4,4-dimethoxybutanenitrile

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: 2,3,4-Trimethoxybenzaldehyde (9.8 g) and 3-cyano-propionaldehyde dimethylacetal (6.35 mL) were treated under the same conditions as in Preparation Example 1 to obtain the title compound.

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

Procedure: 2.0 M Lithium diisopropylamide (2.55 mL) was added dropwise to dry THF (5 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. A solution of 3-cyanopropionaldehyde dimethylacetal (672 mg) in dry THF (5 mL) was then added dropwise to the mixture, and the resulting mixture was stirred at −78° C. for 1 hour. A solution of 3,4,5-trimethoxybenzaldehyde (1.0 g) in dry THF (5 mL) was then added dropwise to the reaction mixture. After stirring at room temperature for 1 hour, a saturated aqueous solution of ammonium chloride was added to the reaction mixture to conduct extraction with ethyl acetate. The resultant organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was dissolved in methanol (6 mL), sulfuric acid (1 mL) was slowly added to the solution, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was weakly alkalified with a 4 M aqueous solution of potassium hydroxide at 0° C. to conduct extraction with chloroform. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:3 to 1:1) to obtain the title compound. the resulting mixture was stirred at −78° C. for 1 hour After stirring at room temperature for 1 hour extraction with ethyl acetate The resultant organic layer was washed with saturated brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The resultant residue was dissolved in methanol (6 mL) sulfuric acid (1 mL) was slowly added to the solution the mixture was stirred at 100° C. for 1 hour was weakly alkalified with a 4 M aqueous solution of potassium hydroxide at 0° C. extraction with chloroform The resultant organic layer was washed with water and saturated brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:3 to 1:1)

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

Procedure: 2,3,4-Trimethoxybenzaldehyde (9.8 g) and 3-cyanopropionaldehyde dimethylacetal (6.35 mL) were treated under the same conditions as in Preparation Example 1 to obtain the title compound.

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

Procedure: 2.0 M Lithium diisopropylamide (2.55 mL) was added dropwise to dry THF (5 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. A solution of 3-cyanopropionaldehyde dimethylacetal (672 mg) in dry THF (5 mL) was then added dropwise to the mixture, and the resulting mixture was stirred at −78° C. for 1 hour. A solution of 3,4,5-trimethoxybenzaldehyde (1.0 g) in dry THF (5 mL) was then added dropwise to the reaction mixture. After stirring at room temperature for 1 hour, a saturated aqueous solution of ammonium chloride was added to the reaction mixture to conduct extraction with ethyl acetate. The resultant organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was dissolved in methanol (6 mL), sulfuric acid (1 mL) was slowly added to the solution, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was weakly alkalified with a 4 M aqueous solution of potassium hydroxide at 0° C. to conduct extraction with chloroform. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:3 to 1:1) to obtain the title compound. the resulting mixture was stirred at −78° C. for 1 hour After stirring at room temperature for 1 hour extraction with ethyl acetate The resultant organic layer was washed with saturated brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The resultant residue was dissolved in methanol (6 mL) sulfuric acid (1 mL) was slowly added to the solution the mixture was stirred at 100° C. for 1 hour was weakly alkalified with a 4 M aqueous solution of potassium hydroxide at 0° C. extraction with chloroform The resultant organic layer was washed with water and saturated brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:3 to 1:1)

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

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

Procedure: Lithium diisopropylamide mono(tetrahydrofuran) (1.5 M in cyclohexane, 22.0 mL, 33.00 mmol) was added to THF (100 mL) at −30° C. and the resulting solution was stirred for 10 min before 3-cyanopropionaldehyde dimethyl acetal (3.90 mL, 29.90 mmol) was added dropwise over 5 min. After 15 min, methyl formate (2.80 mmol, 45.42 mmol) was added and the resulting solution was stirred at −20° C. to −15° C. for 2 h. The reaction mixture was quenched with water (100 mL) and washed with ether (2×50 mL, discarded). The aqueous layer was acidified with 10% HCl and extracted with ether (3×50 mL). The combined ether extracts were washed with brine (3×50 mL), dried (MgSO4), and concentrated. The residue was dissolved in dichloromethane and concentrated to remove traces of THF and provide 2.28 g (49%) of the title compound as a pale yellow oil. was added dropwise over 5 min The reaction mixture was quenched with water (100 mL) washed with ether (2×50 mL, discarded) extracted with ether (3×50 mL) The combined ether extracts were washed with brine (3×50 mL) dried (MgSO4) concentrated The residue was dissolved in dichloromethane concentrated to remove traces of THF

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.370 Grams of methyl methylthiomethyl sulfoxide was dissolved in 20 ml of anhydrous THF, and to which 475 mg of sodium hydride was added under cooling with ice, followed by 50 minutes' stirring at 0°C. and additional 50 minutes' stirring at room temperature. Again icecooling the system, 3.73 ml of 4,4-dimethoxybutyronitrile was added dropwise, followed by 18 hours' stirring and further 23 hours' stirring at 50° - 55°C. The reaction liquid was again cooled with ice while 30 ml of methylene chloride and 1 ml of water were added thereto, and after a little while the temperature was returned to the normal level, followed by 3 hours' stirring. After an overnight's drying with Glauber's salt, the reaction mixture was filtered, and the solvent was evaporated off under reduced pressure. The residue was parted by a column chromatography (Florisil, methylene chloride, ethyl acetate and methanol), to allow the recovery of 457 mg of methyl methylthiomethyl sulfoxide and 4.332 g of a crystalline product. The crystals were dissolved in hot methylene chloride, and the insoluble matter was removed by filtration. The filtrate was concentrated under a reduced pressure to leave 3.70 g of 1-methylsulfinyl-1-methylthio-2-amino-5,5-dimethoxy-1-pentene in light yellow, crystalline form. The yield was 76.5%, and the conversion yield was 94.8%. under cooling with ice stirring at room temperature was added dropwise followed by 18 hours ' stirring and further 23 hours' stirring at 50° - 55°C The reaction liquid were added followed by 3 hours ' stirring After an overnight's drying with Glauber's salt the reaction mixture was filtered the solvent was evaporated off under reduced pressure The crystals were dissolved in hot methylene chloride the insoluble matter was removed by filtration The filtrate was concentrated under a reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.370 Grams of methyl methylthiomethyl sulfoxide was dissolved in 20 ml of anhydrous THF, and to which 475 mg of sodium hydride was added under cooling with ice, followed by 50 minutes' stirring at 0° C. and additional 50 minutes' stirring at room temperature. Again ice-cooling the system 3.73 ml of 4,4-dimethoxybutyronitrile was added dropwise, followed by 18 hours' stirring and further 23 hours' stirring at 50° - 55° C. The reaction liquid was again cooled with ice while 30 ml of methylene chloride and 1 ml of water were added thereto, and after a little while the temperature was returned to the normal level, followed by 3 hours' stirring. After an overnight's drying with Glauber's salt, the reaction mixture was filtered, and the solvent was evaporated off under reduced pressure. The residue was parted by a column chromatography (Florisil, methylene chloride, ethyl acetate and methanol), to allow the recovery of 457 mg of methyl methylthiomethyl sulfoxide and 4.332 g of a crystalline product. The crystals were dissolved in hot methylene chloride, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to leave 3.70 g of 1-methylsulfinyl-1-methylthio-2-amino-5,5-dimethoxy-1-pentene in light yellow, crystalline form. The yield was 76.5%, and the conversion yield was 94.8%. 1-Methylsulfinyl-1-methylthio-2-amino-5,5-dimethoxy-1-pentene (recrystallized from carbon tetrachloride): m.p. 86° - 87° C. under cooling with ice stirring at room temperature was added dropwise followed by 18 hours ' stirring and further 23 hours' stirring at 50° - 55° C The reaction liquid were added followed by 3 hours ' stirring After an overnight's drying with Glauber's salt the reaction mixture was filtered the solvent was evaporated off under reduced pressure The crystals were dissolved in hot methylene chloride the insoluble matter was removed by filtration The filtrate was concentrated under reduced pressure

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.0 M Lithium diisopropylamide (2.55 mL) was added to dry THF (5 mL) at −75° C. under an argon atmosphere, and a solution of 3-cyanopropionaldehyde dimethylacetal (672 mg) in dry THF (5 mL) was then added dropwise to the mixture, and the resulting mixture was stirred at −75° C. for 1 hour. A solution of 3,4,5-trimethoxy-benzaldehyde (1.0 g) in dry THF (5 mL) was then added dropwise to the reaction mixture. After the mixture was warmed to room temperature and stirred for 1 hour, a saturated aqueous solution of ammonium chloride was added to the reaction mixture to conduct extraction with ethyl acetate. The resultant organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was dissolved in methanol (6 mL), sulfuric acid (1 mL) was slowly added to the solution, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was weakly alkalified with an aqueous solution of 4 M potassium hydroxide at 0° C. to conduct extraction with chloroform. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:3 to 1:1) to obtain the title compound. After the mixture was warmed to room temperature stirred for 1 hour extraction with ethyl acetate The resultant organic layer was washed with saturated brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The resultant residue was dissolved in methanol (6 mL) sulfuric acid (1 mL) was slowly added to the solution the mixture was stirred at 100° C. for 1 hour was weakly alkalified with an aqueous solution of 4 M potassium hydroxide at 0° C. extraction with chloroform The resultant organic layer was washed with water and saturated brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:3 to 1:1)

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

Procedure: Lithium diisopropylamide mono(tetrahydrofuran) (1.5 M in cyclohexane, 22.0 mL, 33.00 mmol) was added to THF (100 mL) at −30° C. and the resulting solution was stirred for 10 min before 3-cyanopropionaldehyde dimethyl acetal (3.90 mL, 29.90 mmol) was added dropwise over 5 min. After 15 min, methyl formate (2.80 mmol, 45.42 mmol) was added and the resulting solution was stirred at −20° C. to −15° C. for 2 h. The reaction mixture was quenched with water (100 mL) and washed with ether (2×50 mL, discarded). The aqueous layer was acidified with 10% HCl and extracted with ether (3×50 mL). The combined ether extracts were washed with brine (3×50 mL), dried (MgSO4), and concentrated. The residue was dissolved in dichloromethane and concentrated to remove traces of THF and provide 2.28 g (49%) of the title compound as a pale yellow oil. was added dropwise over 5 min The reaction mixture was quenched with water (100 mL) washed with ether (2×50 mL, discarded) extracted with ether (3×50 mL) The combined ether extracts were washed with brine (3×50 mL) dried (MgSO4) concentrated The residue was dissolved in dichloromethane concentrated to remove traces of THF