A method for preparing dabigatran ester intermediates using a microchannel approach

Abstract

This invention relates to the field of pharmaceutical intermediates, and in particular to a microchannel method for preparing dabigatran ester intermediates. The synthetic route of this invention utilizes a continuous flow microchannel reactor in the preparation of dabigatran ester intermediates, thereby significantly shortening the reaction time to within a few hundred seconds. Simultaneously, the target product obtained through this continuous flow reaction process exhibits high yield and high purity; testing shows that the purity of the target product can reach over 99%, and the yield can reach over 90%. The preparation method of this invention produces few byproducts, can be continuously produced, and has a high degree of automation, showing promising prospects for industrial application.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediates, specifically to a method for preparing dabigatran ester intermediates using a microchannel method. 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, high cost, and uses a batch reactor, requiring several hours for the reaction, resulting in high time costs and 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 problems in existing technologies that hinder the large-scale production of dabigatran ester intermediates, such as long reaction time, low yield, complicated reaction process, and high cost, this invention provides a microchannel method for preparing dabigatran ester intermediates.

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

[0009] A microchannel method for preparing dabigatran ester intermediates, the synthetic route of which is as follows:

[0010]

[0011] Includes the following steps:

[0012] (1) Preparation of compound III in a continuous flow microchannel reactor

[0013] Preparation of material A solution: Mix compound V with solvent, stir well, and set aside;

[0014] Preparation of material B solution: Mix compound IV with solvent, stir well, and set aside;

[0015] Preparation of material C solution: Mix the condensing agent and solvent, stir well, and set aside;

[0016] Solution A, solution B, and solution C are pumped into a microchannel reactor at preset flow rates. The heat exchanger temperature of the microchannel reactor is set at 10–50°C, and the reaction time in the microchannel reactor is set at 60–300 s. A product containing compound III is obtained from the outlet of the microchannel reactor. Then, compound III is obtained through post-processing.

[0017] (2) Preparation of compound I in a continuous flow microchannel reactor

[0018] Preparation of material D solution: Mix compound III with solvent, stir well, and set aside;

[0019] Preparation of material E solution: Mix compound II with solvent, stir well, and set aside;

[0020] Preparation of material F solution: Mix the alkali and solvent, stir well, and set aside;

[0021] Solution D, solution E, and solution F are pumped into a microchannel reactor at preset flow rates. The heat exchanger temperature of the microchannel reactor is set at 10–50°C, and the reaction time in the microchannel reactor is set at 80–240 s. A product containing compound I is obtained from the outlet of the microchannel reactor. Then, compound I is obtained through post-processing.

[0022] Furthermore, in step (1), the condensing agent is any one of 1,1'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, or N,N'-carbonylbis(1,2,4-triazole).

[0023] Furthermore, in step (1), the solvent is one or more of tetrahydrofuran, dichloromethane, toluene, benzene, N,N-dimethylformamide, ethyl acetate, or isopropyl acetate.

[0024] Furthermore, in step (1), the molar ratio of compound V, compound IV and condensing agent is 1:(1-1.5):(1-1.5).

[0025] Furthermore, in step (1), the reaction temperature is 20 to 40°C, which can be, but is not limited to, 20°C, 25°C, 30°C, 35°C, or 40°C.

[0026] Furthermore, in step (1), the reaction time is 80 to 260 s, which can be, but is not limited to, 80 s, 100 s, 120 s, 140 s, 160 s, 180 s, 200 s, 220 s, 240 s, or 260 s.

[0027] Furthermore, in step (2), the molar ratio of compound II, compound III and base is 1:(1-1.5):(1-2).

[0028] Furthermore, in step (2), the base is any one of triethylamine, potassium carbonate, sodium carbonate, or sodium bicarbonate.

[0029] Furthermore, in step (2), the solvent is one or more of tetrahydrofuran, dichloromethane, chloroform, toluene, or ethyl acetate.

[0030] Furthermore, in step (2), the reaction temperature is 20 to 40°C, which can be, but is not limited to, 20°C, 25°C, 30°C, 35°C, or 40°C.

[0031] Furthermore, in step (2), the reaction time is 100 to 220 seconds, which can be, but is not limited to, 100 seconds, 120 seconds, 140 seconds, 160 seconds, 180 seconds, 200 seconds, or 220 seconds.

[0032] Furthermore, the preset flow rates of material A solution, material B solution, and material C solution are 5-8 mL / min; the preset flow rates of material D solution, material E solution, and material F solution are 5-10 mL / min.

[0033] Compared with the prior art, the beneficial effects of the present invention are:

[0034] This invention applies a continuous flow microchannel reactor to the preparation of dabigatran ester intermediates, significantly shortening the reaction time to within a few hundred seconds. The target product obtained through this continuous flow reaction process exhibits high yield and high purity; testing shows that the purity of the target product can reach over 99%, and the yield over 90%. This invention's preparation method produces few byproducts, can be continuously produced, and has a high degree of automation, demonstrating promising prospects for industrial application. Detailed Implementation

[0035] 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.

[0036] A microchannel method for preparing dabigatran ester intermediates, the synthetic route of which is as follows:

[0037]

[0038] Example 1

[0039] (1) Synthesis of Compound III

[0040] Preparation of material A solution: Add compound V (15g, 81.2mmol) to tetrahydrofuran, dilute to 50mL, stir well, and place in raw material tank A;

[0041] Preparation of material B solution: Add compound IV (16.46 g, 93.4 mmol) to tetrahydrofuran, dilute to 80 mL, stir well, and place in raw material tank B;

[0042] Preparation of material C solution: 1,1'-carbonyldiimidazole (15.14 g, 93.4 mmol) was added to tetrahydrofuran, diluted to 80 mL, stirred evenly, and placed in raw material tank C;

[0043] Open the valve at the bottom of the raw material tanks and feed solutions A, B, and C separately into tanks A, B, and C using a feed pump. Set the flow rates for tank A to 5 mL / min, B to 8 mL / min, and C to 8 mL / min using a counting pump. Preheat the solutions A, B, and C by setting the heat exchanger temperature to 25°C and maintaining the reaction time in the channel for 180 s. After the reaction, collect a sample from the outlet of the microchannel reactor to obtain a mixture containing target compound III. Remove the solvent under reduced pressure, dissolve the residue in 100 mL of glacial acetic acid, and heat under reflux for 1 h. Then dilute with 300 mL of water and neutralize with concentrated ammonia. Extract with ethyl acetate, concentrate under vacuum, and purify the crude product by silica gel column chromatography to obtain compound III with a yield of 96.9% and a purity of 99.5%.

[0044] (2) Synthesis of Compound I

[0045] Preparation of material D solution: Add compound III (18.38 g, 56.6 mmol) to tetrahydrofuran, dilute to 100 mL, stir well, and place in raw material tank D;

[0046] Preparation of material E solution: Add compound II (10 g, 51.5 mmol) to tetrahydrofuran, dilute to 50 mL, stir well, and place in raw material tank E;

[0047] Preparation of material F solution: Triethylamine (6.25 g, 61.8 mmol) was added to tetrahydrofuran, diluted to 50 mL, stirred evenly, and placed in raw material tank F;

[0048] Open the valve at the bottom of the raw material tanks, and feed the solutions D, E, and F from raw material tanks D, E, and F respectively using a feed pump. Set the flow rates of raw material tank D to 10 mL / min, E to 5 mL / min, and F to 5 mL / min using a counting pump. Then, preheat the solutions D, E, and F by setting the heat exchanger temperature to 25°C and maintaining the reaction time in the channel for 180 s. After the reaction, collect the sample from the outlet of the microchannel reactor to obtain a mixture containing target compound I. Dilute the reaction mixture with water (150 mL), extract with dichloromethane (200 mL), and separate the liquid phase. Wash the organic phase sequentially with 2N hydrochloric acid and water, dry with sodium sulfate, and concentrate under reduced pressure. Purify the residue by column chromatography to obtain compound I with a yield of 94.8% and a purity of 99.4%.

[0049] Example 2

[0050] (1) Synthesis of Compound III

[0051] Preparation of material A solution: Add compound V (15g, 81.2mmol) to dichloromethane, dilute to 50mL, stir well, and place in raw material tank A;

[0052] Preparation of material B solution: Add compound IV (14.31 g, 81.2 mmol) to dichloromethane, dilute to 80 mL, stir well, and place in raw material tank B;

[0053] Preparation of material C solution: N,N'-dicyclohexylcarbodiimide (16.76 g, 81.2 mmol) was added to dichloromethane, diluted to 80 mL, stirred evenly, and placed in raw material tank C;

[0054] Open the valve at the bottom of the raw material tanks and feed solutions A, B, and C separately into tanks A, B, and C using a feed pump. Set the flow rates for tank A to 5 mL / min, B to 8 mL / min, and C to 8 mL / min using a counting pump. Preheat the solutions A, B, and C by setting the heat exchanger temperature to 50°C and maintaining the reaction time in the channel for 60 s. After the reaction, collect the sample from the outlet of the microchannel reactor to obtain a mixture containing target compound III. Remove the solvent under reduced pressure, dissolve the residue in 100 mL of glacial acetic acid, and heat under reflux for 1 h. Then dilute with 300 mL of water and neutralize with concentrated ammonia. Extract with ethyl acetate, concentrate under vacuum, and purify the crude product by silica gel column chromatography to obtain compound III with a yield of 93.2% and a purity of 99.4%.

[0055] (2) Synthesis of Compound I

[0056] Preparation of material D solution: Add compound III (25.07 g, 77.2 mmol) to dichloromethane, dilute to 100 mL, stir well, and place in raw material tank D;

[0057] Preparation of material E solution: Add compound II (10g, 51.5mmol) to dichloromethane, dilute to 50mL, stir well, and place in raw material tank E;

[0058] Preparation of material F solution: Add potassium carbonate (14.23 g, 103 mmol) to dichloromethane, dilute to 50 mL, stir well, and place in raw material tank F;

[0059] Open the valve at the bottom of the raw material tanks, and feed the solutions D, E, and F from raw material tanks D, E, and F respectively using a feed pump. Set the flow rates of raw material tank D to 10 mL / min, E to 5 mL / min, and F to 5 mL / min using a counting pump. Then, preheat the solutions D, E, and F by setting the heat exchanger temperature to 10°C and maintaining the reaction time in the channel for 240 s. After the reaction, collect the sample from the outlet of the microchannel reactor to obtain a mixture containing target compound I. Dilute the reaction mixture with water (150 mL), extract with dichloromethane (200 mL), and wash the organic phase sequentially with 2N hydrochloric acid and water, dry with sodium sulfate, and concentrate under reduced pressure. Purify the residue by column chromatography to obtain compound I with a yield of 92.5% and a purity of 99.3%.

[0060] Example 3

[0061] (1) Synthesis of Compound III

[0062] Preparation of material A solution: Add compound V (15g, 81.2mmol) to N,N-dimethylformamide, dilute to 50mL, stir well, and place in raw material tank A;

[0063] Preparation of material B solution: Add compound IV (21.45 g, 121.8 mmol) to N,N-dimethylformamide, dilute to 80 mL, stir well, and place in raw material tank B;

[0064] Preparation of material C solution: N,N'-carbonylbis(1,2,4-triazole) (19.98 g, 121.7 mmol) was added to N,N-dimethylformamide, diluted to 80 mL, stirred evenly, and placed in raw material tank C;

[0065] Open the valve at the bottom of the raw material tanks and feed solutions A, B, and C separately into tanks A, B, and C using a feed pump. Set the flow rates for tank A to 5 mL / min, B to 8 mL / min, and C to 8 mL / min using a counting pump. Preheat the solutions A, B, and C by setting the heat exchanger temperature to 10°C and maintaining the reaction time in the channel for 300 s. After the reaction, collect a sample from the outlet of the microchannel reactor to obtain a mixture containing target compound III. Remove the solvent under reduced pressure, dissolve the residue in 100 mL of glacial acetic acid, and heat under reflux for 1 h. Then dilute with 300 mL of water and neutralize with concentrated ammonia. Extract with ethyl acetate, concentrate under vacuum, and purify the crude product by silica gel column chromatography to obtain compound III with a yield of 91.4% and a purity of 99.3%.

[0066] (2) Synthesis of Compound I

[0067] Preparation of material D solution: Add compound III (16.73 g, 51.5 mmol) to toluene, dilute to 100 mL, stir well, and place in raw material tank D;

[0068] Preparation of material E solution: Add compound II (10g, 51.5mmol) to toluene, dilute to 50mL, stir well, and place in raw material tank E;

[0069] Preparation of material F solution: Sodium bicarbonate (4.33 g, 51.5 mmol) was added to toluene, diluted to 50 mL, stirred evenly, and placed in raw material tank F;

[0070] Open the valve at the bottom of the raw material tanks and feed the solutions D, E, and F from raw material tanks D, E, and F respectively using a feed pump. Set the flow rates of raw material tank D to 10 mL / min, E to 5 mL / min, and F to 5 mL / min using a counting pump. Then, preheat the solutions D, E, and F by setting the heat exchanger temperature to 50°C and maintaining the reaction time in the channel for 80 s. After the reaction, collect the sample from the outlet of the microchannel reactor to obtain a mixture containing target compound I. Dilute the reaction mixture with water (150 mL), extract with dichloromethane (200 mL), and wash the organic phase sequentially with 2N hydrochloric acid and water, dry with sodium sulfate, and concentrate under reduced pressure. Purify the residue by column chromatography to obtain compound I with a yield of 90.2% and a purity of 99.2%.

[0071] 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 process for the preparation of a dabigatran intermediate by the microchannel process, characterized by: The synthetic route is as follows: ， The method comprises the following steps: (1) preparing compound III in a continuous flow microchannel reactor Preparation of material A solution: compound V is mixed with a solvent, stirred uniformly, and prepared for use; Preparation of material B solution: compound IV is mixed with a solvent, stirred uniformly, and prepared for use; Preparation of material C solution: a condensing agent is mixed with a solvent, stirred uniformly, and prepared for use; The material A solution, the material B solution and the material C solution are pumped into the microchannel reactor at a preset flow rate, the heat exchanger temperature of the microchannel reactor is set to 10-50 DEG C, the reaction time in the microchannel reactor is set to 60-300 s, and the preset flow rate of the material A solution, the material B solution and the material C solution is 5-8 mL / min; the product containing compound III is obtained from the outlet of the microchannel reactor; and then compound III is obtained through post-treatment; (2) preparing compound I in a continuous flow microchannel reactor Preparation of material D solution: compound III is mixed with a solvent, stirred uniformly, and prepared for use; Preparation of material E solution: compound II is mixed with a solvent, stirred uniformly, and prepared for use; Preparation of material F solution: a base is mixed with a solvent, stirred uniformly, and prepared for use; The material D solution, the material E solution and the material F solution are pumped into the microchannel reactor at a preset flow rate, the heat exchanger temperature of the microchannel reactor is set to 10-50 DEG C, the reaction time in the microchannel reactor is set to 80-240 s, and the preset flow rate of the material D solution, the material E solution and the material F solution is 5-10 mL / min; the product containing compound I is obtained from the outlet of the microchannel reactor; and then compound I is obtained through post-treatment.

2. The process for the preparation of a dabigatran intermediate according to claim 1, characterized in that: In the step (1), the condensing agent is any one of 1,1'-carbonyldiimidazole, N,N'-dicyclohexyl carbodiimide or N,N'-carbonyl di(1,2,4-triazole).

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

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

5. The process for the microchannel process for the preparation of a dabigatran intermediate according to claim 1, characterized in that: In the step (1), the reaction temperature is 20-40 DEG C; and the reaction time is 80-260 s.

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

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

8. The process for the preparation of a dabigatran intermediate according to claim 1, characterized in that: In the step (2), the solvent is one or more of tetrahydrofuran, dichloromethane, trichloromethane, toluene or ethyl acetate.

9. The process for the microchannel process for the preparation of a dabigatran intermediate according to claim 1, characterized in that: In the step (2), the reaction temperature is 20-40 DEG C; and the reaction time is 100-220 s.

Images