ethyl 2-(2-methyl-1,3-dioxolan-2-yl)acetate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of ethyl 2-methyldioxolan-2-ylacetate (2.0 g) in methanol (69 ml) was added 1N sodium hydroxide solution (23 ml), and the mixture was stirred at room temperature overnight. Then, the mixture was neutralized with 1N hydrochloric acid, and the solvent was evaporated under reduced pressure. To the mixture was added ethyl acetate, and the mixture was dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give 2-methyldioxolan-2-ylacetic acid (1.63 g) as colorless the solvent was evaporated under reduced pressure To the mixture was added ethyl acetate the mixture was dried with magnesium sulfate The solvent was evaporated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of ethyl 2-methyldioxolan-2-ylacetate (2.0 g) in methanol (69 ml) was added 1N sodium hydroxide solution (23 ml), and the mixture was stirred at room temperature overnight. Then, the mixture was neutralized with 1N hydrochloric acid, and the solvent was evaporated under reduced pressure. To the mixture was added ethyl acetate, and the mixture was dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give 2-methyldioxolan-2-ylacetic acid (1.63 g) as colorless the solvent was evaporated under reduced pressure To the mixture was added ethyl acetate the mixture was dried with magnesium sulfate The solvent was evaporated under reduced pressure

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ueda et al. (Synthesis of pyrazolone derivatives. XLII. Synthesis and analgesic activity of 2-methyl-1-phenyl-6,7-dihydro-1H,5H-pyrazolo[5,1-b][1,3]oxazin-8-ium bromide. Yakugaku Zasshi (1982), 102(8), 743-7) proposes in Chart I of page 744 and in the last two paragraphs on page 745, the reaction of an ethyl 2-(2-methyl-1,3-dioxolan-2-yl)acetate with phenylhydrazine in the presence of sodium methoxide as a base and benzene as a solvent, thereby obtaining 2-(2-methyl-1,3-dioxolan-2-yl)-N′-phenylacetohydrazide, which is further cyclised after treatment with hydrochloric acid 10% and heating on a water bath at 90° C., to obtain 3-hydroxy-5-methyl-1-phenylpyrazole. However, this method presents the disadvantage that both sodium methoxide and benzene are unsuitable for industrial upscaling, in particular, sodium methoxide is a dangerous and highly toxic reagent and benzene is carcinogenic and therefore unsuitable for use in large quantities. Moreover, the reaction devised by Ueda et al. presents a non-optimal yield for 2-(2-methyl-1,3-dioxolan-2-yl)-N′-phenylacetohydrazide (30%). Most importantly, when the inventors tried to reproduce said reaction with similar conditions and a naphthylhydrazine was used instead of the phenylhydrazine (see Example 26 below), they were unsuccessful in preparing the desired final intermediate in optimal isomeric purity. Adversely, an isomeric mixture (80:20) of 5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-ol (desired isomer) and 3-methyl-1-(naphthalen-2-yl)-1H-pyrazol-5-ol (non-desired isomer) was obtained. This process does not avoid the distal nitrogen of the hydrazine from reacting with the ketone carbonyl of the ketoacetate, thereby generating by-products that make this route not interesting for industrial production.

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ueda et al. (Synthesis of pyrazolone derivatives. XLII. Synthesis and analgesic activity of 2-methyl-1-phenyl-6,7-dihydro-1H,5H-pyrazolo[5,1-b][1,3]oxazin-8-ium bromide. Yakugaku Zasshi (1982), 102(8), 743-7) proposes in Chart I of page 744 and in the last two paragraphs on page 745, the reaction of an ethyl 2-(2-methyl-1,3-dioxolan-2-yl)acetate with phenylhydrazine in the presence of sodium methoxide as a base and benzene as a solvent, thereby obtaining 2-(2-methyl-1,3-dioxolan-2-yl)-N′-phenylacetohydrazide, which is further cyclised after treatment with hydrochloric acid 10% and heating on a water bath at 90° C., to obtain 3-hydroxy-5-methyl-1-phenylpyrazole. However, this method presents the disadvantage that both sodium methoxide and benzene are unsuitable for industrial upscaling, in particular, sodium methoxide is a dangerous and highly toxic reagent and benzene is carcinogenic and therefore unsuitable for use in large quantities. Moreover, the reaction devised by Ueda et al. presents a non-optimal yield for 2-(2-methyl-1,3-dioxolan-2-yl)-N′-phenylacetohydrazide (30%). Most importantly, when the inventors tried to reproduce said reaction with similar conditions and a naphthylhydrazine was used instead of the phenylhydrazine (see Example 26 below), they were unsuccessful in preparing the desired final intermediate in optimal isomeric purity. Adversely, an isomeric mixture (80:20) of 5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-ol (desired isomer) and 3-methyl-1-(naphthalen-2-yl)-1H-pyrazol-5-ol (non-desired isomer) was obtained. This process does not avoid the distal nitrogen of the hydrazine from reacting with the ketone carbonyl of the ketoacetate, thereby generating by-products that make this route not interesting for industrial production.

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Benzene (50 cc), ethyl acetylacetate (30 g, 231 mmol) and ethylene glycol (16 g), followed by p-toluenesulphonic acid (0.5 g), are introduced into a round-bottomed flask fitted with a Dean and Stark apparatus. The mixture is heated under reflux while the azeotrope is distilled off for 2 hours 30 minutes. After the removal of benzene, ethyl 3,3-ethylenedioxybutanoate (37 g) is obtained (B.P.12 =98° C.). are introduced into a round-bottomed flask fitted with a Dean and Stark apparatus The mixture is heated under reflux while the azeotrope is distilled off for 2 hours 30 minutes After the removal of benzene

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Lithium aluminium hydride (2 g, 51 mmol) is added in small portions to anhydrous ethyl ether (200 cc). The mixture is cooled to 0° C. and ethyl 3,3-ethylenedioxybutanoate (3 g, 17 mmol) is then added over 10 minutes as a solution in anhydrous ethyl ether (10 cc). The mixture is stirred for 2 hours 30 minutes at a temperature in the region of 20° C. and is then hydrolysed by adding a saturated sodium sulphate solution (12 cc). After 2 hours the white precipitate is separated off by filtration. The organic phases are dried over magnesium sulphate. 2,2-Ethylenedioxy-4-hydroxybutane (2.22 g) is thus obtained. After 2 hours the white precipitate is separated off by filtration The organic phases are dried over magnesium sulphate

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Lithium aluminium hydride (2 g, 51 mmol) is added in small portions to anhydrous ethyl ether (200 cc). The mixture is cooled to 0° C. and ethyl 3,3-ethylenedioxybutanoate (3 g, 17 mmol) is then added over 10 minutes as a solution in anhydrous ethyl ether (10 cc). The mixture is stirred for 2 hours 30 minutes at a temperature in the region of 20° C. and is then hydrolysed by adding a saturated sodium sulphate solution (12 cc). After 2 hours the white precipitate is separated off by filtration. The organic phases are dried over magnesium sulphate. 2,2-Ethylenedioxy-4-hydroxybutane (2.22 g) is thus obtained. After 2 hours the white precipitate is separated off by filtration The organic phases are dried over magnesium sulphate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of ethyl 2-methyldioxolan-2-ylacetate (2.0 g) in methanol (69 ml) was added 1N sodium hydroxide solution (23 ml), and the mixture was stirred at room temperature overnight. Then, the mixture was neutralized with 1N hydrochloric acid, and the solvent was evaporated under reduced pressure. To the mixture was added ethyl acetate, and the mixture was dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give 2-methyldioxolan-2-ylacetic acid (1.63 g) as colorless the solvent was evaporated under reduced pressure To the mixture was added ethyl acetate the mixture was dried with magnesium sulfate The solvent was evaporated under reduced pressure