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REFERENCE EXAMPLE 3 Synthesis of 2-methyl-4-trifluoromethylthiazole-5-carbonyl chloride 0.50 g of <strong>[117724-63-7]2-methyl-4-trifluoromethylthiazole-5-carboxylic acid</strong> was added to 5 ml of thionyl chloride and reaction was carried out for 2 hours under reflux. After the reaction, the reaction mixture was concentrated to obtain 0.54 g of 2-methyl-4-trifluoromethylthiazole-5-carbonyl chloride.
10.7 g
With thionyl chloride; In 1,2-dichloro-ethane; for 0.5h;Reflux;
to the reaction of <strong>[117724-63-7]2-methyl-4-trifluoromethyl-thiazole-5-carboxylic acid</strong> (0.048mol) and 1, 2-dichloroethane (80 ml), stirring 0.5hr rear, adds by drops two chlorine Asia sulphone (0.102mol), reaction under reflux conditions after the drop finishes 3-4hr, removing solvent to obtain orange red liquid title object 10.7 g.
18.5 g
With thionyl chloride; In dichloromethane; at 35℃;
<strong>[117724-63-7]2-methyl-4-trifluoromethylthiazole-5-carboxylic acid</strong> (100 mmol),Thionyl chloride (150 mmol) and 1,2-dichloroethane (100 mL)React at 3-5 hrs at 35C to the system reflow temperature,Removal of the solvent afforded the title compound (18.5 g).
With bis(trichloromethyl) carbonate; In N,N-dimethyl-formamide; toluene; at 50℃; for 1.25h;
52.8 g (0.25 mol) of <strong>[117724-63-7]2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid</strong> was added to the reaction vessel. 33.4g (0.112mol) of triphosgene, dissolved in 100mL of toluene, and added 1g (0.014mol) of N,N-dimethylformamide at 50 C, and the addition time is 15min. After the addition is completed, it is added dropwise. The acid chloride reaction was carried out for 1 h at a temperature.
REFERENCE EXAMPLE 2 Synthesis of 2-methyl-4-trifluoromethylthiazole-5-carboxylic acid 1.3 g of ethyl 2-methyl-4-trifluoromethylthiazole-5-carboxylate and 0.4 g of potassium hydroxide were dissolved in a mixture of 5 ml each of water and ethanol and reaction was effected at room temperature overnight. After the reaction, the reaction mixture was concentrated and acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was concentrated to obtain 0.89 g of 2-methyl-4-trifluoromethylthiazole-5-carboxylic acid.
21.5 g
With sodium hydroxide; In ethyl acetate; at 40℃; for 1h;
115 g of ethyl 2-methyl-4- (trifluoromethyl) thiazole-5-carboxylate (0.102 mol)Of ethyl acetate solution,50 g of a 40% sodium hydroxide solution was added dropwise to the reaction vessel at room temperature,Dropping speed was controlled so that the internal temperature of the system was lower than 40 C,After the dropwise addition of the sodium hydroxide solution,Insulation reaction 60min.After heat preservation,Taking the organic phase,To this was slowly added 10% hydrochloric acid,Adjusted to the system PH ? 2,At this point a large number of estimates of precipitation,The product was filtered,The filter cake was washed twice with 10% hydrochloric acid and dried in a vacuum oven.Methyl-4- (trifluoromethyl) thiazole-5-carboxylic acid as a light yellow solid, 21.5 g of 2-methyl-4- (trifluoromethyl) 98.8%, and the reaction yield was 98.70%.
C. The reaction mixture was stirred for 2.3 hours at room temperature during which time a yellow solid precipitated. Then triethylamine (1380 g, 13.64 mol) was added slowly. The reaction temperature rose to about 52 C. The contents were gently refluxed for one hour (internal temperature 75.8 C). After cooling to 46 C., a 40% sodium hydroxide solution (prepared from 1304 g 50% NaOH and 326 mL water, 16.3 mol) was added over 10 minutes. An exotherm to 53.6 C. was noted. The mixture was placed under a vacuum of 95 mm and the solvent distilled from the reaction until only water (of saponification) is present in the distillate. To the remaining reaction mixture was added 2 L water and 1.5 kg ice. Then concentrated HCl (1500 mL, 18 mol) was added over a 15 minute period to bring the pH to less than 2. Another 2 L water and 2 kg ice were added, and the product was filtered, washed on the filter with 12 L water, and dried in a vacuum oven to obtain 2-methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid, 825 g as a beige solid, a 75.4% yield at 97.6% purity.
12
[ 363-58-6 ]
[ 62-55-5 ]
[ 117724-63-7 ]
Yield
Reaction Conditions
Operation in experiment
75.4%
With hydrogenchloride; sodium hydroxide; triethylamine; In water; acetonitrile;
Example 2 Preparation of 2-Methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid. The reaction of Example 1 may be carried out as generally described and the ester may be converted to the acid by conventional methods without isolation. The following is an example of one method. To a 22 L flask fitted with a mechanical stirrer, thermocouple, and a reflux condenser, was charged thioacetamide (500.6 g, 6.66 mol) and acetonitrile (4 L). This resulted in an endothermic dissolution. To this solution was added ethyl 2-chloro-4,4,4-trifluoroacetoacetate (1105 g, 5.06 mol) over a period of 40 minutes. A slight exotherm occurred which raised the temperature to 55.8 C. The reaction mixture was stirred for 2.3 hours at room temperature during which time a yellow solid precipitated. Then triethylamine (1380 g, 13.64 mol) was added slowly. The reaction temperature rose to about 52 C. The contents were gently refluxed for one hour (internal temperature 75.8 C). After cooling to 46 C, a 40% sodium hydroxide solution (prepared from 1304 g 50% NaOH and 326 mL water, 16.3 mol) was added over 10 minutes. An exotherm to 53.6 C was noted. The mixture was placed under a vacuum of 95 mm and the solvent distilled from the reaction until only water (of saponification) is present in the distillate. To the remaining reaction mixture was added 2 L water and 1.5 kg ice. Then concentrated HCl (1500 mL, 18 mol) was added over a 15 minute period to bring the pH to less than 2. Another 2 L water and 2 kg ice were added, and the product was filtered, washed on the filter with 12 L water, and dried in a vacuum oven to obtain 2-methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid, 825 g as a beige solid, a 75.4% yield at 97.6% purity.
9-(dichloromethylene)-1,2,3,4-tetrahydro-1,4-methanonaphthalene-5-amine[ No CAS ]
[ 117724-63-7 ]
2-methyl-4-trifluoromethylthiazole-5-carboxylic acid (9-dichloromethylidenebenzonorbornene-5-yl)amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; triethylamine; In dichloromethane; at 25℃; for 20h;
9-Dichloromethylidene-5-amino-benzonorbomene (175 mg, 0.73 mmol), 2- methyl-4-trifluoromethyl-thiazole-5-carboxylic acid (162 mg, 0.77 mmol, 1.05 eq.) and triethylamine (184 mg, 1.8 mmol, 2.5 eq.) were reacted with bis-(2-oxo-3-oxazolidinyl)- phosphinic acid chloride (278 mg, 1.09 mmol, 1.5 eq.) in dichloromethane (10 ml) at 25 0C for 20 hours. The reaction mixture in ethyl acetate was washed successively with water and saturated. Sodium chloride solution, dried over sodium sulphate, evaporated and purified on silica gel (ethyl acetate-hexane-(l:2) to give 250 mg colourless crystals (m.p. 136-139 0C).
Example 2 0.21 g (1.0 mmol) of <strong>[117724-63-7]2-methyl-4-(trifluoromethyl)-1,3-thiazole-5-carboxylic acid</strong>, 0.49 g (2.4 mmol) of 1,3-dicyclohexylcarbodiimide and 0.14 g (1.0 mmol) of 1-hydroxybenzotriazole are suspended in 15 ml of dichloromethane. After 5 minutes, 0.24 g (1.0 mmol) of 5-(3,4-dichlorophenyl)-4-pyrimidinylamine is added. The reaction solution is stirred at room temperature for 8 h and then at 40 C. for 16 h. For work-up, the reaction mixture is filtered, washed with saturated sodium bicarbonate solution, dried over sodium sulphate and concentrated. Column chromatography (cyclohexane/ethyl acetate 2:1) gives 0.15 g (34% of theory) of N-[5-(3,4-dichlorophenyl)-4-pyrimidinyl]-2-methyl-4-(trifluoromethyl)-1,3-thiazole-5-carboxamide of logP (pH 2.3)=2.85.
0.10 ml (1.1 mmol) oxalylchloride and 0.1 ml dimethylformamide are added to a solution consisting of 211.2 mg (1.0 mmol) <strong>[117724-63-7]2-methyl-4-trifluoromethyl-thiazole-5-carboxylic acid</strong> in 9 ml dichloromethane. After stirring for 2 hours at room temperature, this solution is added to a solution consisting of 240.0 mg (1.0 mmol) 4'-chloro-5,3'-difluoro-biphenyl-2-yl-amine and 0.18 ml (1.3 mmol) triethylamine in 9 ml dichloromethane. The reaction mixture is stirred for 16 hours at room temperature and subsequently mixed with 7 ml 2 N hydrochloric acid. The organic phase is dried over magnesium sulphate and concentrated in vacuum.The reaction yields 316.5 mg (73% of the theoretical yield) of N-(4'-chloro-3',5-difluorobiphenyl-2-yl)-2-methyl-4-(trifluoromethyl)-1,3-thiazole-5-carboxamide [log P (pH 2.3)=3.67].
3'-isopropyl-2-methyl-4-trifluoromethyl-1,3-thiazole-5-carboxylic acid anilide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.54 g
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2h;Cooling with ice; Reflux;
0.46 g of <strong>[117724-63-7]2-methyl-4-trifluoromethyl-1,3-thiazole-5-carboxylic acid</strong> (manufactured by Sigma-Aldrich Japan) and 0.30 g of 3-isopropylaniline were dissolved in 20 ml of methylene chloride, and 0.47 g of WSCI/HCl was added thereto while being cooled in ice. The mixture was stirred at room temperature for one hour, and refluxed for one hour to cause reaction. Then, the same reaction and posttreatment operation were performed as in Synthesis Example 1 to thereby obtain 0.54 g of pale yellow oily compound of 3'-isopropyl-<strong>[117724-63-7]2-methyl-4-trifluoromethyl-1,3-thiazole-5-carboxylic acid</strong> anilide. 1H-NMR (CDCl3) deltappm; 7.78-7.00 (5H, m), 2.99-2.79 (1H, m), 2.75 (3H, s), 1.29 (3H, s), 1.22 (3H, s)
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