4-bromo-2-fluoro-1-methylbenzene

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 14.7 g (605.7 mol) of magnesium filings are initially introduced into 50 ml of analytical grade tetrahydrofuran under argon, and 117.7 g (623 mmol) of 4-bromo-2-fluoro-toluene in 500 ml of analytical grade tetrahydrofuran are added, while stirring. A clear solution forms at 35°-40° C. within 2 hours. A solution of 74.0 g (360.5 mmol) of the compound from Example II in 500 ml of analytical grade tetrahydrofuran is added dropwise at room temperature and the mixture is subsequently stirred at about 25° C. for 16 hours, initially with gentle cooling. The solvent is evaporated off and the crude product is subsequently rinsed in 600 ml of ethyl acetate and 800 ml of saturated ammonium chloride solution at 10° C., dried with sodium sulphate and evaporated in vacuo. For purification, the product is taken up in 600 ml of ether, any solid residue is filtered off with suction and the crude product is extracted into the aqueous phase by several extractions with 2M hydrochloric acid. This aqueous phase is covered with a layer of ether and brought to pH 13 with sodium hydroxide solution. After three extractions with ether, the product phase is dried with sodium sulphate and evaporated and the residual solvent is removed under a high vacuum. the mixture is subsequently stirred at about 25° C. for 16 hours, initially with gentle cooling The solvent is evaporated off the crude product is subsequently rinsed in 600 ml of ethyl acetate 800 ml of saturated ammonium chloride solution at 10° C., dried with sodium sulphate evaporated in vacuo For purification any solid residue is filtered off with suction the crude product is extracted into the aqueous phase by several extractions with 2M hydrochloric acid After three extractions with ether the product phase is dried with sodium sulphate evaporated the residual solvent is removed under a high vacuum

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Thirty milliliters of a 1.6-M-n-butyllithium hexane solution and a solution of 9.21 g of 4-bromo-2-fluorotoluene in 30 ml of tetrahydrofuran were added in this order to 30 ml of tetrahydrofuran which had been cooled to −78° C. in a nitrogen atmosphere, and the mixture was then stirred at −78° C. for 1 hour. A solution containing 6.64 g of zinc chloride which had been dehydrated through heat-melting under reduced pressure in 30 ml of tetrahydrofuran was added thereto at −78° C., and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to a solution of 6.63 g of iodobenzene and 0.52 g of tetrakis(triphenylphosphine)palladium (0) in 30 ml of tetrahydrofuran at room temperature, and the mixed solution was stirred for 24 hours. The reaction solution was diluted with 300 ml of ethyl acetate, and the dilute solution was extracted with the addition of 10% hydrochloric acid. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried, and then concentrated. The residue was purified through silica-gel column chromatography (eluent: hexane) to give 6.00 g of oily 3-fluoro-4-methylbiphenyl. was added at −78° C., and the mixture was stirred at room temperature for 1 hour the mixed solution was stirred for 24 hours the dilute solution was extracted with the addition of 10% hydrochloric acid The organic layer was washed with a saturated aqueous solution of sodium chloride dried concentrated The residue was purified through silica-gel column chromatography (eluent: hexane)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Thirty milliliters of a 1.6-M-n-butyllithium hexane solution and a solution of 9.21 g of 4-bromo-2-fluorotoluene in 30 ml of tetrahydrofuran were added in this order to 30 ml of tetrahydrofuran which had been cooled to −78° C. in a nitrogen atmosphere, and the mixture was then stirred at −78° C. for 1 hour. A solution containing 6.64 g of zinc chloride which had been dehydrated through heat-melting under reduced pressure in 30 ml of tetrahydrofuran was added thereto at −78° C., and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to a solution of 6.63 g of iodobenzene and 0.52 g of tetrakis(triphenylphosphine)palladium (0) in 30 ml of tetrahydrofuran at room temperature, and the mixed solution was stirred for 24 hours. The reaction solution was diluted with 300 ml of ethyl acetate, and the dilute solution was extracted with the addition of 10% hydrochloric acid. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried, and then concentrated. The residue was purified through silica-gel column chromatography (eluent: hexane) to give 6.00 g of oily 3-fluoro-4-methylbiphenyl. was added at −78° C., and the mixture was stirred at room temperature for 1 hour the mixed solution was stirred for 24 hours the dilute solution was extracted with the addition of 10% hydrochloric acid The organic layer was washed with a saturated aqueous solution of sodium chloride dried concentrated The residue was purified through silica-gel column chromatography (eluent: hexane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2.96 gms. of 3-fluoro-4-(5-pentyl-1,3-dioxan-2-yl)-benzoic acid (prepared from 2-fluoro-4-bromotoluene by reaction with magnesium according to Grignard and reaction with carbon dioxide giving 3-fluoro-4-methyl-benzoic acid, esterification thereof with ethanol/sulfuric acid giving ethyl 3-fluoro-4-methyl-benzoate, bromination by bromine or N-bromo-succinimide giving ethyl 3-fluoro-4-bromomethylbenzoate, oxidation by dilute nitric acid giving 3-fluoro-terephthalic aldehydic acid and ketalization thereof with 2-pentyl-propane-1,3-diol) and 2.0 gms. of SOCl2 are boiled for 1 hour, then evaporated and the crude acid chloride thus obtained is dissolved in 20 ml of toluene and then 1.5 ml of pyridine and 1.10 gms. of 4-cyano-phenol are added and then boiled for two hours. After separation the organic phase is washed with water, dried over sodium sulfate and evaporated leaving behind 4-cyanophenyl 3-fluoro-4-(5-pentyl-1,3-dioxan-2-yl)-benzoate.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2.96 gms. of 3-fluoro-4-(5-pentyl-1,3-dioxan-2-yl)-benzoic acid (prepared from 2-fluoro-4-bromotoluene by reaction with magnesium according to Grignard and reaction with carbon dioxide giving 3-fluoro-4-methyl-benzoic acid, esterification thereof with ethanol/sulfuric acid giving ethyl 3-fluoro-4-methyl-benzoate, bromination by bromine or N-bromo-succinimide giving ethyl 3-fluoro-4-bromomethylbenzoate, oxidation by dilute nitric acid giving 3-fluoro-terephthalic aldehydic acid and ketalization thereof with 2-pentyl-propane-1,3-diol) and 2.0 gms. of SOCl2 are boiled for 1 hour, then evaporated and the crude acid chloride thus obtained is dissolved in 20 ml of toluene and then 1.5 ml of pyridine and 1.10 gms. of 4-cyano-phenol are added and then boiled for two hours. After separation the organic phase is washed with water, dried over sodium sulfate and evaporated leaving behind 4-cyanophenyl 3-fluoro-4-(5-pentyl-1,3-dioxan-2-yl)-benzoate.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 14.7 g (605.7 mol) of magnesium filings are initially introduced into 50 ml of analytical grade tetrahydrofuran under argon, and 117.7 g (623 mmol) of 4-bromo-2-fluorotoluene in 500 ml of analytical grade tetrahydrofuran are added, while stirring. A clear solution forms at 35°-40° C. within 2 hours. A solution of 74.0 g (360.5 mmol) of the compound from Example II in 500 ml of analytical grade tetrahydrofuran is added dropwise at room temperature and the mixture is subsequently stirred at about 25° C. for 16 hours, initially with gentle cooling. The solvent is evaporated off and the crude product is subsequently rinsed in 600 ml of ethyl acetate and 800 ml of saturated ammonium chloride solution at 10° C., dried with sodium sulphate and evaporated in vacuo. For purification, the product is taken up in 600 ml of ether, any solid residue is filtered off with suction and the crude product is extracted into the aqueous phase by several extractions with 2M hydrochloric acid. This aqueous phase is covered with a layer of ether and brought to pH 13 with sodium hydroxide solution. After three extractions with ether, the product phase is dried with sodium sulphate and evaporated and the residual solvent is removed under a high vacuum. the mixture is subsequently stirred at about 25° C. for 16 hours, initially with gentle cooling The solvent is evaporated off the crude product is subsequently rinsed in 600 ml of ethyl acetate 800 ml of saturated ammonium chloride solution at 10° C., dried with sodium sulphate evaporated in vacuo For purification any solid residue is filtered off with suction the crude product is extracted into the aqueous phase by several extractions with 2M hydrochloric acid After three extractions with ether the product phase is dried with sodium sulphate evaporated the residual solvent is removed under a high vacuum

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (3-fluoro-4-methyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 299.3 [M+H]+) was prepared from 4-bromo-2-fluorotoluene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine. In analogy to the procedure described for the synthesis example 71 (step 1)