ethyl 3-(2,4-dichloro-5-fluorophenyl)-3-oxopropanoate

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

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

Procedure: To a suspension of prewashed sodium hydride (76.8 g) in ether was added 189 g of diethylcarbonate. The mixture was heated to reflux and a solution of 131.84 g of 6-acetyl-1,3-dichloro-4-fluorobenzene in 1500 ml of ether was added dropwise over 5 hours. The mixture was then refluxed 24 hours, cooled, poured onto a mixture of ice and acetic acid and extracted several times with ether. The ether extracts were combined, washed with water, dried and evaporated. The residue was purified by vacuum distillation giving 80 g of ethyl 2,4-dichloro-5-fluorobenzoylacetate. The mixture was heated to reflux The mixture was then refluxed 24 hours cooled extracted several times with ether washed with water dried evaporated The residue was purified by vacuum distillation

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

Procedure: To a suspension of prewashed sodium hydride (76.8 g) in ether was added 189 g of diethylcarbonate. The mixture was heated to reflux and a solution of 131.84 g of 6-acetyl-1,3-dichloro-4-fluorobenzene in 1500 ml of ether was added dropwise over 5 hours. The mixture was then refluxed 24 hours, cooled, poured onto a mixture of ice and acetic acid and extracted several times with ether. The ether extracts were combined, washed with water, dried and evaporated. The residue was purified by vacuum distillation giving 80 g of ethyl 2,4-dichloro-5-fluorobenzoylacetate. The mixture was heated to reflux The mixture was then refluxed 24 hours cooled extracted several times with ether washed with water dried evaporated The residue was purified by vacuum distillation

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

Procedure: Condensation of 2,4-dichloro-5-fluoroacetophenone 2 with diethyl carbonate in the presence of NaH yielded ethyl 2,4-dichloro-5-fluorobenzoylacetate 3. Treatment of the latter with triethyl orthoformate in acetic anhydride gave the carbon homologue enol ether intermediate 4 which was allowed to react with a slight excess of cyclopropylamine in methylene chloride at room temperature to give the enaminoketoester 5. Cyclization of the latter with 1 molar equivalent of NaH in refluxing dioxane yielded ethyl 1,4-dihydro-4-oxo-quinoline-3-carboxylate 6 which was then hydrolysed with aqueous NaOH to give 1-cyclopropyl-6-chloro-7-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (IM) 7. See also Scheme 1 below (Maurer, F. and Grohe, K., DE 3 435 392 through Chem. Abst., Vol. 105, No.5, 1984, pp. 97158e). Compound data:

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

Procedure: 0.15 g of p-toluenesulphonic acid is added to an emulsion of 34.9 g of crude diethyl 2,4-dichloro-5-fluoro-benzoylmalonate (3) in 50 ml of water. The mixture is heated at the boiling point for 3 hours, while stirring thoroughly, the cooled emulsion is extracted several times with methylene chloride, the combined CH2Cl2 solutions are washed once with saturated NaCl solution and dried with Na2SO4 and the solvent is distilled off in vacuo. Fractionation of the residue in vacuo gives 21.8 g of ethyl 2,4-dichloro-5-fluoro-benzoylacetate (4) of boiling point 127° to 142° C./0.09 mbar. The mixture is heated at the boiling point for 3 hours the cooled emulsion is extracted several times with methylene chloride the combined CH2Cl2 solutions are washed once with saturated NaCl solution dried with Na2SO4 the solvent is distilled off in vacuo

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

Procedure: 0.15 g of p-toluenesulphonic acid is added to an emulsion of 34.9 g of crude diethyl 2,4-dichloro-5-fluorobenzoyl-malonate (3) in 50 ml of water. The thoroughly stirred mixture is heated at the boil for 3 hours, the cooled emulsion is extracted several times with methylene chloride, the combined CH2Cl2 solutions are washed once with saturated NaCl solution and dried with Na2SO4, and the solvent is distilled off in vacuo. Fractionation of the residue in vacuo gives 21.8 g of ethyl 2,4-dichloro-5-fluoro-benzoyl-acetate (4) of boiling point 127°-142° C./0.09 mbar. The thoroughly stirred mixture is heated at the boil for 3 hours the cooled emulsion is extracted several times with methylene chloride the combined CH2Cl2 solutions are washed once with saturated NaCl solution dried with Na2SO4 the solvent is distilled off in vacuo

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

Procedure: 0.15 g of p-toluenesulphonic acid is added to an emulsion of 34.9 g of crude diethyl 2,4-dichloro-5-fluorobenzoylmalonate (3) in 50 ml of water. The mixture is heated to boiling, with thorough stirring, for 3 hours, the cooled emulsion is extracted several times with methylene chloride, the combined CH2Cl2 solutions are washed once with saturated NaCl solution, dried with Na2SO4 and the solvent is distilled out in vacuo. Fractionation of the residue under high vacuum provides 21.8 g of ethyl 2,4-dichloro-5-fluorobenzoylacetate (4) of boiling point 127°-142° C./0.09 mbar. The mixture is heated the cooled emulsion is extracted several times with methylene chloride the combined CH2Cl2 solutions are washed once with saturated NaCl solution dried with Na2SO4 the solvent is distilled out in vacuo

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

Procedure: 0.15 g of p-toluenesulphonic acid is added to an emulsion of 34.9 g of crude diethyl 2,4-dichloro-5-fluorobenzoylmalonate (3) in 50 ml of water. The mixture is heated to boiling, with thorough stirring, for 3 hours, the cooled emulsion is extracted several times with methylene chloride, the combined CH2Cl2 solutions are washed once with saturated NaCl solution, dried with Na2SO4 and the solvent is distilled out in vacuo. Fractionation of the residue under high vacuum provides 21.8 g of ethyl 2,4-dichloro-5-fluorobenzoylacetate (4) of boiling point 127°-142° C./0.09 mbar. The mixture is heated the cooled emulsion is extracted several times with methylene chloride the combined CH2Cl2 solutions are washed once with saturated NaCl solution dried with Na2SO4 the solvent is distilled out in vacuo

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

Procedure: 0.15 g of p-toluenesulphonic acid is added to an emulsion of 34.9 g of crude diethyl 2,4-dichloro-5-fluorobenzoylmalonate (3) in 50 ml of water. The mixture is heated to boiling, with thorough stirring, for 3 hours, the cooled emulsion is extracted several times with methylene chloride, the combined CH2Cl2 solutions are washed once with saturated NaCl solution, dried with Na2SO4 and the solvent is distilled out in vacuo. Fractionation of the residue under high vacuum provides 21.8 g of ethyl 2,4-dichloro-5-fluorobenzoylacetate (4) of boiling point 127°-142° C./0.09 mbar. The mixture is heated the cooled emulsion is extracted several times with methylene chloride the combined CH2Cl2 solutions are washed once with saturated NaCl solution dried with Na2SO4 the solvent is distilled out in vacuo

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

Procedure: To a suspension of prewashed sodium hydride (76.8 g) in ether was added 189 g of diethylcarbonate. The mixture was heated to reflux and a solution of 131.84 g of 6-acetyl-1,3-dichloro-4-fluorobenzene in 1500 ml of ether was added dropwise over 5 hours. The mixture was then refluxed 24 hours, cooled, poured onto a mixture of ice and acetic acid and extracted several times with ether. The ether extracts were combined, washed with water, dried and evaporated. The residue was purified by vacuum distillation giving 80 g of ethyl 2,4-dichloro-5-fluorobenzoylacetate. The mixture was heated to reflux The mixture was then refluxed 24 hours cooled extracted several times with ether washed with water dried evaporated The residue was purified by vacuum distillation

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

Procedure: 28.8 g (0.1 mole) of 2,2-dichlorovinyl 2,4-dichloro-5-fluoro-phenyl ketone are added in portions to a solution of 4.6 g of sodium in 80 ml of absolute ethanol at 0°-5° C., while cooling (ice/methanol) and stirring. When the exothermic reaction has subsided, the mixture is stirred at room temperature for a further 30 minutes, the solvent is stripped off in vacuo and the residue is taken up in 100 ml of methylene chloride. The mixture is shaken thoroughly with 100 ml of 2N sulphuric acid, the methylene chloride solution is separated off in a separating funnel and the aqueous phase is extracted another three times with 50 ml of methylene chloride each time. The combined methylene chloride solutions are washed with 100 ml of saturated sodium chloride solution and dried over sodium sulphate. The solvent is then distilled off in vacuo. The brown oily residue crystallizes on standing. Distillation under a fine vacuum gives 22.3 g (79.9%) of ethyl 2,4-dichloro-5-fluoro-benzoylacetate of boiling point 125°-126° C./0.16 mbar. Colorless crystals of melting point 44°-45° C. When the exothermic reaction the mixture is stirred at room temperature for a further 30 minutes the methylene chloride solution is separated off in a separating funnel the aqueous phase is extracted another three times with 50 ml of methylene chloride each time The combined methylene chloride solutions are washed with 100 ml of saturated sodium chloride solution dried over sodium sulphate The solvent is then distilled off in vacuo The brown oily residue crystallizes Distillation under a fine vacuum

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