Preparation process of dabigatran etexilate intermediate
By optimizing the synthesis route of dabigatran ester in an acidic environment, controlling the reaction conditions and solvent selection, the problem of by-product generation in the benzimidazole ring formation step is solved, and a high yield and high purity dabigatran ester intermediate preparation is achieved.
Patent Information
- Application Number
- CN202510196547.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-21
- Publication Date
- 2025-05-27
AI Technical Summary
The benzimidazole ring forming step in the existing dabigatran ester synthesis route produces by-products, affecting product yields and increasing preparation costs.
The compound of formula III is reacted with S-2-bromoethylthiomethyl ester in an acidic environment to form the compound of formula II, and then react with p-aminobenzidine in a polar aprotic solvent to form the compound of formula I, and optimize the cyclization process by controlling the reaction conditions and solvent selection to reduce side reactions.
The product yield and purity of the dabigatran ester intermediate is improved, and the preparation cost is reduced.
Smart Images
Figure CN120040417A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to a preparation process of a dabigatran etexilate intermediate, belonging to the field of preparation of pharmaceutical intermediates. Background Art
[0002] Dabigatran etexilate, a new anticoagulant drug developed by Boehringer Ingelheim GmbH, Germany, with the chemical name of ethyl 3-[[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionate. Dabigatran etexilate is a synthetic direct thrombin inhibitor and a prodrug of dabigatran. It is used to prevent stroke and systemic embolism in patients with non-valvular atrial fibrillation. After oral absorption, it is converted in vivo into dabigatran that binds to the specific fibrin-binding site of thrombin, preventing fibrinogen from being cleaved into fibrin, thus blocking the last step of the coagulation cascade network and thrombus formation.
[0003] In the existing production processes, the synthetic routes all contain a benzimidazole ring-forming step, which usually produces additional reactions to generate by-products, affecting the yield of the final product, causing waste of raw materials and increasing the preparation cost. The specific reaction steps are as follows:
[0004] Summary of the Invention
[0005] Aiming at the above defects existing in the prior art, the present invention provides a preparation process of a dabigatran etexilate intermediate, and the problem to be solved is how to achieve a preparation method with increased product yield.
[0006] The object of the present invention is achieved through the following technical solutions. A preparation process of a dabigatran etexilate intermediate, the preparation method comprising:
[0007] S1: Reacting a compound of formula III with S-2-bromoethyl thioacetate under reflux in an acidic environment to form a compound of formula II;
[0008] S2: Reacting the compound of formula II with 4-aminobenzonitrile by heating in a polar aprotic solvent to form a compound of formula I.
[0009] In the present invention, the ortho - amino group in the compound of formula III that is not substituted by a methyl group first undergoes a nucleophilic attack on the carbonyl carbon of S - 2 - bromoethyl thioester, substituting the methylthio group to form a thioamide intermediate. The intermediate then eliminates methanethiol to form an imine structure, namely the compound of formula II, while releasing an acidic proton. The methyl - substituted amino group acts as a nucleophile to attack the carbon atom of the imine, accompanied by the elimination of a molecule of water to form a five - membered imidazole ring. The overall reaction route is relatively smooth and the product yield is relatively high.
[0010] Further, in step S1, the reaction solvent is one of methanol and ethanol.
[0011] Further, in step S1, one of hydrochloric acid and acetic acid is used as the catalyst.
[0012] One hydrogen in the amino group of the compound of formula III is substituted by a methyl group, so it is a secondary amine with slightly weaker nucleophilicity. The bromine in 2 - bromoethyl thioester is a good leaving group and is prone to nucleophilic substitution under basic conditions. If there is a base in the reaction conditions, it will promote the attack of the amino group on the bromine, resulting in the formation of N - alkylated products rather than cyclization. In an acidic environment, the amino group (-NH -) is protonated to an ammonium ion (-NH 2 + ), significantly reducing its nucleophilicity.
[0013] Moreover, the cyclization in the present invention is an intramolecular process (the amino group attacks the carbonyl carbon of the thioester), and its reaction rate is much higher than the intermolecular side reaction (the substitution of the amino group with bromine). By slowly adding the reactants, the probability of intermolecular collision is reduced, and the substitution reaction of the amino group with bromine can be greatly reduced.
[0014] Further, in step S1, the pH of the reaction environment is ≤2.
[0015] Further, in step S2, the polar aprotic solvent is one of DMF, DMAc, and DMSO.
[0016] Further, in step S2, the reaction temperature is 30 - 80 °C.
[0017] Further, in step S2, one of potassium carbonate and calcium carbonate is added in the reaction to promote the intramolecular cyclization step through deprotonation.
[0018] In summary, compared with the prior art, the present invention has the following advantages:
[0019] In the present invention, by optimizing the reaction conditions, the side reactions in the cyclization reaction are reduced, ensuring a relatively high reaction yield and product purity. BRIEF DESCRIPTION OF THE DRAWINGS
[0020] Figure 1This is the overall synthetic route of the present invention. Detailed implementation manners
[0021] The technical solution of the present invention will be further specifically described below through specific embodiments, but the present invention is not limited to these embodiments.
[0022] A preparation process of a dabigatran etexilate intermediate, the preparation method comprising: S1: reacting a compound of formula III with S-2-bromoethyl thioacetate under reflux in an acidic environment to form a compound of formula II;
[0023] S2: reacting the compound of formula II with 4-aminobenzonitrile by heating in a polar aprotic solvent to form a compound of formula I.
[0024] Preferably, in step S1, the reaction solvent is one of methanol and ethanol.
[0025] Preferably, in step S1, one of hydrochloric acid and acetic acid is used as a catalyst.
[0026] Preferably, in step S1, the pH of the reaction environment is ≤2.
[0027] Preferably, in step S2, the polar aprotic solvent is one of DMF, DMAc, and DMSO.
[0028] Preferably, in step S2, the reaction temperature is 30-80 °C.
[0029] Preferably, in step S2, one of potassium carbonate and calcium carbonate is added during the reaction to promote the intramolecular cyclization step through deprotonation
[0030] Examples
[0031] 34.4 g of the compound of formula III was put into a reaction flask, 150 ml of methanol was added, and the mixture was stirred until completely dissolved. HCl was added to adjust the pH of the reaction system to 2. 20.2 g of S-2-bromoethyl thioacetate was dissolved in 50 mL of methanol solution to prepare a mixed solution, and the mixed solution was slowly added dropwise to the reaction flask, and the mixture was heated to reflux for 6 h. After the reaction was completed, it was cooled to room temperature, filtered by suction, the filter cake was washed with tetrahydrofuran, and after drying, 44.91 g of the compound of formula II was obtained, with a yield of 97.2% and an HPLC purity of 97.5%.
[0032] 37 g of the compound of Formula II was charged into a container, 100 mL of DMF was added, and after stirring to dissolve, the temperature was raised to 30 °C. 11.3 g of 4-aminobenzonitrile, 1.3 g of potassium iodide, and 1.66 g of potassium carbonate were added and reacted for 5 h, and then heated to 90 °C and reacted for 2 h. A large amount of ice water was added to quench the reaction, and the mixture was precipitated at room temperature for 0.5 h, filtered by suction, the filter cake was washed with water, dried, recrystallized with ethyl acetate, and dried under vacuum to obtain 33.3 g of the compound of Formula I, with a yield of 86.4% and a purity of 98%.
[0033] The embodiments of the present invention are not limited to those described in the above embodiments. Without departing from the spirit and scope of the present invention, those of ordinary skill in the art can make various changes and improvements in form and detail, and all of these are considered to fall within the protection scope of the present invention.
Claims
1. A preparation technology of a dabigatran etexilate intermediate, characterized in that, The preparation method comprises: S1: reacting the compound of formula III with S-2-bromoethylthiomethyl ester under reflux in an acidic environment to generate a compound of formula II; S2: heating the compound of formula II and p-aminobenzonitrile in a polar aprotic solvent to react to generate a compound of formula I.
2. the preparation technology of a kind of dabigatran etcxilate intermediate according to claim 1, is characterized in that: In the step S1, the reaction solvent is one of methanol and ethanol.
3. the preparation technology of a kind of dabigatran etcxilate intermediate according to claim 2, is characterized in that: In the step S1, one of hydrochloric acid and acetic acid is used as a catalyst.
4. the preparation technology of a kind of dabigatran etcxilate intermediate according to claim 1, is characterized in that: In the step S1, the pH of the reaction environment is ≤2.
5. the preparation technology of a kind of dabigatran etcxilate intermediate according to claim 1, is characterized in that: In the step S2, the polar aprotic solvent is one of DMF, DMAc and DMSO.
6. the preparation technology of a kind of dabigatran etcxilate intermediate according to claim 1, is characterized in that: In step S2, the reaction temperature is 30-80°C.
7. the preparation technology of a kind of dabigatran etcxilate intermediate according to claim 1, is characterized in that: In step S2, one of potassium carbonate and calcium carbonate is added to the reaction to promote the intramolecular cyclization step through deprotonation.