ethyl 4-sulfanylbutanoate

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:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under a nitrogen flow, 533.2 g of crude 2-fluoro-5-(4-propoxyethoxyphenyl)benzaldehyde was dissolved in 894 ml of N,N-dimethylformamide and cooled to 10° C. or lower 1,8-Diazabicyclo[5.4.0]-7-undecene (450 g, 2.956 mol) was added while keeping the mixture at 0-10° C. After dropping ethyl 4-mercaptobutyrate (438 g, 2.956 mol) slowly, the mixture was heated to 20° C. and then stirred at 20-30° C. for 1 hour. At 20-30° C., 8940 ml of diethyl carbonate was added and subsequently a solution of 20% sodium ethoxide (2012 g and 5.912 mol) in ethanol was dropped. The mixture was stirring at 20-30° C. for 3 hours and then cooled to 5° C. After adding 4.35 L of a 2N hydrochloric acid while maintaining the temperature at 10° C. or lower, phase separation was conducted and the water layer was extracted with 3.75 L of ethyl-acetate. The organic layers were combined and washed with 4 L of water, 4 L of a 5% aqueous sodium hydrogencarbonate solution, and 4 L of a 5% brine. Activated carbon Shirasagi A (45 g) and then tri-n-butyl phosphine (51 ml) were added. The mixture was stirred at room temperature for 20 minutes and then filtered. The residue was washed with 1.2 L of ethyl acetate. The filtrate was concentrated under vacuum, 1.2 L of isopropanol was added and then vacuum concentration was conducted (twice). After addition of 1.2 L of isopropyl ether and vacuum concentration, 900 ml of isopropyl ether was added to the oily matter obtained. Crystals formed during stirring at room temperature were dissolved by heating under reflux. After cooling and stirring for 2.5 hours and stirring for 2 hours while cooling in ice, the mixture was filtered and the residue was washed with 900 ml of ice-cooled isopropyl ether. Through vacuum drying (40° C.), 344.8 g (Yield from 5-bromo-2-fluorobenzaldehyde: 57%) of ethyl 7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate was obtained as pale yellow crystals. at 0-10° C the mixture was heated to 20° C. The mixture was stirring at 20-30° C. for 3 hours cooled to 5° C while maintaining the temperature at 10° C. lower, phase separation the water layer was extracted with 3.75 L of ethyl-acetate washed with 4 L of water, 4 L of a 5% aqueous sodium hydrogencarbonate solution, and 4 L of a 5% brine Activated carbon Shirasagi A (45 g) and then tri-n-butyl phosphine (51 ml) were added The mixture was stirred at room temperature for 20 minutes filtered The residue was washed with 1.2 L of ethyl acetate The filtrate was concentrated under vacuum, 1.2 L of isopropanol was added vacuum concentration After addition of 1.2 L of isopropyl ether and vacuum concentration, 900 ml of isopropyl ether was added to the oily matter obtained Crystals formed during stirring at room temperature were dissolved by heating under reflux After cooling stirring for 2.5 hours stirring for 2 hours while cooling in ice the mixture was filtered the residue was washed with 900 ml of ice- cooled isopropyl ether Through vacuum drying (40° C.)

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

Procedure: Under an argon flow, 30.5 g of crude 2-fluoro-5-(4-propoxyphenyl)benzaldehyde was dissolved in 59 ml of DMF and then cooled to 5° C. After the addition of ethyl 4-mercaptobutyrate (32.6 ml, 229.88 mmol), 1,8-diazabicyclo[5.4.0]-7-undecene (34.4 ml, 229.88 mmol) was dropped slowly, while keeping at 0-10° C. The mixture was heated to 20° C. and stirred at 20-30° C. for 3 hours. At 20-30° C., 590 ml of diethyl carbonate was dropped and subsequently an ethanol solution (156 g, 459.76 mmol) of 20% sodium ethoxide was dropped. After stirring at 20-30° C. for 3 hours, the mixture was cooled to 5° C. After adding 338 ml of a 2N hydrochloric acid while keeping 10° C. or lower, phase separation was conducted. The water layer was extracted with 290 ml of ethyl acetate. The organic layers were combined and washed with 300 ml of water, 300 ml of a 5% aqueous sodium hydrogencarbonate solution and 300 ml of a 5% brine. After the addition of activated carbon, Shirasagi A (3.5 g), followed by the addition of tri-n-butylphosphine (4 ml), the mixture was stirred at room temperature for 20 minutes. After filtration, the residue was washed with 60 ml of ethyl acetate and the filtrate was concentrated under reduced pressure. After addition of 60 ml of isopropyl alcohol, the mixture was concentrated under reduced pressure. Subsequently, 60 ml of isopropyl ether was added and stirred at room temperature. The crystals formed were dissolved on heating under reflux. The solution was cooled for 1.5 hours while being stirred and subsequently stirred for 2 hours while being cooled in ice. After filtration, the residue was washed with 60 ml of ice-cooled isopropyl ether and then dried under vacuum (40° C.), yielding 20.34 g of ethyl 7-(4-propoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate as pale yellow crystals (Yield from 5-bromo-2-fluorobenzaldehyde 48%). was dropped slowly while keeping at 0-10° C The mixture was heated to 20° C. After stirring at 20-30° C. for 3 hours the mixture was cooled to 5° C while keeping 10° C. lower, phase separation The water layer was extracted with 290 ml of ethyl acetate washed with 300 ml of water, 300 ml of a 5% aqueous sodium hydrogencarbonate solution and 300 ml of a 5% brine After the addition of activated carbon, Shirasagi A (3.5 g) followed by the addition of tri-n-butylphosphine (4 ml) the mixture was stirred at room temperature for 20 minutes After filtration the residue was washed with 60 ml of ethyl acetate the filtrate was concentrated under reduced pressure After addition of 60 ml of isopropyl alcohol the mixture was concentrated under reduced pressure Subsequently, 60 ml of isopropyl ether was added stirred at room temperature The crystals formed were dissolved on heating under reflux The solution was cooled for 1.5 hours while being stirred subsequently stirred for 2 hours while being cooled in ice After filtration the residue was washed with 60 ml of ice- cooled isopropyl ether dried under vacuum (40° C.) yielding

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

Procedure: Ethyl 4-(3,4-dimethoxy-6-formylphenylthio)butyrate was synthesized from 6-bromoveratraldehyde and ethyl 4-mercaptobutyrate in the same manner as Example 2. After vacuum concentration of an extracted solution, the residue was crystallized from isopropyl ether to yield ethyl 4-(3,4-dimethoxy-6-formylphenylthio)butyrate (Yield 27%) as slightly yellow crystals. After vacuum concentration of an extracted solution, the residue was crystallized from isopropyl ether

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

Procedure: Ethyl 4-(2-chloro-6-formylphenylthio)butyrate was synthesized from 2,3-dichlorobenzaldehyde and ethyl 4-mercaptobutyrate in the same manner as Example 2. After column chromatography, vacuum concentration yielded ethyl 4-(2-chloro-6-formylpehylthio)butyrate (Yield 70%) as a yellow oily matter. After column chromatography, vacuum concentration

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

Procedure: Ethyl 4-(4-(4-ethoxyphenyl)-2-formylphenylthio)butyrate was synthesized from 5-(4-ethoxyphenyl)-2-fluorobenzaldehyde and ethyl 4-mercaptobutyrate in the same manner as Example 2. After concentration of an extracted solution, crystallization from hexane/isopropyl ether yielded ethyl 4-(4-(4-ethoxyphenyl)-2-formylphenylthio)butyrate (Yield 73%) as yellow crystals. After concentration of an extracted solution, crystallization from hexane/isopropyl ether

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

Procedure: Ethyl 4-(4-bromo-2-formylphenylthio)butyrate was synthesized from 5-bromo-2-fluorobenzaldehyde and ethyl 4-mercaptobutyrate in the same manner as Example 2. After column chromatography, crystallization from hexane/isopropyl ether yielded ethyl 4-(4-bromo-2-formylphenylthio)butyrate (Yield 78%) as yellow crystals. After column chromatography, crystallization from hexane/isopropyl ether

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

Procedure: Under an argon atmosphere, 5-(4-ethoxyphenyl)-2-fluorobenzaldehyde (1.0 g) was dissolved in 2 ml of dimethylformamide and 1.17 g of potassium carbonate was added. Thereafter, 1.18 ml of ethyl 4-mercaptobutyrate was added and was stirred at room temperature for 25 hours. After addition of 20 ml of diethyl carbonate and an ethanol solution (2.8 g) of 20% sodium ethoxide, stirring was conducted at room temperature for three hours. During cooling in ice, 21 ml of a 1N hydrochloric acid was added. The mixture was extracted with 50 ml and additional 20 ml of ethyl acetate. The organic layers were combined and washed with 20 ml of water twice. The resulting organic layer was concentrated to yield crystals, which crystals were loosen in 2 ml of isopropyl alcohol added. The crystals were filtered out and were washed with 4 ml of isopropyl ether twice. After vacuum drying, ethyl 7-(4-ethoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (0.8 g, Yield 57%) was obtained. was conducted at room temperature for three hours During cooling in ice The mixture was extracted with 50 ml and additional 20 ml of ethyl acetate washed with 20 ml of water twice The resulting organic layer was concentrated to yield crystals, which crystals added The crystals were filtered out and were washed with 4 ml of isopropyl ether twice After vacuum drying

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

Procedure: Under an argon atmosphere, 2-fluorobenzaldehyde (5 g) was dissolved in 15 ml of dimethylformamide and potassium carbonate (8.35 g) was added. Ethyl 4-mercaptobutyrate (8.6 ml) was added at room temperature and was stirred at room temperature for 14 hours. After the addition of 100 ml of ethyl acetate, the mixture was washed with 50 ml of water twice, 50 ml of a 0.5N hydrochloric acid, and 50 ml of water three times. After drying with anhydrous sodium sulfate, the mixture was concentrated. The concentrated matter was subjected to silica gel chromatography (hexane/ethyl acetate=4/1) purification. The resulting effective fractions were concentrated to yield ethyl 4-(2-formylphenylthio)butyrate (6.86 g, Yield 67%). the mixture was washed with 50 ml of water twice After drying with anhydrous sodium sulfate the mixture was concentrated The concentrated matter was subjected to silica gel chromatography (hexane/ethyl acetate=4/1) purification The resulting effective fractions were concentrated

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under a nitrogen flow, 533.2 g of crude 2-fluoro-5-(4-propoxyethoxyphenyl)benzaldehyde was dissolved in 894 ml of N,N-dimethylformamide and cooled to 10° C. or lower 1,8-Diazabicyclo[5.4.0]-7-undecene (450 g, 2.956 mol) was added while keeping the mixture at 0-10° C. After dropping ethyl 4-mercaptobutyrate (438 g, 2.956 mol) slowly, the mixture was heated to 20° C. and then stirred at 20-30° C. for 1 hour. At 20-30° C., 8940 ml of diethyl carbonate was added and subsequently a solution of 20% sodium ethoxide (2012 g and 5.912 mol) in ethanol was dropped. The mixture was stirring at 20-30° C. for 3 hours and then cooled to 5° C. After adding 4.35 L of a 2N hydrochloric acid while maintaining the temperature at 10° C. or lower, phase separation was conducted and the water layer was extracted with 3.75 L of ethyl-acetate. The organic layers were combined and washed with 4 L of water, 4 L of a 5% aqueous sodium hydrogencarbonate solution, and 4 L of a 5% brine. Activated carbon Shirasagi A (45 g) and then tri-n-butyl phosphine (51 ml) were added. The mixture was stirred at room temperature for 20 minutes and then filtered. The residue was washed with 1.2 L of ethyl acetate. The filtrate was concentrated under vacuum, 1.2 L of isopropanol was added and then vacuum concentration was conducted (twice). After addition of 1.2 L of isopropyl ether and vacuum concentration, 900 ml of isopropyl ether was added to the oily matter obtained. Crystals formed during stirring at room temperature were dissolved by heating under reflux. After cooling and stirring for 2.5 hours and stirring for 2 hours while cooling in ice, the mixture was filtered and the residue was washed with 900 ml of ice-cooled isopropyl ether. Through vacuum drying (40° C.), 344.8 g (Yield from 5-bromo-2-fluorobenzaldehyde: 57%) of ethyl 7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate was obtained as pale yellow crystals. at 0-10° C the mixture was heated to 20° C. The mixture was stirring at 20-30° C. for 3 hours cooled to 5° C while maintaining the temperature at 10° C. lower, phase separation the water layer was extracted with 3.75 L of ethyl-acetate washed with 4 L of water, 4 L of a 5% aqueous sodium hydrogencarbonate solution, and 4 L of a 5% brine Activated carbon Shirasagi A (45 g) and then tri-n-butyl phosphine (51 ml) were added The mixture was stirred at room temperature for 20 minutes filtered The residue was washed with 1.2 L of ethyl acetate The filtrate was concentrated under vacuum, 1.2 L of isopropanol was added vacuum concentration After addition of 1.2 L of isopropyl ether and vacuum concentration, 900 ml of isopropyl ether was added to the oily matter obtained Crystals formed during stirring at room temperature were dissolved by heating under reflux After cooling stirring for 2.5 hours stirring for 2 hours while cooling in ice the mixture was filtered the residue was washed with 900 ml of ice- cooled isopropyl ether Through vacuum drying (40° C.)