1-methylsulfonylpropan-2-one

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

Procedure: To a 25 mL volume three-necked flask with Dean-Stark, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39) (1.01 g), 1-methylsulfonyl-2-propanone (7-2-1) (613 mg), and toluene (2.9 ml) were added under a nitrogen atmosphere. Water was removed by azeotropic distillation at 60° C. under 100 mmHg for 4 hours. The mixture was concentrated under reduced pressure. To the residue, toluene (1.73 g) and methanol (1.90 ml) were added, then lithium hydroxide monohydrate (80 mg) was added at 0° C. After the mixture was stirred at 0° C. for 4 hours and at 5° C. for 20 hours, 20 w/w % of sulfuric acid was added to adjust pH to less than 1. To the mixture was added toluene and water, and then the organic layer was removed. The aqueous layer was extracted with toluene 2 times. The organic layers were combined, and concentrated under reduced pressure to give 1.28 g of 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydro-3-pyridazinone ((2-34)-(1)-39). Water was removed by azeotropic distillation at 60° C. under 100 mmHg for 4 hours The mixture was concentrated under reduced pressure To the residue, toluene (1.73 g) and methanol (1.90 ml) were added lithium hydroxide monohydrate (80 mg) was added at 0° C 20 w/w % of sulfuric acid was added To the mixture was added toluene and water the organic layer was removed The aqueous layer was extracted with toluene 2 times concentrated under reduced pressure

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

Procedure: To a 50 ml volume three-necked flask, 1-methylsulfonyl-2-propanone (7-2-1) (2.01 g), methanol (10 ml) and benzylhydrazine monohydrochloride (14-c) (2.56 g) were added under a nitrogen atmosphere at room temperature, then additional methanol (10 ml) was added. The resulting reaction mixture was stirred at room temperature for three days, and filtered to give the primary crystal. The filtrate was concentrated under reduced pressure, and filtered again to give the crystal. The crystal was combined with the primary crystal to give 4.2 g of 1-benzyl-2-(1-methylsulfonyl-2-propylidene)hydrazine monohydrochloride (5-2-3). Additionally, the hydrochloride (5-2-3) (0.28 g) was dissolved in saturated aqueous sodium hydrogen carbonate solution (5.0 ml), and extracted with tert-butyl methyl ether (5.0 ml) 2 times. Then, the organic layer was concentrated under reduced pressure to give 0.22 g of 1-benzyl-2-(1-methylsulfonyl-2-propylidene)hydrazine (5-2-3′). NMR data of Compound (5-2-3′) is shown below. The resulting reaction mixture filtered to give the primary crystal The filtrate was concentrated under reduced pressure filtered again to give the crystal

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

Procedure: To a 200 ml volume four-necked flask, 1-methylsulfonyl-2-propanone (7-2-1) (10.21 g) and ethanol (50 ml) were added under a nitrogen atmosphere and cooled to 0° C. Hydrazine monohydrate (14-b) (3.9 ml) was added dropwise. After stirring at room temperature for 23.5 hours, the mixture was concentrated under reduced pressure to give 10.69 g of (1-methylsulfonyl-2-propylidene)hydrazine (5-2-2). the mixture was concentrated under reduced pressure

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

Procedure: To a 20 ml volume two-necked flask, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39) (0.50 g), tetrahydrofuran (anhydrous) (9 ml), and 1-methylsulfonyl-2-propanone (7-2-1) (0.30 g) were added under a nitrogen atmosphere and stirred at room temperature for 22 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to column chromatography (hexane:acetone=3:1) to give 0.25 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-34-(1)-39). The reaction mixture was concentrated under reduced pressure

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

Procedure: To a 100 ml volume four-necked flask, 1-methylsulfonyl-2-propanone (7-2-1) (4.99 g) and toluene (36.0 g) were added under a nitrogen atmosphere, and added dropwise 40 wt % of aqueous monomethylhydrazine solution (14-a) (3.96 g) at room temperature. The resulting mixture was stirred at room temperature for 16 hours, and then added additional 40 wt % of aqueous monomethylhydrazine solution (0.35 g). The resulting mixture was stirred for 24 hours, and refluxed with Dean-Stark apparatus under reduced pressure at the internal temperature of 50° C. After refluxing, the resulting mixture was cooled to 0° C., and filtered to give 3.56 g of 1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine (5-2-1). The resulting mixture was stirred for 24 hours refluxed with Dean-Stark apparatus under reduced pressure at the internal temperature of 50° C After refluxing the resulting mixture was cooled to 0° C. filtered

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

Procedure: 15.1 g of o-nitrobenzaldehyde, 16.8 g of 3-aminocrotonic acid piperidide and 13.6 g of methylsulphonylacetone are stirred in 100 ml of hexamethylphosphoric acid triamide for 10 hours under nitrogen at a bath temperature of 115° C. The mixture is cooled and dissolved in 600 ml of ethyl acetate and the solution is washed with a mixture of 600 ml of water, 90 ml of methanol and 90 ml of sodium chloride solution. The organic phase is separated off and the aqueous phase, in which a dark brown product precipitates, is filtered. The crystalline product is dried by azeotropic distillation on a rotary evaporator and treated twice in methanol/chloroform with animal charcoal. The filtrate is evaporated and the residue is recrystallised from isopropanol. 2,6-Dimethyl- 3-piperidinocarbonyl-4-(2-nitrophenyl)-5-methylsulphonyl-1,4-dihydropyridine, which is thus obtained, melts at 275°-276° C. The mixture is cooled the solution is washed with a mixture of 600 ml of water, 90 ml of methanol and 90 ml of sodium chloride solution The organic phase is separated off the aqueous phase, in which a dark brown product precipitates is filtered The crystalline product is dried by azeotropic distillation on a rotary evaporator treated twice in methanol/chloroform with animal charcoal The filtrate is evaporated the residue is recrystallised from isopropanol

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

Procedure: 4.5 g of o-nitrobenzaldehyde, 6.3 g of 3-aminocrotonic acid tert.-butyl ester and 4.1 g of methylsulphonylacetone are stirred in 30 ml of hexamethylphosphoric acid triamide for 8 hours under nitrogen at a bath temperature of 110° C. The mixture is cooled and dissolved in 200 ml of ethyl acetate and the solution is treated with a mixture of 200 ml of water, 30 ml of methanol and 30 ml of sodium chloride solution. The aqueous phase is separated off and the organic phase is washed three times with 50 ml of water, twice with 50 ml of 1 N hydrochloric acid, twice with 50 ml of sodium bicarbonate and once with 50 ml of 2 N sodium carbonate solution. The organic phase is separated off and dried. The residue is recrystallised from isopropanol. 2,6-Dimethyl-3-carbotert.-butoxy-4-(2-nitrophenyl)-5-methylsulphonyl-1,4-dihydro pyridine, which is thus obtained, melts at 152°-155° C. The mixture is cooled The aqueous phase is separated off the organic phase is washed three times with 50 ml of water The organic phase is separated off dried The residue is recrystallised from isopropanol

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

Procedure: 23.0 g of aminocrotonic acid methyl ester and 40.8 g of methylsulphonylacetone are added to 30.2 g of o-nitrobenzaldehyde dissolved in 200 ml of hexamethylphosphoric acid triamide. The mixture is then stirred for 3 hours at a bath temperature of 90°-100° C. The mixture is cooled and dissolved in 1,000 ml of ethyl acetate and the solution is washed with 400 ml of half-saturated sodium chloride solution, with twice 200 ml of 2 N sodium carbonate solution and with twice 500 ml of water. The ethyl acetate solution is dried with sodium carbonate and evaporated. Crystallisation of the residue from ethyl acetate/ether gives 2,6-dimethyl-3-carbomethoxy-5-methylsulphonyl- 4-(2-nitrophenyl)- 1,4-dihydropyridine of melting point 211°-212° C. The mixture is cooled the solution is washed with 400 ml of half-saturated sodium chloride solution, with twice 200 ml of 2 N sodium carbonate solution and with twice 500 ml of water The ethyl acetate solution is dried with sodium carbonate evaporated Crystallisation of the residue from ethyl acetate/ether

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

Procedure: To a 25 mL volume three-necked flask with Dean-Stark, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39) (1.01 g), 1-methylsulfonyl-2-propanone (7-2-1) (613 mg), and toluene (2.9 ml) were added under a nitrogen atmosphere. Water was removed by azeotropic distillation at 60° C. under 100 mmHg for 4 hours. The mixture was concentrated under reduced pressure. To the residue, toluene (1.73 g) and methanol (1.90 ml) were added, then lithium hydroxide monohydrate (80 mg) was added at 0° C. After the mixture was stirred at 0° C. for 4 hours and at 5° C. for 20 hours, 20 w/w % of sulfuric acid was added to adjust pH to less than 1. To the mixture was added toluene and water, and then the organic layer was removed. The aqueous layer was extracted with toluene 2 times. The organic layers were combined, and concentrated under reduced pressure to give 1.28 g of 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydro-3-pyridazinone ((2-34)-(1)-39). Water was removed by azeotropic distillation at 60° C. under 100 mmHg for 4 hours The mixture was concentrated under reduced pressure To the residue, toluene (1.73 g) and methanol (1.90 ml) were added lithium hydroxide monohydrate (80 mg) was added at 0° C 20 w/w % of sulfuric acid was added To the mixture was added toluene and water the organic layer was removed The aqueous layer was extracted with toluene 2 times concentrated under reduced pressure

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

Procedure: To a 50 ml volume three-necked flask, 1-methylsulfonyl-2-propanone (7-2-1) (2.01 g), methanol (10 ml) and benzylhydrazine monohydrochloride (14-c) (2.56 g) were added under a nitrogen atmosphere at room temperature, then additional methanol (10 ml) was added. The resulting reaction mixture was stirred at room temperature for three days, and filtered to give the primary crystal. The filtrate was concentrated under reduced pressure, and filtered again to give the crystal. The crystal was combined with the primary crystal to give 4.2 g of 1-benzyl-2-(1-methylsulfonyl-2-propylidene)hydrazine monohydrochloride (5-2-3). Additionally, the hydrochloride (5-2-3) (0.28 g) was dissolved in saturated aqueous sodium hydrogen carbonate solution (5.0 ml), and extracted with tert-butyl methyl ether (5.0 ml) 2 times. Then, the organic layer was concentrated under reduced pressure to give 0.22 g of 1-benzyl-2-(1-methylsulfonyl-2-propylidene)hydrazine (5-2-3′). NMR data of Compound (5-2-3′) is shown below. The resulting reaction mixture filtered to give the primary crystal The filtrate was concentrated under reduced pressure filtered again to give the crystal

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

Procedure: To a 200 ml volume four-necked flask, 1-methylsulfonyl-2-propanone (7-2-1) (10.21 g) and ethanol (50 ml) were added under a nitrogen atmosphere and cooled to 0° C. Hydrazine monohydrate (14-b) (3.9 ml) was added dropwise. After stirring at room temperature for 23.5 hours, the mixture was concentrated under reduced pressure to give 10.69 g of (1-methylsulfonyl-2-propylidene)hydrazine (5-2-2). the mixture was concentrated under reduced pressure

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

Procedure: To a 20 ml volume two-necked flask, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39) (0.50 g), tetrahydrofuran (anhydrous) (9 ml), and 1-methylsulfonyl-2-propanone (7-2-1) (0.30 g) were added under a nitrogen atmosphere and stirred at room temperature for 22 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to column chromatography (hexane: acetone=3:1) to give 0.25 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-34-(1)-39). The reaction mixture was concentrated under reduced pressure