1-(2,4-dichloro-5-fluorophenyl)ethanone

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

Procedure: A mixture of 229.6 g of 1,3-dichloro-4-fluorobenzene and 205.34 g of aluminum chloride was heated at 80° C. A 56 g portion of acetic anhydride was added dropwise over 2 hours, then the reaction ws heated at 100° C. for 8 hours, poured onto a mixture of concentrated hydrochloric acid and ice and extracted several times with ether. The ether extracts were combined, washed with water, dried and the solvents evaporated. The solid was purified by vacuum distillation, giving 156.63 g of 6-acetyl-1,3-dichloro-4-fluorobenzene. the reaction ws heated at 100° C. for 8 hours extracted several times with ether washed with water dried the solvents evaporated The solid was purified by vacuum distillation

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

Procedure: A mixture of 229.6 g of 1,3-dichloro-4-fluorobenzene and 205.34 g of aluminum chloride was heated at 80° C. A 56 g portion of acetic anhydride was added dropwise over 2 hours, then the reaction ws heated at 100° C. for 8 hours, poured onto a mixture of concentrated hydrochloric acid and ice and extracted several times with ether. The ether extracts were combined, washed with water, dried and the solvents evaporated. The solid was purified by vacuum distillation, giving 156.63 g of 6-acetyl-1,3-dichloro-4-fluorobenzene. the reaction ws heated at 100° C. for 8 hours extracted several times with ether washed with water dried the solvents evaporated The solid 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: Namely, 2,4-dichloro-5-fluoroacetophenone is subjected to a haloform reaction in a 12% sodium hypophosphite aqueous solution to obtain 2,4-dichloro-5-fluorobenzoic acid. Then, this benzoic acid is reacted with an alcohol or with a phenol in the presence of an acid catalyst to obtain the above-mentioned fluorine-containing benzoate.

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

Procedure: A mixture of 229.6 g of 1,3-dichloro-4-fluorobenzene and 205.34 g of aluminum chloride was heated at 80° C. A 56 g portion of acetic anhydride was added dropwise over 2 hours, then the reaction ws heated at 100° C. for 8 hours, poured onto a mixture of concentrated hydrochloric acid and ice and extracted several times with ether. The ether extracts were combined, washed with water, dried and the solvents evaporated. The solid was purified by vacuum distillation, giving 156.63 g of 6-acetyl-1,3-dichloro-4-fluorobenzene. the reaction ws heated at 100° C. for 8 hours extracted several times with ether washed with water dried the solvents evaporated The solid was purified by vacuum distillation

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a warm solution of 1,3-dichloro4-fluorobenzene at 70° C. (175.0 gm), anhydrous aluminum chloride was added in small portion with stirring (260.0 g). Then acetic anhydride was added in small portion with stirring (125 mL) followed by an additional amount of aluminum chloride (159.0 g). The temperature was slowly raised to 120° C. with stirring for 25 hours. The thick reaction mixture was cooled and poured into 400 cc of concentrated hydrochloric acid containing ice. The oil was extracted with methylene chloride, washed with water, dried over anhydrous magnesium sulfate and concentrated to give 165.0 g of oil (2). with stirring (125 mL) with stirring for 25 hours The thick reaction mixture was cooled containing ice The oil was extracted with methylene chloride washed with water dried over anhydrous magnesium sulfate concentrated

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a warm solution of 1,3-dichloro4-fluorobenzene at 70° C. (175.0 gm), anhydrous aluminum chloride was added in small portion with stirring (260.0 g). Then acetic anhydride was added in small portion with stirring (125 mL) followed by an additional amount of aluminum chloride (159.0 g). The temperature was slowly raised to 120° C. with stirring for 25 hours. The thick reaction mixture was cooled and poured into 400 cc of concentrated hydrochloric acid containing ice. The oil was extracted with methylene chloride, washed with water, dried over anhydrous magnesium sulfate and concentrated to give 165.0 g of oil (2). with stirring (125 mL) with stirring for 25 hours The thick reaction mixture was cooled containing ice The oil was extracted with methylene chloride washed with water dried over anhydrous magnesium sulfate concentrated

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

Procedure: A mixture of 229.6 g of 1,3-dichloro-4-fluorobenzene and 205.34 g of aluminum chloride was heated at 80° C. A 56 g portion of acetic anhydride was added dropwise over 2 hours, then the reaction was heated at 100° C. for 8 hours, poured onto a mixture of concentrated hydrochloric acid and ice and extracted several times with ether. The ether extracts were combined, washed with water, dried and the solvents evaporated. The solid was purified by vacuum distillation, giving 156.63 g of 6-acetyl-1,3-dichloro-4-fluorobenzene. the reaction was heated at 100° C. for 8 hours extracted several times with ether washed with water dried the solvents evaporated The solid was purified by vacuum distillation