CN116239572A

CN116239572A - Preparation method of dabigatran etexilate intermediate

Info

Publication number: CN116239572A
Application number: CN202310177315.2A
Authority: CN
Inventors: 仲召亮; 张维冰; 尹强; 张磊; 徐春涛
Original assignee: Suqian Shengji Pharmaceutical Technology Co ltd
Current assignee: Suqian Shengji Pharmaceutical Technology Co ltd
Priority date: 2023-02-28
Filing date: 2023-02-28
Publication date: 2023-06-09

Abstract

The invention discloses a preparation method of dabigatran etexilate intermediate, which is characterized in that an amino acid ester compound and a cyano compound are subjected to polymerization reaction under the action of anhydrous aluminum chloride serving as a catalyst, and a target compound III dabigatran etexilate is prepared by one-step direct reaction. The beneficial effects of the invention are as follows: the method has the advantages of simple reaction operation, mild reaction conditions, simple separation of products and impurities, and higher purity of the obtained products, and is suitable for industrial production.

Description

Preparation method of dabigatran etexilate intermediate

Technical Field

The invention relates to the technical field related to preparation of pharmaceutical intermediates, in particular to a dabigatran etexilate amidine synthesis process.

Background

Dabigatran etexilate, chemical name 3- [ [ [2- [ [ [4- [ [ [ (hexyloxy) carbonyl ] amino ] iminomethyl ] phenyl ] amino ] methyl ] -1-methyl-1H-benzimidazol-5-yl ] carbonyl ] (pyridin-2-yl) amino ] ethyl propionate, chemical formula C34H41N7O5, is the most clinically leading new generation oral anticoagulant drug Direct Thrombin Inhibitor (DTIs), is thrombin inhibitor dabigatran etexilate capsule (trade name Pradaxa) developed by boildingham, germany, was marketed in germany and uk first at 4 months of 2008, and was approved by the FDA again at 10 month 19 of 2010 for preventing stroke and systemic embolism in non-valvular atrial fibrillation patients. The chemical structure is as follows: for preventing stroke and systemic embolism in non-valvular atrial fibrillation patients, the chemical structural formula is as follows:

based on the structure of dabigatran etexilate, several documents (CN 105348262, WO2013/144903, journal of Chemical Research,2016,40 (8), 461, WO2013/24384, WO2016/27077, hetercycles, 2013,87 (8), 1699, WO 2014/167577) all describe the following synthetic routes: the compound I is synthesized into an amidine compound II by acid catalysis, namely a Pinner amidine method, and the compound II reacts with n-hexyl chloroformate under alkaline conditions to prepare dabigatran etexilate, wherein the synthetic route is as follows:

the method adopts the Pinner amidine synthesis method, can be carried out at normal temperature and normal pressure, has higher reaction yield, but has more complex preparation process, is quite inconvenient to synthesize by using hydrogen chloride gas, has larger pollution, longer reaction period, has strong corrosiveness and high toxicity to the hydrogen chloride gas in industrial production, has high equipment requirements, adopts equipment made of materials such as enamel and the like, has strict safety measures, has higher reaction requirements, needs to strictly control the moisture and the feeding proportion of reaction raw materials, keeps lower reaction temperature, has longer reaction time and has difficult separation of product impurities.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide a novel synthesis process of the ester derivative of dabigatran, which is characterized in that the dabigatran is prepared by directly reacting an amino acid ester compound with a cyano compound, the reaction steps for preparing dabigatran are reduced, the dosage of chemicals is reduced, the atomic economy of the reaction is increased, the use of hydrogen chloride gas is avoided, the requirements of reaction equipment are reduced, the reaction pollution is reduced, the reaction operation is simple, the reaction condition is mild, the separation of products and impurities is simple, the purity of the obtained products is higher, and the method is suitable for industrial production, and the reaction route is shown as follows:

the invention provides a novel synthesis process of dabigatran etexilate derivative, which is characterized in that dabigatran etexilate is prepared by directly reacting an amino acid ester compound with a cyano compound under the action of a catalyst, so that the reaction steps for preparing dabigatran etexilate are reduced, the dosage of chemicals is reduced, the atomic economy of the reaction is improved, the use of hydrogen chloride gas is avoided, the requirements of reaction equipment are reduced, the reaction pollution is reduced, the reaction operation is simple, the reaction condition is mild, the separation of products and impurities is simple, the purity of the obtained products is higher, and the method is suitable for industrial production, and the reaction route is shown as follows:

the invention adopts the following technical scheme:

a preparation method of dabigatran etexilate intermediate, which comprises the following steps,

in the first step, reactant I (3- [ [ [2- [ [ (4-cyanophenyl) amino ] methyl ] -1-methyl-1H-benzimidazole-5-yl ] carbonyl ] pyridine-2-amino ] ethyl propionate compound) is taken and dissolved in a solvent, a desiccant is added for drying, filtering is carried out, and then a catalyst is added into the solution for stirring and mixing for 5min, so that aluminum chloride and the reactant I are combined for reaction, and a positively charged compound is generated.

And secondly, dissolving a reactant II (hexyl carbamate) in a solvent, adding a drying agent for drying, filtering, gradually dripping the obtained solution into the solution obtained in the first step, heating for reaction, filtering, washing, distilling under reduced pressure and recrystallizing the product after the reaction is finished to obtain a target product compound III (dabigatran etexilate).

Further, the catalyst is one of anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous ferric chloride, anhydrous tin chloride and anhydrous trimethylaluminum, preferably anhydrous aluminum chloride.

Further, the catalyst is supported by silica.

Further, the solvent of the first step reaction and the second step reaction is one or a mixed solution of more than one of toluene, hexane and tetrahydrofuran, and toluene is preferred.

Further, the reaction temperature of the second step is 50-60 ℃.

Further, the molar ratio of the reactant I to the catalyst used in the first step is 1:0.05 to 0.1, preferably 1:0.08.

further, the molar ratio of the usage of the reactant I to the usage of the reactant II is 1:1 to 1.05.

Further, the reaction time required by the second step reaction is 4-6 h.

Further, the solutions of the reactant I and the reactant II in the first step and the second step are all dry anhydrous sodium sulfate.

Furthermore, the product obtained in the second step is recrystallized and purified by taking toluene as a solvent.

The beneficial effects of the invention are as follows: 1. the reaction is reduced from two steps to one step, the reaction steps for preparing dabigatran etexilate are reduced, the dosage of chemicals is reduced, and the atomic economy of the reaction is improved; 2. the use of hydrogen chloride gas is avoided, the requirements of reaction equipment are reduced, and the reaction pollution is reduced; 3. compared with the original route, the method has the advantages of simple reaction operation, mild reaction conditions, simple separation of the product and the impurity, and higher purity of the obtained product, and is suitable for industrial production.

Drawings

FIG. 1 is a schematic illustration of a reaction scheme of the present invention;

FIG. 2 is a schematic diagram of a reaction scheme of a preparation route of dabigatran etexilate in the prior art;

FIG. 3 is a schematic representation of the chemical structure of the ester derivative of dabigatran of the invention.

Detailed Description

The following description of the embodiments of the present invention will be made clearly and completely with reference to the embodiments of the present invention and the accompanying drawings, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

Example 1

Under the protection of dry nitrogen, 48.2g (0.1 mol) of compound I is dissolved in 200ml of toluene, another 14.5g (0.05 mol) of compound II, namely hexyl carbamate is dissolved in 100ml of toluene, the obtained solutions of compound I and compound II are dried by anhydrous sodium sulfate, 0.008mol of anhydrous aluminum chloride/silicon dioxide load (aluminum chloride reacts with cyano to generate positively charged compound) is added into the solution of compound I, the mixture is stirred for 30 minutes after dripping, then the solution of reactant II is gradually dripped into the obtained solution after dripping, the mixture is heated to 50 ℃, the mixture is stirred for 4 hours after the reaction is completed, cooling to about 0deg.C, slowly dripping the reaction solution into 1M hydrochloric acid solution, controlling pH of the quenching solution to be no more than 6, slowly heating to room temperature after quenching, standing for layering, extracting the water layer with toluene for 2 times, mixing toluene layers, washing with saturated sodium bicarbonate solution and saturated saline water, removing solvent from the organic layer under reduced pressure to dry, adding 80M1 toluene while hot, stirring to dissolve completely, cooling to about-10deg.C, crystallizing for 8-10 hr, vacuum filtering, filtering to obtain solid, eluting with 10M1 cold toluene, filtering to obtain high purity dabigatran compound III, weighing 57.7g, and yield 92.0%. The purity was 98.8%.

Example 2

Under the protection of dry nitrogen, 48.2g (0.1 mol) of compound I is dissolved in 200ml of toluene, 14.5g (0.05 mol) of compound II, namely, hexyl carbamate is dissolved in 100ml of hexane, the obtained solutions of the compound I and the compound II are dried by anhydrous sodium sulfate, 0.008mol of anhydrous aluminum chloride/silicon dioxide is added into the solution of the compound I to load, the mixture is dropwise stirred for 30 minutes, then the solution of the reactant II is gradually dropwise added into the obtained solution, the mixture is heated to 50 ℃ after the dropwise addition, the mixture is stirred for 4 hours, the temperature is reduced to about 0 ℃ after the reaction is completed, slowly dripping the reaction solution into 1M hydrochloric acid solution, controlling the pH of the quenching solution to be not more than 6, after quenching, slowly heating to room temperature, standing for layering, extracting the water layer with toluene for 2 times, merging the toluene layers, washing the water layer with saturated sodium bicarbonate solution and saturated saline water respectively, decompressing and desolventizing the organic layer to dryness, adding 80M1 toluene when the water layer is hot, stirring to be fully dissolved, cooling to about minus 10 ℃, crystallizing for 8-10 hours, suction filtering, leaching the solid with 10M1 cold toluene, filtering, drying the solid, and obtaining the high-purity dabigatran etexilate compound III, weighing 56.8g, and obtaining the yield of 90.6%. The purity was 98.7%.

Example 3

Under the protection of dry nitrogen, 48.2g (0.1 mol) of compound I is dissolved in 200ml of toluene, another 14.5g (0.1 mol) of compound II, namely, hexyl carbamate is dissolved in 100ml of toluene, the obtained solutions of the compound I and the compound II are dried by anhydrous sodium sulfate, 0.008mol of anhydrous aluminum chloride/silicon dioxide is added into the solution of the compound I to load, the mixture is dropwise stirred for 30 minutes, then the solution of the reactant II is gradually dropwise added into the obtained solution, the mixture is heated to 60 ℃ after the dropwise addition, the mixture is stirred for 4 hours, the temperature is reduced to about 0 ℃ after the reaction is completed, slowly dripping the reaction solution into 1M hydrochloric acid solution, controlling the pH of the quenching solution to be not more than 6, after quenching, slowly heating to room temperature, standing for layering, extracting the water layer with toluene for 2 times, merging the toluene layers, washing the water layer with saturated sodium bicarbonate solution and saturated saline water respectively, decompressing and desolventizing the organic layer to dryness, adding 80M1 toluene when the water layer is hot, stirring to be fully dissolved, cooling to about minus 10 ℃, crystallizing for 8-10 hours, suction filtering, leaching the solid with 10M1 cold toluene, filtering, drying the solid, and obtaining the high-purity dabigatran etexilate compound III, weighing 57.9g, and obtaining the yield of 92.3%. The purity is 98.5%.

Example 4

Under the protection of dry nitrogen, 48.2g (0.1 mol) of compound I is dissolved in 200ml of toluene, another 14.5g (0.1 mol) of compound II, namely, hexyl carbamate is dissolved in 100ml of toluene, the obtained solutions of the compound I and the compound II are dried by anhydrous sodium sulfate, 0.008mol of anhydrous aluminum chloride/silicon dioxide is added into the solution of the compound I to load, the mixture is dropwise stirred for 30 minutes, then the solution of the reactant II is gradually dropwise added into the obtained solution, the mixture is heated to 50 ℃ after the dropwise addition, the mixture is stirred for 5 hours, the temperature is reduced to about 0 ℃ after the reaction is completed, slowly dripping the reaction solution into 1M hydrochloric acid solution, controlling the pH of the quenching solution to be not more than 6, after quenching, slowly heating to room temperature, standing for layering, extracting the water layer with toluene for 2 times, merging the toluene layers, washing the water layer with saturated sodium bicarbonate solution and saturated saline water respectively, decompressing and desolventizing the organic layer to dryness, adding 80M1 toluene when the water layer is hot, stirring to be fully dissolved, cooling to about minus 10 ℃, crystallizing for 8-10 hours, suction filtering, leaching the solid with 10M1 cold toluene, filtering, drying the solid, and obtaining the high-purity dabigatran etexilate compound III, weighing 57.8g, and the yield is 92.2%. The purity was 98.6%.

Example 5

Under the protection of dry nitrogen, 48.2g (0.1 mol) of compound I is dissolved in 200ml of toluene, another 14.5g (0.1 mol) of compound II, namely, hexyl carbamate is dissolved in 100ml of toluene, the obtained solutions of the compound I and the compound II are dried by anhydrous sodium sulfate, 0.008mol of anhydrous aluminum chloride/silicon dioxide is added into the solution of the compound I to load, the mixture is dropwise stirred for 30 minutes, then the solution of the reactant II is gradually dropwise added into the obtained solution, the mixture is heated to 50 ℃ after the dropwise addition, the mixture is stirred for 6 hours, the temperature is reduced to about 0 ℃ after the reaction is completed, slowly dripping the reaction solution into 1M hydrochloric acid solution, controlling the pH of the quenching solution to be not more than 6, after quenching, slowly heating to room temperature, standing for layering, extracting the water layer with toluene for 2 times, merging the toluene layers, washing the water layer with saturated sodium bicarbonate solution and saturated saline water respectively, decompressing and desolventizing the organic layer to dryness, adding 80M1 toluene when the water layer is hot, stirring to be fully dissolved, cooling to about minus 10 ℃, crystallizing for 8-10 hours, suction filtering, leaching the solid with 10M1 cold toluene, filtering, drying the solid, and obtaining the high-purity dabigatran etexilate compound III, weighing 57.9g, and obtaining the yield of 92.3%. The purity was 98.8%.

Example 6

Under the protection of dry nitrogen, 48.2g (0.1 mol) of compound I is dissolved in 200ml of toluene, another 14.5g (0.1 mol) of compound II, namely, hexyl carbamate is dissolved in 100ml of toluene, the obtained solutions of the compound I and the compound II are dried by anhydrous sodium sulfate, 0.005mol of anhydrous aluminum chloride/silicon dioxide is added into the solution of the compound I to load, the mixture is dropwise stirred for 30 minutes, then the solution of the reactant II is gradually dropwise added into the obtained solution, the mixture is heated to 50 ℃ after the dropwise addition, the mixture is stirred for 4 hours, the temperature is reduced to about 0 ℃ after the reaction is completed, slowly dripping the reaction solution into 1M hydrochloric acid solution, controlling the pH of the quenching solution to be not more than 6, after quenching, slowly heating to room temperature, standing for layering, extracting the water layer with toluene for 2 times, merging the toluene layers, washing the water layer with saturated sodium bicarbonate solution and saturated saline water respectively, decompressing and desolventizing the organic layer to dryness, adding 80M1 toluene when the water layer is hot, stirring to be fully dissolved, cooling to about minus 10 ℃, crystallizing for 8-10 hours, suction filtering, leaching the solid with 10M1 cold toluene, filtering, drying the solid, and obtaining the high-purity dabigatran etexilate compound III, weighing 57.0g, and obtaining the product with the yield of 91.0%. The purity was 98.8%.

Example 7

Under the protection of dry nitrogen, 48.2g (0.1 mol) of compound I is dissolved in 200ml of toluene, 14.5g (0.1 mol) of compound II, namely, hexyl carbamate is dissolved in 100ml of toluene, the obtained solutions of the compound I and the compound II are dried by anhydrous sodium sulfate, 0.010mol of anhydrous aluminum chloride/silicon dioxide is added into the solution of the compound I to load, the mixture is dropwise stirred for 30 minutes, then the solution of the reactant II is gradually dropwise added into the obtained solution, the mixture is heated to 50 ℃ after the dropwise addition, the mixture is stirred for 4 hours, the temperature is reduced to about 0 ℃ after the reaction is completed, slowly dripping the reaction solution into 1M hydrochloric acid solution, controlling the pH of the quenching solution to be not more than 6, after quenching, slowly heating to room temperature, standing for layering, extracting the water layer with toluene for 2 times, merging the toluene layers, washing the water layer with saturated sodium bicarbonate solution and saturated saline water respectively, decompressing and desolventizing the organic layer to dryness, adding 80M1 toluene when the water layer is hot, stirring to be fully dissolved, cooling to about minus 10 ℃, crystallizing for 8-10 hours, suction filtering, leaching the solid with 10M1 cold toluene, filtering, drying the solid, and obtaining the high-purity dabigatran etexilate compound III, weighing 57.2g, and obtaining the yield of 91.2%. The purity was 98.7%.

Example 8

Under the protection of dry nitrogen, 48.2g (0.1 mol) of compound I is dissolved in 200ml of toluene, and another 15.2g (0.105 mol) of compound II, namely, hexyl carbamate is dissolved in 100ml of toluene, the obtained solutions of the compound I and the compound II are dried by anhydrous sodium sulfate, 0.008mol of anhydrous aluminum chloride/silicon dioxide is added into the solution of the compound I to load, the mixture is dropwise stirred for 30 minutes, then the solution of the reactant II is gradually dropwise added into the obtained solution, the mixture is heated to 50 ℃ after the dropwise addition, the mixture is stirred for 4 hours, the temperature is reduced to about 0 ℃ after the reaction is completed, slowly dripping the reaction solution into 1M hydrochloric acid solution, controlling the pH of the quenching solution to be not more than 6, after quenching, slowly heating to room temperature, standing for layering, extracting the water layer with toluene for 2 times, merging the toluene layers, washing the water layer with saturated sodium bicarbonate solution and saturated saline water respectively, decompressing and desolventizing the organic layer to dryness, adding 80M1 toluene when the water layer is hot, stirring to be fully dissolved, cooling to about minus 10 ℃, crystallizing for 8-10 hours, suction filtering, leaching the solid with 10M1 cold toluene, filtering, drying the solid, and obtaining the high-purity dabigatran etexilate compound III, weighing 58.0g, and obtaining the yield of 92.8%. The purity is 98.5%.

Example 9

Under the protection of dry nitrogen, 48.2g (0.1 mol) of compound I is dissolved in 200ml of toluene, 14.5g (0.1 mol) of compound II, namely, hexyl carbamate is dissolved in 100ml of toluene, the obtained solutions of the compound I and the compound II are dried through anhydrous sodium sulfate, 0.008mol of anhydrous trimethylaluminum is added into the solution of the compound I, stirring is completed for 30 minutes, then the solution of the reactant II is gradually dropwise added into the obtained solution, heating is completed until the temperature reaches 50 ℃, stirring is carried out for 4 hours, after the reaction is completed, cooling is carried out until the temperature reaches about 0 ℃, the reaction solution is slowly dripped into 1M hydrochloric acid solution, the pH value of quenching solution is controlled to be not more than 6, after the quenching is completed, the quenching is slowly carried out until the temperature reaches room temperature, standing and layering is carried out, the water layer is extracted by toluene for 2 times, a toluene layer is combined, the saturated sodium bicarbonate solution and saturated saline solution are respectively used for washing, the organic layer is decompressed and desolventized to dryness, 80M1 toluene is added while the solution is stirred until the solution is completely dissolved, cooling is carried out until the solution is cooled to about-10 ℃, leaching is carried out for 8-10 hours, leaching is carried out for leaching, the solution is slowly drops until the solid phase is cooled to reach 1M 1, the solid phase is filtered, the solid phase is obtained is dehydrated, and the solid phase is 1M is dehydrated, and the solid phase is 1 g, and the solid phase is obtained is 2g, and the solid phase is obtained, and the solid phase is 2g, and the solid phase is 57, and the solid phase, and the purity is obtained is 2g and the solid, and the 2g is obtained is 2 and after 2g is 2 and dried. The purity was 98.7%.

Comparative document (CN 106543144 a) example

Example 1

An industrialized preparation method of dabigatran etexilate comprises the following specific steps:

(1) Preparation of ethyl 3- (3- ((2- (4-cyanophenyl) amino) acetamido) -4- (methylamino) -N- (pyridin-2-yl) benzamide) propionate (4)

200kg of chloroform is pumped into a 500L reaction kettle, a feeding port is opened, and 11.3kg of (4-cyanoanilino) acetic acid and 12.2kg of CDI are sequentially fed; after the material is fed, stirring is started, a cooling liquid is sleeved in a jacket, the temperature in the kettle is reduced to 0-5 ℃, and the reaction is carried out for 3 hours in a heat-preserving way; opening a feeding port, and slowly feeding 3kg of compound under slight negative pressure; after the addition, discharging the refrigerating fluid in the jacket, adding tap water, gradually heating to room temperature, stirring for reaction for 24 hours, sampling, detecting by HPLC, wherein the content of the compound 3 is less than or equal to 1%, the content of the compound 4 is more than or equal to 95.0%, and stopping the reaction; pumping 50kg of water, stirring, pumping hot water into a jacket for circulation, decompressing and distilling to recover chloroform (applicable) until the chloroform is dry, and rapidly stirring residual liquid to disperse solids; performing filtering, drying, inspecting, packaging and warehousing; 28.2kg of off-white solid is obtained, the HPLC purity is 99.3%, and the molar yield is 97.2%; mp is 112.4-112.9 ℃;

(2) Preparation of ethyl 3- (2- (((4-cyanophenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-amido) propionate (5)

141kg of 1, 2-dichloroethane, 16.9kg of phosphoric acid and 428.2kg of compound are put into a 500L reaction kettle, and steam is heated to 80-85 ℃ for reflux reaction for 10 hours; closing steam, clamping tap water, cooling to room temperature, slowly adding ammonia water from a high-level tank, and adjusting pH to be 9; standing, layering, washing the organic phase with water for one time, drying, filtering, pumping the filtrate back into the reaction kettle, stirring, pumping hot water into a jacket for circulation, and distilling under reduced pressure to recover 1, 2-dichloroethane (applicable) until dry; pumping 35kg of methanol, stirring, heating the steam until the residue is dissolved and clarified after the steam flows back, closing the steam, clamping the steam into tap water, slowly cooling to room temperature, carrying out centrifugal filtration, leaching with a small amount of methanol, drying, checking, packaging and warehousing; 22.5kg of off-white solid is obtained, the HPLC purity is 98.9%, and the molar yield is 82.7%; mp is 152.1-152.9 ℃;

(3) Preparation of ethyl 3- (2- (((4-formamidiophenyl) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamide) propanoate hydrochloride (7)

Pumping 89.5kg of anhydrous methanol into the dry and clean reaction kettle, stirring, and cooling the jacket to below 10 ℃ by cooling liquid; slowly dripping 146.5kg of acetyl chloride from a high-level tank, after dripping, stirring for 3 hours at the temperature below 10 ℃ to obtain a hydrogen chloride/methanol/methyl acetate solution, and detecting the molar concentration of the solution by a titration method to be 9.7mol/L; under slight negative pressure, adding 22.5kg of compound 5, heating to 40 ℃ by steam, stirring and reacting for 10 hours; slowly adding concentrated ammonia water dropwise from a high-level tank, adjusting pH to be 9, heating to 50 ℃ by steam, and stirring for reaction for 10 hours; vacuum distilling to recover methanol and methyl acetate, pumping 67.5kg of water and 180kg of ethyl acetate into a reaction kettle, stirring, heating to 80-90 ℃ with steam, refluxing for 30 minutes, and dissolving and clarifying residues; closing steam, clamping tap water, and slowly cooling to room temperature; carrying out throwing filtration, sequentially stirring and washing filter cakes with water twice, stirring and washing with ethyl acetate twice, drying, sending to a detector, packaging and warehousing;

18.7kg of off-white solid was obtained with an HPLC purity of 97.6% and a molar yield of 74.8%; mp is 120.6 to 121.3 ℃;

(4) Preparation of ethyl 3- (2- (((4- (N' - ((hexyloxy) carbonyl) formamidine) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [ d ] imidazole-5-carboxamide) propionate (1)

Pumping 93.5kg of isopropyl ether into a dry and clean reaction kettle, opening a feeding port, adding 718.7kg of compound, and stirring at room temperature until the compound is dissolved and clarified; sequentially pumping 5.3kg of triethylamine and 8.6kg of n-hexyl bromoformate, and stirring at room temperature for reaction for 6 hours; cooling liquid is sleeved in the jacket, the temperature is reduced to be lower than the internal temperature of 5 ℃, and 93.5kg of water is slowly dripped from the overhead tank; after dripping, continuing to keep the temperature at 0-5 ℃ and stirring and crystallizing for 5 hours; carrying out centrifugal filtration, and fully washing a filter cake twice by using a proper amount of water to obtain pale yellow solid; pumping 150kg of cyclohexanone into the crystallization kettle, opening a feeding port, adding the obtained pale yellow solid wet product, and stirring for 30 minutes at room temperature to dissolve most of the solid; suction filtering, discarding filter cake, transferring filtrate into a distillation kettle, heating with steam, and distilling under reduced pressure to recover cyclohexanone (which can be used mechanically) until it is dry; pumping 84kg of isopropanol into the reaction kettle, opening a feeding port, adding 1kg of active carbon, stirring, heating with steam to reflux for 30 minutes, performing suction filtration while the hot, transferring filtrate into a crystallization kettle, clamping a cooling liquid, cooling to the internal temperature below 10 ℃, and stirring for crystallization for 3 hours; filtering, washing, drying, inspecting, packaging and warehousing; 11.5kg of off-white solid is obtained, the HPLC purity is 99.6%, the maximum single impurity is 0.06%, and the molar yield is 52.5%; mp is 132.3-132.7 ℃.

In conclusion, compared with the prior art, the technical scheme provided by the invention has the advantages of few steps, simplicity in operation, low pollution, higher yield and higher purity of the obtained product, and is suitable for the requirement of industrial production.

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.

Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.

Claims

1. The preparation method of the dabigatran etexilate intermediate is characterized by comprising the following steps:

firstly, dissolving a reactant I in a solvent, adding a drying agent for drying, filtering, adding a catalyst into the obtained solution, and stirring and mixing for 5min;

and secondly, dissolving the reactant II in a solvent, adding a drying agent for drying, filtering the solution, gradually dripping the solution into the solution obtained in the first step, heating the solution for reaction, and obtaining the target product compound III after the reaction is finished.

2. The method for preparing dabigatran etexilate intermediate according to claim 1, wherein the method comprises the following steps: the catalyst is one of anhydrous aluminum chloride, zinc chloride, ferric chloride, stannic chloride and anhydrous trimethylaluminum.

3. The method for preparing dabigatran etexilate intermediate according to claim 1, wherein the method comprises the following steps: the catalyst is supported by silica.

4. The method for preparing dabigatran etexilate intermediate according to claim 1, wherein the method comprises the following steps: the solvent for the first step reaction and the second step reaction is one or a mixed solution of more of toluene, hexane and tetrahydrofuran.

5. The method for preparing dabigatran etexilate intermediate according to claim 1, wherein the method comprises the following steps: the reaction temperature of the second step is 50-60 ℃.

6. The method for preparing dabigatran etexilate intermediate according to claim 1, wherein the method comprises the following steps: the mole ratio of the reactant I to the catalyst in the first step is 1:0.05 to 0.1.

7. The method for preparing dabigatran etexilate intermediate according to claim 1, wherein the method comprises the following steps: the molar ratio of the usage amount of the reactant I to the usage amount of the reactant II is 1:1 to 1.05.

8. The method for preparing dabigatran etexilate intermediate according to claim 1, wherein the method comprises the following steps: the reaction time required by the second step reaction is 4-6 h.

9. The method for preparing dabigatran etexilate intermediate according to claim 1, wherein the method comprises the following steps: and drying the solutions of the reactant I and the reactant II by using anhydrous sodium sulfate.

10. The method for preparing dabigatran etexilate intermediate according to claim 1, wherein the method comprises the following steps: and (3) recrystallizing and purifying the product obtained in the second step by taking toluene as a solvent.