diethyl 2-chloropropanedioate

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

Procedure: A mixture of 38.6 g (0.3 mole) of 4-chlorophenol, 70 g (0.36 mole) of diethylchloromalonate and 69.1 g (0.5 mole) of anhydrous potassium carbonate in 750 ml of acetone was heated at reflux for 48 hr, cooled, filtered and the filtrate concentrated. The residue was diluted with 250 ml of ethyl ether and was washed successively with two 100 ml portions of a 1% NaOH solution, once with H2O and once with brine, dried (sodium sulfate) and concentrated to give an oil which gradually crystallized. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration and dried to yield 72.6 g (84%) of white solid. An analytical sample, mp 43.5°-45° C. (lit. mp 58°-60° C.), was recrystallized from petroleum ether (60°-110° C.). was heated at reflux for 48 hr cooled filtered the filtrate concentrated The residue was diluted with 250 ml of ethyl ether was washed successively with two 100 ml portions of a 1% NaOH solution, once with H2O and once with brine dried (sodium sulfate) concentrated to give an oil which gradually crystallized The solid was triturated with petroleum ether (30°-60° C.) collected by filtration dried

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

Procedure: To a solution of 6.9 g (0.3 mole) of sodium pellets dissolved in 400 ml of absolute ethanol was successively added a solution of 37.9 g (0.305 mole) of guaiacol in 50 ml of ethanol followed by a solution of 68.1 g (0.35 mole) of diethylchloromalonate in 50 ml of ethanol. The mixture was heated at reflux for 28 hr and then stirred at ambient temperature for 3 days. The mixture was filtered and the filtrate was concentrated. The residue was partitioned between salt water and ethyl ether. The layers were separated and the aqueous layer was extracted twice with 150 ml portions of ethyl ether. The combined organic layers were washed with brine, dried (sodium sulfate0 and concentrated to give a yellow oil. The oil was subjected to vacuum distillation and 66.6 g (79%) of the title compound was collected as a clear oil, bp 136°-153° C. at 0.3 mm. The mixture was heated at reflux for 28 hr The mixture was filtered the filtrate was concentrated The residue was partitioned between salt water and ethyl ether The layers were separated the aqueous layer was extracted twice with 150 ml portions of ethyl ether The combined organic layers were washed with brine dried (sodium sulfate0 concentrated to give a yellow oil The oil was subjected to vacuum distillation and 66.6 g (79%) of the title compound was collected as a clear oil, bp 136°-153° C. at 0.3 mm

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-benzoylpyrrole (855 mg, 5 mmol), diethyl chloromalonate (973 mg, 5 mmol) and manganese(III) acetate dihydrate (4560 mg, 15 mmol) in acetic acid (30 mL) was stirred at 80° C. for four hours. The reaction was cooled to room temperature, diluted with diethyl ether and filtered. The filtrate was washed with 10% aqueous sodium hydroxide and saturated aqueous sodium chloride, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography on silica (70-30, hexanes-ethyl acetate) to provide 1.46 g (75%) of diethyl (5-benzoylpyrrol-2-yl)acetoxymethane-dicarboxylate. The reaction was cooled to room temperature filtered The filtrate was washed with 10% aqueous sodium hydroxide and saturated aqueous sodium chloride dried (Na2SO4) concentrated under reduced pressure The residue was purified by column chromatography on silica (70-30, hexanes-ethyl acetate)

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

Procedure: Diethyl chloromalonate (9.73 g, 50 mmol) was added to a stirred mixture of 3-hydroxy-2-aminopyridine (5.51 g, 50 mmol), triethylamine (6.97 mL, 50 mmol) and EtOH (100 mL) at room temperature. The mixture was heated at reflux for 17 h and allowed to attain room temperature. The precipitate formed was filtered off, washed with EtOH and dried to give the product as a white solid: yield 3.85 g (35%); mp 160-162° C. Anal. (C10H10N2O4) C, H, N. The mixture was heated at reflux for 17 h to attain room temperature The precipitate formed was filtered off washed with EtOH dried

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

Procedure: 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).

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

Procedure: Diethyl chloromalonate (9.73 g, 50 mmol) was added to a stirred mixture of 3-hydroxy-2-aminopyridine (5.51 g, 50 mmol), triethylamine (6.97 mL, 50 mmol) and EtOH (100 mL) at room temperature. The mixture was heated at reflux for 17 h and allowed to attain room temperature. The precipitate formed was filtered off, washed with EtOH and dried to give the product as a white solid: yield 3.85 g (35%); mp 160-162° C. Anal. (C10H10N2O4) C, H, N. The mixture was heated at reflux for 17 h to attain room temperature The precipitate formed was filtered off washed with EtOH dried

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

Procedure: 15 mmol of ClCH(COOC2H5)2 and 10 mmol of sodium selenide were heated in 50 ml of ethanol under reflux for 2 hours. After completion of the reaction, the reaction solution was slightly acidified with 1N HCl. Then, after insoluble material was removed from the solution, the reaction solvent was distilled off to obtain HSeCH(COOC2H5)2. The thus obtained HSeCH(COOC2H5)2 was put in aqueous ammonia and the reaction was allowed to proceed at 50° C. for 6 hours. After completion of the reaction, the solvent was distilled off to obtain HSeCH(CONH2)2. To the thus obtained HSeCH(CONH2)2 were added 50 ml of tetrahydrofuran and then 2 mmol of lithium aluminum hydride. The resulting mixture was heated under reflux for 10 hours to reduce the amide. After completion of the reaction, the insoluble portion was removed and the solvent was distilled off under reduced pressure. Then, the residue was purified by using cation exchange resin to obtain 2 mmol of 2-seleno-1,3-diaminopropane HSeCH(CH2NH2)2. To the thus obtained HSeCH(CH2NH2)2 was added 20 ml of an aqueous solution containing 2 mmol of potassium tetrachloroplatinate(II) and the resulting mixture was allowed to stand at room temperature for 4 days, so that a precipitate was formed. The precipitate was separated by filtration and dried to obtain 1.1 mmol of HSeCH(CH2NH2)2PtCl2. under reflux for 2 hours After completion of the reaction Then, after insoluble material was removed from the solution the reaction solvent was distilled off

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

Procedure: 15 mmol of ClCH(COOC2H5)2 and 10 mmol of sodium selenide were heated in 50 ml of ethanol under reflux for 2 hours. After completion of the reaction, the reaction solution was slightly acidified with 1N HCl. Then, after insoluble material was removed from the solution, the reaction solvent was distilled off to obtain HSeCH(COOC2H5)2. The thus obtained HSeCH(COOC2H5)2 was put in aqueous ammonia and the reaction was allowed to proceed at 50° C. for 6 hours. After completion of the reaction, the solvent was distilled off to obtain HSeCH(CONH2)2. To the thus obtained HSeCH(CONH2)2 were added 50 ml of tetrahydrofuran and then 2 mmol of lithium aluminum hydride. The resulting mixture was heated under reflux for 10 hours to reduce the amide. After completion of the reaction, the insoluble portion was removed and the solvent was distilled off under reduced pressure. Then, the residue was purified by using cation exchange resin to obtain 2 mmol of 2-seleno-1,3-diaminopropane HSeCH(CH2NH2)2. To the thus obtained HSeCH(CH2NH2)2 was added 20 ml of an aqueous solution containing 2 mmol of potassium tetrachloroplatinate(II) and the resulting mixture was allowed to stand at room temperature for 4 days, so that a precipitate was formed. The precipitate was separated by filtration and dried to obtain 1.1 mmol of HSeCH(CH2NH2)2PtCl2. under reflux for 2 hours After completion of the reaction Then, after insoluble material was removed from the solution the reaction solvent was distilled off