Preparation method of dexlansoprazole
By reacting an alcohol solvent, 2-mercaptobenzimidazole, 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyrimidine hydrochloride with an inorganic base, combined with microwave heating and ultrasonic treatment, the problem of high impurity content in the preparation of dexlansoprazole was solved, and the preparation of high-purity and high-yield products was achieved.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- GUILIN HUAXIN PHARMACY CO LTD
- Filing Date
- 2026-01-15
- Publication Date
- 2026-04-28
AI Technical Summary
The existing preparation process of dexlansoprazole has a high impurity content, especially sulfone and sulfur impurities, which are difficult to control effectively.
The impurity content was reduced by reacting an alcohol solvent, 2-mercaptobenzimidazole, 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyrimidine hydrochloride with an inorganic base, followed by the addition of L-(+)-diethyl tartrate and a titanium catalyst, and purification by microwave heating and ultrasonic treatment combined with a recrystallization solvent.
It significantly reduces the content of sulfone and sulfur impurities, improves product purity and yield, and has a simple process with a high yield.
Smart Images
Figure CN121930211A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of dexlansoprazole preparation technology, specifically relating to a method for preparing dexlansoprazole. Background Technology
[0002] Dexlansoprazole (CAS No.: 138530-94-6) is the enantiomer of the proton pump inhibitor lansoprazole. Proton pump inhibitors are benzimidazole derivatives used to treat peptic ulcers. Currently, lansoprazole is mostly used in capsule form, with Takeda Pharmaceutical's dexlansoprazole sustained-release capsules being a well-established example, used to treat heartburn symptoms such as corrosive esophagitis and erosive esophagitis. However, impurities are difficult to control during the preparation of proton pump inhibitors (PPIs), therefore, researching a preparation method for dexlansoprazole that can effectively reduce impurity content is of great significance. Currently, dexlansoprazole is often synthesized using the Sharpless asymmetric oxidation method, but asymmetric oxidation processes are often accompanied by many defects, and many impurities cannot be effectively controlled, resulting in a high impurity content in the produced dexlansoprazole. Summary of the Invention
[0003] Therefore, the technical problem to be solved by the present invention is to overcome the defects of existing dexlansoprazole with high impurity content, especially high sulfone and sulfur impurities, and to provide a method for preparing dexlansoprazole.
[0004] To solve the above problems, the present invention provides the following solution: A method for preparing dexlansoprazole includes the following steps: 1) The alcohol solvent, 2-mercaptobenzimidazole, and 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyrimidine hydrochloride were stirred until clear. An inorganic base was added to carry out the reaction. After the reaction was completed, the temperature was lowered, the mixture was filtered, the filtrate was concentrated, water was added to precipitate a white solid, the solid was filtered and dried to obtain intermediate 1. Intermediate 1 2) Mix intermediate 1 with solvent, add L-(+)-diethyl tartrate and water, perform the first heating, then add titanium catalyst, perform the second heating, cool down, add organic base and oxidant, stir the reaction, after the reaction is completed, quench the reaction, and post-process to obtain crude dexlansoprazole. 3) Mix crude lansoprazole, organic solvent, and organic base, microwave until dissolved, let stand, sonicate, add recrystallization solvent to crystallize, filter, and dry to obtain lansoprazole product.
[0005] In one optional embodiment, the reaction temperature in step 1) is 55-65°C and the reaction time is 1-4 hours; The alcohol solvent is selected from at least one of methanol and ethanol; The inorganic base mentioned in step 1) is selected from sodium hydroxide or potassium hydroxide.
[0006] In an optional embodiment, the mass ratio of 2-mercaptobenzimidazole, alcohol solvent, and 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyrimidine hydrochloride in step 1) is 1:(10-15):(1.6-2.0). The mass ratio of 2-mercaptobenzimidazole to inorganic base is 1:0.9-1.1; In step 1), the amount of water added is 1.2-1.5 times that of the alcohol solvent.
[0007] In an optional embodiment, the post-processing step in step 2) includes: after the quenching reaction is completed, the mixture is allowed to stand and separate into layers, the organic phase is extracted 2-4 times with a mixed solution of ammonia and methanol, the resulting aqueous phases are combined, ethyl acetate is added to the combined aqueous phase, the pH of the mixed solution is adjusted to 7.5-8, the organic phase obtained after standing and separating into layers is dried, activated carbon is added and stirred, filtered, the filtrate is concentrated, crystallized with n-heptane, dried, and crude dexlansoprazole is obtained.
[0008] In one optional embodiment, the volume ratio of ammonia to methanol in the post-treatment step (2) is 1:10-14, and the ammonia concentration is 20-30 wt%.
[0009] In one optional embodiment, in step 2), the first heating temperature is 55-65℃, the holding time is 20-50min, the second heating temperature is 55-65℃, the holding time is 20-60min, and the cooling temperature is 5-20℃. In step 2), the stirring reaction temperature is 0-5℃ and the stirring reaction time is 1-5h.
[0010] In one optional embodiment, the reaction is quenched using a sodium thiosulfate solution with a mass fraction of 20-30%. In step 2), the mass ratio of intermediate 1, solvent, diethyl L-(+)-tartrate and water is 1:(10-14):(1.1-1.4):(12-16). The mass ratio of intermediate 1, titanium catalyst, organic base and oxidant is 1:(0.7-0.9):(0.2-0.5):(1.4-1.9).
[0011] In an optional embodiment, the solvent in step 2) is selected from at least one of toluene and ethylbenzene, the titanium catalyst is selected from tetraisopropyl titanate, the organic base is selected from one of triethylamine and diethylamine, and the oxidant is selected from cumene hydroperoxide.
[0012] In one optional embodiment, the mass ratio of crude dexlansoprazole to triethylamine in step 3) is 100:1-1.5; In step 3), the ratio of crude lansoprazole to ethyl acetate is 1:3.8-4.5, in g:ml.
[0013] In one optional embodiment, the recrystallization solvent is n-heptane, and the amount added is 4-6 times the mass of crude lansoprazole; In step 3), the microwave heating power is 200-300W, the time is 1-10 minutes, the resting time is 20-40 minutes, the ultrasonic treatment power is 80-100W, the time is 20-60 minutes, and the temperature is 10-20℃. The organic solvent mentioned in step 3) is selected from ethyl acetate, and the organic base is selected from triethylamine and diethylamine.
[0014] The technical solution of this invention has the following advantages: The present invention provides a method for preparing dexlansoprazole. First, an alcohol solvent, 2-mercaptobenzimidazole, and 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyrimidine hydrochloride are stirred until clear. An inorganic base is added to react. After the reaction is complete, the mixture is cooled, filtered, and the filtrate is concentrated. Water is added to precipitate a white solid, which is then filtered and dried to obtain intermediate 1. Next, intermediate 1 is mixed with a solvent, and L-(+)-diethyl tartrate and water are added. The mixture is heated for the first time, then a titanium catalyst is added for the second heating. The mixture is cooled, and an organic base and an oxidant are added. The mixture is stirred to react. After the reaction is complete, the reaction is quenched, and the mixture is post-treated to obtain crude dexlansoprazole. Then, the crude dexlansoprazole, an organic solvent, and an organic base are mixed, microwave-heated until dissolved, allowed to stand, sonicated, and a recrystallization solvent is added to precipitate crystals. The crystals are then filtered and dried to obtain the dexlansoprazole product. This invention obtains intermediate compound 1 and crude dexlansoprazole through the above method. Then, the crude dexlansoprazole is subjected to a unique microwave heating-static-ultrasound combination treatment in the presence of organic solvent and organic base, combining the advantages of ultrasonic dispersion and microwave rapid heating. This treatment can greatly reduce the encapsulation rate of impurities, and the precipitated product has uniform particle size and significantly reduced content of sulfone and sulfur impurities.
[0015] The method of this invention is not only simple in process, but also has a high yield, high product purity and few impurities. Attached Figure Description
[0016] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the accompanying drawings used in the description of the specific embodiments or the prior art will be briefly introduced below.
[0017] Figure 1 This is the 1H NMR spectrum of dexlansoprazole prepared in Example 1 of this invention. Detailed Implementation
[0018] The following embodiments are provided to further understand the present invention and are not limited to the preferred embodiments described herein, nor do they limit the scope of protection of the present invention.
[0019] Experimental steps or conditions not specified in the following embodiments of this invention can be implemented according to conventional experimental steps and conditions used in existing literature in this field. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagents or instruments.
[0020] The following HPLC test conditions for the examples and comparative products were as follows: octadecylsilane-bonded silica gel was used as the packing material, and water-triethylamine-acetonitrile (75:1:40) was used as the mobile phase (pH adjusted to 6.5 with phosphoric acid); the detection wavelength was 285 nm, the column temperature was 30 °C, and the flow rate was 1.0 ml / min.
[0021] Example 1
[0022] This embodiment provides a method for preparing dexlansoprazole, including the following steps:
[0023] 1) Add 8000g methanol, 630g 2-mercaptobenzimidazole, and 1190g 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyrimidine hydrochloride to a reaction vessel, stir until clear, add 635g sodium hydroxide, and react at 60℃ for 2.5h. After the reaction is complete, cool down, filter, concentrate the filtrate to half its volume, add 10000g water to precipitate a white solid, filter, and dry the filter cake under vacuum at 50℃ for 8h to obtain intermediate 1 with a yield of 92%. 2) In a reaction vessel, add 540g of intermediate 1 and 6500g of toluene. Under stirring, add 692g of L-(+)-diethyl tartrate and 8000g of water. Heat to 60℃ and maintain for 30 minutes. Then add 480g of tetraisopropyl titanate and maintain at 60℃ for 45 minutes. After the maintenance, cool to 10℃, then add 180g of triethylamine. Cool to 0℃ and add 850g of cumene hydroperoxide dropwise. Stir and react for 3 hours. Add 1000ml of 30% sodium thiosulfate solution to quench the reaction. Allow to stand and separate into layers. The organic phase was extracted three times with a mixed solution of ammonia and methanol (volume ratio of ammonia to methanol: 1:10, ammonia concentration: 28 wt%). The resulting aqueous phases were combined, and ethyl acetate (volume ratio of aqueous phase to ethyl acetate: 3:2) was added to the combined aqueous phase. The pH of the mixed solution was then adjusted to 8. After standing and separating the layers, the resulting organic phase was dried with anhydrous magnesium sulfate, and 5.4 g of activated carbon was added and stirred for 20 minutes. The mixture was filtered, and the filtrate was concentrated to one-fifth of its volume. Crystallization was performed using n-heptane, followed by drying to obtain crude dexlansoprazole with a yield of 81%. 3) Mix 100g of crude lansoprazole, 400ml of ethyl acetate, and 1.1g of triethylamine. Microwave the mixture until dissolved (200W for 2 minutes). Let it stand for 20 minutes, then sonicate at 15℃ (80W) for 20 minutes. Add 500g of n-heptane to crystallize. Filter and dry to obtain the lansoprazole product with a yield of 75%, purity of 99.8%, optical purity of approximately 100%, sulfone impurities of 0.06%, and sulfur impurities of 0.03%.
[0024] Example 2
[0025] This embodiment provides a method for preparing dexlansoprazole, including the following steps:
[0026] 1) Add 8500g methanol, 630g 2-mercaptobenzimidazole, and 1200g 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyrimidine hydrochloride to a reaction vessel, stir until clear, add 620g sodium hydroxide, and react at 60℃ for 3h. After the reaction is complete, cool down, filter, concentrate the filtrate to half its volume, add 10000g water to precipitate a white solid, filter, and dry the filter cake under vacuum at 50℃ for 8h to obtain intermediate 1 with a yield of 91%. 2) In a reaction vessel, add 540g of intermediate 1 and 6000g of toluene. Under stirring, add 685g of L-(+)-diethyl tartrate and 8000g of water. Heat to 65℃ and hold for 40 minutes. Then add 460g of tetraisopropyl titanate and hold at 60℃ for 45 minutes. After holding at 60℃, cool to 10℃, then add 190g of triethylamine. Cool to 0℃ and add 850g of cumene hydroperoxide dropwise. Stir and react for 3 hours. Add 1000ml of 30% sodium thiosulfate solution to quench the reaction. Allow to stand and separate into layers. Organic The aqueous phase was extracted three times with a mixed solution of ammonia and methanol (volume ratio of ammonia to methanol: 1:10, ammonia concentration: 28 wt%). The resulting aqueous phases were combined, and ethyl acetate (volume ratio of aqueous phase to ethyl acetate: 3:2) was added to the combined aqueous phase. The pH of the mixed solution was then adjusted to 7.5. After standing and separating the layers, the resulting organic phase was dried with anhydrous magnesium sulfate, and 5.4 g of activated carbon was added and stirred for 20 minutes. The mixture was filtered, and the filtrate was concentrated to one-fifth of its volume. Crystallization was performed using n-heptane, followed by drying to obtain crude dexlansoprazole with a yield of 83%. 3) Mix 100g of crude lansoprazole, 420ml of ethyl acetate, and 1g of triethylamine. Microwave the mixture until dissolved (200W for 3 minutes). Let it stand for 15 minutes, then sonicate at 15℃ (80W) for 30 minutes. Add 500g of n-heptane to crystallize. Filter and dry to obtain the lansoprazole product with a yield of 74%, purity of 99.9%, optical purity of approximately 100%, sulfone impurities of 0.04%, and sulfur impurities of 0.02%.
[0027] Example 3
[0028] This embodiment provides a method for preparing dexlansoprazole, including the following steps:
[0029] 1) Add 8500g methanol, 620g 2-mercaptobenzimidazole, and 1210g 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyrimidine hydrochloride to a reaction vessel, stir until clear, add 600g sodium hydroxide, and react at 60℃ for 2h. After the reaction is complete, cool down, filter, concentrate the filtrate to half its volume, add 10000g water to precipitate a white solid, filter, and dry the filter cake under vacuum at 50℃ for 8h to obtain intermediate 1 with a yield of 88%. 2) In a reaction vessel, add 540g of intermediate 1 and 6000g of toluene. Under stirring, add 675g of L-(+)-diethyl tartrate and 8000g of water. Heat to 65℃ and hold for 20 minutes. Then add 450g of tetraisopropyl titanate and hold at 60℃ for 30 minutes. After holding at 60℃, cool to 10℃, then add 180g of triethylamine. Cool to 0℃ and add 850g of cumene hydroperoxide dropwise. Stir and react for 4 hours. Add 1000ml of 30% sodium thiosulfate solution to quench the reaction. Allow to stand and separate into layers. Organic The aqueous phase was extracted three times with a mixed solution of ammonia and methanol (volume ratio of ammonia to methanol 1:10, ammonia concentration 28wt%). The resulting aqueous phases were combined, and ethyl acetate (volume ratio of aqueous phase to ethyl acetate 3:2) was added to the combined aqueous phase. The pH of the mixed solution was then adjusted to 7.5. After standing and separating the layers, the resulting organic phase was dried with anhydrous magnesium sulfate, and 5.4 g of activated carbon was added and stirred for 20 minutes. The mixture was filtered, and the filtrate was concentrated to one-fifth of its volume. Crystallization was performed using n-heptane, followed by drying to obtain crude dexlansoprazole with a yield of 80%. 3) Mix 100g of crude lansoprazole, 420ml of ethyl acetate, and 1.2g of triethylamine. Microwave the mixture until dissolved (200W for 1 minute). Let it stand for 15 minutes, then sonicate at 15℃ (80W) for 25 minutes. Add 550g of n-heptane to crystallize. Filter and dry to obtain the lansoprazole product with a yield of 71%, purity of 99.9%, optical purity of approximately 100%, sulfone impurities of 0.05%, and sulfur impurities of 0.03%.
[0030] Comparative Example 1 This comparative example provides a method for preparing dexlansoprazole, which differs from Example 1 in that, in step 3), 100g of crude dexlansoprazole, 400ml of ethyl acetate, and 1.1g of triethylamine are mixed, stirred and dissolved at room temperature for 42min, 500g of n-heptane is added to crystallize, filtered, and dried to obtain the dexlansoprazole product with a yield of 71%, purity of 99.6%, optical purity of approximately 100%, sulfone impurities of 0.19%, and sulfur impurities of 0.12%.
[0031] Comparative Example 2 This comparative example provides a method for preparing dexlansoprazole, which differs from Example 1 in that, in step 3), 100g of crude dexlansoprazole, 400ml of ethyl acetate, and 1.1g of triethylamine are mixed and microwaved until dissolved (power 200W, time 2 minutes). Then, it is immediately sonicated at 15℃ (power 80W) for 20 minutes, 500g of n-heptane is added to crystallize, filtered, and dried to obtain the dexlansoprazole product with a yield of 74%, purity of 99.7%, optical purity of approximately 100%, sulfone impurities of 0.11%, and sulfur impurities of 0.09%.
[0032] Obviously, those skilled in the art can make other modifications based on the above embodiments, and the obvious modifications therefrom are still within the protection scope of this invention.
Claims
1. A method for preparing dexlansoprazole, characterized in that, Includes the following steps: 1) The alcohol solvent, 2-mercaptobenzimidazole, and 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyrimidine hydrochloride were stirred until clear. An inorganic base was added to carry out the reaction. After the reaction was completed, the temperature was lowered, the mixture was filtered, the filtrate was concentrated, water was added to precipitate a white solid, the solid was filtered and dried to obtain intermediate 1. Intermediate 1 2) Mix intermediate 1 with solvent, add L-(+)-diethyl tartrate and water, perform the first heating, then add titanium catalyst, perform the second heating, cool down, add organic base and oxidant, stir the reaction, after the reaction is completed, quench the reaction, and post-process to obtain crude dexlansoprazole. 3) Mix crude dexlansoprazole with an organic solvent and an organic base, microwave heat until dissolved, let stand, sonicate, add recrystallization solvent to crystallize, filter, and dry to obtain dexlansoprazole.
2. The preparation method according to claim 1, characterized in that, In step 1), the reaction temperature is 55-65℃ and the reaction time is 1-4 hours. The alcohol solvent is selected from at least one of methanol and ethanol; The inorganic base mentioned in step 1) is selected from sodium hydroxide or potassium hydroxide.
3. The preparation method according to claim 1 or 2, characterized in that, In step 1), the mass ratio of 2-mercaptobenzimidazole, alcohol solvent, and 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyrimidine hydrochloride is 1:(10-15):(1.6-2.0). The mass ratio of 2-mercaptobenzimidazole to inorganic base is 1:0.9-1.1; In step 1), the amount of water added is 1.2-1.5 times that of the alcohol solvent.
4. The preparation method according to claim 1, characterized in that, The post-processing steps described in step 2) include: after the quenching reaction is completed, the mixture is allowed to stand and separate into layers. The organic phase is extracted 2-4 times with a mixed solution of ammonia and methanol. The resulting aqueous phases are combined. Ethyl acetate is added to the combined aqueous phases. The pH of the mixed solution is then adjusted to 7.5-8. The organic phase obtained after standing and separating into layers is dried. Activated carbon is added and stirred. The mixture is filtered, the filtrate is concentrated, crystallized with n-heptane, and dried to obtain crude dexlansoprazole.
5. The preparation method according to claim 4, characterized in that, In step 2), the volume ratio of ammonia to methanol in the post-treatment step is 1:10-14, and the concentration of ammonia is 20-30 wt%.
6. The preparation method according to claim 1, characterized in that, In step 2), the first heating temperature is 55-65℃, the holding time is 20-50min, the second heating temperature is 55-65℃, the holding time is 20-60min, and the cooling temperature is 5-20℃. In step 2), the stirring reaction temperature is 0-5℃ and the stirring reaction time is 1-5h.
7. The preparation method according to claim 1 or 2, characterized in that, The reaction was quenched using a 20-30% sodium thiosulfate solution. In step 2), the mass ratio of intermediate 1, solvent, diethyl L-(+)-tartrate and water is 1:(10-14):(1.1-1.4):(12-16). The mass ratio of intermediate 1, titanium catalyst, organic base and oxidant is 1:(0.7-0.9):(0.2-0.5):(1.4-1.9).
8. The preparation method according to claim 1 or 2, characterized in that, The solvent in step 2) is selected from at least one of toluene and ethylbenzene, the titanium catalyst is selected from tetraisopropyl titanate, the organic base is selected from one of triethylamine and diethylamine, and the oxidant is selected from cumene hydroperoxide.
9. The preparation method according to claim 1 or 2, characterized in that, In step 3), the mass ratio of crude lansoprazole to triethylamine is 100:1-1.
5. In step 3), the ratio of crude lansoprazole to ethyl acetate is 1:3.8-4.5, in g:ml.
10. The preparation method according to claim 1 or 2, characterized in that, The recrystallization solvent is n-heptane, and the amount added is 4-6 times the crude mass of dexlansoprazole. In step 3), the microwave heating power is 200-300W, the time is 1-10 minutes, the resting time is 20-40 minutes, the ultrasonic treatment power is 80-100W, the time is 20-60 minutes, and the temperature is 10-20℃. The organic solvent mentioned in step 3) is selected from ethyl acetate, and the organic base is selected from triethylamine and diethylamine.