ethyl 3-oxo-3-(2,3,4,5,6-pentafluorophenyl)propanoate

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

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

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 20 ml of chloroform solution of ethyl 3-ethoxy-2-pentafluorobenzoylacrylate prepared from 5.6 g of ethyl 2,3,4,5,6-pentafluorobenzoylacetate by normal process was added 2-amino-3,5-difluoro-6-(p-methoxybenzylamino)pyridine until the disappearance of the ethyl acrylate spot in TLC analysis. The solution was concentrated under reduced pressure. To the residue were added 4.3 g of anhydrous potassium carbonate and 15 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 15 minutes and allowed to cool. The solution was separated by adding 100 ml of chloroform and 1 liter of distilled water, and the chloroform layer was washed twice with 1 liter of distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitate was dispersed in ethanol, collected by filtration, and washed with ethanol and diisopropylether successively to obtain 6.15 g of the title compound as a colorless powder. The solution was concentrated under reduced pressure To the residue were added 4.3 g of anhydrous potassium carbonate and 15 ml of N,N-dimethylformamide to cool The solution was separated by adding 100 ml of chloroform and 1 liter of distilled water the chloroform layer was washed twice with 1 liter of distilled water dried over anhydrous magnesium sulfate concentrated under reduced pressure The precipitate was dispersed in ethanol collected by filtration washed with ethanol and diisopropylether successively

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 2.62 g (20.4 mmol) of 3-acetamidopyrrolidine dissolved in 50 mL of pyridine and cooled to 0° C. was added 2.06 g (20.4 mmol) of triethylamine and 5.24 g (18.6 mmol) of ethyl 2,3,4,5,6-pentafluorobenzoylacetate, from step 2 above. The solution was stirred at 0° C. for 1 hour, then at room temperature overnight. The solvent was removed by evaporation under vacuum and the residue was dissolved in chlorform, which was washed with 0.5N HCl and 5% potassium carbonate solution. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue was further dried by adding and distilling off ethylene dichloride, chloroform and methylene, followed by further drying under vacuum. The crystalline residue was washed with hexane and dried to afford 6.8 g of the title compound as a tan solid, mp 90°-92° C. MS M/Z: 391 (M+H). IR (CDCl3): 1635, 1680, 1740 cm-1. NMR (CDCl3) d: 1.26 (m, 3H), 2.00 (m, 5H), 2.22 (m, 2H), 3.54 (m,1H), 3.77 (m, 2H), 3.85 (m, 1H), 3.98 (m, 1H), 4.22 (m, 2H), 5.75 (m, 1H). Analysis calculated for C17H18F4N2O4 : C, 52.31; H, 4.65; N, 7.18. Found: C, 52.47; H, 4.67; N, 7.33. at room temperature overnight The solvent was removed by evaporation under vacuum the residue was dissolved in chlorform which was washed with 0.5N HCl and 5% potassium carbonate solution The organic layer was dried over magnesium sulfate filtered evaporated The residue was further dried by adding distilling off ethylene dichloride, chloroform and methylene by further drying under vacuum The crystalline residue was washed with hexane dried

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 20 ml of chloroform solution of ethyl 3-ethoxy-2-pentafluorobenzoylacrylate prepared from 5.6 g of ethyl 2,3,4,5,6-pentafluorobenzoylacetate by normal process was added 2-amino-3,5-difluoro-6-(p-methoxybenzylamino)pyridine until the disappearance of the ethyl acrylate spot in TLC analysis. The solution was concentrated under reduced pressure. To the residue were added 4.3 g of anhydrous potassium carbonate and 15 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 15 minutes and allowed to cool. The solution was separated by adding 100 ml of chloroform and 1 liter of distilled water, and the chloroform layer was washed twice with 1 liter of distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitate was dispersed in ethanol, collected by filtration, and washed with ethanol and diisopropylether successively to obtain 6.15 g of the title compound as a colorless powder. The solution was concentrated under reduced pressure To the residue were added 4.3 g of anhydrous potassium carbonate and 15 ml of N,N-dimethylformamide to cool The solution was separated by adding 100 ml of chloroform and 1 liter of distilled water the chloroform layer was washed twice with 1 liter of distilled water dried over anhydrous magnesium sulfate concentrated under reduced pressure The precipitate was dispersed in ethanol collected by filtration washed with ethanol and diisopropylether successively

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

Procedure: A stirred solution of ethyl (pentafluorobenzoyl)acetate 1 (5.77 g, 20 mmol), Ac2O (8.02 mL, 8.34 g, 80 mmol) and triethyl orthoformate (5.1 mL, 4.54 g, 30 mmol) was heated at 130° C. for 1.5 h. The mixture was concentrated in vacuo and dried under high vacuum for 3 hours. The crude product 2 was dissolved in anhydrous CH2Cl2 (10 mL) and cyclopropyl amine (2.15 mL, 1.75 g, 30 mmol) was added very slowly at room temperature. After 1.5 h, the solvent was removed by evaporation to yield 3 as a dark yellow solid (7.55 g crude, quantitative) that was used in the next step without further purification. The mixture was concentrated in vacuo dried under high vacuum for 3 hours The crude product 2 was dissolved in anhydrous CH2Cl2 (10 mL) the solvent was removed by evaporation

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 20 ml of chloroform solution of ethyl 3-ethoxy-2-pentafluorobenzoylacrylate prepared from 5.6 g of ethyl 2,3,4,5,6-pentafluorobenzoylacetate by normal process was added 2-amino-3,5-difluoro-6-(p-methoxybenzylamino)pyridine until the disappearance of the ethyl acrylate spot in TLC analysis. The solution was concentrated under reduced pressure. To the residue were added 4.3 g of anhydrous potassium carbonate and 15 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 15 minutes and allowed to cool. The solution was separated by adding 100 ml of chloroform and 1 liter of distilled water, and the chloroform layer was washed twice with 1 liter of distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitate was dispersed in ethanol, collected by filtration, and washed with ethanol and diisopropylether successively to obtain 6.15 g of the title compound as a colorless powder. The solution was concentrated under reduced pressure To the residue were added 4.3 g of anhydrous potassium carbonate and 15 ml of N,N-dimethylformamide to cool The solution was separated by adding 100 ml of chloroform and 1 liter of distilled water the chloroform layer was washed twice with 1 liter of distilled water dried over anhydrous magnesium sulfate concentrated under reduced pressure The precipitate was dispersed in ethanol collected by filtration washed with ethanol and diisopropylether successively

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

Procedure: 70.5 g of ethyl pentafluorobenzoylacetate (0.25 mol), 66.6 g of triethyl orthoformate (0.45 mol) and 77.4 g of diacetyl oxide (0.72 mol) were stirred at 150° C. for 2.5 hours. Fractions having a lower boiling point were evaporated under reduced pressure. To the residue was added 250 ml of anhydrous ethanol. 14.5 g of cyclopropylamine (0.25 mol) was added to the solution under cooling of ice water and the reaction was then carried out at room temperature for 2 hours. The resultingt mixture was filtered under suction. The residue was re-crystallized from a mixture of petroleum ether and cyclohexane to yield 62.8 g (0.18 mol) of ethyl 2-(pentafluorobenzoyl)-3-cyclopropylaminoacrylate in 72.0% yield, mp 88-91° C. were evaporated under reduced pressure To the residue was added 250 ml of anhydrous ethanol The resultingt mixture was filtered under suction The residue was re-crystallized from a mixture of petroleum ether and cyclohexane

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

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

Procedure: 70.5 g of ethyl pentafluorobenzoylacetate (0.25 mol), 66.6 g of triethyl orthoformate (0.45 mol) and 77.4 g of diacetyl oxide (0.72 mol) were stirred at 150° C. for 2.5 hours. Fractions having a lower boiling point were evaporated under reduced pressure. To the residue was added 250 ml of anhydrous ethanol. 14.5 g of cyclopropylamine (0.25 mol) was added to the solution under cooling of ice water and the reaction was then carried out at room temperature for 2 hours. The resultingt mixture was filtered under suction. The residue was re-crystallized from a mixture of petroleum ether and cyclohexane to yield 62.8 g (0.18 mol) of ethyl 2-(pentafluorobenzoyl)-3-cyclopropylaminoacrylate in 72.0% yield, mp 88-91° C. were evaporated under reduced pressure To the residue was added 250 ml of anhydrous ethanol The resultingt mixture was filtered under suction The residue was re-crystallized from a mixture of petroleum ether and cyclohexane

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

Procedure: The [4-amino(mono- or poly-fluoro)phenyl]alkanoic acids and esters required as intermediates are prepared by a sequence of reactions involving nitration of a suitable phenylalkanoic acid followed by reduction of the nitro group. For example, 2,3,5,6-tetrafluorophenylacetic acid is converted to 4-amino-2,3,5,6-tetrafluorophenylacetic acid by this method. The [4-amino-(mono- or poly-fluoro)benzoyl]alkanoic acids and esters are prepared by the reaction of ammonia or sodium amide with (4-halobenzoyl)alkanoic acids. For example, the reaction of sodium amide with ethyl 2,3,4,5,6-pentafluorobenzoylacetate yields ethyl(4-amino-2,3,5,6-tetrafluorobenzoyl)acetate. are prepared by a sequence of reactions

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

Procedure: A mixture consisting of 100 g (0.47 mol) of pentafluorobenzoic acid, 900 ml of benzene and 350 ml (4.80 mol) of thionyl chloride was heated under reflux for 40 hours. After completion of the reaction, the reaction solution was concentrated under a reduced pressure. After repetition of evaporation with benzene (900 ml×2), the resulting residue was dissolved in 500 ml of ether. A mixture consisting of 11.5 g (0.47 mol) of magnesium, 450 ml of ethanol and 20 ml of carbon tetrachloride was stirred at room temperature for 1 hour, and 71.6 ml (0.47 mol) of diethyl malonate dissolved in 900 ml of ether was added dropwise thereto. After 17 hours of stirring at the same temperature, the reaction solution was evaporated to dryness under a reduced pressure, and the residue was dissolved in 1,500 ml of ether. To this was added dropwise the above acid chloride at room temperature, followed by 63 hours of stirring at the same temperature. After completion of the reaction, the reaction solution was washed with 10% citric acid and water in that order, and then dried over anhydrous sodium sulfate, subsequently evaporating the solvent. The residue was mixed with 300 ml of water and 1.00 g (5.81 mol) of p-toluenesulfonic acid, heated under reflux for 6 hours, mixed with 2,500 ml of benzene and then washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The resulting residue was purified by distillation under a reduced pressure (10 mmHg, 118°-120° C.) to yield 89.7 g (67%) of the title compound. was heated under reflux for 40 hours After completion of the reaction the reaction solution was concentrated under a reduced pressure After repetition of evaporation with benzene (900 ml×2) the resulting residue was dissolved in 500 ml of ether was added dropwise After 17 hours of stirring at the same temperature the reaction solution was evaporated to dryness under a reduced pressure the residue was dissolved in 1,500 ml of ether To this was added dropwise the above acid chloride at room temperature followed by 63 hours of stirring at the same temperature After completion of the reaction the reaction solution was washed with 10% citric acid and water in that order dried over anhydrous sodium sulfate subsequently evaporating the solvent heated under reflux for 6 hours washed with water The organic layer was dried over anhydrous sodium sulfate the solvent was evaporated The resulting residue was purified by distillation under a reduced pressure (10 mmHg, 118°-120° C.)