1,3,5-trifluorobenzene

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

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

Conditions: temp:225.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 600 ml Hastelloy pressure reactor (Parr Instrument Co., Moline, Ill.) equipped with the standard stirrer, thermowell, and valves was used. The reactor was charged with 0.833 moles of 1,3,5-trifluorobenzene (110 g), 4.6 moles of 29% ammonia in water (270 g), and 0.44 moles of magnesium oxide (17.8 g). The reactor was purged with argon, and heated to 225° C. until the maximum pressure (about 1400 psig) was reached. As the reaction proceeded, the pressure dropped at a rate of about 20 lbs./hour for about 6 hours. The reactor was then cooled and the contents allowed to settle. The oils were drained from the reactor bottom until salts/water are observed. The salts float on the oils and settle slowly in the aqueous ammonia. The aqueous salts were extracted 2 or 3 times with MTBE. The MTBE was combined with the oils and charged to a distillation column packed with stainless steel packing (ProPak). The salts were centrifuged, washed with water, and discarded. The product was isolated by distilling MTBE at atm. Pressure, then distilling DFA at 20 to 50 mm. A 600 ml Hastelloy pressure reactor (Parr Instrument Co., Moline, Ill.) equipped with the standard stirrer The reactor was purged with argon the pressure dropped at a rate of about 20 lbs The reactor was then cooled The aqueous salts were extracted 2 or 3 times with MTBE charged to a distillation column washed with water The product was isolated by distilling MTBE at atm

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

Procedure: In a further embodiment, the present invention relates to a method for the two step preparation of 3,5-difluoroaniline from 1,3,5-trichlorobenzene. First, an amount of 1,3,5-trichlorobenzene is reacted with a fluoride-containing compound to obtain 1,3,5-trifluorobenzene. Second, the 1,3,5-trifluorobenzene is reacted with aqueous ammonia and a metal oxide or metal hydroxide to obtain the product 3,5-difluoroaniline.

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

Procedure: In a further embodiment, the present invention relates to a method for the two step preparation of 3,5-difluoroaniline from 1,3,5-trichlorobenzene. First, an amount of 1,3,5-trichlorobenzene is reacted with a fluoride-containing compound to obtain 1,3,5-trifluorobenzene. Second, the 1,3,5-trifluorobenzene is reacted with aqueous ammonia and a metal oxide or metal hydroxide to obtain the product 3,5-difluoroaniline. containing compound

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

Procedure: One embodiment of the present invention relates to the discovery that 3,5-difluoroaniline can be synthesized at high yields and high purity by fluorinating 1,3,5-trichlorobenzene in the presence of a polar solvent to make an intermediate 1,3,5-trifluorobenzene, and then aminating the 1,3,5-trifluorobenzene in the presence of aqueous or anhydrous ammonia to obtain the desired 3,5-difluoroaniline. at high yields

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A DMSO (25 mL, 0.1M) solution containing 4-N—BOC-aminopiperidine (500 mg, 2.5 mmol, 1.0 eq), 1,3,5-trifluorobenzene (256 μL, 2.5 mmol, 1.0 eq), and potassium carbonate (691 mg, 5.0 mmol, 2.0 eq) was heated to 100° C. for 18 h. The resulting mixture was cooled to RT, poured in H2O (ca 50 mL), and extracted (3×) with EtOAc. The combined extracts were washed (2×) with H2O, dried over MgSO4, and concentrated in vocuo. The resulting solid was purified via flash chromatography using 1:1 Hexane/EtOAc as the mobile phase. Isolated 572 mg (1.83 mmol, 73% yield). The resulting mixture was cooled to RT extracted (3×) with EtOAc The combined extracts were washed (2×) with H2O dried over MgSO4 concentrated in vocuo The resulting solid was purified via flash chromatography Isolated 572 mg (1.83 mmol, 73% yield)

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

Procedure: Sodium hydride (7.56 g, 0.189 mol; 60% in oil) was washed with n-hexane to eliminate the oil, and N,N-dimethylformamide (100 ml) was added thereto to make a suspension. To the thus prepared suspension, 4-methoxyphenol (25.84 g, 0.208 mol) was gradually added with stirring, and stirring was continued until the generation of hydrogen gas ceased. 1,3,5-Trifluorobenzene (30.00 g, 0.227 mol) and cuprous chloride (0.50 g) were added thereto. The resultant mixture was heated under reflux for 8 hours with stirring. After allowed to cool, the reaction mixture was poured into ice-water and extracted with toluene. The toluene layer was dried over anhydrous magnesium sulfate. The solvent was removed, and the residual oil was distilled under reduced pressure to give 4-(3,5-difluorophenoxy)anisole (25.42 g). B.P., 98.5° C./0.2 mmHg. was added stirring under reflux for 8 hours with stirring to cool extracted with toluene The toluene layer was dried over anhydrous magnesium sulfate The solvent was removed the residual oil was distilled under reduced pressure

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

Procedure: A stirred solution of 10.0 grams (0.076 mole) of 1,3,5-trifluorobenzene in 150 ml of anhydrous tetrahydrofuran, under an argon atmosphere, was cooled to -78° and 4.8 grams (0.076 mole) of n-butyllithium (as 48.7 ml of a 1.55 molar solution in hexane) was added dropwise during a 30-minute period. Upon completion of addition the reaction mixture was stirred at -78° for eight hours. A quantity of fresh, crushed dry ice, sufficient to cause the reaction mixture to become a thick slurry, was added to the reaction vessel. The reaction mixture was allowed to warm to ambient temperature as it was stirred for 26 hours. The tetrahydrofuran was removed from the reaction mixture under reduced pressure. The residue was washed into a separatory funnel with 100 ml of aqueous 2N sodium hydroxide and 200 ml of diethyl ether. The aqueous base layer was separated and the organic layer extracted with two 100 ml portions of aqueous 2N sodium hydroxide. The organic layer was discarded and the combined aqueous base layer and extracts were washed with 100 ml of diethyl ether, cooled, and acidified with concentrated hydrochloric acid. The mixture was saturated with sodium chloride and extracted with three portions of 150 ml each of diethyl ether. The combined ether extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a solid residue. The residue was recrystallized from toluene to give 10.2 grams of 2,4,6-trifluorobenzoic acid; mp 225°-227°. Upon completion of addition the reaction mixture was added to the reaction vessel was stirred for 26 hours The tetrahydrofuran was removed from the reaction mixture under reduced pressure The residue was washed into a separatory funnel with 100 ml of aqueous 2N sodium hydroxide and 200 ml of diethyl ether The aqueous base layer was separated the organic layer extracted with two 100 ml portions of aqueous 2N sodium hydroxide the combined aqueous base layer and extracts were washed with 100 ml of diethyl ether cooled extracted with three portions of 150 ml each of diethyl ether The combined ether extracts were dried with magnesium sulfate filtered The filtrate was concentrated under reduced pressure to a solid residue The residue was recrystallized from toluene

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

Procedure: A stirred solution of 10.0 grams (0.076 mole) of 1,3,5-trifluorobenzene in 150 ml of anhydrous tetrahydrofuran, under an argon atmosphere, was cooled to -78° and 4.8 grams (0.076 mole) of n-butyllithium (as 48.7 ml of a 1.55 molar solution in hexane) was added dropwise during a 30-minute period. Upon completion of addition the reaction mixture was stirred at -78° for eight hours. A quantity of fresh, crushed dry ice, sufficient to cause the reaction mixture to become a thick slurry, was added to the reaction vessel. The reaction mixture was allowed to warm to ambient temperature as it was stirred for 26 hours. The tetrahydrofuran was removed from the reaction mixture under reduced pressure. The residue was washed into a separatory funnel with 100 ml of aqueous 2N sodium hydroxide and 200 ml of diethyl ether. The aqueous base layer was separated and the organic layer extracted with two 100 ml portions of aqueous 2N sodium hydroxide. The organic layer was discarded and the combined aqueous base layer and extracts were washed with 100 ml of diethyl ether, cooled, and acidified with concentrated hydrochloric acid. The mixture was saturated with sodium chloride and extracted with three portions of 150 ml each of diethyl ether. The combined ether extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a solid residue. The residue was recrystallized from toluene to give 10.2 grams of 2,4,6-trifluorobenzoic acid; mp 225°-227°. Upon completion of addition the reaction mixture was added to the reaction vessel was stirred for 26 hours The tetrahydrofuran was removed from the reaction mixture under reduced pressure The residue was washed into a separatory funnel with 100 ml of aqueous 2N sodium hydroxide and 200 ml of diethyl ether The aqueous base layer was separated the organic layer extracted with two 100 ml portions of aqueous 2N sodium hydroxide the combined aqueous base layer and extracts were washed with 100 ml of diethyl ether cooled extracted with three portions of 150 ml each of diethyl ether The combined ether extracts were dried with magnesium sulfate filtered The filtrate was concentrated under reduced pressure to a solid residue The residue was recrystallized from toluene

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Palladium on carbon (10%, 300 mg), aqueous sodium hydroxide solution (35% strength, 26.5 g, 232 mmol, 3.7 equivalents), 62 g of water and 1,3,5-trichloro-2,4,6-trifluorobenzene (15 g, 62 mmol) were placed in a pressure vessel. After flushing with nitrogen, the pressure vessel was heated to 140° C. and pressurized with 30 bar of hydrogen. A hydrogen pressure of 30 bar was maintained at 140° C. for 12 hours. After cooling to 20-25° C., the pressure vessel was depressurized. The reaction solution was subjected to an azeotropic distillation via a distillation attachment; the distillate went over at a temperature of 99.5° C. After separation of the phases, the lower organic phase comprised the title compound. Washing with water and drying gave 8.05 g of 1,3,5-trifluorobenzene (98% of theory). After flushing with nitrogen A hydrogen pressure of 30 bar was maintained at 140° C. for 12 hours After cooling to 20-25° C. The reaction solution was subjected to an azeotropic distillation via a distillation attachment went over at a temperature of 99.5° C After separation of the phases Washing with water drying

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Palladium on carbon (10%, 410 mg), 100 g of water, 21.8 g of 1,3,5-trichloro-2,4,6-trifluorobenzene and 32.9 g of sodium acetate (4.5 equivalents) were placed in a pressure vessel. After flushing with nitrogen, the pressure vessel was heated to 140° C. and pressurized with 12 bar of hydrogen. A hydrogen pressure of 12 bar was maintained at 140° C. for about 12 hours while stirring vigorously. After cooling to 20-25° C., the pressure vessel was depressurized. The two-phase reaction solution was filtered and the phases were then separated. This gave a yield of 88.2% of 1,3,5-trifluorobenzene. After flushing with nitrogen A hydrogen pressure of 12 bar was maintained at 140° C. for about 12 hours After cooling to 20-25° C. The two-phase reaction solution was filtered the phases were then separated