* 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 triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 10℃;
Take 100g HYDROXY rabeprazole (473.35mmol) was added to a 2L three-necked flask, followed by addition of 1L of tetrahydrofuran, 71.10g mercaptobenzimidazole (473.35mmol), 136.58g triphenylphosphine (520.69mmol).Open stirred and the temperature controlled at 0-10 .After added dropwise 90.678g (520.69mmol) azodicarboxylic acid diethyl ester.After completion of the dropwise addition, the reaction was kept 5h-10h, the reaction gusset fully monitored.After completion of the reaction, tetrahydrofuran was evaporated to dryness, then recrystallized from methanol to give 130.0 g of rabeprazole sulfide composition, yield 80percent.
Reference:
[1] Patent: CN106674198, 2017, A, . Location in patent: Paragraph 0020-0021
With thionyl chloride; In dichloromethane; at 20 - 25℃;Product distribution / selectivity;
(Reference Example 4) <strong>[118175-10-3]2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine</strong> (5.0 g (23.7 mmol)) was dissolved in dichloromethane (40 ml), and thionyl chloride (4.23 g (35.6 mmol)) was added dropwise thereto so that the temperature did not exceed 25C. Following stirring at room temperature, disappearance of the raw materials was confirmed by TLC, and 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (6.23 g) was obtained by concentrating under a reduced pressure (yield: 99.0%).
99.2%
With thionyl chloride; In 1,2-dimethoxyethane; at 20 - 25℃;Product distribution / selectivity;
(Reference Example 3) <strong>[118175-10-3]2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine</strong> (5.0 g (23.7 mmol)) was dissolved in dimethoxyethane (40 ml), and thionyl chloride (4.23 g (35.6 mmol)) was added dropwise thereto so that the temperature did not exceed 25C. Following stirring at room temperature, disappearance of the raw materials was confirmed by TLC, and 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (6.25 g) was obtained by concentrating under a reduced pressure (yield: 99.2%).
99%
70 g of the 2-hydroxymethyl-4-(3-methoxy propoxy)-3 -methyl pyridine obtained in example 3 was dissolved in 135 ml of methylene dichloride to obtain a solution. 73.1 g (0.61 mol) of thionyl chloride was drop wise added to this solution at 0C. The obtained mixture was stirred at room temperature for 2 hrs. After the completion of reaction, the reaction mixture was distilled to remove the methylene dichloride & thionyl chloride under vacuum. The obtained residue was cooled to 5C and neutralized using saturated sodium bicarbonate solution to pH-7.5 and extracted with methylene dichloride. The methylene dichloride layer dried over sodium sulfate & filtered. The obtained filtrate concentrated to obtain 76 g (99 %) of 2-chloromethyl-4-(3-methoxy propoxy)-3-methyl pyridine as a brown oil
97.3%
With thionyl chloride; In toluene; at 20 - 25℃;Product distribution / selectivity;
Synthesis of 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (Reference Example 1) <strong>[118175-10-3]2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine</strong> (5.0 g (23.7 mmol)) was dissolved in toluene (40 ml), and thionyl chloride (4.23 g (35.6 mmol)) was added dropwise thereto so that the temperature did not exceed 25C. Following stirring at room temperature, disappearance of the raw materials was confirmed by TLC, and 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (6.13 g) was obtained by concentrating under a reduced pressure (yield: 97.3%). To a mixed solution of 2-hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (12.02 g (56.9 mmol)) and toluene (96.0 ml) was added dropwise thionyl chloride (8.11 g (68.2 mmol)), so that the internal temperature did not exceed 25C, which was stirred for about 90 minutes at room temperature. Ethanol (24.0 ml) was added to this mixed solution to obtain a 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine solution.
97.4%
With thionyl chloride; In ethyl acetate; at 20 - 25℃;Product distribution / selectivity;
(Reference Example 2) <strong>[118175-10-3]2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine</strong> (5.0 g (23.7 mmol)) was dissolved in ethyl acetate (40 ml), and thionyl chloride (4.23 g (35.6 mmol)) was added dropwise thereto so that the temperature did not exceed 25C. Following stirring at room temperature, disappearance of the raw materials was confirmed by TLC, and 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (6.14 g) was obtained by concentrating under a reduced pressure (yield: 97.4%).
92.2%
With thionyl chloride; In dichloromethane; at 20℃; for 2.0h;
General procedure: To a solution of commercial 9a or 9b or 9c (3.56 mmol) in dichloromethane (20 mL) was added SOCl2 (2.8 mL). After 2 h stirring at room temperature, the reaction mixture was quenched with 2 M NaOH solution to pH 7-8. The solution was extracted several times with DCM, and the combined organic layers were washed saturated salt solution, dried over anhydrous MgSO4 and then evaporated in vacuo.
With thionyl chloride; In chloroform; at 20℃; for 5.0h;
50g 4-(3-methoxy-propoxy)-2,3-dimethyl-pyridine N-oxide, 150ml acetic anhydride and 8 drops of concentrated sulfuric acid were put into a reaction flask and reacted at 90 Cfor 3 hours in oil bath. The acetic anhydride was vaporized under vacuum. 100ml water and 20g sodium hydroxide at ambient temperature were added to the flask and reacted at 50 C for 1 hour in water bath. And then the reaction solution was cooled, extracted by chloroform, dried, filtered and concentrated till dry. 200ml fresh chloroform and 30ml thionyl chloride were added to the residue and the reaction took place at ambient temperature for 5 hours and the reaction solution was concentrated under vacuum. After that, 400ml water was added to the residue and the pH value was adjusted to 8 with sodium carbonate solution. Finally, the expected product (brown semi-solid) was produced after the procedures of extracting the reaction solution by chloroform, drying and concentration.
2-acetoxymethyl-4-(3-methoxy propoxy)-3-methyl pyridine[ No CAS ]
[ 118175-10-3 ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; water; at 20 - 50℃; for 1.0h;
50g 4-(3-methoxy-propoxy)-2,3-dimethyl-pyridine N-oxide, 150ml acetic anhydride and 8 drops of concentrated sulfuric acid were put into a reaction flask and reacted at 90 Cfor 3 hours in oil bath. The acetic anhydride was vaporized under vacuum. 100ml water and 20g sodium hydroxide at ambient temperature were added to the flask and reacted at 50 C for 1 hour in water bath. And then the reaction solution was cooled, extracted by chloroform, dried, filtered and concentrated till dry. 200ml fresh chloroform and 30ml thionyl chloride were added to the residue and the reaction took place at ambient temperature for 5 hours and the reaction solution was concentrated under vacuum. After that, 400ml water was added to the residue and the pH value was adjusted to 8 with sodium carbonate solution. Finally, the expected product (brown semi-solid) was produced after the procedures of extracting the reaction solution by chloroform, drying and concentration.
With sodium hydroxide; In ethanol; at 20 - 55℃;
145 g (1.42 mol) of the acetic anhydride was added over 30 minutes to 150 g (0.71 mol) of 4-(3-methoxy propoxy)-2, 3-dimethyl pyridine-N-oxide at O0C. The solution was heated to 900C and stirred for 6 hrs. After the completion of reaction, it was distilled under reduced pressure to remove acetic anhydride. The obtained residue containing 2- <n="14"/>acetoxymethyl-4-(3-methoxy propoxy)-3-methyl pyridine was added in 34.2 g (0.85 mol) of sodium hydroxide & 450 ml of ethanol at room temperature. The reaction mixture was stirred at 55 0C for 2 hrs. After completion of reaction, remove ethanol by distillation under reduced pressure. The obtained residue was diluted with 1500 ml of water & extracted with methylene dichloride (500 ml X 2 & 100 ml X 1). The combined organic layer was dried over sodium sulfate. The methylene dichloride layer was concentrated to obtain 98 g (79 %) of 2-hydroxymethyl -4-(3-methoxy propoxy)-3 -methyl pyridine as brown oil
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 10℃;
Take 100g HYDROXY rabeprazole (473.35mmol) was added to a 2L three-necked flask, followed by addition of 1L of tetrahydrofuran, 71.10g mercaptobenzimidazole (473.35mmol), 136.58g triphenylphosphine (520.69mmol).Open stirred and the temperature controlled at 0-10 .After added dropwise 90.678g (520.69mmol) azodicarboxylic acid diethyl ester.After completion of the dropwise addition, the reaction was kept 5h-10h, the reaction gusset fully monitored.After completion of the reaction, tetrahydrofuran was evaporated to dryness, then recrystallized from methanol to give 130.0 g of rabeprazole sulfide composition, yield 80%.
2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95.7%
With thionyl chloride; In ethyl acetate; at 5 - 20℃; for 3.0h;
Take 40 g of <strong>[118175-10-3]3-methyl-2-hydroxymethyl-4-(3-methoxypropoxy)pyridine</strong> prepared according to Example 2.Add 80 g of ethyl acetate and stir evenly, then cool to 5C, add 27.3 g of thionyl chloride dropwise, and finish dropping in about 1 hour.After dripping, the temperature was raised to room temperature and reacted for 2 hours, and a large amount of solid materials were precipitated.Filter, rinse the filter cake with an appropriate amount of ethyl acetate, and dry it after discharging to obtain the title compound with a molar yield of 95.7% and a purity of 99.94%.