ethyl 3-amino-4,4,4-trifluorobut-2-enoate

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

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 30 ml of dried tetrahydrofuran (THF) cooled to -5° C. was added, under nitrogen, 3.6 g of sodium hydride as a 60% dispersion mineral oil. To the stirred slurry was added a solution of 10 g of ethyl 3-amino-4,4,4-trifluoro-2-butenoate in 30 ml of THF over a period of 30 minutes. After stirring at -5° C. for 1 hour, the reaction mixture was cooled to -65° C. and a solution of N, N-dimethyl-2-chloro-5-isocyanatobenzenesulfonamide (Example A-4 above) in 30 ml of THF was added dropwise maintaining the temperature below -60° C. The mixture was stirred at -65° C. for 2 hours and allowed to warm to room temperature. After stirring for 17 hours, solvent was removed using a rotary evaporator. About 50 ml of water was added to the residue. The resulting mixture was filtered to remove a small amount of undissolved solid and the filtrate was acidified with hydrochloric acid. The resulting precipitate was filtered to give 13 g of the title compound as a beige solid, m.p. 281°-283° C. was added, under nitrogen the reaction mixture was cooled to -65° C. maintaining the temperature below -60° C The mixture was stirred at -65° C. for 2 hours to warm to room temperature After stirring for 17 hours solvent was removed a rotary evaporator About 50 ml of water was added to the residue The resulting mixture was filtered to remove a small amount of undissolved solid The resulting precipitate was filtered

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

Procedure: By the method of Example 1, Step G, 19.67 grams (0.080 mole) of 2,3-dichloro-5-nitrophenylmethyl isocyanate, 2.102 grams (0.088 mole) of sodium hydride, and 14.59 grams (0.080 mole) of ethyl 3-amino-4,4,4-trifluoro-2-butenoate were reacted in 80 mL of N,N-dimethylformamide, yielding 17.14 grams of 3-(2,3-dichloro-5-nitrophenylmethyl)-6-trifluoromethyluracil as a brown solid. The NMR spectrum was consistent with the proposed structure. This reaction was repeated.

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

Procedure: By the method of Example 1, Step G, 19.67 grams (0.080 mole) of 2,3-dichloro-5-nitrophenylmethyl isocyanate, 2.102 grams (0.088 mole) of sodium hydride, and 14.59 grams (0.080 mole) of ethyl 3-amino-4,4,4-trifluoro-2-butenoate were reacted in 80 mL of N,N-dimethylformamide, yielding 17.14 grams of 3-(2,3-dichloro-5-nitrophenylmethyl)-6-trifluoromethyluracil as a brown solid. The NMR spectrum was consistent with the proposed structure. This reaction was repeated.

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

Procedure: Under a nitrogen atmosphere, a stirred suspension of 0.62 gram (0.01 5 mole) of 60% sodium hydride (in mineral oil) in 30 mL of N,N-dimethylformamide was cooled to below 7° C., and a solution of 2.8 grams (0.015 mole) of ethyl 3-amino-4,4,4-trifluoro-2-butenoate in 15 mL of N,N-dimethylformamide was added dropwise at a rate to maintain the reaction mixture below 7° C. Upon completion of addition, the reaction mixture was stirred for about 45 minutes, during which time the reaction mixture temperature was about 2°-4° C. After this time a solution of 3.2 grams of 2,3,5-trichlorophenylmethyl isocyanate in 10 mL of N,N-dimethylformamide was added dropwise at a rate to maintain the reaction mixture temperature at about 2°-4° C. Upon completion of addition, the reaction mixture was stirred for about 10 minutes at 2°-4° C. and then warmed to 70°-85° C., where it was stirred for 3 hours. After this time the reaction mixture was allowed to cool to ambient temperature, where it stirred for about 16 hours. The reaction mixture was then poured into water, and the mixture was extracted with ethyl acetate. The extract was then washed with one portion of water. The water layer and the wash were combined and acidified with concentrated hydrochloric acid. The resultant solid was collected by filtration, yielding, when dried, 0.5 gram of solid. To collect additional product, the ethyl acetate extract was again washed, this time with five 150 mL portions of water. The combined washes were acidified with concentrated hydrochloric acid. The resultant solid was collected by filtration. The solid was dissolved in ethyl acetate and washed with water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding a solid residue. The solid was combined with the 0.5 gram of material collected above, yielding 2.7 grams of 3-(2,3,5-trichlorophenylmethyl)-6-trifluoromethyluracil, mp 199°-202° C. The NMR spectrum was consistent with the proposed structure. was cooled to below 7° C. to maintain the reaction mixture below 7° C Upon completion of addition was about 2°-4° C to maintain the reaction mixture temperature at about 2°-4° C Upon completion of addition the reaction mixture was stirred for about 10 minutes at 2°-4° C. warmed to 70°-85° C. where it was stirred for 3 hours where it stirred for about 16 hours the mixture was extracted with ethyl acetate The extract was then washed with one portion of water The resultant solid was collected by filtration yielding when dried To collect additional product the ethyl acetate extract was again washed The resultant solid was collected by filtration The solid was dissolved in ethyl acetate washed with water The organic layer was dried with sodium sulfate filtered The filtrate was concentrated under reduced pressure yielding a solid residue collected above

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

Procedure: Under a nitrogen atmosphere, a stirred suspension of 0.62 gram (0.01 5 mole) of 60% sodium hydride (in mineral oil) in 30 mL of N,N-dimethylformamide was cooled to below 7° C., and a solution of 2.8 grams (0.015 mole) of ethyl 3-amino-4,4,4-trifluoro-2-butenoate in 15 mL of N,N-dimethylformamide was added dropwise at a rate to maintain the reaction mixture below 7° C. Upon completion of addition, the reaction mixture was stirred for about 45 minutes, during which time the reaction mixture temperature was about 2°-4° C. After this time a solution of 3.2 grams of 2,3,5-trichlorophenylmethyl isocyanate in 10 mL of N,N-dimethylformamide was added dropwise at a rate to maintain the reaction mixture temperature at about 2°-4° C. Upon completion of addition, the reaction mixture was stirred for about 10 minutes at 2°-4° C. and then warmed to 70°-85° C., where it was stirred for 3 hours. After this time the reaction mixture was allowed to cool to ambient temperature, where it stirred for about 16 hours. The reaction mixture was then poured into water, and the mixture was extracted with ethyl acetate. The extract was then washed with one portion of water. The water layer and the wash were combined and acidified with concentrated hydrochloric acid. The resultant solid was collected by filtration, yielding, when dried, 0.5 gram of solid. To collect additional product, the ethyl acetate extract was again washed, this time with five 150 mL portions of water. The combined washes were acidified with concentrated hydrochloric acid. The resultant solid was collected by filtration. The solid was dissolved in ethyl acetate and washed with water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding a solid residue. The solid was combined with the 0.5 gram of material collected above, yielding 2.7 grams of 3-(2,3,5-trichlorophenylmethyl)-6-trifluoromethyluracil, mp 199°-202° C. The NMR spectrum was consistent with the proposed structure. was cooled to below 7° C. to maintain the reaction mixture below 7° C Upon completion of addition was about 2°-4° C to maintain the reaction mixture temperature at about 2°-4° C Upon completion of addition the reaction mixture was stirred for about 10 minutes at 2°-4° C. warmed to 70°-85° C. where it was stirred for 3 hours where it stirred for about 16 hours the mixture was extracted with ethyl acetate The extract was then washed with one portion of water The resultant solid was collected by filtration yielding when dried To collect additional product the ethyl acetate extract was again washed The resultant solid was collected by filtration The solid was dissolved in ethyl acetate washed with water The organic layer was dried with sodium sulfate filtered The filtrate was concentrated under reduced pressure yielding a solid residue collected above

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred suspension of 2.7 grams (0.066 mole) of 60% sodium hydride (in mineral oil) in 125 mL of tetrahydrofuran was cooled to -20° C., and 11.0 grams (0.060 mole) of ethyl 3-amino-4,4,4-trifluoro-2-butenoate was added dropwise. Upon completion of addition, the reaction mixture was stirred for about 10 minutes, and 10.9 grams (0.060 mole) of 2-fluoro-4-nitrophenyl isocyanate was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature, where it was stirred for one hour. After this time the reaction mixture was warmed to reflux, where it was stirred for about 16 hours. The reaction mixture was then cooled to about ambient temperature, and 8.3 grams (0.060 mole) of potassium carbonate and 17.1 grams (0.120 mole) of methyl iodide were added. Upon completion of addition, the reaction mixture was warmed to reflux, where it was stirred for about 7 hours. The reaction mixture was cooled to ambient temperature and stirred with diethyl ether and water. The organic layer was separated, washed with water, and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was combined with a previous run (0.070 mole) of this reaction, and the mixture was subjected to column chromatography on silica gel. Elution was accomplished with heptane, 1:1 heptane-methylene chloride, and methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 17.7 grams of 3-(2-fluoro-4-nitrophenyl)-1-methyl-6-trifluoromethyluracil; mp 135°-136° C. The NMR spectrum was consistent with the proposed structure. Upon completion of addition Upon completion of addition to warm to ambient temperature where it was stirred for one hour After this time the reaction mixture was warmed to reflux where it was stirred for about 16 hours The reaction mixture was then cooled to about ambient temperature Upon completion of addition the reaction mixture was warmed to reflux where it was stirred for about 7 hours The reaction mixture was cooled to ambient temperature The organic layer was separated washed with water dried with magnesium sulfate The mixture was filtered the filtrate was concentrated under reduced pressure to a residue The residue was combined with a previous run (0.070 mole) of this reaction Elution concentrated under reduced pressure

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

Procedure: A solution of 22.7 g of ethyl 4,4,4-trifluoro-3-amino-2-butenoate is added dropwise with stirring and cooling at 0-5° C. under a nitrogen atmosphere to 5.1 g of a previously introduced sodium hydride dispersion (60%) in 60 ml of n-methylpyrrolidine, and stirring is continued at 22° C. until the evolution of hydrogen has ceased. Then, 23.7 g of 2-ethoxycarbonylamino-3-fluoro-5-chloropyridine (Example H1) are added and the reaction mixture is heated for approx. 5 hours at 120° C. It is then cooled, 16.7 9 of methyl iodide are added dropwise, and stirring is continued overnight at 22° C. After the reaction mixture has been taken up in ethyl acetate, it is washed with ice-water, dried over sodium sulfate, filtered and evaporated. The residue obtained is recrystallized from ethyl acetate/n-hexane. This gives the desired title compound of m.p. 133-134° C. stirring It is then cooled stirring it is washed with ice-water dried over sodium sulfate filtered evaporated The residue obtained is recrystallized from ethyl acetate/n-hexane

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

Procedure: A solution of 22.7 g of ethyl 4,4,4-trifluoro-3-amino-2-butenoate is added dropwise with stirring and cooling at 0-5° C. under a nitrogen atmosphere to 5.1 g of a previously introduced sodium hydride dispersion (60%) in 60 ml of n-methylpyrrolidine, and stirring is continued at 22° C. until the evolution of hydrogen has ceased. Then, 23.7 g of 2-ethoxycarbonylamino-3-fluoro-5-chloropyridine (Example H1) are added and the reaction mixture is heated for approx. 5 hours at 120° C. It is then cooled, 16.7 9 of methyl iodide are added dropwise, and stirring is continued overnight at 22° C. After the reaction mixture has been taken up in ethyl acetate, it is washed with ice-water, dried over sodium sulfate, filtered and evaporated. The residue obtained is recrystallized from ethyl acetate/n-hexane. This gives the desired title compound of m.p. 133-134° C. stirring It is then cooled stirring it is washed with ice-water dried over sodium sulfate filtered evaporated The residue obtained is recrystallized from ethyl acetate/n-hexane

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

Procedure: Under a nitrogen atmosphere, while cooling and stirring, a solution of 22.7 g 4,4,4-trifluoro-3-amino-2-butenoic acid ethyl ester is added dropwise to 5.1 g of a sodium hydride dispersion (60%) in 60 ml N-methylpyrrolidine at 0-5° C. and stirred at 22° C. until hydrogen evolution is complete. Then 23.7 g 2-ethoxicarbonylamino-3-fluoro-5-chloropyridine (Example H1) is added and the reaction mixture heated for about 5 hours to 120° C. The mixture is then cooled, 16.7 g methyl iodide is added dropwise and stirring is continued overnight at 22° C. After the reaction mixture has been taken up in ethyl acetate, it is washed with ice water, dried over sodium sulfate, filtered, and concentrated by evaporation. The residue obtained is recrystallized from ethyl acetate/n-hexane. The title compound is obtained with a melting point of 133-134° C. Under a nitrogen atmosphere, while cooling the reaction mixture heated for about 5 hours to 120° C The mixture is then cooled stirring it is washed with ice water dried over sodium sulfate filtered concentrated by evaporation The residue obtained is recrystallized from ethyl acetate/n-hexane

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A slurry of 1.4 g. of sodium hydride in 25 ml. of dry tetrahydrofuran (THF) was cooled to -10° C. To the cooled and stirred slurry was added a solution of 10.0 g. of ethyl 3-amino-4,4,4-trifluoro-2-butenoate in 50 ml. of THF. The addition of this solution was made over a period of 30 minutes. The resultant light brown reaction mixture was cooled to -70° C. A solution of 13.3 g. of 6-isocyanato-2- methyl-3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine in 75 ml. of THF was added to the chilled reaction mixture over a period of 10 minutes. After stirring at -70° C. for 30 minutes, the temperature was allowed to rise slowly to 10° C. At that point 3.6 ml. of acetic acid was added to the mixture. A beige solid precipitated. 19.0 Grams of the solid was recovered by filtering it from the reaction mixture. To the cooled was added a solution of 10.0 g The addition of this solution After stirring at -70° C. for 30 minutes to rise slowly to 10° C A beige solid precipitated 19.0 Grams of the solid was recovered by filtering it from the reaction mixture

Conditions: temp:-62.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: As described above 1-methyl-4-nitro-2-(2-propynyloxy)benzene was made, mp 75°-77° C. This compound, (26 g) was reduced using iron in ethanol and water to give 4-methyl-3-(2-propynyloxy)benzenamine isolated as the hydrochloride salt mp >250° C. This amine salt was converted to the isocyanate analogue using phosgene in ethyl acetate as solvent, i.e. 4-isocyanato-4-methyl- 2-(2-propynyloxy)benzene, bp 78°-80° C./0.05 mm. Ethyl 3-amino-4,4,4-trifluoro-2-butenoate (19.6 g) was converted to its sodium salt using sodium hydride (4.6 g., 60%) in THF (100 ml). This solution was chilled to -62° C. and treated with a solution of the isocyanate (20 g) in THF (15 ml) over 2 minutes. The reaction warmed to -48° C. before cooling again. After stirring to ambient temperature and overnight the solvent was removed, water (250 ml) added, filtered to remove the precipitate and acidified whereupon a second precipitate was obtained. This solid was collected on a filter washed with water and re-extracted into aqueous sodium bicarbonate. After filtering the clear filtrate was acidified and the resulting cream precipitate was collected on a filter, washed with water and dried to give 3-[4-methyl-3-(2-propynyloxy)phenyl]-6- (trifluoromethyl)-2,4-(1H,3H)-pyrimidinedione, mp 202°-204° C. The reaction warmed to -48° C. before cooling again was removed water (250 ml) added filtered to remove the precipitate was obtained This solid was collected on a filter washed with water re-extracted into aqueous sodium bicarbonate After filtering the clear filtrate the resulting cream precipitate was collected on a filter washed with water dried