2,3,4-trifluorophenol

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

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

Procedure: 1-(4-Bromophenyl)-2-chloro-9-methyl-1,9-dihydro-6H-purin-6-one (150 mg, 0.4417 mmol) and 2,3,4-trifluorophenol (130.8 mg, 0.8834 mmol) are added to a vial, and the sealed mixture is heated with stirring at 140° C. for 23 h. Silica gel column chromatography (MeOH:CH2Cl2=0.5:99.5) gives the title compound as a white solid. 1H NMR (400 MHz, CDCl3) 7.66 (3H, m), 7.24 (2H, m), 7.00 (2H, m), 3.58 (3H, s). MS (M+1): 451.08; RT=1.31 min. The IC50 determined as described in Example 6 is 100 nanomolar or less. is heated

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium carbonate (19.50 g, 0.184 mol) was dispersed into a solution of 2,3,4-trifluorophenol (13.64 g, 0.092 mol) in acetone (300 mL). To the stirred suspension was added the solution of benzyl bromide (17.31 g, 101.21 mmol) in acetone (100 mL) dropwisely. The mixture was heated under reflux at 50° C. for 24 h, allowed to cool to room temperature, and filtered. The filter cake was washed with acetone (50 mL×3), and acetone was removed under reduced pressure. The residue was dissolved in ethyl acetate (500 mL). The solution was washed with 5% sodium hydroxide (50 mL), water (150 mL) and brine (150 mL) sequentially and dried over Na2SO4. The solvent was removed in vacuo to yield a pale yellow solid (19.89 g, 90% yield). 1H NMR (400 MHz, CDCl3): δ 7.40 (m, 5H), 6.85 (m, 1H), 6.64 (m, 1H), 5.15 (s, 2H). The mixture was heated to cool to room temperature filtered The filter cake was washed with acetone (50 mL×3), and acetone was removed under reduced pressure The residue was dissolved in ethyl acetate (500 mL) The solution was washed with 5% sodium hydroxide (50 mL), water (150 mL) and brine (150 mL) sequentially dried over Na2SO4 The solvent was removed in vacuo

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium carbonate (19.50 g, 0.184 mol) was dispersed into a solution of 2,3,4-trifluorophenol (13.64 g, 0.092 mol) in acetone (300 mL). To the stirred suspension was added the solution of benzyl bromide (17.31 g, 101.21 mmol) in acetone (100 mL) dropwisely. The mixture was heated under reflux at 50° C. for 24 h, allowed to cool to room temperature, and filtered. The filter cake was washed with acetone (50 mL×3), and acetone was removed under reduced pressure. The residue was dissolved in ethyl acetate (500 mL). The solution was washed with 5% sodium hydroxide (50 mL), water (150 mL) and brine (150 mL) sequentially and dried over Na2SO4. The solvent was removed in vacuo to yield a pale yellow solid (19.89 g, 90% yield). 1H NMR (400 MHz, CDCl3): δ 7.40 (m, 5H), 6.85 (m, 1H), 6.64 (m, 1H), 5.15 (s, 2H). The mixture was heated to cool to room temperature filtered The filter cake was washed with acetone (50 mL×3), and acetone was removed under reduced pressure The residue was dissolved in ethyl acetate (500 mL) The solution was washed with 5% sodium hydroxide (50 mL), water (150 mL) and brine (150 mL) sequentially dried over Na2SO4 The solvent was removed in vacuo

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium carbonate (19.50 g, 183.96 mmol) was dispersed into a solution of 2,3,4-trifluorophenol (13.64 g, 92.10 mmol) in acetone (300 mL). To the stirred suspension was added benzyl bromide (17.31 g, 101.21 mmol) dropwisely. The mixture was heated under reflux at 50° C. for 24 h. The acetone was removed under reduced pressure and the residue was dissolved in water (300 mL). The solution was extracted with ethyl acetate (100 mL×2). The combined organic extracts were washed with 5% sodium hydroxide (100 mL) and brine (100 mL) sequentially and dried over Na2SO4. The solvent was removed in vacuo to yield a pale yellow solid (19.89 g, 90.7% yield). 1H NMR (400 MHz, CDCl3): δ 7.40 (m, 5H), 6.85 (m, 1H), 6.64 (m, 1H), 5.15 (s, 2H). The mixture was heated The acetone was removed under reduced pressure the residue was dissolved in water (300 mL) The solution was extracted with ethyl acetate (100 mL×2) The combined organic extracts were washed with 5% sodium hydroxide (100 mL) and brine (100 mL) sequentially dried over Na2SO4 The solvent was removed in vacuo

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

Procedure: 2,3,4-Trifluorophenol was protected with hydroxy protection reagent (examples include BnBr, BnCl) at ambient temperature in the presence of base (include Na2CO3, K2CO3, NaHCO3, KHCO3, t-BuOK, t-BuONa) in appropriate inert solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer acetone and methyl ethyl ketone). The reaction proceeds for several hours (3-12 h, prefer 5-10 h). 1-(Benzyloxy)-2,3,4-trifluorobenzene is obtained after conventional workup. The reaction proceeds for several hours (3-12 h, prefer 5-10 h)

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

Procedure: 10.0 g (29.7 mmol) of the dithioacetal 6 are dissolved in 100 ml of dichloro-methane, and 2.6 ml (30.0 mmol) of trifluoromethanesulfonic acid are added dropwise with ice/common salt cooling. After 5 minutes, the cooling is removed, and the batch is stirred at room temperature for 45 minutes. The batch is subsequently cooled to −70° C., a mixture of 7.5 ml (54.0 mmol) of triethylamine and 6.67 g (45.0 mmol) of trifluorophenol in 30 ml of dichloromethane is added, and the mixture is stirred at −70° C. for 1 hour. 24.2 ml (0.150 mol) of triethylamine tris(hydrofluoride) are then added, and, after 5 minutes, 42.9 g (0.150 mol) of DBH, suspended in 60 ml of dichloromethane, are added in portions over the course of about 30 minutes. After 90 minutes, the batch is allowed to thaw and is hydro-lysed using 1 M sodium hydroxide solution and aqueous hydrogen sulfite solution. The organic phase is separated off, washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent is removed under reduced pressure, and the residue is filtered through silica gel with n-heptane, giving the spiro compound 7 as a colourless solid of melting point: 43° C. cooling the cooling is removed The batch is subsequently cooled to −70° C. is added the mixture is stirred at −70° C. for 1 hour after 5 minutes are added in portions over the course of about 30 minutes After 90 minutes The organic phase is separated off washed with saturated sodium chloride solution dried over sodium sulfate The solvent is removed under reduced pressure the residue is filtered through silica gel with n-heptane

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

Procedure: 10.0 g (29.7 mmol) of the dithioacetal 6 are dissolved in 100 ml of dichloro-methane, and 2.6 ml (30.0 mmol) of trifluoromethanesulfonic acid are added dropwise with ice/common salt cooling. After 5 minutes, the cooling is removed, and the batch is stirred at room temperature for 45 minutes. The batch is subsequently cooled to −70° C., a mixture of 7.5 ml (54.0 mmol) of triethylamine and 6.67 g (45.0 mmol) of trifluorophenol in 30 ml of dichloromethane is added, and the mixture is stirred at −70° C. for 1 hour. 24.2 ml (0.150 mol) of triethylamine tris(hydrofluoride) are then added, and, after 5 minutes, 42.9 g (0.150 mol) of DBH, suspended in 60 ml of dichloromethane, are added in portions over the course of about 30 minutes. After 90 minutes, the batch is allowed to thaw and is hydro-lysed using 1 M sodium hydroxide solution and aqueous hydrogen sulfite solution. The organic phase is separated off, washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent is removed under reduced pressure, and the residue is filtered through silica gel with n-heptane, giving the spiro compound 7 as a colourless solid of melting point: 43° C. cooling the cooling is removed The batch is subsequently cooled to −70° C. is added the mixture is stirred at −70° C. for 1 hour after 5 minutes are added in portions over the course of about 30 minutes After 90 minutes The organic phase is separated off washed with saturated sodium chloride solution dried over sodium sulfate The solvent is removed under reduced pressure the residue is filtered through silica gel with n-heptane

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In an autoclave having an inner volume of 100 ml, 3.0 g (0.0126 mole) of 3,4,5,6-tetrafluorophthalic acid containing no sulfate ion, 0.5 g (0.0125 mole) of sodium hydroxide, and 50 g of water were placed and heated for reaction at 200° C. for 25 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with 150 ml of diisopropyl ether. By analyzing this extract by gas chromatography using a 2 m column packed with SE52 and kept at 50° C., the reaction was found to have produced 2.9 mole % of 1,2,3,4-tetrafluorobenzene, 89.1 mole % of trifluorophenol, and substantially no 2,3,4,5-tetrafluorobenzoic acid based on the 3,4,5,6-tetrafluorophthalic acid used as the starting material [pH 2.75 at 25° C. at the time of charging]. After completion of the reaction the reaction mixture was cooled to room temperature extracted with 150 ml of diisopropyl ether this extract by gas chromatography kept at 50° C.

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

Procedure: We have studied the method of the U.S. Pat. No. 2,439,237 to determine whether or not it can be applied to 3,4,5,6-tetrafluorophthalic acid which is the starting material for the present invention. As indicated in a comparative experiment (control), 3,4,5,6-tetrafluorophthalic acid was simply heated in an alkaline aqueous solution in accordance with the method of the U.S. Patent for the purpose of decarbonating the acid. The reaction which ensued mainly gave rise to trifluorophenol having fluorine atoms substituted by hydroxyl groups and failed to produce 2,3,4,5-tetrafluorobenzoic acid selectively. It may be safely concluded that the fluorine atom at the para position of a benzene ring posessing such an electron-attracting group as the --COOH group is more susceptible to the nucleophilic substitution reaction than the chlorine atom at the same position. By the method of the U.S. Pat. No. 2,439,237, therefore, the alkaline substance is believed to form a phenol by substitution of the fluorine atom. It is, accordingly, proper to conclude that the method, when applied to 3,4,5,6-tetrafluorophthalic acid, is liable to induce secondary reactions and is not useful for the decarboxylation aimed at by the present invention. Methods for the decarboxylation of 3,4,5,6-tetrafluorophthalic acid are described in G. G. Yacobson et al, Journal of General Chemistry, 36, No. 1,144 (1966) and British Pat. No. 2,122,190. The former method causes this acid to react in dimethylformamide as a solvent at a temperature of 145° C. This method, however, dose not deserve commercialization because it produce 2,3,4,5-tetrafluorobenzoic acid in low a yield of 44.0 mol %. The latter method causes the acid to react in an organic solvent, and that at a temperature of 200° C. It does not produce any 2,3,4,5-tetrafluorobenzoic acid but barely gives rise to 1,2,3,4,-tetrafluorobenzene in a yield of 0.5%. was simply heated in an alkaline aqueous solution in accordance with the method of the U.S The reaction which

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

Procedure: 1-(4-Bromophenyl)-2-chloro-9-methyl-1,9-dihydro-6H-purin-6-one (150 mg, 0.4417 mmol) and 2,3,4-trifluorophenol (130.8 mg, 0.8834 mmol) are added to a vial, and the sealed mixture is heated with stirring at 140° C. for 23 h. Silica gel column chromatography (MeOH:CH2Cl2=0.5:99.5) gives the title compound as a white solid. 1H NMR (400 MHz, CDCl3) 7.66 (3H, m), 7.24 (2H, m), 7.00 (2H, m), 3.58 (3H, s). MS (M+1): 451.08; RT=1.31 min. The IC50 determined as described in Example 6 is 100 nanomolar or less. is heated

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