destroy any excess chloromethyl methyl ether The reaction mixture was extracted with ethyl acetate (2×250 ml) The combined organic extracts were washed with brine dried over magnesium sulfate filtered concentrated in vacuo to give a brown syrup The crude mixture was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexanes (1:4)

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

Procedure: Chloromethyl methyl ether (1.2 ml, 15.8 mmol) was added dropwise to a stirred solution containing 3,4-dihydroxybenzaldehyde (1 g, 7.25 mmol) and triethylamine (2 ml) in dimethylformamide (100 ml). After stirring at room temperature for 2 days, water (100 ml) was added to destroy any excess chloromethyl methyl ether. The reaction mixture was extracted with ethyl acetate (2×250 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a brown syrup. The crude mixture was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexanes (1:4) to give first 3,4-bismethoxymethoxybenzaldehyde (0.4 g) as a light yellow syrup, and then the monomethoxymethylated derivatives of 3,4-dihydroxybenzaldehyde. to destroy any excess chloromethyl methyl ether The reaction mixture was extracted with ethyl acetate (2×250 ml) The combined organic extracts were washed with brine dried over magnesium sulfate filtered concentrated in vacuo to give a brown syrup The crude mixture was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexanes (1:4)

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

Procedure: In 260 ml of ethanol were dissolved 33.37 g of the 2'-hydroxy-4',6'-bis(methoxymethoxy)acetophenone obtained in Production Example 11 and 32.20 g of the 3,4-bis(methoxymethoxy)benzaldehyde obtained in Production Example 24, and 300 ml of a saturated solution of potassium hydroxide in ethanol was added to the solution and the mixture was stirred for 24 hours to effect a reaction. After the reaction, the pH value of the reaction liquid was adjusted to about 6 by 6 N hydrochloric acid, and the formed precipitate was recovered by filtration, washed with water and dried to obtain 53.17 g (yield=87.9%) of 2'-hydroxy-3,4,4',6'-tetrakis(methoxymethoxy)chalcone.

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 200 ml of dimethylformamide was dissolved 32.66 g of 3,4-dihydroxybenzaldehyde, and the solution was cooled to -5° C. and 200 ml of N,N-diisopropylethylamine was added to the solution. Then, 70 ml of chloromethyl methyl ether was gradually added to the mixture, and the mixture was stirred overnight to effect reaction. After the reaction, the reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate three times. The organic layer was washed with water three times and shaken with a saturated aqueous solution of sodium chloride, and the organic layer was dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation, and the obtained residue was recrystallized from ethyl acetate to obtain 41.20 g (yield=86.37%) of 3,4-bis(methoxymethoxy)benzaldehyde. reaction After the reaction the mixture was extracted with ethyl acetate three times The organic layer was washed with water three times shaken with a saturated aqueous solution of sodium chloride the organic layer was dried with anhydrous sodium sulfate filtered The solvent was removed from the filtrate by distillation the obtained residue was recrystallized from ethyl acetate

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 200 ml of dimethylformamide was dissolved 32.66 g of 3,4-dihydroxybenzaldehyde, and the solution was cooled to -5° C. and 200 ml of N,N-diisopropylethylamine was added to the solution. Then, 70 ml of chloromethyl methyl ether was gradually added to the mixture, and the mixture was stirred overnight to effect reaction. After the reaction, the reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate three times. The organic layer was washed with water three times and shaken with a saturated aqueous solution of sodium chloride, and the organic layer was dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation, and the obtained residue was recrystallized from ethyl acetate to obtain 41.20 g (yield=86.37%) of 3,4-bis(methoxymethoxy)benzaldehyde. reaction After the reaction the mixture was extracted with ethyl acetate three times The organic layer was washed with water three times shaken with a saturated aqueous solution of sodium chloride the organic layer was dried with anhydrous sodium sulfate filtered The solvent was removed from the filtrate by distillation the obtained residue was recrystallized from ethyl acetate

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 200 ml of dimethylformamide was dissolved 32.66 g of 3,4-dihydroxybenzaldehyde, and the solution was cooled to -5° C. and 200 ml of N,N-diisopropylethylamine was added to the solution. Then, 70 ml of chloromethyl methyl ether was gradually added to the mixture, and the mixture was stirred overnight to effect reaction. After the reaction, the reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate three times. The organic layer was washed with water three times and shaken with a saturated aqueous solution of sodium chloride, and the organic layer was dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation, and the obtained residue was recrystallized from ethyl acetate to obtain 41.20 g (yield=86.37%) of 3,4-bis(methoxymethoxy)benzaldehyde. reaction After the reaction the mixture was extracted with ethyl acetate three times The organic layer was washed with water three times shaken with a saturated aqueous solution of sodium chloride the organic layer was dried with anhydrous sodium sulfate filtered The solvent was removed from the filtrate by distillation the obtained residue was recrystallized from ethyl acetate

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

Procedure: A solution of CH3PPh3Br (10.72 g, 30 mmol) in anhydrous DMF (50 mL) under argon atmosphere was cooled to 0-5° C. Sodium hydride (2.0 g, 60% suspension in mineral oil, 50 mmol, 1.66 eq.) was added in portions. The mixture was stirred at room temperature for 1 hour and then 3,4-di-(methoxymethoxy)-benzaldehyde (6 g, 26.52 mmol) was added in portions. The resulting mixture was stirred at room temperature until completion of the reaction (about 2 hours). The mixture was cooled again to 0-5° C. and water (5 mL) was slowly injected to decompose the excess NaH. After an additional 10 min, the mixture was mixed with water (200 mL) and extracted with CH2Cl2 (2×200 mL). The organic layer was washed with water (200 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was mixed with hexanes and loaded to a silica gel column that was eluted with a mixed solvent of hexane and EtOAc to afford, after evaporation, 3.974 g of 3,4-di(methoxymethoxy)styrene as a yellowish oil (17.72 mmol, yield 66.8%). MS (ESI) m/z: 225 (M+1)+ and 247 (M+23)+. The resulting mixture was stirred at room temperature until completion of the reaction (about 2 hours) The mixture was cooled again to 0-5° C. After an additional 10 min extracted with CH2Cl2 (2×200 mL) The organic layer was washed with water (200 mL) dried over anhydrous sodium sulfate filtered evaporated The residue was mixed with hexanes was eluted with a mixed solvent of hexane and EtOAc to afford