60705-25-1

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: To a mixture of 3-nitrobenzaldehyde (7.56 g), methyl 4,4-dimethoxyacetoacetate (9,69 g) and acetic acid (600 mg) in benzene (25 ml) was added portionwise each one fifth portion of piperidine (851 mg) in benzene (5 ml) for each 20 minutes' interval and the mixture was heated to reflux for 4 hours under azeotropic dehydration. After cooling, the reaction mixture was diluted with benzene (50 ml), washed twice with diluted aqueous sodium bicarbonate solution, and in turn, with water and saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give crude reddish brown oily methyl (3-nitrobenzylidene)-4,4-dimethylacetoacetate (17.82 g) which was used in the following reaction without any further purification. A mixture of above oil (17.82 g) and methyl 3-aminocrotonate (6.33 g) was heated at 60° to 65° C. for 4.5 hours, at 100° to 105° C. for 8 hours and 45 minutes. The reaction mixture was chromatographed on a column of silica-gel (440 g) and eluted with a mixture of benzene and ethyl acetate (10:1, v/v) to give crystalline product (10.46 g) of dimethyl 2-methyl-4-(3-nitrophenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate. Thus obtained crystals (720 mg) were recrystallized from diisopropyl ether (10 ml) to give pure specimen (560 mg), mp 99° to 100° C. the mixture was heated to reflux for 4 hours under azeotropic dehydration After cooling washed twice with diluted aqueous sodium bicarbonate solution in turn, with water and saturated aqueous solution of sodium chloride, dried over magnesium sulfate evaporated to dryness under reduced pressure to give crude reddish brown oily methyl (3-nitrobenzylidene)-4,4-dimethylacetoacetate (17.82 g) which was used in the following reaction without any further purification was heated at 60° to 65° C. for 4.5 hours, at 100° to 105° C. for 8 hours and 45 minutes The reaction mixture was chromatographed on a column of silica-gel (440 g) eluted with a mixture of benzene and ethyl acetate (10:1

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

Procedure: To a mixture of 3-nitrobenzaldehyde (7.56 g), methyl 4,4-dimethoxyacetoacetate (9,69 g) and acetic acid (600 mg) in benzene (25 ml) was added portionwise each one fifth portion of piperidine (851 mg) in benzene (5 ml) for each 20 minutes' interval and the mixture was heated to reflux for 4 hours under azeotropic dehydration. After cooling, the reaction mixture was diluted with benzene (50 ml), washed twice with diluted aqueous sodium bicarbonate solution, and in turn, with water and saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give crude reddish brown oily methyl (3-nitrobenzylidene)-4,4-dimethylacetoacetate (17.82 g) which was used in the following reaction without any further purification. A mixture of above oil (17.82 g) and methyl 3-aminocrotonate (6.33 g) was heated at 60° to 65° C. for 4.5 hours, at 100° to 105° C. for 8 hours and 45 minutes. The reaction mixture was chromatographed on a column of silica-gel (440 g) and eluted with a mixture of benzene and ethyl acetate (10:1, v/v) to give crystalline product (10.46 g) of dimethyl 2-methyl-4-(3-nitrophenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate. Thus obtained crystals (720 mg) were recrystallized from diisopropyl ether (10 ml) to give pure specimen (560 mg), mp 99° to 100° C. the mixture was heated to reflux for 4 hours under azeotropic dehydration After cooling washed twice with diluted aqueous sodium bicarbonate solution in turn, with water and saturated aqueous solution of sodium chloride, dried over magnesium sulfate evaporated to dryness under reduced pressure to give crude reddish brown oily methyl (3-nitrobenzylidene)-4,4-dimethylacetoacetate (17.82 g) which was used in the following reaction without any further purification was heated at 60° to 65° C. for 4.5 hours, at 100° to 105° C. for 8 hours and 45 minutes The reaction mixture was chromatographed on a column of silica-gel (440 g) eluted with a mixture of benzene and ethyl acetate (10:1

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

Procedure: To a solution of 2-nitrobenzaldehyde (6.80 g), methyl 4,4-dimethoxyacetoacetate (8.72 g) and acetic acid (0.54 g) in benzene (30 ml), was added piperidine (0.46 g), in a similar manner to aforementioned examples 1-(i) and 2-(i), and the mixture was heated to reflux for 2 hours under azeotropic dehydration. The reaction mixture, after cooling, was diluted with benzene (100 ml), washed three times with water, and in turn with diluted aqueous sodium bicarbonate solution and water, dried over magnesium sulfated and evaporated to dryness under reduce pressure to give oily methyl 2-(2-nitrobenzylidene)-4,4-dimethoxyacetoacetate (14.73 g). A mixture of the above obtained oil (14.70 g) and isopropyl 3-aminocrotonate (7.09 g) was heated at 60° to 63° C. for 2 hours and at 85° to 90° C. for about 10 hours. The reaction mixture was treated with ethyl acetate to give yellowish crystals which were collected by filtration and washed with methanol. The filtrate was concentrated and the residue was treated with methanol to give additional crystals. The combined crystals (11.10 g) were recrystallized from methanol to give pure crystals of isopropyl 2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-1,4-dihydropyridine-3-carboxylate, m.p. 143°-145° C. in a similar manner to aforementioned examples 1-(i) and 2-(i), and the mixture was heated to reflux for 2 hours under azeotropic dehydration The reaction mixture, after cooling washed three times with water in turn with diluted aqueous sodium bicarbonate solution and water, dried over magnesium evaporated to dryness

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

Procedure: A mixture of 2-nitrobenzaldehyde (6.8009 g), methyl 4,4-dimethoxyacetoacetate (8.7204 g), acetic acid (0.5405 g) and piperidine (0.4598 g) in benzene (30 ml) was heated to reflux for 2 hours under azeptropic dehydration. The reaction mixture was diluted with benzene (100 ml), washed twice with water, and in turn with diluted aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give crude oily methyl 2-(2-nitrobenzylidene)-4,4-dimethoxyacetoacetate (15.23 g). A mixture of thus obtained crude oil (15.23 g) and ethyl 3-aminocrotonate (6.6840 g) was heated at around 65° C. for 6 hours and then at 98° to 100° C. for 5 hours. The resultant viscous brown oil was dissolved in ethyl acetate, washed three times with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give brown oil (19.40 g). The residual oil was crystallized by trituration with methanol (10 ml) to give yellowish crystalline powder (12.77 g) of ethyl 2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-1,4-dihydropyridine-3-carboxylate. An additional 0.53 g of crystals was recovered from the mother liquor. Recrystallization from methanol gave yellowish granules, m.p. 122°-124° C. was heated to reflux for 2 hours under azeptropic dehydration washed twice with water in turn with diluted aqueous sodium bicarbonate solution and water, dried over magnesium sulfate evaporated to dryness under reduced pressure to give crude oily methyl 2-(2-nitrobenzylidene)-4,4-dimethoxyacetoacetate (15.23 g) A mixture

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

Procedure: A mixture of 2-nitrobenzaldehyde (6.8009 g), methyl 4,4-dimethoxyacetoacetate (8.7204 g), acetic acid (0.5405 g) and piperidine (0.4598 g) in benzene (30 ml) was heated to reflux for 2 hours under azeptropic dehydration. The reaction mixture was diluted with benzene (100 ml), washed twice with water, and in turn with diluted aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give crude oily methyl 2-(2-nitrobenzylidene)-4,4-dimethoxyacetoacetate (15.23 g). A mixture of thus obtained crude oil (15.23 g) and ethyl 3-aminocrotonate (6.6840 g) was heated at around 65° C. for 6 hours and then at 98° to 100° C. for 5 hours. The resultant viscous brown oil was dissolved in ethyl acetate, washed three times with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give brown oil (19.40 g). The residual oil was crystallized by trituration with methanol (10 ml) to give yellowish crystalline powder (12.77 g) of ethyl 2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-1,4-dihydropyridine-3-carboxylate. An additional 0.53 g of crystals was recovered from the mother liquor. Recrystallization from methanol gave yellowish granules, m.p. 122°-124° C. was heated to reflux for 2 hours under azeptropic dehydration washed twice with water in turn with diluted aqueous sodium bicarbonate solution and water, dried over magnesium sulfate evaporated to dryness under reduced pressure to give crude oily methyl 2-(2-nitrobenzylidene)-4,4-dimethoxyacetoacetate (15.23 g) A mixture

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

Procedure: 1-(i) To a mixture of 2-cyanobenzaldehyde (5.0 g), methyl 4,4-dimethoxyacetoacetate (7.39 g) and acetic acid (0.458 g) in benzene (15 ml) was added portionwise each one third of a solution of piperidine (390 mg) in benzene (5 ml) for each 20 minutes' interval. The mixture was heated to reflux for 2 hours and the resulting water was removed off azeotropically during the reaction course. After cooling, the reaction mixture was shaken with a mixture of benzene (50 ml) and water (30 ml), and the organic layer was separated and washed with diluted aqueous sodium bicarbonate solution and water. The aqueous washings were extracted with benzene (30 ml). The benzene extract was combined with the above organic layer, washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The oily residue (14.8 g) was chromatographed on a column of silica-gel (200 g) and eluted with a mixture of benzene and ethyl acetate (25:1 v/v) to give an oily methyl 2 -(2-cyanobenzylidene)-4,4-dimethoxyacetoacetate (6.90 g). The thin layer chromatogram and N.M.R. spectrum of this product show that it consisted of a mixture of two stereoisomers. The mixture was heated to reflux for 2 hours the resulting water was removed off azeotropically during the reaction course After cooling the organic layer was separated washed with diluted aqueous sodium bicarbonate solution and water The aqueous washings were extracted with benzene (30 ml) The benzene extract washed with water dried over magnesium sulfate evaporated to dryness under reduced pressure The oily residue (14.8 g) was chromatographed on a column of silica-gel (200 g) eluted with a mixture of benzene and ethyl acetate (25:1 v/v)

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

Procedure: 1-(i) To a mixture of 2-cyanobenzaldehyde (5.0 g), methyl 4,4-dimethoxyacetoacetate (7.39 g) and acetic acid (0.458 g) in benzene (15 ml) was added portionwise each one third of a solution of piperidine (390 mg) in benzene (5 ml) for each 20 minutes' interval. The mixture was heated to reflux for 2 hours and the resulting water was removed off azeotropically during the reaction course. After cooling, the reaction mixture was shaken with a mixture of benzene (50 ml) and water (30 ml), and the organic layer was separated and washed with diluted aqueous sodium bicarbonate solution and water. The aqueous washings were extracted with benzene (30 ml). The benzene extract was combined with the above organic layer, washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The oily residue (14.8 g) was chromatographed on a column of silica-gel (200 g) and eluted with a mixture of benzene and ethyl acetate (25:1 v/v) to give an oily methyl 2 -(2-cyanobenzylidene)-4,4-dimethoxyacetoacetate (6.90 g). The thin layer chromatogram and N.M.R. spectrum of this product show that it consisted of a mixture of two stereoisomers. The mixture was heated to reflux for 2 hours the resulting water was removed off azeotropically during the reaction course After cooling the organic layer was separated washed with diluted aqueous sodium bicarbonate solution and water The aqueous washings were extracted with benzene (30 ml) The benzene extract washed with water dried over magnesium sulfate evaporated to dryness under reduced pressure The oily residue (14.8 g) was chromatographed on a column of silica-gel (200 g) eluted with a mixture of benzene and ethyl acetate (25:1 v/v)

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

Procedure: Following the procedure stated in Referential example 1, reaction of farnesyl bromide which had been prepared from 22 g of nerolidol with 19 g of methyl 4,4-dimethoxyacetoacetate was carried out and the reaction mixture was purified by the silica gel (200 g) column chromatography to yield 12.8 g of the desired product. the reaction mixture was purified by the silica gel (200 g) column chromatography

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

Procedure: In 350 ml of anhydrous ethanol was dissolved 17.4 g of sodium metal, and to this was added dropwise 160 g of methyl 4,4-dimethoxyacetoacetate with stirring at room temperature. One hour later, geranyl bromide prepared from 130 g of geraniol was added dropwise to the above-obtained mixture under ice-cooling. The mixture was then allowed to stand overnight at room temperature and refluxed for one hour. To this reaction mixture was added 42 g of sodium hydroxide in a mixture of 1.4 1. of ethanol and 1.18 1. of water, and the mixture was heated under reflux for 6 hours and extracted with n-hexane. The n-hexane extract was distilled under reduced pressure to give 134 g of the desired product, b.p. 92°-95° C./0.05 mmHg. was added dropwise to the above-obtained mixture under ice- cooling refluxed for one hour in a mixture of 1.4 1 under reflux for 6 hours extracted with n-hexane The n-hexane extract was distilled under reduced pressure

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