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CAS No. : | 134469-07-1 |
Formula : | C7H6N2S |
M.W : | 150.20 |
SMILES Code : | SC1=NC2=CC=CC=C2N1 |
MDL No. : | MFCD00005593 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H301-H317-H373-H412 |
Precautionary Statements: | P260-P264-P270-P272-P273-P280-P301+P310+P330-P302+P352-P314-P333+P313-P405-P501 |
Class: | 6.1 |
UN#: | 2811 |
Packing Group: | Ⅲ |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 2 Preparation of 2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridinyl]methyl]-sulfinyl]-lH-benzimidazole sodium (Rabeprazole Sodium) 2-Mercapto benzimidazole (15 g) was suspended in 500 ml Purified water and Sodium hydroxide (8 g). To this was slowly added about 25 g of 2-Chloromethyl- 3-methyl-4-(methoxy propoxy)pyridine hydrochloride. The reaction mass was stirred for 2 hours at 20 - 30 C and solids were filtered to obtain 2-[[[4-(3- methoxy-propoxy)-3-methyl-2-pyridinyl]methyl]-thio]-lH-benzimidazole.The above wet material was suspended in 700 ml Purified Water, Sodium hydroxide (8 g) and Pyridine (17.0 ml). To this 215 g of sodium hypochlorite solution having a chlorine content of 3.2% was slowly added at 5- 10 C in 2 hours. The reaction mass was maintained at 5 - 8 C for 2 - 4 hours. After completion of the reaction, excess sodium hypochlorite was decomposed using EPO <DP n="10"/>5% aqueous sodium thiosulphate solution. The reaction mass was saturated with about 210 gm of sodium chloride and extracted with 300 ml of dichloromethane twice. The organic layer was dried over Sodium sulphate and concentrated under vacuum to yield a residue.To this residue, about 200 ml of Ethyl acetate was added and heated to 45 - 50 C for 30 mins for dissolution. This solution was then added slowly to about 600ml of n-Heptane under stirring, filtered under nitrogen atmosphere, washed with 30 ml of n-Heptane and dried in an oven at 45-50 C to give 28.0 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.8% | With triethylamine; In acetonitrile; at 23℃; for 24h; | Analytical grade 250 mL of acetonitrile and 15.0 g (0.1 mol) of 2-mercaptobenzimidazole were added to the three-necked flask at room temperature. 13.3 g (0.05 mol) of 2-chloromethyl-3-methyl-4-(3-methoxypropoxy)pyridine hydrochloride and 13 mL of triethylamine were added and stirred at room temperature for 24 h. The reaction solution was evaporated to dryness, and then 50 mL of dichloromethane and 50 mL of water were successively added, and the mixture was shaken, and the mixture was allowed to stand for separation to obtain an organic dichloromethane layer. After evaporating to dryness, 16.6 g of a thioether compound was obtained in a yield of 96.8%. |
89.3% | With sodium hydroxide; In ethanol; at 68℃; for 4h; | 2-Chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine hydrochloride (0.50 g, 1.88 mmol) was placed in a 125 ml eggplant-shaped flask, and 11 ml of ethanol was added to dissolve it.Further, 1H-benzimidazole-2-thiophenol (0.28 g, 1.88 mmol) and 4 ml of NaOH (80 g/L) were added, and refluxed at 68 C for 4 hr. Pour the reaction solution into a 100 ml beaker.Naturally cooled to room temperature, a white solid precipitated.Recrystallization of ethyl acetate and petroleum ether (2:1) gave white needle crystals0.58 g, yield 89.3%. |
With sodium hydroxide; In water; at 20 - 30℃; for 2h; | Example 1 :Preparation of 2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridinyl]methyl]- thio]-lH-benzimidazole (Rabeprazole Sulphide).2-Mercapto benzimidazole (15 g) was suspended in 500 ml Purified water and Sodium hydroxide (8 g). To this was slowly added about 25 g of 2-Chloromethyl -3-methyl-4-(methoxy propoxy)pyridine hydrochloride. The reaction mass was stirred for 2 hours at 20 - 30 C and solids were filtered and the wet material can be directly taken up for oxidation or optionally dried in an oven at 45-50 C to give 31 gm of the title compound. |
With sodium hydroxide; In methanol; at 50 - 60℃; for 4.5h; | The condensation reaction: In a first preparation tank into a clean reaction 32.6kg of methanol, stirred at a rotation speed of 35Hz, of 2-chloro-3-methyl-4-methoxy-propoxy pyridine hydrochloride 25.00kg, stirring It was dissolved to prepare a 2-chloro-3-methyl-4-methanol solution methoxypropoxy pyridine hydrochloride standby.In the second reaction tank clean methanol was prepared 98.8kg, at 40Hz rotational speed of sodium hydroxide was added under stirring 8.15kg, 20-25 temperature after mixing of 2-mercaptobenzimidazole 14.11kg, warmed to 50-60 , temperature 50-60 deg.] C was added the above prepared 2-chloro-3-methyl-4-methoxy-propoxy pyridine hydrochloride in methanol, adding about 30min completed.Maintaining the temperature and the reaction was continued 4h, 2-chloromethyl-phase detection methyl-4-methoxypropoxy pyridine hydrochloride residue is not greater than 0.5%, the reaction was terminated, and filtered.5.4kg washed with methanol and the combined filtrate and the washings, temperature 40-50 deg.] C, and concentrated in vacuo to a reduced pressure of -0.08 ~ -0.1Mpa methanol-free effluent, 66.3kg of methylene chloride was added, washed with 87.5kg of purified water was added and stirred to dissolve a the organic phase left, the aqueous phase was added 8.3kg of dichloromethane, washed once, treated with waste water, the combined organic phases washed with 62.4kg of purified water was added, the waste water phase, the organic phase in the temperature 25 ~ 30 , the degree of vacuum -0.08 ~ -0.1Mpa distillation under reduced pressure to stop the precipitated solid was distilled, petroleum ether was added dropwise with stirring 33.0kg crystallization, crystal growing temperature 0-5 deg.] C for 3 hours by centrifugation, washed, and dried, to obtain rabeprazole sulfide.Table 1 gives the amount of raw materials and a condensation reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | 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 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | 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%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In toluene; for 4h;Reflux; | At room temperature 4-(3-methoxypropoxy)-2,3-dimethylpyridine N-oxide (12g, 56.8mmol) was dissolved in ethyl acetate (142ml), followed by addition of trifluoroacetic anhydride (29.8g, 142mmol).The reaction was refluxed for three hours.The reaction was terminated by TLC, and the reaction mixture was concentrated to give a trifluoroacetate intermediate.The reaction intermediate was dissolved in toluene (71 ml), then 2-benzimidazolethiol (8.53 g, 56.8 mmol) was added, and the reaction was heated under reflux for four hours.The reaction was terminated by TLC, and the reaction solution was adjusted to pH 7-8 with a saturated aqueous sodium carbonate solution, and then separated.Adding the aqueous extracted three times with ethyl acetate, the organic phase with saturated brine, dried over anhydrous sodium sulfate, and concentratedUsing PE to PE/EA (10:1 to 1:3) as a mobile phase, silica gel column chromatography gave the target product rabeprazole thioether (17.17 g, 88% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.3% | With sodium hydroxide; In ethanol; at 68℃; for 4h; | 2-Chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine hydrochloride (0.50 g, 1.88 mmol)Placed in a 125ml eggplant-shaped bottle,Add 11ml of ethanol to dissolve it.Join again1H-benzimidazole-2-thiophenol(0.28g, 1.88mmol)And 4ml NaOH (80g/L),Reflux for 4h at 68 ,TLC monitored the reaction completely.Pour the reaction solution into a 100 ml beaker.Cool naturally to room temperature,Precipitating a white solid,Ethyl acetate and petroleum ether (2:1)Recrystallization gave 0.58 g of white needle crystals with a yield of 89.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetone; at 20℃; for 4.0h; | General procedure: [Method 1] A mixture of 2-chloro-N-substituted acetamide(1a-l) (0.01 mol), 2-mercapto benzimidazole (2) (0.01mol) and K2CO3 (0.02 mol) was stirred in acetone (20 ml)for 4 hours at room temperature. The resultant product waspoured into ice-water and stirred vigorously for 1 hour. Theseparated precipitate was collected, dried and recrystallizedfrom ethanol to obtain 3a-l. |