Process for preparing dabigatran etexilate intermediate through microchannel reactor
By using a continuous flow microchannel reactor in the preparation of dabigatran ester intermediates, the problems of long reaction time, low yield and high cost in the existing process are solved, and efficient and high-speed intermediate synthesis is achieved, which is suitable for the use of high-quality intermediates. Industrial application.
Patent Information
- Application Number
- CN202411342089.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-25
- Publication Date
- 2025-01-03
AI Technical Summary
The existing dabigatran ester intermediate has a long reaction time, low yield, cumbersome reaction process and high cost, making it difficult to be suitable for industrial production.
The continuous flow microchannel reactor is adopted to control the reaction temperature and time through a multi-step flow reaction process, and the use of appropriate catalysts and solvents to shorten the reaction time and improve product yield and purity.
It significantly shortens the reaction time, improves the yield and purity of the product, reduces by-products, is suitable for industrial continuous production, and reduces production costs.
Smart Images
Figure CN119241506A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to a process for preparing a dabigatran etexilate intermediate by using a microchannel reactor, and belongs to the technical field of drug intermediate synthesis. Background Art
[0002] Dabigatran etexilate, chemically named 3-[[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester, was developed by German Boehringer Ingelheim Company and approved by the European Commission in March 2008 for marketing in Germany and the United Kingdom under the trade name Pradaxa, which is clinically used to prevent venous thromboembolism in patients after total hip or total knee replacement. Dabigatran etexilate is a new type of direct thrombin inhibitor and a prodrug of dabigatran, which has the advantages of oral administration, strong efficacy, no need for special medication monitoring and few drug interactions.
[0003] Formula I compound is an important intermediate for preparing dabigatran etcxilate medicine, and the following synthetic route is generally adopted in the prior art: The above reaction requires a three-step reaction in a tank reactor to obtain the target compound. The reaction takes several hours, has a high time cost, and has a low synthesis efficiency.
[0004] Wherein, about the third step reaction, a kind of preparation method of dabigatran etcxilate intermediate cyclization product is disclosed in patent CN104844571A, specifically comprising the following steps: (1) ((4-cyano) phenyl) aminoacetic acid (II), carbonyl diimidazole and the first solvent are added to reaction flask, and it is warming up to T1 to carry out the first reaction, and the reaction time is t1; (2) 3-((3-amino-4-methylbenzoyl) pyridine-2-amino) ethyl propionate is added to be warming up to T2 to continue the second reaction, and the reaction time is t2; (3) it is warming up to T3 to continue the third reaction, and the reaction time is t3; (4) the first solvent is boiled off to obtain the cyclization product crude product, and the second solvent is added to recrystallize and refine to obtain the dabigatran etcxilate intermediate cyclization product (I). It can be seen from the technical scheme that the third step reaction needs to go through three temperature-raising processes, and the reaction history is extremely loaded down with trivial details, and the production cost is relatively high, and it is not suitable for industrialized production. Summary of the invention
[0005] The present invention aims at the defects existing in the above prior art and provides a process for preparing a dabigatran etexilate intermediate by a microchannel reactor, which solves the problems that the existing preparation process has a long reaction time, a low yield, a complicated reaction process and a high cost.
[0006] The objective of the present invention is achieved by the following technical scheme, a green synthesis method of an aliskiren intermediate, the method comprising the following steps: S1: Preparation of compound III in a continuous flow microchannel reactor; Preparation of material solution A: Mix the compound of formula V with a solvent, stir evenly, and set aside; Preparation of material solution B: Mix the compound of formula IV with the solvent, stir evenly, and set aside; Preparation of material solution C: Mix the catalyst and the solvent, stir evenly, and set aside; The material solution A, the material solution B and the material solution C are respectively pumped into the microchannel reactor at a preset flow rate, the heat exchanger temperature of the microchannel reactor is set at 40-50° C., and the reaction time of the microchannel reactor is set at 180-360 s; a product containing the compound of formula III is obtained from the outlet of the microchannel reactor, and the compound of formula III is obtained after post-treatment; S2: preparing compound I in a continuous flow microchannel reactor; Preparation of material solution D: Mix the compound of formula III with the solvent, stir evenly, and set aside; Preparation of material solution E: Mix the compound of formula II with the solvent, stir evenly, and set aside; Preparation of material solution F: Mix the alkali and the solvent, stir evenly, and set aside; The material solution D, the material solution E and the material solution F are respectively pumped into the microchannel reactor at a preset flow rate, 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 the compound of formula I is obtained from the outlet of the microchannel reactor, and the compound of formula I is obtained after post-treatment.
[0007] Furthermore, in step S1, the catalyst is selected from one of trimethylsilyl iodide and trimethylsilyldiazomethane.
[0008] Furthermore, in step S1, the solvent is one or more of tetrahydrofuran, dichloromethane, toluene, N,N-dimethylformamide, ethyl acetate, and isopropyl acetate.
[0009] Furthermore, in step S1, the mass molar ratio of the compound of formula V, the compound of formula IV and the catalyst is 1:1.2-1.6:1.44-1.92.
[0010] Furthermore, in step S1, the reaction temperature is 43-48° C., and the reaction time is 240-320 s.
[0011] Furthermore, in step S2, the molar ratio of the compound of formula II, the compound of formula III and the base is 1:1.2~1.5:1.44~2.
[0012] Furthermore, in step S2, the base is any one of triethylamine, pyridine, and triphenylphosphine.
[0013] Furthermore, in step S2, the solvent is one or more of tetrahydrofuran, dichloromethane, chloroform, toluene or ethyl acetate.
[0014] Furthermore, in step S2, the reaction temperature is 30-40° C., and the reaction time is 150-200 s.
[0015] Furthermore, the preset flow rates of the material solution A, the material solution B and the material solution C are 5 to 8 mL / min; the preset flow rates of the material solution D, the material solution E and the material solution F are 5 to 10 mL / min.
[0016] In summary, compared with the prior art, the present invention has the following advantages: 1. In the present invention, a continuous flow microchannel reactor is used for the preparation of a dabigatran etexilate intermediate, which greatly shortens the reaction time and can control the reaction time to within several hundred seconds. At the same time, the target product obtained by the continuous flow reaction process has the characteristics of high yield and high purity.
[0017] 2. In the present invention, the preparation method has few by-products, can be produced continuously, has a high degree of automation, and has good prospects for industrial application. BRIEF DESCRIPTION OF THE DRAWINGS
[0018] Figure 1 This is the synthetic route of the present invention. DETAILED DESCRIPTION
[0019] The technical solution of the present invention is further specifically described below through specific embodiments, but the present invention is not limited to these embodiments.
[0020] (1) Synthesis of compound of formula III: Prepare material solution A: add the compound of formula V (22.46 g, 0.1 mol) into 80 mL of tetrahydrofuran, stir evenly, and place in raw material tank 1; Prepare material solution B: add the compound of formula IV (14.18 g, 0.12 mol) into 50 mL of tetrahydrofuran, stir evenly, and place in raw material tank 2; Prepare material solution C: add trimethylsilyl iodide (28.81 g, 0.144 mol) into 80 mL of tetrahydrofuran, stir evenly, and place in raw material tank 3; Open the valve at the bottom of the raw material tank, and use the feed pump to deliver material solution A in raw material tank 1, material solution B in raw material tank 2, and material solution C in raw material tank 3 respectively. Use the counting pump to set the flow rate of raw material tank 1 to 5 mL / min, the flow rate of raw material tank 2 to 8 mL / min, and the flow rate of raw material tank 3 to 8 mL / min. Then preheat material solution A, material solution B, and material solution C, set the temperature of the heat exchanger to 43°C, and maintain the reaction time in the channel for 240 s.
[0021] After the reaction is completed, a sample is collected from the outlet of the microchannel reactor to obtain a target mixture containing a compound of formula III, the solvent is removed under reduced pressure, the residue is dissolved in 150 mL of acetic acid, heated to reflux for 30 min, and after the reaction is completed and cooled, it is diluted with 300 mL of water and then neutralized with triethylamine. Ethyl acetate is used for extraction, vacuum concentration, and the crude product is purified by silica gel column chromatography to obtain 29 g of a compound of formula III, with a product yield of 94.7% and a product purity of 99.5%.
[0022] (2) Synthesis of the compound of formula I: Preparation of material solution D: Add the compound of formula III (24.51 g, 0.08 mol) into 100 mL of tetrahydrofuran, stir evenly, and place in raw material tank 4; Preparation of material solution E: Add the compound of formula II (12.95 g, 0.067 mol) into 50 mL of tetrahydrofuran, stir evenly, and place in raw material tank 5; Prepare material solution F: add triethylamine (9.71 g, 0.096 mol) into 50 mL of tetrahydrofuran, stir evenly, and place in raw material tank 6; Open the valve at the bottom of the raw material tank, and use the feed pump to deliver material solution D in raw material tank 4, material solution E in raw material tank 5, and material solution F in raw material tank 6 respectively. Use the counting pump to set the flow rate of raw material tank 4 to 5 mL / min, the flow rate of raw material tank 5 to 10 mL / min, and the flow rate of raw material tank 6 to 8 mL / min, then preheat material solution D, material solution E, and material solution F, set the temperature of the heat exchanger to 30°C, and maintain the reaction time in the channel for 150 s.
[0023] After the reaction was completed, a sample was taken from the outlet of the microchannel reactor to obtain a target mixture containing compound I, the reaction mixture was diluted with water, the liquid was extracted with dichloromethane, the organic phase was washed with 2N hydrochloric acid and water in sequence, dried with sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 45.65 g of compound I, the product yield was 95%, and the product purity was 99.4%.
[0024] This example is a comparative example of Example 1, wherein the mass molar ratio of the compound of formula V, the compound of formula IV and the catalyst is 1:1.6:1.92, and other conditions remain unchanged, to obtain 29.07 g of the compound of formula III, the product yield is 94.9%, and the product purity is 99.5%.
[0025] This example is a comparative example of Example 1, wherein the molar ratio of the compound of formula II, the compound of formula III and the base is 1:1.5:2, and the other conditions remain unchanged, to obtain 45.75 g of the compound of formula I, with a product yield of 95.2% and a product purity of 99.4%.
[0026] The implementation of the present invention is not limited to the above-mentioned embodiments. Without departing from the spirit and scope of the present invention, ordinary technicians in this field can make various changes and improvements to the present invention in form and detail, and these are considered to fall within the protection scope of the present invention.
Claims
1. a process for preparing a dabigatran etcxilate intermediate by microchannel reactor, characterized in that, The method comprises the following steps: S1: Preparation of compound III in a continuous flow microchannel reactor; Preparation of material solution A: Mix the compound of formula V with a solvent, stir evenly, and set aside; Preparation of material solution B: Mix the compound of formula IV with the solvent, stir evenly, and set aside; Preparation of material solution C: Mix the catalyst and the solvent, stir evenly, and set aside; The material solution A, the material solution B and the material solution C are respectively pumped into the microchannel reactor at a preset flow rate, the heat exchanger temperature of the microchannel reactor is set at 40-50° C., and the reaction time of the microchannel reactor is set at 180-360 s; a product containing the compound of formula III is obtained from the outlet of the microchannel reactor, and the compound of formula III is obtained after post-treatment; S2: preparing compound I in a continuous flow microchannel reactor; Preparation of material solution D: Mix the compound of formula III with the solvent, stir evenly, and set aside; Preparation of material solution E: Mix the compound of formula II with the solvent, stir evenly, and set aside; Preparation of material solution F: Mix the alkali and the solvent, stir evenly, and set aside; The material solution D, the material solution E and the material solution F are respectively pumped into the microchannel reactor at a preset flow rate, 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 the compound of formula I is obtained from the outlet of the microchannel reactor, and the compound of formula I is obtained after post-treatment.
2. a kind of technology of preparing dabigatran etcxilate intermediate by micro passage reactor according to claim 1, is characterized in that: In the step S1, the catalyst is selected from one of trimethylsilyl iodide and trimethylsilyldiazomethane.
3. a kind of technology of preparing dabigatran etcxilate intermediate by micro passage reactor according to claim 1, is characterized in that: In the step S1, the solvent is one or more of tetrahydrofuran, dichloromethane, toluene, N,N-dimethylformamide, ethyl acetate, and isopropyl acetate.
4. a kind of technology of preparing dabigatran etcxilate intermediate by micro passage reactor according to claim 1, is characterized in that: In the step S1, the mass molar ratio of the compound of formula V, the compound of formula IV and the catalyst is 1:1.2-1.6:1.44-1.
92.
5. a kind of technology of preparing dabigatran etcxilate intermediate by micro passage reactor according to claim 1, is characterized in that: In the step S1, the reaction temperature is 43-48° C., and the reaction time is 240-320 s.
6. a kind of technology of preparing dabigatran etcxilate intermediate by micro passage reactor according to claim 1, is characterized in that: In the step S2, the molar ratio of the compound of formula II, the compound of formula III and the base is 1:1.2-1.5:1.44-2.
7. a kind of technology of preparing dabigatran etcxilate intermediate by micro passage reactor according to claim 1, is characterized in that: In the step S2, the base is any one of triethylamine, pyridine, and triphenylphosphine.
8. a kind of technology of preparing dabigatran etcxilate intermediate by micro passage reactor according to claim 1, is characterized in that: In step S2, the solvent is one or more of tetrahydrofuran, dichloromethane, chloroform, toluene or ethyl acetate.
9. a kind of technology of preparing dabigatran etcxilate intermediate by micro passage reactor according to claim 1, is characterized in that: In step S2, the reaction temperature is 30-40° C., and the reaction time is 150-200 s.
10. a kind of technology of preparing dabigatran etcxilate intermediate by microchannel reactor according to claim 1, is characterized in that: The preset flow rates of the material solution A, material solution B and material solution C are 5 to 8 mL / min; the preset flow rates of the material solution D, material solution E and material solution F are 5 to 10 mL / min.