A kind of high-purity dabigatran etexilate and its preparation method and application

Abstract

A high-purity dabigatran etexilate and its preparation method and its application. The present invention provides a high-purity dabigatran etexilate or its pharmaceutically acceptable salt, the purity of the dabigatran etexilate is not less than 99.0%, and the content of impurity B is no more than 0.1%. The preparation method of the present invention comprises the following steps: (1) 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazole-5-yl]carbonyl]pyridine-2-ylamino]ethyl propionate (compound 1) is subjected to pinner reaction and then salified with p-toluenesulfonic acid to obtain 3-[[[2-[[(4-amidinophenyl)amino]methyl]-1-methyl-1H-benzimidazole-5-yl]carbonyl]pyridine-2-ylamino]ethyl propionate p-toluenesulfonate (compound 2); (2) compound 2 is reacted with hexyl chloroformate to obtain dabigatran etexilate. The preparation method of the present invention controls the generation of impurity A, thereby significantly reducing the generation of impurity B and achieving the control of impurity C in dabigatran etexilate mesylate, thereby significantly improving the quality of the drug and ensuring the safety of drug use.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemicals, and specifically relates to high-purity dabigatran etexilate, a preparation method thereof and an application thereof. Background Art

[0002] Dabigatran etexilate is a non-peptide thrombin inhibitor. After oral administration through gastrointestinal absorption, it is converted into dabigatran with direct anticoagulant activity in the body. Dabigatran binds to the fibrin-specific binding site of thrombin, preventing fibrinogen from being cleaved into fibrin, thereby blocking the final step of the coagulation waterfall network and thrombosis. In addition, dabigatran can dissociate from the fibrin-thrombin complex and exert a reversible anticoagulant effect.

[0003] WO2014 / 192030 discloses a method for preparing dabigatran etexilate, comprising the following steps:

[0004]

[0005] But impurity A content is higher in the Formula 5 compound that the method makes, impurity A will derive and produce impurity B close to dabigatran etexilate structure in the preparation of follow-up dabigatran etexilate, and impurity B cannot realize effective purification by methods such as conventional recrystallization, even in the last preparation dabigatran etexilate mesylate step still cannot purify and remove and derive into impurity C (thereby easily causing the problem of deriving impurity C content exceeding the standard), and then affect the purity and the quality of dabigatran etexilate mesylate, impurity C content far exceeds the limit (≤0.1%) of " Chemical Drug Impurity Research Technical Guiding Principles " regulation, cannot reach the standard for registration and listing, cause immeasurable loss to enterprise. For this reason, a kind of highly purified dabigatran etexilate preparation method is urgently needed to be developed.

[0006] Summary of the invention

[0007] The object of the present invention is to provide a high-purity dabigatran etexilate or a pharmaceutically acceptable salt thereof, wherein the purity of the dabigatran etexilate is not less than 99.0%, and the content of impurity B is not more than 0.1%.

[0008]

[0009] In a preferred technical solution of the present invention, the purity of dabigatran etexilate or a pharmaceutically acceptable salt thereof is not less than 99.2%, preferably not less than 99.4%.

[0010] In a preferred technical solution of the present invention, the content of impurity B in the dabigatran etexilate or a pharmaceutically acceptable salt thereof does not exceed 0.05%, preferably does not exceed 0.03%.

[0011] In the preferred technical solution of the present invention, the content of impurity C in the pharmaceutically acceptable salt of dabigatran etexilate does not exceed 0.1%, preferably does not exceed 0.05%, and more preferably does not exceed 0.03%.

[0012] In the preferred technical scheme of the present invention, the pharmaceutically acceptable salt of dabigatran etexilate is selected from any one or a combination of its p-toluenesulfonate, methanesulfonate, sulfonate, hydrochloride, hydrobromide, sulfate, phosphate, nitrate, tartrate, fumarate, maleate, citrate, acetate, formate, benzoate, cinnamate, succinate, and malonate.

[0013] Another object of the present invention is to provide a high-purity intermediate of the structure shown in Formula I or a pharmaceutically acceptable salt thereof, wherein the purity of the intermediate of the structure shown in Formula I or a pharmaceutically acceptable salt thereof is not less than 97%, and the content of impurity A therein is not more than 1.0%.

[0014]

[0015] In a preferred technical solution of the present invention, the content of impurity A in the intermediate of the structure represented by formula I or a pharmaceutically acceptable salt thereof does not exceed 0.8%, preferably does not exceed 0.6%, and more preferably does not exceed 0.5%.

[0016] In the preferred technical scheme of the present invention, the pharmaceutically acceptable salt of the intermediate of the structure shown in Formula I is selected from any one of its p-toluenesulfonate, methanesulfonate, sulfonate, hydrochloride, hydrobromide, sulfate, phosphate, nitrate, tartrate, fumarate, maleate, citrate, acetate, formate, benzoate, cinnamate, succinate and malonate.

[0017] Another object of the present invention is to provide a method for preparing dabigatran etexilate, comprising the following steps: (1) subjecting compound 1 to a pinner reaction and then reacting the compound with p-toluenesulfonic acid to form a salt to obtain compound 2; and (2) reacting compound 2 with hexyl chloroformate to obtain dabigatran etexilate.

[0018]

[0019] In the preferred technical scheme of the present invention, the step (1) comprises the following steps: reacting compound 1 with HCl / ethanol, p-toluenesulfonic acid or its monohydrate and aqueous ammonia; cooling the obtained reaction mixture to precipitate a solid, filtering, treating the filter cake to obtain a crude compound 2, and purifying to obtain a purified compound 2.

[0020] In the preferred technical scheme of the present invention, the filter cake treatment in step (1) comprises the following steps: placing the filter cake in water at room temperature and stirring, separating, and collecting solids; then placing the solids in ethanol at room temperature and stirring, precipitating solids at room temperature or at reduced temperature, and drying to obtain the product.

[0021] In the preferred technical scheme of the present invention, in the purification of step (1), the obtained crude compound 2 is added to a purification solvent, stirred, separated, and the solid is collected, rinsed, and dried to obtain the product.

[0022] In a preferred technical solution of the present invention, the purification solvent is selected from any one of DMF, H2O, acetone, tetrahydrofuran, DMSO, ethanol or a combination thereof.

[0023] In the preferred technical solution of the present invention, in the DMF / H2O combination, the volume ratio of DMF:H2O is 1:1-1:10, preferably 1:2-1:8, more preferably 1:3-1:6, and even more preferably 1:3.5-1:4.5.

[0024] In a preferred technical solution of the present invention, in the acetone / DMSO combination, the volume ratio of acetone:DMSO is 2-3:1, preferably 1.5:1.

[0025] In a preferred technical solution of the present invention, in the purification step (1), the mass volume ratio of the crude compound 2 to the purification solvent is 1:3-20, preferably 1:5-15.

[0026] In a preferred technical solution of the present invention, in the purification of step (1), the separation is selected from any one of filtration, centrifugation, and membrane treatment, or a combination thereof.

[0027] In a preferred technical solution of the present invention, in the purification step (1), the elution solvent is selected from any one of DMF, ethanol, acetone, tetrahydrofuran, water or a combination thereof.

[0028] In the preferred technical scheme of the present invention, in the purification of step (1), the mass volume ratio of the crude compound 2 to the elution solvent is 1:1-10, preferably 1:2-5.

[0029] In the preferred technical scheme of the present invention, in the purification of step (1), the drying is selected from any one of vacuum drying, reduced pressure drying, normal pressure drying, spray drying, boiling drying or a combination thereof.

[0030] In the preferred technical solution of the present invention, in the purification step (1), the drying temperature is 25-80°C, preferably 35-65°C, and more preferably 40-50°C.

[0031] In a preferred technical solution of the present invention, the content of impurity A in the compound 2 prepared in step (1) does not exceed 0.8%, preferably does not exceed 0.6%, and more preferably does not exceed 0.5%.

[0032] In the preferred technical solution of the present invention, the purity of dabigatran etexilate prepared in step (2) is not less than 99.0%, preferably not less than 99.2%, more preferably not less than 99.4%.

[0033] In the preferred technical solution of the present invention, the content of impurity B in the dabigatran etexilate prepared in step (2) is no more than 0.1%, preferably no more than 0.05%, and more preferably no more than 0.03%.

[0034] Another object of the present invention is to provide the use of the high-purity dabigatran etexilate of the present invention in preparing a medicament for preventing and / or treating thrombotic diseases.

[0035] In a preferred technical solution of the present invention, the thrombotic disease is selected from arterial thrombotic disease or venous thrombotic disease.

[0036] In a preferred technical solution of the present invention, the thrombotic disease is selected from any one of deep vein thrombosis of the lower extremities, reocclusion after bypass surgery or angioplasty (PT(C)A), peripheral arterial disease occlusion, pulmonary embolism, disseminated intravascular coagulation, coronary thrombosis, stroke, and shunt or stent occlusion or its complications.

[0037] Another object of the present invention is to provide a pharmaceutical composition, which contains the high-purity dabigatran etexilate of the present invention and one or a combination of a P-gp inhibitor, a P-gp inducer, a P-gp substrate drug, a non-steroidal anti-inflammatory drug, a proton pump inhibitor, an H2 receptor inhibitor, and an anticoagulant drug.

[0038] In the preferred technical scheme of the present invention, the P-gp inhibitor is selected from one of ketoconazole, itraconazole, dronedarone, amiodarone, quinidine, verapamil, clarithromycin, felodipine, nicardipine, nifedipine, nitrendipine, tacrolimus, mifepristone, terfenadine, and cyclosporine, or a combination thereof.

[0039] In the preferred technical solution of the present invention, the P-gp inducer is selected from one of rifampicin, carbamazepine, phenytoin, flucloxacillin, indinavir, nelfinavir, ritonavir, saquinavir, verapamil, atorvastatin, carbamazepine, caffeine, vincristine, and paclitaxel, or a combination thereof.

[0040] In a preferred technical solution of the present invention, the P-gp substrate drug is selected from one of digoxin, bunitolol, talinolol, celiprolol, doxorubicin, daunorubicin, and lovastatin, or a combination thereof.

[0041] In the preferred technical scheme of the present invention, the non-steroidal anti-inflammatory drug is selected from one or a combination of aspirin, acetaminophen, indomethacin, naproxen, naproxen, diclofenac, ibuprofen, nimesulide, rofecoxib, and celecoxib.

[0042] In a preferred technical solution of the present invention, the proton pump inhibitor is selected from one of omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole, or a combination thereof.

[0043] In a preferred technical solution of the present invention, the H2 receptor inhibitor is selected from one of ranitidine, cimetidine, famotidine, nizatidine, roxatidine, ethylbromide, mifetidine or a combination thereof.

[0044] In the preferred technical solution of the present invention, the anticoagulant drug is selected from one or a combination of ordinary heparin, low molecular weight heparin (enoxaparin, dalteparin), heparin derivatives (fondaparinux sodium), warfarin, rivaroxaban, and apixaban.

[0045] Unless otherwise specified, when the present invention relates to the percentage between liquids, the percentage is volume / volume percentage; when the present invention relates to the percentage between liquids and solids, the percentage is volume / weight percentage; when the present invention relates to the percentage between solids and liquids, the percentage is weight / volume percentage; the rest are weight / weight percentages.

[0046] Compared with the prior art, the present invention has the following beneficial technical effects:

[0047] 1. The preparation method of the present invention significantly reduces the generation of impurity B by controlling the generation of impurity A and realizes the control of impurity C in dabigatran etexilate mesylate, effectively solves the technical problem that the impurity B structure is extremely similar to dabigatran etexilate and is difficult to effectively remove and affects the quality of the drug, and significantly improves the quality of the drug and ensures the safety of drug use.

[0048] 2. The purification method of the present invention is simple to operate, significantly shortens the production cycle and significantly reduces its cost, and has the advantages of being green and environmentally friendly, low energy consumption, and conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 The purity spectrum of embodiment 8 dabigatran etcxilate;

[0050] Figure 2 Example 8 Purity spectrum of dabigatran etexilate mesylate. DETAILED DESCRIPTION

[0051] The following are some specific embodiments to illustrate the present invention. It is necessary to point out that the following specific embodiments are only used to further illustrate the present invention and do not limit the protection scope of the present invention. Some non-essential modifications and adjustments made by others based on the present invention still fall within the protection scope of the present invention.

[0052] Example 1 Preparation of dabigatran etexilate

[0053] (1) Synthesis of Compound 2

[0054] The temperature in the reaction bottle was controlled to be lower than 25°C, and p-toluenesulfonic acid monohydrate (266 g) and ethyl 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]pyridin-2-ylamino]propanoate (Compound 1) (348 g) were added to a reaction bottle containing a hydrochloric acid ethanol solution (including 640 g of ethanol and a total weight of 1040 g). The mixture was kept at 25-30°C and stirred. After reacting for 20 hours, a transition state (imidate hydrochloride) was generated, which was slowly added to a reaction bottle containing a mixed solution of concentrated aqueous ammonia (1800 g) and ethanol (640 g). The addition time was controlled to be 1-1.5 hours, and the reaction temperature was not higher than 30°C. After the addition was completed, the mixture was kept at 20-30°C and stirred for 2 hours, and then a freshly prepared 3% sodium hydroxide aqueous solution (75.0 g of sodium hydroxide and 2400 g of water) (2475.0 g) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0-10°C, kept stirred for 2 hours, discharged, centrifuged until no liquid was dripped out, and washed with purified water to pH 7-8 to obtain a filter cake containing compound 2. The filter cake was refluxed and refined with ethanol (1680 g) and purified water (80 g) to obtain 350 g of ethyl 3-[[[2-[[(4-amidinophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]pyridin-2-ylamino]propanoate p-toluenesulfonate (compound 2), wherein the impurity A content was 1.78%.

[0055] (2) Synthesis of dabigatran etexilate

[0056] 100 g of ethyl 3-[[[2-[[(4-amidinophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]pyridin-2-ylamino]propanoate p-toluenesulfonate (Compound 2) obtained in step (1), 1300 g of dichloromethane and 75 g of triethylamine (molar equivalent is 5.0 eq) were added to a reaction kettle and stirred. 66 g of n-hexyl chloroformate (molar equivalent is 2.7 eq) and 100 g of dichloromethane were slowly added at 10-20° C. After the reaction was complete, 1000 g of water was used for washing for 15 min. The organic phase was separated and 100 g of 1.1% dilute hydrochloric acid solution was added. 00g is stirred and washed for 30min, then separates organic phase and washes saturated sodium bicarbonate solution 500g for 15min, finally separates organic phase and is evaporated to dryness, adds ethyl acetate 530g, is warming up to 50-55 ℃ of beating 1h, slowly is cooled to 0-10 ℃, insulated and stirred 1h, the blowing is centrifugal, and the filter cake is dripped with ethyl acetate 180g once, and is centrifuged to dryness, and the filter cake is dripped with ethyl acetate, and is slowly cooled to 0-10 ℃ after being insulated at 40-50 ℃ and stirred for 1h, insulated and stirred 1h, the blowing is centrifugal, and the filter cake is dripped with ethyl acetate 180g once, and is centrifuged to dryness, 40-50 ℃ of vacuum drying.Make 53g dabigatran etcxilate, purity is 98.53%, wherein, impurity B content 0.49%.

[0057] Example 2 Purification of compound 2

[0058] 5 g of 3-[[[2-[[(4-amidinophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]pyridin-2-ylamino]propionic acid ethyl p-toluenesulfonate (Compound 2) prepared in Example 1 and 25 ml of acetone were added to a reaction flask, the temperature was raised to 50° C., stirred for 15 min, filtered, rinsed with 10 ml of acetone, and dried to obtain a refined product of Compound 2, wherein the content of impurity A was 1.37%.

[0059] Example 3 Purification of compound 2

[0060] 5 g of 3-[[[2-[[(4-amidinophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]pyridin-2-ylamino]propionic acid ethyl p-toluenesulfonate (Compound 2) prepared in Example 1 and 25 ml of tetrahydrofuran were added to a reaction flask, the temperature was raised to 50° C., stirred for 15 min, filtered, rinsed with 10 ml of tetrahydrofuran, and dried to obtain a refined product of Compound 2, wherein the content of impurity A was 1.25%.

[0061] Example 4 Purification of compound 2

[0062] 5 g of 3-[[[2-[[(4-amidinophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]pyridin-2-ylamino]propionic acid ethyl p-toluenesulfonate (Compound 2) prepared in Example 1 and 25 ml of DMF were added to a reaction flask, refluxed, stirred for 15 min, cooled to 4° C. for crystallization, filtered, rinsed with 10 ml of DMF, and dried to obtain a refined product of Compound 2, wherein the content of impurity A was 16.20%.

[0063] Example 5 Purification of compound 2

[0064] 5 g of 3-[[[2-[[(4-amidinophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]pyridin-2-ylamino]propionic acid ethyl p-toluenesulfonate (Compound 2) prepared in Example 1, 10 ml of DMSO and 15 ml of acetone were added to a reaction flask, the temperature was raised to 50° C., stirred for 15 min, filtered, rinsed with 10 ml of acetone, and dried to obtain a refined product of Compound 2, wherein the content of impurity A was 1.42%.

[0065] Example 6 Purification of compound 2

[0066] 5 g of 3-[[[2-[[(4-amidinophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]pyridin-2-ylamino]propionic acid ethyl p-toluenesulfonate (Compound 2) prepared in Example 1 and 25 ml of ethanol were added to a reaction flask, refluxed, stirred for 15 min, cooled to 4°C for crystallization, filtered, rinsed with 10 ml of ethanol, and dried to obtain a refined product of Compound 2, wherein the content of impurity A was 1.70%.

[0067] Example 7 Purification of compound 2

[0068] 5 g of 3-[[[2-[[(4-amidinophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]pyridin-2-ylamino]propionic acid ethyl p-toluenesulfonate (Compound 2) prepared in Example 1, 5 ml of DMF and 20 ml of water were added to a reaction flask, stirred at 60° C. for 15 min, cooled to 4° C. for crystallization, filtered, rinsed with 10 ml of water and dried to obtain a refined product of Compound 2, wherein the content of impurity A was 0.77%.

[0069] Example 8

[0070] (1) Synthesis of Compound 2

[0071] Add 225kg 30-40% HCl / ethanol to a dry and clean 500L reactor, add 24.4kg p-toluenesulfonic acid monohydrate under stirring, and stir until dissolved. Control the temperature at 20-30℃, add 47kg compound 1 in batches, about 1-2 hours, continue to pass dry HCl gas after addition, pass HCl gas to saturation. Stir until the reaction is complete. Control the temperature below 30℃, add ammonia water to adjust the pH value to 9-10, control the temperature to 25-30℃, stir until the reaction is complete, cool to below 5℃, keep warm and grow crystals for 3-4 hours, centrifuge, slurry the filter cake with 600kg purified water at room temperature for 30 minutes, centrifuge, rinse with 120kg purified water twice, and slurry the filter cake with 150kg ethanol at room temperature for 0.5h, cool to below 0℃, crystallize for 1 hour, spin dry, and rinse with 40kg ethanol. The filter cake was dried by air blast at 50°C to obtain 52.5 kg of crude compound 2, in which the content of impurity A was 0.68%.

[0072] Add 480 kg of purified water to a 1000 L kettle, heat to 45-50 ° C, and set aside. Add 115 kg of DMF to another 500 L kettle, add 48 kg of crude compound 2, heat to 60C-70 ° C to dissolve, pump the solution into the above hot water, control the temperature at 50-55 ° C, stir for 15 minutes, and centrifuge. Rinse the kettle with 200 kg of 40-50 ° C purified water and rinse the filter cake. Dry the filter cake at 50 ° C with air blast to obtain 39.5 kg of refined compound 2, in which the content of impurity A is 0.27%.

[0073] (2) Synthesis of dabigatran etexilate

[0074] In a 1000L reactor, add 82kg DMF, add 28.5kg of compound 2 obtained in step (1), and add 21.5kg triethylamine under stirring. Stir for 0.5h, protect with nitrogen, add 215kg dichloromethane, cool to 5-10°C, add 42.4kg dichloromethane solution of n-hexyl chloroformate (prepared by dissolving 17.4kg n-hexyl chloroformate in 25kg dichloromethane), control the temperature at 5°C-15°C until the addition is complete, stir until the reaction is complete, add 360kg water, separate the phases, extract the aqueous phase with 215kg dichloromethane x2 times, combine the organic phases, wash with 228kg 5% potassium carbonate solution, wash the organic phase with 228kg water x2 times, separate the phases, add 25kg anhydrous magnesium sulfate to the organic phase, dry, filter, and rinse the filter cake with 20kg dichloromethane. The filtrate was concentrated under reduced pressure, 165 kg of ethyl acetate was added, stirred at 25 ° C for 4 h, cooled to 5 ° C for crystallization for 3 hours, centrifuged, rinsed with 15 kg of ethyl acetate, and dried with air at 45 ° C to obtain 23.5 kg of dabigatran etexilate with a purity of 99.47% and an impurity B content of 0.02%.

[0075] (3) Synthesis of dabigatran etexilate mesylate

[0076] In 50L reactor, add 16.5kg acetone and 2.06kg dabigatran etcxilate, stir and warm to 40 ℃ to dissolve completely, add 89.5g activated carbon, insulate and stir for 20 minutes. Heat filtration, filtrate proceeds to 50L reactor Zhao Hong, controls 35-40 ℃, drips the acetone solution of 298.7g methanesulfonic acid. Dropwise addition is completed, insulation 35-40 ℃, reacts 30 minutes. Cool down 20-25 ℃ and stir for 30 minutes, filter. Filter cake 30-35 ℃ of vacuum drying. Obtain light yellow solid 2.18kg, purity is 99.70%, and impurity C content is 0.02%.

[0077] Example 9 Purification of compound 2

[0078] 4 g of ethyl 3-[[[2-[[(4-amidinophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]pyridin-2-ylamino]propanoate p-toluenesulfonate (Compound 2) prepared in step (1) of Example 8 and 10 ml of DMF were added to a reaction flask, stirred and mixed at room temperature, and then 40 ml of water was added. The mixture was stirred for 15 min, filtered, rinsed with 10 ml of water, and dried to obtain 3.37 g of a refined product of Compound 2, wherein the content of impurity A was 0.36%.

[0079] The above description of the specific embodiments of the present invention does not limit the present invention. Those skilled in the art may make various changes or modifications based on the present invention. As long as they do not depart from the spirit of the present invention, they should all fall within the scope of protection of the claims of the present invention.

Claims

1. A preparation method of dabigatran etexilate, characterized in that, The steps include: (1) Compound 1 is subjected to a pinner reaction and then salified with p-toluenesulfonic acid to obtain compound 2; (2) reacting compound 2 with hexyl chloroformate to obtain dabigatran etexilate, ， The step (1) comprises the following steps: reacting compound 1 with HCl / ethanol, p-toluenesulfonic acid or its monohydrate and aqueous ammonia; cooling the obtained reaction mixture to precipitate solid, filtering, treating the filter cake to obtain a crude compound 2, purifying to obtain a purified compound 2, The filter cake treatment in step (1) comprises the following steps: placing the filter cake in water at room temperature and stirring, separating, and collecting solids; then placing the solids in ethanol at room temperature and stirring, precipitating solids at room temperature or at reduced temperature, and drying to obtain: In the purification of step (1), the obtained crude compound 2 is added to a purification solvent, stirred, separated, the solid is collected, rinsed, and dried to obtain the product. The purification solvent is a combination of DMF and H2O, and the volume ratio of DMF to H2O is 1:3.5-1:4.

5. In the purification of step (1), the mass volume ratio of the crude compound 2 to the purification solvent is 1:5-15. In the purified product of compound 2 obtained in step (1), the content of impurity A does not exceed 0.5%, the purity of dabigatran etexilate obtained in step (2) is not less than 99.4%, and the content of impurity B in dabigatran etexilate does not exceed 0.03%, 。 2. The preparation method according to claim 1, characterized in that: In the purification of step (1), the separation is selected from any one of filtration, centrifugation and membrane treatment.

3. The preparation method according to claim 1, characterized in that: In the purification of step (1), the elution solvent is water, and the mass volume ratio of the crude compound 2 to the elution solvent is 1:2-5.

4. The preparation method according to claim 1, characterized in that: In the purification of step (1), the drying is selected from any one of reduced pressure drying, normal pressure drying, spray drying and boiling drying, and the drying temperature is 25-80°C.

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