A method for preparing an amidine intermediate of dabigatran etexilate
Through the catalytic synthesis method of p-aminobenzaldehyde and ammonia gas and with chloroformate n-hexyl lipid, the problems of many by-products and complex operations in the prior art are solved, and high product yield and reaction selectivity are achieved, which is suitable for industrial production.
Patent Information
- Application Number
- CN202411951211.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-27
- Publication Date
- 2025-04-01
AI Technical Summary
There are problems in the synthesis process of existing dabigatran ester amidine intermediates with many by-products, complex operations and harsh reaction conditions, making it difficult to achieve high product yield and reaction selectivity.
The Schiff base reaction was performed with p-aminobenzaldehyde and ammonia gas to obtain an imine compound, followed by reaction with n-hexyl chloroformate, and a scandium metal catalyst and triethylamine were used as activator and base catalyst to obtain an amidine compound.
It reduces the generation of by-products, improves the reaction selectivity and product purity, is simple to operate, mild reaction conditions, and is suitable for industrial production.
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Figure CN119735526A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to a method for preparing an amidine intermediate of dabigatran etexilate, and belongs to the field of preparation of drug intermediates. Background Art
[0002] Dabigatran etexilate is a new type of anticoagulant drug developed by Boehringer Ingelheim in Germany. In April 2008, it was first launched in Germany and the UK under the trade name Pradaxa for the prevention and treatment of acute venous thrombosis. It is the first new type of oral anticoagulant drug launched in the market in 50 years after warfarin. It is a non-peptide thrombin inhibitor and a prodrug of dabigatran. After oral gastrointestinal absorption, it is converted into dabigatran with direct anticoagulant activity in the body, which binds to the fibrin-specific binding site of thrombin, preventing fibrinogen from being cleaved into fibrin, thereby blocking the last step of the coagulation waterfall network and thrombosis.
[0003] The synthesis process of dabigatran lipid in the prior art includes the synthesis process of amidine compound intermediates. Patent document CN105669651 records a synthesis method of amidine intermediate compounds by strong base catalysis. The scheme adopts Pinner reaction under strong alkaline conditions to prepare another amidine intermediate compound p-chlorobenzamidine, avoiding the use of highly corrosive hydrogen chloride reagents. This route has certain industrial application potential, but still needs to solve the stability problem of amino-substituted benzimidazole intermediates to avoid cumbersome operations such as repeated salt formation and dissociation; at the same time, the Pinner amidination reaction under a strong alkaline environment has more by-products and more stringent conditions. The reaction route is as follows: .
[0004] Therefore, there is an urgent need to find a synthesis method with fewer by-products, simple operation, mild reaction and good reaction selectivity. Summary of the invention
[0005] The present invention aims at the defects existing in the above prior art and provides a method for preparing an amidine intermediate of dabigatran etexilate, which solves the problem of how to realize a preparation method which increases product yield, reduces by-product generation and improves reaction selectivity.
[0006] The objective of the invention is to be achieved through the following technical solutions, a method for preparing an amidine intermediate of dabigatran etcxilate, the method comprising the following steps: S1: dissolving p-aminobenzaldehyde, a compound of formula I, in an organic solvent, stirring and mixing, adding an amination reagent dropwise, heating under reflux for reaction, and separating the product after the reaction is completed to obtain a compound of formula II; S2: dissolving the compound of formula II in an organic solvent, adding an activating agent, then adding the compound of formula III, n-hexyl chloroformate, adding a base catalyst, heating for reaction, and separating the product after the reaction is completed to obtain the compound of formula IV.
[0007] The preparation route of the present invention is: The invention aims to provide a method for preparing an amidine intermediate of dabigatran etexilate, which avoids the corrosion of equipment by using strong acid, uses p-aminobenzaldehyde as a raw material to react with ammonia to produce an imine compound, i.e., a compound of formula II, and reacts the compound of formula II with n-hexyl chloroformate after activation to produce an amidine compound. The reaction route has a single substituent, avoids the generation of many by-products by the reaction, and is simple to operate, has mild reaction conditions, good reaction selectivity, low pollution, and is suitable for industrial production.
[0008] In the above-mentioned method for preparing amidine intermediates, preferably, in step S2, the activator used in the reaction is one of a complex of rare earth metal element scandium complexed with C5Me4SiMe3 ligand, Cp3Sc, and Cp2TiMe.
[0009] In the above-mentioned method for preparing the amidine intermediate, preferably, the activator is a completely coordinated compound, the activator is a completely coordinated compound, the coordination ratio of C5Me4SiMe3 and the rare earth metal element scandium (Sc) complex is 1:6, the coordination ratio of cyclopentadienyl (Cp) ligand and scandium (Sc) is 3:1, and the coordination ratio of cyclopentadienyl (Cp) ligand to methyl and titanium (Ti) is 2:1:1.
[0010] In the above-mentioned method for preparing amidine intermediates, preferably, in step S1, the organic solvent used in the reaction is one of ethanol, methanol, toluene, benzene and benzyl alcohol; in step S2, the organic solvent used in the reaction is one of toluene, benzene and ethanol.
[0011] Furthermore, the organic solvent used in the reaction in step S1 is ethanol, and the organic solvent used in the reaction in step S2 is toluene.
[0012] In the above-mentioned method for preparing amidine intermediates, preferably, in step S2, the base catalyst is one of triethylamine and pyridine.
[0013] Furthermore, in step S2, the base catalyst is triethylamine.
[0014] In the above-mentioned method for preparing the amidine intermediate, preferably, in the step S1, the reaction condition is to react under reflux for 6 to 8 hours; in the step S2, the reaction condition is to react under reflux for 10 to 12 hours.
[0015] Furthermore, in step S1, the reaction condition is to react under reflux for 6 hours, and in step S2, the reaction condition is to react under reflux for 10 hours.
[0016] In the above-mentioned method for preparing the amidine intermediate, preferably, in step S1, the amination reagent used in the reaction is aqueous ammonia.
[0017] In the above-mentioned method for preparing the amidine intermediate, preferably, in step S2, the amount of the activator and the catalyst used are both 5-10 mol% of the compound of formula II.
[0018] Furthermore, in step S2, the amount of the activator and the catalyst used is 8 mol% of the compound of formula II.
[0019] In the above-mentioned method for preparing amidine intermediates, preferably, in step S2, the molar ratio of the compound of formula II to the compound of formula III and the catalyst is 1:1 to 1.5.
[0020] Furthermore, in step S2, the molar ratio of the compound of formula II to the compound of formula III and the catalyst is 1:1.2.
[0021] In summary, compared with the prior art, the present invention has the following advantages: In the present invention, the problem of corrosion to equipment caused by reagents such as hydrogen chloride is avoided, the single amine substituent effectively reduces the generation of reaction by-products, reduces the pollution of the amidination reaction, and at the same time increases the selectivity of the amidination reaction, improves the atom economy of the reaction, and the obtained product is easy to separate, the process operation is simple, the reaction conditions are mild, and the requirements of green chemistry are met. BRIEF DESCRIPTION OF THE DRAWINGS
[0022] Figure 1 This is the overall synthesis route of the present invention. DETAILED DESCRIPTION
[0023] 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.
[0024] Example 1 100 mL of ethanol was placed in a container, 12.1 g (0.1 mol) of p-aminobenzaldehyde was added and stirred until completely dissolved, 100 mL (0.1 mol) of ammonia solution (1 mol / L) was slowly added dropwise, the temperature was raised to 80°C and refluxed for 6 h. After the reaction was complete, the solution was cooled to room temperature, the pH value was adjusted to neutral, the solvent was evaporated, the residue was dissolved with chloroform, and washed 2 to 3 times with 150 mL of saturated brine, the organic phase was separated, the solvent was evaporated under reduced pressure, and recrystallized with benzene to obtain 13.05 g of compound II, the product yield was 96.6%, and the product purity was 98.5%.
[0025] 50 mL of toluene solution was placed in a container, 10.51 g (0.08 mol) of compound II was weighed and dissolved in the solution, and 3 g (0.0064 mol) of scandium metal catalyst (C 5 Me 4 SiMe 3 The ligand is complexed with Sc), stirred and mixed evenly, 15.75g (0.096mol) of n-hexyl chloroformate and 0.65g (0.0064mol) of triethylamine were added to the solution, and the reaction was refluxed at 120°C for 10h. After the reaction was completed, it was cooled to room temperature and quenched by adding sodium bicarbonate solution. The reactants were filtered, separated, and the aqueous layer was extracted 2 to 3 times with 30mL of toluene. The aqueous phases were combined, washed 2 to 3 times with saturated brine, and the organic phases were combined, the solvent was evaporated, and recrystallized with toluene to obtain 20.48g of compound IV, with a product yield of 97.3% and a product purity of 99.5%.
[0026] Example 2 50 mL of toluene solution was placed in a container, 10.51 g (0.08 mol) of compound II was weighed and dissolved in the solution, 1.44 g (0.0064 mol) of scandium metal catalyst (Cp3Sc) was added, and the mixture was stirred and mixed evenly. 15.75 g (0.096 mol) of n-hexyl chloroformate and 0.65 g (0.0064 mol) of triethylamine were added to the solution, and the mixture was refluxed at 120 ° C for 10 h. After the reaction was completed, the mixture was cooled to room temperature and quenched by adding sodium bicarbonate solution. The reactants were filtered, separated into layers, and the aqueous layer was extracted 2 to 3 times with 30 mL of toluene. The aqueous phases were combined, washed 2 to 3 times with saturated brine, and the organic phases were combined, the solvent was evaporated, and the mixture was recrystallized with toluene to obtain 19.81 g of compound IV with a product yield of 94.1% and a product purity of 99.7%.
[0027] Example 3 50 mL of toluene solution was placed in a container, 10.51 g (0.08 mol) of compound II was weighed and dissolved in the solution, 1.33 g (0.0064 mol) of titanium metal catalyst (Cp2TiMe) was added, and the mixture was stirred and mixed evenly. 15.75 g (0.096 mol) of n-hexyl chloroformate and 0.65 g (0.0064 mol) of triethylamine were added to the solution, and the mixture was refluxed at 120 ° C for 10 h. After the reaction was completed, the mixture was cooled to room temperature and quenched by adding sodium bicarbonate solution. The reactants were filtered, separated into layers, and the aqueous layer was extracted 2 to 3 times with 30 mL of toluene. The aqueous phases were combined, washed 2 to 3 times with saturated brine, and the organic phases were combined, the solvent was evaporated, and the mixture was recrystallized with toluene to obtain 19.26 g of compound IV with a product yield of 91.5% and a product purity of 99.5%.
[0028] 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 method for preparing an amidine intermediate of dabigatran etexilate, characterized in that, The preparation method comprises: S1: dissolving p-aminobenzaldehyde, a compound of formula I, in an organic solvent, stirring and mixing, adding an amination reagent dropwise, heating under reflux for reaction, and separating the product after the reaction is completed to obtain a compound of formula II; S2: dissolving the compound of formula II in an organic solvent, adding an activating agent, then adding the compound of formula III, n-hexyl chloroformate, adding a base catalyst, heating for reaction, and separating the product after the reaction is completed to obtain the compound of formula IV.
2. a kind of amidine intermediate preparation method of dabigatran etcxilate according to claim 1, it is characterized in that: In the step S2, the activator used in the reaction is one of a complex of a rare earth metal element scandium complexed with a C5Me4SiMe3 ligand, Cp3Sc, and Cp2TiMe.
3. a kind of amidine intermediate preparation method of dabigatran etcxilate according to claim 2, is characterized in that: The activator is a fully coordinated compound, the coordination ratio of C5Me4SiMe3 to the rare earth metal element scandium (Sc) complex is 1:6, the coordination ratio of cyclopentadienyl (Cp) ligand to scandium (Sc) is 3:1, and the coordination ratio of cyclopentadienyl (Cp) ligand to methyl and titanium (Ti) is 2:1:
1.
4. a kind of amidine intermediate preparation method of dabigatran etcxilate according to claim 1, is characterized in that: In the step S1, the organic solvent used in the reaction is one of ethanol, methanol, toluene, benzene and benzyl alcohol; in the step S2, the organic solvent used in the reaction is one of toluene, benzene and ethanol.
5. a kind of amidine intermediate preparation method of dabigatran etcxilate according to claim 1, it is characterized in that: In the step S2, the base catalyst is one of triethylamine and pyridine.
6. a kind of amidine intermediate preparation method of dabigatran etcxilate according to claim 1, it is characterized in that: In the step S1, the reaction condition is to react under reflux for 6 to 8 hours; in the step S2, the reaction condition is to react under reflux for 10 to 12 hours.
7. a kind of amidine intermediate preparation method of dabigatran etcxilate according to claim 1, it is characterized in that: In step S1, the amination reagent used in the reaction is aqueous ammonia.
8. a kind of amidine intermediate preparation method of dabigatran etcxilate according to claim 1, it is characterized in that: In step S2, the amount of the activator and the catalyst used is 5-10 mol% of the compound of formula II.
9. a kind of amidine intermediate preparation method of dabigatran etcxilate according to claim 1, it is characterized in that: In the step S2, the molar ratio of the compound of formula II to the compound of formula III and the catalyst is 1:1-1.5.