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Structure of 117977-20-5 * Storage: {[proInfo.prStorage]}
* 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.
(Reference Example 5-1) 2-Chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (53.2 g (200 mmol)), denatured ethanol (320 ml), 2-benzimidazole thiol (30.2 g (201 mmol)) and sodium hydroxide (26.8 g (670 mmol)) were added together and reacted for about 2 hours at 50°C. After disappearance of the raw materials had been confirmed by TLC, this solution was concentrated under a reduced pressure and ethyl acetate (430 ml) and water (340 ml) were added thereto, followed by stirring and standing, and the water layer was then separated. The organic layer was washed with 10percent aqueous sodium hydroxide solution (110 ml) and water (2 x 110 ml) and concentrated under a reduced pressure to obtain crude 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1 H-benzimidazole (69.0 g) (HPLC purity 98.7percent, yield 101percent). 2-Chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (26.6 g (100 mmol)), denatured ethanol (160 ml), 2-benzimidazole thiol (15.0 g (100 mmol)) and sodium hydroxide (13.4 g (335 mmol)) were added together and reacted for about 2 hours at 50°C. After disappearance of the raw materials had been confirmed by TLC, this solution was concentrated under a reduced pressure, toluene (30 ml) and water (168 ml) were added thereto. After stirring and still standing the water layer was separated. The organic layer was washed with 10percent aqueous sodium hydroxide solution (50 ml) and water (2 x 50 ml) and concentrated under a reduced pressure to obtain crude 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1 H-benzimidazole (34.8 g) (HPLC purity 98.7percent, yield 101percent).
100%
With sodium hydroxide In ethanol at 50℃; for 2 h;
Reference Example 5-1; 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole-producing Step 2-Chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (53.2 g (200 mmol)), denatured ethanol (320 ml), 2-benzimidazolethiol (30.2 g (201 mmol)), and sodium hydroxide (26.8 g (670 mmol)) were added together, and reaction was carried out for approximately 2 hours at 50° C. After it had been confirmed by TLC that the starting material had disappeared, vacuum concentration was carried out, and ethyl acetate (430 ml) and water (340 ml) were then added. After stirring and then leaving to stand, the aqueous layer was separated off. The organic layer was washed with a 10percent sodium hydroxide aqueous solution (110 ml), and twice with water (110 ml), and then vacuum concentration was carried out, thus obtaining crude 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (69.0 g) (HPLC purity 98.7percent, yield 101percent). The crude 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (5.00 g) was crystallized using ethyl acetate (25 ml), and then filtration was carried out, thus obtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (4.80 g) (HPLC purity 99.2percent, yield 96.0percent).Reference Example 6-1 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole-producing step 2-Chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (26.6 g (100 mmol)), denatured ethanol (160 ml), 2-benzimidazolethiol (15.0 g (100 mmol)), and sodium hydroxide (13.4 g (335 mmol)) were added together, and reaction was carried out for approximately 2 hours at 50° C. After it had been confirmed by TLC that the starting material had disappeared, vacuum concentration was carried out, and toluene (300 ml) and water (168 ml) were then added. After stirring and then leaving to stand, the aqueous layer was separated off. The organic layer was washed with a 10percent sodium hydroxide aqueous solution (50 ml), and twice with water (50 ml), and then vacuum concentration was carried out, thus obtaining crude 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (34.8 g) (HPLC purity 98.7percent, yield 101percent).
77.5%
With sodium hydroxide In water; acetone at 25 - 30℃; for 2 h;
EXAMPLE 7: PREPARATION OF 2-[4-(3-METHOXYPROPOXY)-S-METHYL-PYRIDIN- 2-YLMETHYLSULFANYL]-1 H-BENZIMIDAZ0LE (RABEPRAZOLE SULFIDE) (FORMULA Hb)-USING 2.5 EQUIVALENTS OF SODIUM HYDROXIDE:A solution of sodium hydroxide (113 g) in water (1200 ml) was taken into a round bottom flask and 2-mercaptobenzimidazole (170 g) was added to it. Acetone (600 ml) was added to it followed by the addition of a solution of 2-chloromethyl-4-(3- methoxypropoxy)-3-methyl-pyridine (300 g) in water (600 ml) at 25 to 35 0C. The reaction mass was maintained at 25 to 35 0C for about 2 hours and then reaction completion was checked using thin layer chromatography. After the reaction was completed, water (1200 ml) was added to the reaction mass and stirred for about 2 hours. The separated solid was filtered and washed with a mixture water (of 300 ml) and acetone (150 ml). The wet material was taken into a solution of sodium hydroxide (30 g) in water (3000 ml) and stirred for about 60 minutes. The reaction mass was filtered and the solid was washed with water (3000 ml). The wet material was dried at 55 to 60 0C for about 4 hours. The dry material was taken into another round bottom flask and ethyl acetate (600 ml) was added to it. The mixture was heated to reflux for getting clear dissolution and maintained for about 1 hour. Then the solution was cooled to 25 to 35 0C and maintained for about 2 hours. The separated solid was filtered and washed with ethyl acetate (300 ml). The wet material was dried at 55 to 60 0C for about 5 hours to yield 300 g of the title compound (percent yield: 77.5percent).
Reference：
[1] Patent: EP1775292, 2007, A1, . Location in patent: Page/Page column 13; 14
[2] Patent: US2007/225502, 2007, A1, . Location in patent: Page/Page column 2-3; 5-6
[3] Patent: WO2008/45777, 2008, A2, . Location in patent: Page/Page column 30
[4] Patent: US5045552, 1991, A,
[5] Patent: EP1775292, 2007, A1, . Location in patent: Page/Page column 17
[6] Patent: WO2008/1392, 2008, A2, . Location in patent: Page/Page column 18
[7] Patent: WO2009/116072, 2009, A2, . Location in patent: Page/Page column 14
[8] Organic Process Research and Development, 2013, vol. 17, # 10, p. 1272 - 1276
[9] Patent: WO2014/91450, 2014, A1, . Location in patent: Page/Page column 14-15
With sodium hydroxide; In ethanol; at 50℃; for 2h;Product distribution / selectivity;
(Reference Example 5-1) 2-Chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (53.2 g (200 mmol)), denatured ethanol (320 ml), 2-benzimidazole thiol (30.2 g (201 mmol)) and sodium hydroxide (26.8 g (670 mmol)) were added together and reacted for about 2 hours at 50C. After disappearance of the raw materials had been confirmed by TLC, this solution was concentrated under a reduced pressure and ethyl acetate (430 ml) and water (340 ml) were added thereto, followed by stirring and standing, and the water layer was then separated. The organic layer was washed with 10% aqueous sodium hydroxide solution (110 ml) and water (2 x 110 ml) and concentrated under a reduced pressure to obtain crude 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1 H-benzimidazole (69.0 g) (HPLC purity 98.7%, yield 101%). 2-Chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (26.6 g (100 mmol)), denatured ethanol (160 ml), 2-benzimidazole thiol (15.0 g (100 mmol)) and sodium hydroxide (13.4 g (335 mmol)) were added together and reacted for about 2 hours at 50C. After disappearance of the raw materials had been confirmed by TLC, this solution was concentrated under a reduced pressure, toluene (30 ml) and water (168 ml) were added thereto. After stirring and still standing the water layer was separated. The organic layer was washed with 10% aqueous sodium hydroxide solution (50 ml) and water (2 x 50 ml) and concentrated under a reduced pressure to obtain crude 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1 H-benzimidazole (34.8 g) (HPLC purity 98.7%, yield 101%).
100%
With sodium hydroxide; In ethanol; at 50℃; for 2h;Product distribution / selectivity;
Reference Example 5-1; 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole-producing Step 2-Chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (53.2 g (200 mmol)), denatured ethanol (320 ml), 2-benzimidazolethiol (30.2 g (201 mmol)), and sodium hydroxide (26.8 g (670 mmol)) were added together, and reaction was carried out for approximately 2 hours at 50 C. After it had been confirmed by TLC that the starting material had disappeared, vacuum concentration was carried out, and ethyl acetate (430 ml) and water (340 ml) were then added. After stirring and then leaving to stand, the aqueous layer was separated off. The organic layer was washed with a 10% sodium hydroxide aqueous solution (110 ml), and twice with water (110 ml), and then vacuum concentration was carried out, thus obtaining crude 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (69.0 g) (HPLC purity 98.7%, yield 101%). The crude 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (5.00 g) was crystallized using ethyl acetate (25 ml), and then filtration was carried out, thus obtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (4.80 g) (HPLC purity 99.2%, yield 96.0%).Reference Example 6-1 2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole-producing step 2-Chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (26.6 g (100 mmol)), denatured ethanol (160 ml), 2-benzimidazolethiol (15.0 g (100 mmol)), and sodium hydroxide (13.4 g (335 mmol)) were added together, and reaction was carried out for approximately 2 hours at 50 C. After it had been confirmed by TLC that the starting material had disappeared, vacuum concentration was carried out, and toluene (300 ml) and water (168 ml) were then added. After stirring and then leaving to stand, the aqueous layer was separated off. The organic layer was washed with a 10% sodium hydroxide aqueous solution (50 ml), and twice with water (50 ml), and then vacuum concentration was carried out, thus obtaining crude 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (34.8 g) (HPLC purity 98.7%, yield 101%).
77.5%
With sodium hydroxide; In water; acetone; at 25 - 30℃; for 2h;
EXAMPLE 7: PREPARATION OF 2-[4-(3-METHOXYPROPOXY)-S-METHYL-PYRIDIN- 2-YLMETHYLSULFANYL]-1 H-BENZIMIDAZ0LE (RABEPRAZOLE SULFIDE) (FORMULA Hb)-USING 2.5 EQUIVALENTS OF SODIUM HYDROXIDE:A solution of sodium hydroxide (113 g) in water (1200 ml) was taken into a round bottom flask and 2-mercaptobenzimidazole (170 g) was added to it. Acetone (600 ml) was added to it followed by the addition of a solution of 2-chloromethyl-4-(3- methoxypropoxy)-3-methyl-pyridine (300 g) in water (600 ml) at 25 to 35 0C. The reaction mass was maintained at 25 to 35 0C for about 2 hours and then reaction completion was checked using thin layer chromatography. After the reaction was completed, water (1200 ml) was added to the reaction mass and stirred for about 2 hours. The separated solid was filtered and washed with a mixture water (of 300 ml) and acetone (150 ml). The wet material was taken into a solution of sodium hydroxide (30 g) in water (3000 ml) and stirred for about 60 minutes. The reaction mass was filtered and the solid was washed with water (3000 ml). The wet material was dried at 55 to 60 0C for about 4 hours. The dry material was taken into another round bottom flask and ethyl acetate (600 ml) was added to it. The mixture was heated to reflux for getting clear dissolution and maintained for about 1 hour. Then the solution was cooled to 25 to 35 0C and maintained for about 2 hours. The separated solid was filtered and washed with ethyl acetate (300 ml). The wet material was dried at 55 to 60 0C for about 5 hours to yield 300 g of the title compound (% yield: 77.5%).
With sodium hydroxide; In ethanol;
EXAMPLE 31 2-[{4-(3-Methoxypropoxy)-3-methylpyridine-2-yl}methylthio]-1H-benzimidazole STR93 20 cc of ethanol was added to a mixture comprising 280 mg (1.8 mmol) of 2-mercapto-1H-benzimidazole, 470 mg (2 mmol) of 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine and 100 mg (2.4 mmol) of sodium hydroxide. The obtained mixture was stirred at 50 C. for 3 hours. After the completion of the reaction, the reaction mixture was distilled to remove the ethanol. The obtained residue was purified by silica gel column chromatography to obtain 590 mg of 2-[{4-(3-methoxypropoxy)-3-methylpyridine-2-yl}methylthio]-1H-benzimidazole as a pale yellow crystal. 1 H-NMR(CDCl3) delta; 2.09(t, J=6.1 Hz, 2H), 2.26(s, 3H), 3.35(s, 3H), 3.56(t, J=6.1 Hz, 2H), 4.13(t, J=6.1 Hz, 2H), 4.37(s, 2H), 6.76(d, J=6.1 Hz, 1H), 7.1~7.25(m, 2H), 7.5(br, s, 2H), 8.33(d, J=6.1 Hz, 1H).
With sodium hydroxide; In ethanol; water; toluene; at 65℃; for 1.5h;Product distribution / selectivity;
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. To this 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridin solution was added 2-benzimidazole thiol (8.71 g (58.0 mmol)) at room temperature. A 25% aqueous sodium hydroxide solution (40.6 g) was added gradually as the temperature (internal temperature) was gradually raised to 65C. The reaction mixture was stirred for about an hour and a half at 65C (internal temperature). Water (60.0 ml) was added to the reaction mixture at 65C, after which 25% aqueous sodium hydroxide solution (0.2 g) was added and stirred. This reaction mixture was allowed to stand, and the water layer was separated. The organic layer was washed with water (20.0 ml) twice, and toluene (79.6 ml) and methanol (21.5 ml) were added to the organic layer to obtain a 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole solution. This 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole solution was cooled to 30C (external temperature), and a solution of mcpba (70.2% purity; 14.39 g (58.5 mmol)), methanol (12.4 ml) and toluene (10.5 ml) were added over the course of about 1 hour so as not to exceed an internal temperature of -25C, and then stirred for an hour and a half. 25% Aqueous sodium hydroxide solution (22.73 g) and water (17.6 ml) were added to the reaction mixture and stirred. This reaction mixture was allowed to stand, and the organic layer was separated to obtain an aqueous alkali solution containing 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1 H-benzimidazole.
With sodium hydroxide; In water; at 25 - 35℃; for 4h;
Example 2: Preparation of Rabeprazole sulfide compound of formula-12:A solution of 300 grams of 2-chloromethyl-4(3-methoxy propyloxy)-3 -methyl pyridine in 600 ml water is slowly added to a solution of 170 grams of 2-mercapto-lH- benzimidazole in 1200 ml of an aqueous solution of sodium hydroxide (113 grams) at 25-35C. Stirred the reaction mixture for 4 hours. Quenched the reaction mixture with water and extracted reaction mixture with methylene chloride. Separated the organic and aqueous phases. Washed the organic phase with water. This organic layer containing sulfide compound of formula-12 can be used directly for oxidation step with out distillation and isolation of sulfide compound.
With sodium hydroxide; In ethanol; at 20 - 55℃;
H g (0.27mol) of sodium hydroxide was added in 350 ml of ethanol at room temperature. The mixture was stirred at 55C for 30 minutes and cooled. 30 g (0.2mol) of 2-mercapto benzimidazole and 50 g (0.21 mol) of 2-chloromethyl-4-(3-methoxy propoxy) -3- methylpyridine was added in above mixture. The obtained reaction mixture was stirred at 55C for 2 hrs. After completion of the reaction, the reaction mixture was distilled to remove ethanol. 500 ml of ethyl acetate was added in residue. The ethyl acetate layer was extracted with 5 % sodium hydroxide aqueous solution. The ethyl acetate layer was dried over sodium sulfate & distilled out ethyl acetate under reduced pressure. The obtained residue was dissolved in methylene dichloride & filtered the suspended particles. Distilled out the methylene dichloride, residue dissolved in 500 ml of ethyl acetate and cooled the mixture to 0 0C .The precipitated solid was filtered, wash with ethyl acetate and dried the product under vacuum to obtain 50.4 g (67.8 %) crude title compound as a off white crystalline solid. The obtained crude compound was further purified in ethyl acetate to obtain pure 2-[4-(3-methoxy propoxy-3-methylpyridine-2-yl) methyl thio]-lH- benzimidazole
Example 2: Preparation of 2-({ r4-(3-methoxypropoxy)-3-methylpyridin-2-yllmethyl}sulfanyl)- lH-benzimidazole (Formula VII) Sodium hydroxide (24.3 g) was added to de-ionized water (500 mL) and the mixture was stirred. The mixture was cooled to 25C to 30C. Denatured spirit (100 mL) and 2- mercaptobenzimidazole (Formula VI) (63.7 g) were added to the reaction mixture and it was stirred at 25C to dissolve the solid material. The product obtained in Example 1 was dissolved in 100 mL of methylated ethanol and added to the reaction mixture at 25C to 30C for 20 minutes to 30 minutes. The reaction mixture was stirred at 25C to 30C for 30 minutes to 60 minutes. De-ionized water (500 mL) was added at 25 C to 30C for 30 minutes to 45 minutes. The mixture was stirred at 25C to 30C for 60 minutes to 70 minutes. The solid obtained was filtered and washed with de-ionized water (2 X 500 mL). The wet solid obtained was dried at 50C to 55C till the moisture content was not more than 0.5% w/w in an oven to obtain the title compound. Yield: 1.32 w/w
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-[4-(3-methoxy-propoxy)-3-methylpyridine-2-yl]-methylthio}-1H-5-difluoromethoxyl-benzimidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66.2%
With sodium hydroxide; In methanol; at 20℃; for 0.5h;
General procedure: A mixture of 10a or 10b or 10c (3.29 mmol), different mercapto intermediates (3.33 mmol), and NaOH solution (0.05 g/mL, 8 mL) in MeOH (30 mL) was stirred at room temperature for 0.5-2 h. The reaction solution was concentrated in vacuo, then diluted in 20 mL of water and extracted with ethyl acetate. The organic phase was dried over anhydrous MgSO4 and then dried under vacuum. The crude material was purified by normal phase column chromatography (100:1 DCM/MeOH) to afford compound 6, and 11b-11e.
With tetrabutylammomium bromide; potassium carbonate; In ethanol; at 70℃; for 1h;
42g 2-chloromethyl-4-(3-methoxy-propoxy)-3-methyl pyridine, 29g 5-difluoromethoxyl-2-mercapto benzimidazole, 0.3g tetrabutyl ammonium bromide, 35g potassium carbonate and 200ml anhydrous ethanol were put into a reaction flask and reacted at 70 C for one hour. After filtration and concentration, the residue was mixed with 300ml dichloromethane, water-washed, dried, filtered, concentrated till dry, and then mixed with 100ml ethyl acetate for recrystallization, thereby a solid product was obtained.
With thionyl chloride; In dichloromethane; at -10 - -5℃;
Example 1 : Preparation of 2-(chloromethyl)-4-(3-methoxypropoxy)-3-methyl pyridine (Formula V) Dichloromethane (300 mL) was added to [4-(3-methoxypropoxy)-3-methylpyridin-2- yl]methanol (Formula IV) hydrochloride (100 g) and the reaction mixture was cooled to -10C to -5C. Thionyl chloride (57.7 g) was added to the reaction mixture at -10C to -5C for 30 minutes to 60 minutes. The reaction mixture was stirred at -10C to -5C for 30 minutes to 60 minutes. The pH was adjusted to 7.0 to 7.5 with the aqueous sodium carbonate solution (prepared by dissolving 120 g of sodium carbonate in 500 mL of de-ionized water at 20C to 25C) at -10C to -5C. The temperature of the reaction mixture was raised to 0C to 5C. The mixture was allowed to settle for 10 minutes to 20 minutes and the layers obtained were separated. The organic layer was concentrated at 15C to 30C at 50 mm to 100 mm Hg of pressure. The residue obtained was dissolved in denatured spirit (100 mL). The mixture was concentrated at 15C to 30C at 20 mm to 30 mm Hg of pressure. The residue obtained was used in the next step.
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