| 94% |
With sodium hydroxide; In ethanol; acetone; at 20 - 45℃; for 3h;Large scale; |
The reactor was filled with 12.0 kg of absolute ethanol.Stir and add 1.09 kg of sodium hydroxide (27.25 mol, 2.05 eq). After stirring for 30 minutes, the internal temperature is controlled at 20 to 25C.EL2 2.40 kg (13.32 mol, 1.00 eq) and EL3 3.10 kg (13.96 mol, 1.05 eq) were successively added.Acetone 4.0kg, the reaction solution was heated to an internal temperature of 40 to 45C, and the reaction was conducted for 3 hours. TLC monitored EL2 disappeared. The reaction is complete. The internal temperature of the reaction solution is reduced to 25 to 30C.After stirring for 30 minutes, the insoluble material was removed by filtration.The filter cake was washed once with acetone 1.5 kg, and the filtrate was concentrated under reduced pressure (bath temperature 40-45C).The residue was added with 13.2 kg of ethyl acetate and cooled down to 0-5C.Stir for 3h and filter. The filter cake was washed once with ethyl acetate of 0-10 C 1.5 kg,40 ~ 45 C vacuum drying 8 ~ 10 hours. Obtained 4.14 kg of Intermediate 1 (EL1) in 94% yield.Purity was 95.5% by HPLC. |
| 90% |
With sodium carbonate; In methanol;Reflux; |
Methanol was stirred at 25-35 0C and cooled to 20-25 0C. To the cold solution, 2-chloromethyl-3,5-dimethyl-4-methoxy-pyridine hydrochloride (1 mol), 2-mercapto-5-methoxy-benzimidazole (1 mol) and sodium carbonate (2.2 mol) and heated to reflux temperature. After completion of the reaction, the by-product formed was removed by filtration. Methanol was removed by distillation from the filtrate until small amount of methanol remains. The residue was dissolved in toluene and washed with aqueous solution of sodium carbonate. The organic layer was distilled under vacuum and cooled. To the residue toluene was added and seeded with qualified compound of formula (II). The obtained solid was filtered, washed with toluene and dried to obtain title compound. Yield: 80-90 %; Purity: 99%. |
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With sodium hydroxide; In ethanol; water; for 2h;Heating / reflux;Product distribution / selectivity; |
Reference Example 1; (according to EP5129):Preparation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)thio]-1 H- benzimidazole Form I2-chloromethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride (25 g) and 2-mercapto-5- methoxy benzimidazole (20 g) were dissolved in 95% ethanol (200 ml). To this sodium hydroxide solution (8 g of sodium hydroxide dissolved in 20 ml of water) was added and refluxed for 2 hours. The sodium chloride formed was filtered off and the solution was concentrated to residue. The residue was then recrystallised from 70% of ethanol (30 ml) to yield 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)thio]-1 H-benzimidazole Form I (7 g). Example 2: <n="21"/>Preparation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)thio]-1 H- benzimidazole Form I2-chloromethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride (50 g) and 2-mercapto-5- methoxy benzimidazole (40 g) were dissolved in 95% ethanol (400 ml). To this sodium hydroxide solution (16 g of sodium hydroxide dissolved in 40 ml of water) was added and refluxed for 2 hours. The sodium chloride formed was filtered off and the solution was concentrated to residue. The residue was then recrystallised from 70% methanol (60 ml) at50-550C, chilled to -5 to O0C and maintained for 2 hours. The solid was filtered and dried at 40-450C under vacuum to yield 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridinyl)methyl)thio]-1 H-benzimidazole Form I (21.0 g). Example 3:Preparation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)thio]-1 H- benzimidazole Form I2-chloromethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride (100 g) and 2-mercapto-5- methoxy benzimidazole (80 g) were dissolved in 95% ethanol (800 ml). To this sodium hydroxide solution (32 g of sodium hydroxide dissolved in 80 ml of water) was added and refluxed for 2 hours. The sodium chloride formed was filtered off and the solution was concentrated to residue. The residue was then dissolved in methylene chloride (120 ml) and stripped off methylene chloride with ethyl acetate (40 ml). Further ethyl acetate (160 ml) was added and heated to dissolve at 50-550C1 cooled to room temperature, chilled to - 5 to O0C, maintained for 1 hour. The solid was filtered and dried at 40-450C under vacuum to yield 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)thio]-1 H-benzimidazole Form I (47.0 g). |
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With sodium hydroxide; tetrabutylammomium bromide; In dichloromethane; water; at 5 - 20℃; for 2h;pH 10.0 - 10.5; |
Example 4:Preparation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)thio]-1 H- benzimidazole Form Il <n="22"/>2-hydroxymethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride (300 g) was charged to dichloromethane (1770 ml) and cooled to 15 - 20 C. Thionyl chloride (240 g) was added slowly at 15 to 20 C and the contents were stirred at 25 to 30 C for 1 hour. After reaction 5 completion, water (300 ml) was added at 15 to 20 C and allowed to attain 25 to 3O0C. To this reaction mass 2-mercapto-5-methoxy benzimidazole (252 g) and tetrabutyl ammonium bromide (6 g) was added, and the pH of the reaction mass was adjusted to 10.0 to 10.5 at 5 to 15C using 30% sodium hydroxide solution and stirred for 2 hours at 15 to 2O0C maintaining pH 10.0 -to 10.5. After reaction completion the dichloromethane10 layer was separated and the aqueous layer was extracted with dichloromethane (370 ml x 2). The dichloromethane layer was then washed with water until the pH of the aqueous layer was 7.0 to 7.5, dried over sodium sulphate and partially concentrated at temperature below 50 C under vacuum. Ethyl acetate (240 ml) was added and stripped off to remove traces of dichloromethane, further ethyl acetate (800 ml) was added and heated to 50 to15 60 C, cooled to room temperature, chilled to 10 to -5 C and maintained for 1 hour. The product was then filtered, washed with chilled ethyl acetate (200 ml). The product was then dried at 30 to 35 C to yield 5-methoxy-2-[[(4-methoxy-3,5-dimethyl~2- pyridinyl)methyl)thio]-1 H benzimidazole form II (392 g, 80.6% yield). |
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With sodium hydroxide; In water; ethyl acetate; at 25 - 55℃; for 2.5h; |
2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride (IV) (100.0 g) and 2-mercapto-5-methoxy benzimidazole (III) (81.0 g) were taken in RBF. Ethyl Acetate (400 mL) was added to RBF at 25C to 350C. Sodium hydroxide (50.0 g) solution in water (200 mL) was added to the reaction mass within 30 mins. The reaction0 mass was stirred for 1 hr and heated to 500C to 55C for 1 hr. After completion of the reaction on TLC, reaction mass was cooled to 250C to 300C. Water (200 mL) was added and stirred to separate the organic and aqueous layers. Aqueous layer was extracted with ethyl acetate (150 mL) and separated. The combined ethyl acetate layer was charcaolised (5.0 g) and stirred for 30 mins. The reaction mass was filtered through hyflow bed and washed with ethyl acetate (50 mL). The pH of the organic layer was adjusted to about 6.0 to 6.5 with acetic acid (0.5 mL) and cooled to 5C to 100C.Sodium molybdate (1.33 g) solution in water (13.2 mL) was added to the reaction mass and stirred for 15 mins. 50% hydrogen peroxide (37.0 g) was added into the reaction mass within 1.5 hrs at 5C to 12C. The reaction mass was stirred for 5 hrs.After completion of the reaction on TLC, the reaction mass is treated with sodium thiosulphate (11.0 g) solution in water (11.0 mL). Sodium hydroxide (6.0 g) solution in water (6 mL) was added into the reaction mass to adjust the pH of about 7.0 to 7.5. The reaction mass was further cooled to 00C to 5C and stirred for 60 mins. The product was filtered and washed with mixture of methanol (50 mL) and water (50 mL) followed by washing with chilled ethyl acetate (75 mL).Crude omeprazole (120.0 g) wet-cake as obtained above and methanol (160 mL) were taken in another RBF at 25C to 35C. Sodium hydroxide (15.8 g) solution in water (176 mL) was added into the reaction mass. Charcaol (2.6 g) was added and stirred for 30 mins. The reaction mass was filtered on hyflow bed and washed with mixture of methanol (10 mL) and water (10 mL). The filtrate was treated with sodium hydrosulphite (2.0 g). The reaction mass was slowly treated with acetic acid (22.5 mL) to adjust the pH of about 7.5 to 7.9. The product was filtered and washed with water(244 mL) and dried at 400C to 45C to obtain 100.0 g crystalline omeprazole Form B. Yield 68% based on input 2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride (IV).HPLC purity: 99.87%Individual Impurities are as under:Im purity- A at RRT 0.44 : 0.01% Impurity-B at RRT 0.46 : Not detectedImpuriry-C at RRT 0.80 : 0.02%Impurity-D at RRT 0.90 : Not detectedImpurity-E at RRT 3.26 : Not detectedUnk Impurity: 0.03% Total Impurities : 0.13%Impurity-A: 5-methoxy- 1 H-benzimidazole-2-thiolImpurity-B: 2-[(R,S)]-[(3,5-dimethylpyridine-2-yl)methyl]sulphinyl]-5-methoxy-lH- benzimidazole Impurity-C: 5-methoxy-2[[4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulphanyl]- lH-benzimidazole [Omeprazole Sulfide]Impurity-D: 5-methoxy-2[[4-methoxy-3,5-dimethylpyridin-2-yl)methyl]suIphonyl]- lH-benzimidazole [Omeprazole Sulfone] Impurity-E: 4-methoxy-2-[[(R,S)-(5-methoxy- 1 H-benzimidazole-2-yl)- sulphinyl]methyl)-3,5-dimethylpyridine- 1 -oxide [Omeprazole N-Oxide] |
| 130 g |
With sodium hydroxide; In methanol; water; at 30 - 35℃; |
2-mercapto-5-methoxy benzimidazole (83.10 gm) was added at 30-35C to a solution of NaOH (42 gm) in Methanol (200 ml) and Water (100 ml) to form a 1st reaction mass. A solution of 2-Chloromethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride ( 100 gm) in methanol (50 ml) and water (150 ml) mixture was added to the 1st reaction mass in 90- 120 min at 30-35C and the reaction mass stirred for 10-15 hrs and the reaction followed by TLC and HPLC.The reaction mass was worked up by addition of Water(900 ml), stirred for 2 hours, and filtered, washed with water(2x300 ml); suck dried, filtered and dried at 42-46C for 24-30 hrs in an oven to afford stage- 1 intermediate with M./C content < 0.5% and a Dry Wt: - 130 gm |
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With sodium hydroxide; In methanol; at 86℃; for 2.5h; |
Solubility in methanol is added to 70% sodium hydroxide solution, after mixing, adding stirring 2-mercapto-5-methoxy-benzimidazole, and then continue adding 2-chloromethyl -3, 5-dimethyl-4-methoxy pyridine hydrochloride, the mixed temperature of the solution rises to 86 C, thermal insulation 2.5h, wait for the temperature to drop to 22 C time, concentrated under reduced pressure, by adding dichloromethane, extraction, water washing, the recovered methylene chloride, by adding ethyl acetate, the 18 C conditions, and stirring crystallization 4.5h, centrifugal, 47 C drying under the conditions, obtain amazingel sulfide; |
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With sodium hydroxide; In dichloromethane; water; at 55℃; for 2h; |
A solution of 11.1 g of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride And 2-mercapto-5-methoxybenzimidazole 9.8 g was added to a 500 ml three-necked flask,Add 150 ml of methylene chloride, the reaction solution is white turbid liquid,The water bath was heated to 55 C. At this temperature,Dropping the concentration of 17% aqueous sodium hydroxide solution, drop finished, the reaction solution gradually white turbid liquid into a light yellow transparent liquid, 55 C under the time reaction 2 hours, Samples were taken as 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride Content below 0.5%The reaction was stopped and the reaction solution was allowed to cool to room temperature and washed three times with 150 ml of purified water to separate the organic phase. |
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With sodium hydroxide; In dichloromethane; water; at 0 - 5℃; for 2h;Reflux; |
1) will5-methoxy-2-mercaptobenzimidazole 100g dispersed in 500mlIn dichloromethane,Cool down to 0 ~ 5 ° C,To the above system, 44 ml of an aqueous solution of 15 wtpercent sodium hydroxide was added dropwise, and after the addition was completed,Temperature control 0 ~ 5 ° C,Continue to drop by 125g2-Chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride and 125 mla solution made of water,After the addition is completed,Warming up to reflux for 2 h,Then cool down to 15 ° C,Let stand for liquid separation,200 ml of water was added to the dichloromethane phase.Stir for 15min,The liquid phase was separated to give a dichloromethane phase. |
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