* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With thionyl chloride; In 1,4-dioxane; at 50℃; for 3h;
At the temperature,2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine (250 g, 1.13 mol) in dioxane (2.5 L) was added thionyl chloride 0.11 L, 1.47 mol).The mixture was stirred at 50 C for 3 h,Cool to room temperature.Diluted with methylene chloride,Washed successively with saturated sodium bicarbonate solution and brine solution.Dried over anhydrous magnesium sulfate,filter,The solvent was distilled off under reduced pressure,2-Chloromethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine 245 g,Yield 90.5%.
With methanol; sodium hydroxide; water; at 20 - 30℃;pH 12.5 - 13.5;
e) 2-Hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine 34.8 g of the product obtained in the previous step corresponding to 18.7 g (0.071 mole) 2-acetoxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine were dissolved at room temperature in 15 ml of a mixture of methanol/water (1:1), the pH of which was adjusted with aqueous sodium hydroxide (33percent) to 13. The reaction was carried out at a temperature of from 25 to 30°C and a pH of from 12.5 to 13.5, adjusted by the addition of sodium hydroxide. The end was determined by HPLC method. The mixture was neutralized with 36percent hydrochloric acid and extracted with methylene chloride. The organic layers were dried and concentrated to 60 ml. The yield was 95-97percent, determined by HPLC.
3-methyl-4-(2,2,2-trifluoroethoxy)-2-chloromethylpyridine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With bis(trichloromethyl) carbonate; Triphenylphosphine oxide; In toluene; at 20 - 60℃; for 6h;
Ph3PO (43.78 g, 157.5 mmol) was dissolved in toluene (100 mL) in a 500 mL three-necked flask and BTC(14.84 g, 50 mmol) was dissolved in toluene (60 mL) and placed in a 150 mL constant pressure dropping funnel,BTC was added dropwise at room temperature, and the temperature was raised to 60 ° C after completion of the dropwise addition.After incubation for 4 hours, 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine(33.15 g, 150 mmol) was dissolved in 75 mL of toluene and added at 40 ° C to precipitate a white solid. After the reaction was carried out for 2 hours, the reaction was stopped and the white solid was obtained by filtration to dryness 2-chloromethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine hydrochloride 40.01 g, product yield 97percent
84%
With thionyl chloride; In dichloromethane; toluene; at 0 - 20℃; for 4h;
f) 2-Chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine hydrochloride 160 ml of toluene were added to 14.9 g (0.067 mole) of <strong>[103577-66-8]2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine</strong> in methylene chloride followed by distillation of methylene chloride. The solution was purified with 2.7 g of acivated charcoal, filtered and washed with 36 ml of toluene. To this solution 5.4 ml (0.075 mole) of thionyl chloride in 27 ml of toluene were added dropwise and maintained for 3 hours. The gas was removed under vacuum at room temperature, then the resulting mixture was cooled to a temperature of from 0 to 5°C and stirred for one hour. The product was filtered, washed with 3 ml of toluene and dried in a vacuum dryer at 35-40°C. The yield was 15.65 g (84 percent).
With thionyl chloride; In dichloromethane; for 1h;Industry scale; Heating / reflux;
EXAMPLE 1 [Production Method of 2-(((3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methyl)thi o)benzimidazole monohydrate] 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyri dine (87.4 kg) was dissolved in methylene chloride (655 L), thionyl chloride (41.1 L) was added to the solution, and the mixture was heated under reflux for about 60 minutes. Water (183 kg) was added to the mixture, and the mixture was concentrated. To the residue were added methanol (656 L) and 2-benzimidazolethiol (59. 8 kg), then the pH was adjusted to 11.0 - 11.5 with a 30percent aqueous solution of sodium hydroxide, and the mixture was reacted for 30 minutes. To the reaction solution was added water (524 kg) and the mixture was recrystallized. pH was adjusted to 8.5 - 10.0 with 35percent hydrochloric acid, and then the precipitated crystals were filtered. The crystals were washed with an aqueous methanol solution (methanol:water = 5:5 (weight ratio)) and water, and then dried to obtain 141.6 kg of 2-(((3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methyl)thi o)benzimidazole monohydrate as white crystals (yield: 96.5percent).
To the resultant mixture was added dropwise 0.2 L. of 30percent aqueous sodium hydroxide solution at about 30° C. to adjust its pH at 13, followed by stirring at about 35° C. for 12 hours. The resultant mixture was left standing, and the supernatant was taken off. To the resultant residue was added 100 ml. of methanol, followed by stirring at about 45° C. for about 30 minutes to solubilize the precipitated crystals. While the resultant solution was kept at about 20° C., 0.5 L. of water was added in order to precipitate crystals. The resultant mixture was cooled down to about 5° C. and kept standing. The precipitated crystals were collected by filtration, washed with water and dissolved into a mixed solution of 75 ml. of 35percent hydrochloric acid, 0.4 L. of water and 2.5 g. of diatomaceous earth. The resultant solution was adjusted to a pH of about 3 with a 30percent aqueous sodium hydroxide solution, and the insolubles were filtered off. The filtrate was washed three times, each with 200 ml. of methylenechloride. After addition of 5.0 g. of activated charcoal, the mixture was stirred at about 40° C. for about 12 hours. The activated charcoal was filtered off, and 80 ml. of ethanol was added to the filtrate. The resultant mixture was neutralized to pH 7 with 30percent aqueous sodium hydroxide solution to precipitate crystals. The mixture was cooled down to below 5° C., and the precipitated crystals were collected by filtration and washed with wacter. The obtained crystals were dried at about 37° C. under reduced pressure for about 24 hours to give 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine as white crystals. Yield:95 g.(46percent based on 2,3-lutidine).
17
[ 75-09-2 ]
[ 103577-66-8 ]
[ 134469-07-1 ]
lansoprazole sulphide hydrate[ No CAS ]
[ 103577-40-8 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; sodium hydroxide; thionyl chloride; In methanol; water;
REFERENCE EXAMPLE 5 Production of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]-methyl]thio]benzimidazole monohydrate 49.9 g. of <strong>[103577-66-8]2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine</strong> was dissolved into 0.4 L. of methylene-chloride, followed by dropwise addition of 24 ml. of thionylchloride for about 30 minutes. The mixture was allowed to react at more than about 30° C. for about 1 hour. After completion of the reaction, 0.1 L. of water was added, and the methylenechloride was evaporated off under reduced pressure. The residue was dissolved into 0.4 L. of methanol, followed by addition of 34.2 g. of 2-benzimidazolethiol. To the mixture was added dropwise 60 ml. of a 30percent aqueous sodium hydroxide solution at about 25° C. for about 1 hour. The mixture was allowed to react at room temperature for about 0.5 hour. To the resultant mixture was added 0.3 L. of water, followed by stirring at below 10° C. for about 30 minutes. The resultant mixture was adjusted to a pH of about 9 with 35percent hydrochloric acid in order to precipitate crystals. The resultant crystals were collected by filtration and washed with, in turn, 0.1 L. of 50percent methanol and 0.2 L. of water. The obtained crystals were dried with hot air at below 50° C. to give 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]-methyl]thio]benzimidazole as white crystals. Yield:81.0 g. (96.7percent based on HYD).
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