A method for synthesizing a dabigatran ester intermediate

Abstract

This invention relates to the field of pharmaceutical intermediates, and in particular to a method for synthesizing dabigatran ester intermediates. The synthetic route includes the following steps: (1) reacting compound V with compound IV in the presence of a condensing agent to obtain compound III; (2) reacting compound III with compound II in the presence of a base to obtain compound I. This invention improves upon the traditional synthetic route for dabigatran ester intermediates. The method features mild reaction conditions, simple operation, and high yield and purity, making it suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediates, specifically to a method for synthesizing dabigatran ester intermediate. Background Technology

[0002] Dabigatran etexilate, chemically known as ethyl 3-[[[2-[[[4-[[[(hexoxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionate, was developed by Boehringer Ingelheim in Germany and approved by the European Commission for marketing in Germany and the UK in March 2008 under the brand name Pradaxa. Clinically, it is used to prevent venous thromboembolism in patients after total hip or total knee replacement surgery. Dabigatran etexilate is a novel direct thrombin inhibitor and a prodrug of dabigatran, offering advantages such as oral administration, high potency, no need for special monitoring, and minimal drug interactions.

[0003] Compound I is an important intermediate in the preparation of dabigatran etexilate. The following synthetic route is generally used in existing technologies:

[0004]

[0005] The above reaction uses compounds VI and II as starting materials, and proceeds through three steps to obtain the target intermediate compound I. This synthetic route has low yield and high cost, making it unsuitable for industrial production.

[0006] For example, in the third step of the reaction, CN104844571A discloses a method for preparing a dabigatran ester intermediate cyclized product. The specific steps are as follows: (1) ((4-cyano)phenyl)aminoacetic acid (II), carbonyl diimidazole and the first solvent are added to a reaction flask, and the temperature is raised to T1 for the first reaction, with a reaction time of t1; (2) ethyl 3-((3-amino-4-methylbenzoyl)pyridine-2-amino)propionate is added and the temperature is raised to T2 for the second reaction, with a reaction time of t2; (3) the temperature is raised to T3 for the third reaction, with a reaction time of t3; (4) the first solvent is evaporated to obtain the crude cyclized product, and the second solvent is added for recrystallization to obtain the dabigatran ester intermediate cyclized product (I). It can also be seen from this technical solution that the third step alone requires three heating processes, the reaction process is extremely complicated, the production cost is high, and it is not suitable for industrial production. Summary of the Invention

[0007] To address the aforementioned problems, the present invention aims to provide a method for preparing dabigatran ester intermediates with high yield and low cost. This method has simple process steps, is safe to produce and does not pollute the environment during the entire preparation process, and is easy to industrialize.

[0008] To achieve the above objectives, the present invention provides the following technical solution:

[0009] A method for synthesizing a dabigatran ester intermediate, the synthetic route of which is as follows:

[0010]

[0011] Specifically, the following steps are included:

[0012] (1) In the presence of a condensing agent, compound V is reacted with compound IV to obtain compound III;

[0013] (2) In the presence of a base, compound III reacts with compound II to obtain compound I.

[0014] Furthermore, in step (1), the condensing agent used is any one of 1,1'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, or N,N'-carbonylbis(1,2,4-triazole).

[0015] Furthermore, in step (1), the solvent used is one or more of tetrahydrofuran, dichloromethane, toluene, benzene, N,N-dimethylformamide, ethyl acetate, or isopropyl acetate.

[0016] Furthermore, in step (1), the molar ratio of compound V, compound IV and condensing agent is 1:(1-1.5):(1-1.5).

[0017] Furthermore, in step (1), the reaction temperature is 10–50°C.

[0018] Furthermore, in step (2), the molar ratio of compound II, compound III and base is 1:(1-1.5):(1-2).

[0019] Furthermore, in step (2), the base is any one of triethylamine, potassium carbonate, sodium carbonate, or sodium bicarbonate.

[0020] Furthermore, in step (2), the solvent used is one or more of tetrahydrofuran, dichloromethane, chloroform, toluene, or ethyl acetate.

[0021] Furthermore, in step (2), the reaction temperature is 10–50°C.

[0022] Compared with the prior art, the beneficial effects of the present invention are:

[0023] This invention improves the traditional synthetic route for dabigatran ester intermediates. The method has mild reaction conditions, is simple to operate, and has high yield and purity, making it suitable for large-scale industrial production. Detailed Implementation

[0024] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0025] A method for synthesizing a dabigatran ester intermediate, the synthetic route of which is as follows:

[0026]

[0027] Example 1

[0028] (1) Synthesis of Compound III

[0029] Compound IV (16.46 g, 93.4 mmol), 1,1'-carbonyldiimidazole (15.14 g, 93.4 mmol), and tetrahydrofuran (200 mL) were added to a reactor. The mixture was stirred at 25 °C for 1 h. Then, compound V (15 g, 81.2 mmol) was added, and the reaction was stirred at 25 °C. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was dissolved in 100 mL of glacial acetic acid and heated under reflux for 1 h. The solution was then diluted with 300 mL of water and neutralized with concentrated ammonia. The solution was extracted with ethyl acetate, concentrated under vacuum, and the crude product was purified by silica gel column chromatography to give compound III in 93.7% yield and 99.2% purity.

[0030] (2) Synthesis of Compound I

[0031] Compound III (18.38 g, 56.6 mmol), triethylamine (6.25 g, 61.8 mmol), and tetrahydrofuran (100 mL) were added to a reactor and stirred to dissolve. Then, a tetrahydrofuran solution of compound II (10 g, 51.5 mmol) (50 mL) was added, and the reaction mixture was stirred at 25 °C. After the reaction was complete, the reaction mixture was diluted with water (150 mL), extracted with dichloromethane (200 mL), and the organic phase was washed successively with 2N hydrochloric acid and water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound I in 92.2% yield and 99.4% purity.

[0032] Example 2

[0033] (1) Synthesis of Compound III

[0034] Compound IV (14.31 g, 81.2 mmol), N,N'-dicyclohexylcarbodiimide (16.76 g, 81.2 mmol), and dichloromethane (200 mL) were added to a reactor. The mixture was stirred at 50 °C for 1 h. Then, compound V (15 g, 81.2 mmol) was added, and the reaction was stirred at 50 °C. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was dissolved in 100 mL of glacial acetic acid and heated under reflux for 1 h. The solution was then diluted with 300 mL of water and neutralized with concentrated ammonia. The solution was extracted with ethyl acetate, concentrated under vacuum, and the crude product was purified by silica gel column chromatography to give compound III in 90.2% yield and 99.3% purity.

[0035] (2) Synthesis of Compound I

[0036] Compound III (25.07 g, 77.2 mmol), potassium carbonate (14.23 g, 103 mmol), and dichloromethane (100 mL) were added to a reactor and stirred to dissolve. Then, a solution of compound II (10 g, 51.5 mmol) in dichloromethane (50 mL) was added, and the reaction mixture was stirred at 10 °C. After the reaction was complete, the reaction mixture was diluted with water (150 mL), extracted with dichloromethane (200 mL), and the organic phase was washed successively with 2N hydrochloric acid and water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound I in 89.4% yield and 99.1% purity.

[0037] Example 3

[0038] (1) Synthesis of Compound III

[0039] Compound IV (21.45 g, 121.8 mmol), N,N'-carbonylbis(1,2,4-triazole) (19.98 g, 121.7 mmol), and N,N-dimethylformamide (200 mL) were added to a reactor. The mixture was stirred at 10 °C for 1 h. Then, compound V (15 g, 81.2 mmol) was added, and the reaction was stirred at 10 °C. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was dissolved in 100 mL of glacial acetic acid and heated under reflux for 1 h. The solution was then diluted with 300 mL of water and neutralized with concentrated ammonia. The solution was extracted with ethyl acetate, concentrated under vacuum, and the crude product was purified by silica gel column chromatography to give compound III in 88.7% yield and 99.1% purity.

[0040] (2) Synthesis of Compound I

[0041] Compound III (16.73 g, 51.5 mmol), sodium bicarbonate (4.33 g, 51.5 mmol), and toluene (100 mL) were added to the reactor and stirred to dissolve. Then, a toluene (50 mL) solution of compound II (10 g, 51.5 mmol) was added, and the reaction mixture was stirred at 50 °C. After the reaction was complete, the reaction mixture was diluted with water (150 mL), extracted with dichloromethane (200 mL), and the organic phase was washed successively with 2N hydrochloric acid and water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound I in 87.5% yield and 99.2% purity.

[0042] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing a dabigatran ester intermediate, characterized in that: Its synthetic route is as follows: Specifically, the following steps are included: (1) In the presence of a condensing agent, compound V is reacted with compound IV to obtain compound III; (2) In the presence of a base, compound III reacts with compound II to obtain compound I.

2. The method for synthesizing the dabigatran ester intermediate according to claim 1, characterized in that: In step (1), the condensing agent is any one of 1,1'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, or N,N'-carbonylbis(1,2,4-triazole).

3. The method for synthesizing the dabigatran ester intermediate according to claim 1, characterized in that: In step (1), the solvent used is one or more of tetrahydrofuran, dichloromethane, toluene, benzene, N,N-dimethylformamide, ethyl acetate or isopropyl acetate.

4. The method for synthesizing the dabigatran ester intermediate according to claim 1, characterized in that: In step (1), the molar ratio of compound V, compound IV and condensing agent is 1:(1-1.5):(1-1.5).

5. The method for synthesizing the dabigatran ester intermediate according to claim 1, characterized in that: In step (1), the reaction temperature is 10–50°C.

6. The method for synthesizing the dabigatran ester intermediate according to claim 1, characterized in that: In step (2), the molar ratio of compound II, compound III and base is 1:(1-1.5):(1-2).

7. The method for synthesizing the dabigatran ester intermediate according to claim 1, characterized in that: In step (2), the base is any one of triethylamine, potassium carbonate, sodium carbonate, or sodium bicarbonate.

8. The method for synthesizing the dabigatran ester intermediate according to claim 1, characterized in that: In step (2), the solvent used is one or more of tetrahydrofuran, dichloromethane, chloroform, toluene, or ethyl acetate.

9. The method for synthesizing the dabigatran ester intermediate according to claim 1, characterized in that: In step (2), the reaction temperature is 10–50°C.

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