diethyl 2-fluoropropanedioate

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 heterogeneous mixture of urea (641 mg, 10.67 mmol) and diethylfluoromalonate (1.96 g, 10.67 mmol) in EtOH (11 mL) was added 2.68 M NaOEt in EtOH (7.96 mL, 21.34 mmol). The mixture was heated at reflux for 60 h and then allowed to cool to room temperature. The mixture was filtered and the cake was then dissolved in warm water and the resulting solution was acidified with concentrated HCl to pH 2. The mixture was allowed to cool to room temperature and then cooled in an ice bath before filtering. The cake was washed with water and dried to afford 5-fluoropyrimidine-2,4,6-triol as a slightly off white solid (1.45 g, 93%). The mixture was heated at reflux for 60 h The mixture was filtered the cake was then dissolved in warm water to cool to room temperature cooled in an ice bath before filtering The cake was washed with water dried

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

実験手順: To a heterogeneous mixture of urea (641 mg, 10.67 mmol) and diethylfluoromalonate (1.96 g, 10.67 mmol) in EtOH (11 mL) was added 2.68 M NaOEt in EtOH (7.96 mL, 21.34 mmol). The mixture was heated at reflux for 60 h and then allowed to cool to room temperature. The mixture was filtered and the cake was then dissolved in warm water and the resulting solution was acidified with concentrated HCl to pH 2. The mixture was allowed to cool to room temperature and then cooled in an ice bath before filtering. The cake was washed with water and dried to afford 5-fluoropyrimidine-2,4,6-triol as a slightly off white solid (1.45 g, 93%). The mixture was heated at reflux for 60 h The mixture was filtered the cake was then dissolved in warm water to cool to room temperature cooled in an ice bath before filtering The cake was washed with water dried

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

実験手順: Sodium hydride (60% in oil, 3.9 g, 96.5 mmol) was washed with hexanes in a round bottom flask under argon and cooled with an ice water bath. EtOH (100 mL) was slowly added. The resulting mixture was warmed to RT and stirred for 30 minutes. To the base mixture, diethyl 2-fluoromalonate (5.7 g, 32.2 mmol) was added, followed by morpholinoformamidine hydrobromide (6.8 g, 32.2 mmol). The mixture was heated to 90-95° C. with stirring under argon. After 12 hours, the reaction was cooled to room temperature and the EtOH was removed in vacuo. The resulting white solid was dissolved in water (25 mL) and acidified with conc. HCl to pH=3-4. A white precipitate formed which was collected on a Büchner filter, washed with water (2×50 mL), air dried on the filter, and dried in vacuo to give 5-fluoro-2-morpholinopyrimidine-4,6-diol (0.87 g, 12%). LC/MS (m/z): 216.0 (MH+), Rt 0.63 minutes. cooled with an ice water bath The mixture was heated to 90-95° C. with stirring under argon After 12 hours the reaction was cooled to room temperature the EtOH was removed in vacuo The resulting white solid was dissolved in water (25 mL) A white precipitate formed which was collected on a Büchner filter washed with water (2×50 mL), air dried on the filter dried in vacuo

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

実験手順: An exemplary approach to fluoxastrobin is illustrated in Scheme 1. According to Scheme 1, the synthesis begins with chlorination of diethyl malonate (1) with a suitable chlorinating agent, for example, sulfuryl chloride. The resulting diethyl 2-chloromalonate (2) is converted to diethyl 2-fluoromalonate (3) with a suitable fluorinating reagent, such as a hydrogen fluoride-triethylamine complex. The ensuing cyclization in formamide provides 5-fluoropyrimidine-4,6-diol (4), which is treated with a suitable chlorinating agent, for example phosphorus oxychloride to give 4,6-dichloro-5-fluoropyrimidine (5). As further indicated in Scheme 2, 4,6-dichloro-5-fluoropyrimidine (5) is reacted with (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13) in an appropriate solvent and in the presence of a base to yield (E)-(2-((6-halo-5-fluoropyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O-methyl oxime (14), which is further reacted with 2-chlorophenol to give fluoxastrobin. As described above, the last two steps of the synthesis may be carried out as a one-pot process, i.e. without isolation of the intermediate, (E)-(2-((6-halo-5-fluoropyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O-methyl oxime (14).

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

実験手順: To a heterogeneous mixture of urea (641 mg, 10.67 mmol) and diethylfluoromalonate (1.96 g, 10.67 mmol) in EtOH (11 mL) was added 2.68 M NaOEt in EtOH (7.96 mL, 21.34 mmol). The mixture was heated at reflux for 60 h and then allowed to cool to room temperature. The mixture was filtered and the cake was then dissolved in warm water and the resulting solution was acidified with concentrated HCl to pH 2. The mixture was allowed to cool to room temperature and then cooled in an ice bath before filtering. The cake was washed with water and dried to afford 5-fluoropyrimidine-2,4,6-triol as a slightly off white solid (1.45 g, 93%). The mixture was heated at reflux for 60 h The mixture was filtered the cake was then dissolved in warm water to cool to room temperature cooled in an ice bath before filtering The cake was washed with water dried

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: According to the procedure of J. Chem. Soc. 1959, 3286, a solution of 0.92 g (40 mmol) of sodium metal dissolved in 20 mL of methaol was treated with 2.08 g (22 mmol) of acetamidine hydrochloride. After 5 minutes, to this stirred mixture was added 3.6 g (20 mmol) of diethyl fluoromalonate. The reaction mixture was heated to reflux for 18 hours, cooled to 23° C., and then concentrated in vacuo. The residue was dissolved in water, neutralized with aqueous 3N HCl (6 mL), and chilled. A precipitate which formed was isolated by filtration and triturated with a 1:1 mixture of diethyl ether/ethyl acetate. The resulting crude product (1.36 g, 47%) was used without further purification. The reaction mixture was heated to reflux for 18 hours concentrated in vacuo The residue was dissolved in water chilled A precipitate which formed was isolated by filtration triturated with a 1:1 mixture of diethyl ether/ethyl acetate The resulting crude product (1.36 g, 47%) was used without further purification

反応条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: According to the procedure of J. Chem. Soc. 1959, 3286, a solution of 0.92 g (40 mmol) of sodium metal dissolved in 20 mL of methaol was treated with 2.08 g (22 mmol) of acetamidine hydrochloride. After 5 minutes, to this stirred mixture was added 3.6 g (20 mmol) of diethyl fluoromalonate. The reaction mixture was heated to reflux for 18 hours, cooled to 23° C., and then concentrated in vacuo. The residue was dissolved in water, neutralized with aqueous 3N HCl (6 mL), and chilled. A precipitate which formed was isolated by filtration and triturated with a 1:1 mixture of diethyl ether/ethyl acetate. The resulting crude product (1.36 g, 47%) was used without further purification. The reaction mixture was heated to reflux for 18 hours concentrated in vacuo The residue was dissolved in water chilled A precipitate which formed was isolated by filtration triturated with a 1:1 mixture of diethyl ether/ethyl acetate The resulting crude product (1.36 g, 47%) was used without further purification

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

実験手順: 2-fluoro malonic acid diethyl ester (670 μL) was added to a THF (8 mL) suspension of sodium hydride (170 mg) under ice-cooling, and the reaction solution was agitated under ice-cooling for 20 minutes and further agitated at room temperature for 1 hour. After dropping the THF (2 mL) solution of (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid ethyl ester (1 g) obtained above to the reaction solution over 10 minutes and the reaction solution was agitated at room temperature for 30 minutes, and heated to reflux for 8 hours. After the reaction solution was allowed to be cooled to room temperature, ethyl acetate and water was added and the organic layer was washed with a saturated ammonium chloride solution. After drying the organic layer over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: from hexane to hexane:ethyl acetate=1:1), and 593 mg (56%) of (E)-2-fluoro-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid ethyl ester was obtained. The physical properties of the compound are as follows. cooling cooling for 20 minutes further agitated at room temperature for 1 hour obtained above to the reaction solution over 10 minutes the reaction solution was agitated at room temperature for 30 minutes heated to reflux for 8 hours the organic layer was washed with a saturated ammonium chloride solution After drying the organic layer over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The obtained residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: from hexane to hexane:ethyl acetate=1:1)

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

実験手順: To a heterogeneous mixture of urea (641 mg, 10.67 mmol) and diethylfluoromalonate (1.96 g, 10.67 mmol) in EtOH (11 mL) was added 2.68 M NaOEt in EtOH (7.96 mL, 21.34 mmol). The mixture was heated at reflux for 60 h and then allowed to cool to room temperature. The mixture was filtered and the cake was then dissolved in warm water and the resulting solution was acidified with concentrated HCl to pH 2. The mixture was allowed to cool to room temperature and then cooled in an ice bath before filtering. The cake was washed with water and dried to afford 5-fluoropyrimidine-2,4,6-triol as a slightly off white solid (1.45 g, 93%). The mixture was heated at reflux for 60 h The mixture was filtered the cake was then dissolved in warm water to cool to room temperature cooled in an ice bath before filtering The cake was washed with water dried

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

実験手順: Sodium (646 mg, 28 mmol) is dissolved in methanol (50 ml) under a nitrogen atmosphere. Cyclopropanecarboximidamide hydrochloride (3.40 g, 28 mmol) is added in one portion. The mixture is stirred at room temperature for 0.25 h, then filtered upon hyflocel. The filtrate is concentrated in vacuo. This free base is added to a solution of sodium (1.29 g, 56 mmol) in methanol (50 ml) under a nitrogen atmosphere, at room temperature. Diethylfluoromalonate (5 g, 28 mmol) is added and the mixture is stirred at 60° C. for 5 h. The solvent is evaporated and the yellowish solid obtained is dissolved in 60 ml of water. The pH is adjusted at 6 with a 5 N HCl solution and the white precipitate formed is filtered and dried. 2-cyclopropyl-5-fluoro-4,6-pyrimidinediol 3 (3.6 g, 76%) is obtained as a white powder and used in the next step without further purification. filtered upon hyflocel The filtrate is concentrated in vacuo the mixture is stirred at 60° C. for 5 h The solvent is evaporated the yellowish solid obtained the white precipitate formed is filtered dried