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With thionyl chloride; potassium carbonate In <i>N</i>-methyl-acetamide
EXAMPLE III 3-Chloro-2-fluoro-5-(trifluoromethyl)benzonitrile was prepared as follows: Thionyl chloride, 6.0 g (50 mmol) was added to a slurry of 4.0 g (16 mmol) 3-chloro-2-fluoro-5-(trifluoromethyl) benzamide and 15 mL dimethylformamide at 0° C. After stirring for one hour the reaction mixture was diluted with 25 mL pentane and neutralized by dropwise addition of a saturated potassium carbonate solution and filtered. The pentane solution was dried and distilled to yield 3-chloro-2-fluoro-5-(trifluoromethyl) benzonitrile in 71percent yield, bp 75°-85° C./20 mm Hg.
With thionyl chloride; potassium carbonate; In N-methyl-acetamide;
EXAMPLE III 3-Chloro-2-fluoro-5-(trifluoromethyl)benzonitrile was prepared as follows: Thionyl chloride, 6.0 g (50 mmol) was added to a slurry of 4.0 g (16 mmol) 3-chloro-2-fluoro-5-(trifluoromethyl) benzamide and 15 mL dimethylformamide at 0 C. After stirring for one hour the reaction mixture was diluted with 25 mL pentane and neutralized by dropwise addition of a saturated potassium carbonate solution and filtered. The pentane solution was dried and distilled to yield 3-chloro-2-fluoro-5-(trifluoromethyl) benzonitrile in 71% yield, bp 75-85 C./20 mm Hg.
1-(2-Chloro-6-cyano-4-trifluoromethylphenyl)-4-pentafluoroethylpyrimidin-6-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(c) 1-(2-Chloro-6-cyano-4-trifluoromethylphenyl)-4-pentafluoroethylpyrimidin-6-one (compound No 4 in Table I) was prepared by the reaction of <strong>[129931-47-1]3-chloro-4-fluoro-5-cyano-trifluoromethylbenzene</strong> and 4-pentafluoroethylpyrimidin-6-one. 1 H NMR delta(CDCl3 /d6 -DMS0): 8.15 (1H,s); 8.09 (2H,m); 7.09 (1H,s).
PREPARATION 2 This description illustrates the preparation of 3-chloro-4-fluoro-5-cyano-trifluoromethylbenzene. A solution of 3-amino-5-chloro-4-fluorotrifluoromethylbenzene (3g) in acetonitrile (10ml) was added dropwise to a stirred suspension of copper (I) cyanide (1.26g) in dry acetonitrile (50ml) whilst the reaction temperature was maintained at 0 C. After the addition was complete, the reaction mixture was allowed to warm to the ambient temperature (about 23 C.) and left overnight. The reaction mixture was poured into water, extracted with diethyl ether, dried over anhydrous magnesium sulphate and filtered. Evaporation of the solvent, under reduced pressure, gave a brown oil, which was flushed through a plug of silica gel using petroleum ether (boiling range 60-80 C.) containing diethyl ether (20% by volume) as eluent. After removal of the solvent, under reduced pressure, kugelrohr distillation of the residue gave two fractions, the first of which (boiling point 110 C. at 15mmHg) was predominantly composed of 3-chloro-4-fluoro-5-cyano-trifluoromethylbenzene. This material was used without further purification. 1 H NMR delta(CDCl3) 7.95 (1H, m); 7.85 (1H, m).
With potassium fluoride; In N-methyl-acetamide; toluene;
PREPARATION 7 This description illustrates an alternate preparation of 3-chloro-4-fluoro-5-cyano-trifluoromethylbenzene. Dry potassium fluoride (1.94g) was added to a flask containing dry toluene (31 ml), dry dimethylformamide (7.8ml) and a catalytic amount of 18-crown-6. The stirred mixture was heated to reflux, and approximately 25 mls of the distillate was collected. After cooling to ambient temperature, 3-cyano-4,5-dichloro-trifluoromethylbenzene (4g) was added in one portion, and the stirred mixture was heated to 130 C. for 16 hours, and then to 145 C. for 24 hours. After cooling to ambient temperature, the reaction mixture was filtered, the residue washed with ethyl acetate, and the combined filtrate washed with brine. After drying over anhydrous magnesium sulphate, evaporation under reduced pressure gave a brown oil which was subjected to kugelrohr distillation, to give 3-chloro-4-fluoro-5-cyano-trifluoromethylbenzene as a pale yellow liquid (3.17g). 1 H NMR delta(CDCl3) 7.95 (1H,dq); 7.85 (1H,dq)
1-(2-Chloro-6-cyano-4-trifluoromethylphenyl)-3-cyano-5-trifluoromethyl-2-pyridone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(m) 1-(2-Chloro-6-cyano-4-trifluoromethylphenyl)-3-cyano-5-trifluoromethyl-2-pyridone (Compound No 17 in Table II) was prepared by the reaction of <strong>[129931-47-1]3-chloro-4-fluoro-5-cyano-trifluoromethylbenzene</strong> and 3-cyano-5-trifluoromethyl-2-pyridone. 1 H NMR delta(CDCl13): 8.15 (2H,d); 8.05 (1H,d); 7.78 (1H,d)
1-(2-chloro-6-cyano-4-trifluoromethylphenyl)-3-dimethyl-aminopyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N-methyl-acetamide; mineral oil;
Step (d) A solution of 3-dimethyl-aminopyrazole (440mg) in dimethylformamide (3ml) was added in small portions to a suspension of sodium hydride (160mg of a 60% suspension in mineral oil) in dimethylformamide (2ml). The reaction mixture was stirred until all effervescence had stopped and then it was added to a solution of 2-fluoro-3-chloro-5-trifluoromethylbenzonitrile (1g) in dimethylformamide (15ml) under a nitrogen atomsphere. After one hour of stirring the mixture was poured into brine and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulphate and the solvent evaporated under reduced pressure to give a yellow solid (910mg) which was purified by recrystallisation from hexane to give 1-(2-chloro-6-cyano-4-trifluoromethylphenyl)-3-dimethyl-aminopyrazole. melting point: 115-116 C. 1 H NMR delta(CDCl3): 7.94 (1H,d); 7.90 (1H,d); 7.86 (1H,d); 6.03 (1H,d); 2.98 (6H,s)
1-(2-Chloro-6-cyano-4-trifluoromethylphenyl)-3-nitro-5-trifluoromethyl-2-pyridone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(h) 1-(2-Chloro-6-cyano-4-trifluoromethylphenyl)-3-nitro-5-trifluoromethyl-2-pyridone (Compound No 15 in Table II) was prepared by the reaction of 3-chloro-4-fluoro-5-cyanotrifluoromethylbenzene and 3-nitro-5-trifluoromethyl-2-pyridone. 1 H NMR delta(CDCl3): 8.65 (1H,d); 8.17 (1H,d); 8.08 (1H,d); 7.89 (1H,m).
1-(2-Chloro-6-cyano-4-trifluoromethylphenyl)-4-trifluoromethyl-2-pyridone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(g) 1-(2-Chloro-6-cyano-4-trifluoromethylphenyl)-4-trifluoromethyl-2-pyridone (Compound No 14 of Table II) was prepared by reacting 3-chloro-4-fluoro-5-cyanotrifluoromethylbenzene and 4-trifluoromethyl-2-pyridone. 1 H NMR delta(CDCl3) 8.10 (1H,d); 8.0 (1H,d); 7.26 (1H,dd); 7.04 (1H,s); 6.55 (1H,dd).
1-(2-Chloro-6-cyano-4-trifluoromethylphenyl)-5-bromo-4-trifluoromethyl-2-pyridone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(i) 1-(2-Chloro-6-cyano-4-trifluoromethylphenyl)-5-bromo-4-trifluoromethyl-2-pyridone (Compound No 16 in Table II) was prepared by the reaction of 3-chloro-4-fluoro-5-cyanotrifluoromethylbenzene and 5-bromo-4-trifluoromethyl-2-pyridone. 1 H NMR delta(CDCl3) 8.10 (1H,d); 8.01 (1H,d); 7.45 (1H,s); 7.13 (1H,s).
5-(2-hydroxyisopropyl)-4-trifluoromethyl-pyrimidin-6-one[ No CAS ]
1-(2-chloro-6-cyano-4-trifluoromethylphenyl)-5-(2-hydroxyisopropyl)-4-trifluoromethylpyrimidin-6-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage 1 1-(2-chloro-6-cyano-4-trifluoromethylphenyl)-5-(2-hydroxyisopropyl)-4-trifluoromethylpyrimidin-6-one was prepared from <strong>[129931-47-1]3-chloro-4-fluoro-5-cyano-trifluoromethylbenzene</strong> and 5-(2-hydroxyisopropyl)-4-trifluoromethyl-pyrimidin-6-one (Preparation 2) according to the general method disclosed in EP 0 398 499 for the preparation of Compound A1 in Table A1. Melting Point: 125.6 - 127.6C, 1H NMR delta(CDCl3): 8.14(s,1H); 8.05(s,1H); 7.99(s,1H); 3.45(s,1H); 1.75(d,6H).
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