A method for the continuous production of volorat fumarate
By employing continuous production processes and technologies such as tubular reactors and fully automated hydrogenation reactors, the problems of long production cycles and numerous by-products in traditional batch processes have been solved, enabling efficient and safe production of vonoprazan fumarate and improving product yield and purity.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SHANDONG LUKANG PHARMA
- Filing Date
- 2026-03-12
- Publication Date
- 2026-06-09
AI Technical Summary
Existing methods for producing vonoprazan fumarate suffer from problems such as long production cycles, numerous byproducts, and cumbersome post-processing. Traditional batch reactor processes are inefficient and cannot meet the demands of modern production.
A continuous production process is adopted, in which solutions A, B and C are mixed in a tubular reactor, and the reaction is carried out using a fully automated hydrogenation reactor and an immobilized palladium-carbon catalyst. Combined with centrifugal extraction and stirring crystallization, the final product is obtained by filtration and drying to obtain vonoprazan fumarate.
Shorten reaction time, reduce reaction risks, decrease byproducts, improve product yield and quality, and achieve an efficient and safe production process.
Smart Images
Figure CN122167393A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of chemical material preparation technology, specifically to a method for the continuous production of vonoprazan fumarate. Background Technology
[0002] Vonoprazan fumarate tablets are a novel PPI-potassium competitive acid blocker developed by Takeda Pharmaceutical Company of Japan. It works by competitively inhibiting potassium ions in hydrogen / sodium ATPase, making it a reversible potassium antagonist. It was first approved for marketing in Japan in February 2015 under the brand name Takecab. In December 2019, the original Vonoprazan fumarate tablets were imported into China under the brand name "Walker," becoming the first potassium competitive acid blocker approved for the Chinese market, providing a new clinical option for the treatment of reflux esophagitis.
[0003] The synthesis of vonoprazan fumarate is mainly carried out using the traditional batch reactor process, which suffers from drawbacks such as long production cycle, numerous byproducts, and cumbersome post-processing. In recent years, continuous production methods have gradually gained favor among some enterprises due to their advantages such as shorter reaction time, higher safety factor, higher selectivity, and larger annual output, representing an upgrade to the traditional batch reactor process.
[0004] Therefore, how to develop a method for the continuous production of vonoprazan fumarate is a technical problem that urgently needs to be solved by those skilled in the art. Summary of the Invention
[0005] In view of this, the present invention provides a method for the continuous production of vonoprazan fumarate.
[0006] A method for continuous production of vonoprazan fumarate includes the following steps:
[0007] Step 1: Preparation of solution A: Add 5-(2-fluorophenyl)-1 H Pyrrole-3-carboxaldehyde was dissolved in an organic solvent by stirring and set aside. Preparation of solution B: Add pyridine-3-sulfonyl chloride to an organic solvent and stir to dissolve. Set aside for later use. Preparation of solution C: N,N - Diisopropylethylamine was dissolved in an organic solvent by stirring and set aside. Solution A, solution B and solution C are mixed and reacted in a tubular reactor. The effluent is collected and pumped into a centrifugal extractor for centrifugation. The heavy phase is collected. Step 2: Using a fully automated hydrogenation reactor with an immobilized palladium-carbon catalyst, the heavy phase, hydrogen gas, and monomethylamine gas obtained in Step 1 are mixed and reacted, and the effluent is collected. Step 3: Add fumaric acid to the effluent obtained in step 2, stir to crystallize, filter, and dry to obtain vonoprazan fumaric acid.
[0008] Furthermore, the reaction solvent in step 1 is one or more of dichloromethane, chloroform, or 1,2-dichloroethane, preferably dichloromethane.
[0009] Further, in step 1, the preparation of solution A, 5-(2-fluorophenyl)-1 H The mass ratio of pyrrole-3-carboxaldehyde to the organic solvent is 1:2; For the preparation of solution B, the mass ratio of pyridine-3-sulfonyl chloride to organic solvent is 6:5; Preparation of solution C, N,N The mass ratio of diisopropylethylamine to organic solvent is 1:1.
[0010] Further, in step 1, solutions A, B, and C are mixed in a tubular reactor at a flow rate of 20-100 g / min, preferably 50-60 g / min, for solution A, 40-100 g / min, preferably 40-50 g / min, and for solution C, 20-100 g / min, preferably 30-40 g / min. The reaction temperature is 10-100℃, preferably 30-40℃.
[0011] Furthermore, in step 1, the centrifugation speed is 800-1000 rpm, and the centrifugation time is 0.5-1 h.
[0012] Further, in step 2, the heavy phase, hydrogen gas, and monomethylamine gas obtained in step 1 are mixed and reacted at a flow rate of 50-100 g / min, preferably 50-60 g / min for the heavy phase, a flow rate of 100-500 mL / min, preferably 200-300 mL / min for the hydrogen gas, and a flow rate of 10-100 mL / min, preferably 50-100 mL / min for the monomethylamine gas. The reaction pressure is 2-10 MPa, preferably 3-4 MPa, and the reaction temperature is 10-100℃, preferably 40-50℃.
[0013] Furthermore, in step 3, the mass ratio of the effluent obtained in step 2 to fumaric acid is 1:0.5.
[0014] Further, in step 3, fumaric acid is added to the effluent obtained in step 2, the temperature is controlled at 30-40℃, the stirring speed is 80-100 rpm, the stirring time is 1 hour, the filter cloth has a pore size of 800 μm, the drying temperature is 40-50℃, and the drying time is 8-10 hours.
[0015] The beneficial effects of this invention are as follows: This invention utilizes a continuous reaction process, which can shorten reaction time, reduce reaction concentration, thereby reducing the risk of the reaction, decreasing the generation of by-product impurities, and thus improving product yield and quality. Attached Figure Description
[0016] Figure 1 The HPLC chromatogram of vonoprazan fumarate, the product of Example 1; Figure 2 The HPLC chromatogram of vonoprazan fumarate, the product of Example 2; Figure 3 The HPLC chromatogram of vonoprazan fumarate, the product of Example 3. Detailed Implementation
[0017] 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.
[0018] Example 1 A method for the continuous production of vonoprazan fumarate includes the following steps: Step 1: Preparation of Solution A: Add 10 kg of 5-(2-fluorophenyl)-1 H Pyrrole-3-carboxaldehyde was dissolved in 20 kg of dichloromethane by stirring and set aside. Preparation of solution B: Add 12 kg of pyridine-3-sulfonyl chloride to 10 kg of dichloromethane and stir to dissolve. Set aside for later use. Preparation of solution C: Add 10 kg N,N - Diisopropylethylamine was dissolved in 10 kg of dichloromethane by stirring and set aside. Solutions A, B, and C were mixed in a tubular reactor at a flow rate of 20 g / min for solution A, 40 g / min for solution B, and 20 g / min for solution C. The reaction temperature was 10 °C. The effluent was collected and pumped into a centrifugal extractor for centrifugation at 800 rpm for 0.5 h. The heavy phase was collected. Step 2: A fully automated hydrogenation reactor was used, employing a palladium-on-carbon catalyst with a palladium loading of 10 wt% (catalyst dosage was 5-(2-fluorophenyl)-1... H The heavy phase, hydrogen, and monomethylamine gas obtained in step 1 were mixed and reacted at a flow rate of 50 g / min for the heavy phase, 100 mL / min for the hydrogen, and 10 mL / min for the monomethylamine gas. The reaction pressure was 2 MPa and the reaction temperature was 10 °C. The effluent was collected. Step 3: Add 5 kg of fumaric acid to 60 kg of the effluent obtained in step 2, control the temperature at 30°C, stir to induce crystallization, stir at 80 rpm for 1 hour, filter (filter cloth with 800 mesh pore size), and dry (drying temperature 40°C for 8 hours) to obtain 21 kg of vonoprazan fumaric acid, with a total yield of 87.5% and a purity of 99.76%.
[0019] Example 2 A method for the continuous production of vonoprazan fumarate includes the following steps: Step 1: Preparation of Solution A: Add 10 kg of 5-(2-fluorophenyl)-1 H Pyrrole-3-carboxaldehyde was dissolved in 20 kg of dichloromethane by stirring and set aside. Preparation of solution B: Add 12 kg of pyridine-3-sulfonyl chloride to 10 kg of dichloromethane and stir to dissolve. Set aside for later use. Preparation of solution C: Add 10 kg N,N - Diisopropylethylamine was dissolved in 10 kg of dichloromethane by stirring and set aside. Solutions A, B, and C were mixed in a tubular reactor at a flow rate of 60 g / min for solution A, 70 g / min for solution B, and 60 g / min for solution C. The reaction temperature was 50 °C. The effluent was collected and pumped into a centrifugal extractor for centrifugation at 800 rpm for 0.5 h. The heavy phase was collected. Step 2: A fully automated hydrogenation reactor was used, employing a palladium-on-carbon catalyst with a palladium loading of 10 wt% (catalyst dosage was 5-(2-fluorophenyl)-1... H (15% of the mass of pyrrole-3-carboxaldehyde), the heavy phase obtained in step 1, hydrogen gas and monomethylamine gas are mixed and reacted at a flow rate of 75 g / min for the heavy phase, 300 mL / min for the hydrogen gas, and 50 mL / min for the monomethylamine gas. The reaction pressure is 6 MPa and the reaction temperature is 55 °C. The effluent is collected. Step 3: Add 5 kg of fumaric acid to 60 kg of the effluent obtained in Step 2, control the temperature at 35℃, stir to crystallize at 90 rpm for 1 hour, filter (filter cloth with 800 μm pore size), and dry (drying temperature at 45℃ for 9 hours) to obtain 22 kg of vonoprazan fumaric acid, with a total yield of 90.2% and a purity of 99.76%.
[0020] Example 3 A method for the continuous production of vonoprazan fumarate includes the following steps: Step 1: Preparation of Solution A: Add 10 kg of 5-(2-fluorophenyl)-1 HPyrrole-3-carboxaldehyde was dissolved in 20 kg of dichloromethane by stirring and set aside. Preparation of solution B: Add 12 kg of pyridine-3-sulfonyl chloride to 10 kg of dichloromethane and stir to dissolve. Set aside for later use. Preparation of solution C: Add 10 kg N,N - Diisopropylethylamine was dissolved in 10 kg of dichloromethane by stirring and set aside. Solutions A, B, and C were mixed in a tubular reactor at flow rates of 100 g / min for solution A, 100 g / min for solution B, and 100 g / min for solution C. The reaction temperature was 100°C. The effluent was collected and pumped into a centrifugal extractor for centrifugation at 800 rpm for 0.5 h. The heavy phase was collected. Step 2: A fully automated hydrogenation reactor was used, employing a palladium-on-carbon catalyst with a palladium loading of 10 wt% (catalyst dosage was 5-(2-fluorophenyl)-1... H The heavy phase, hydrogen, and monomethylamine gas obtained in step 1 were mixed and reacted at a flow rate of 100 g / min for the heavy phase, 500 mL / min for the hydrogen, and 100 mL / min for the monomethylamine gas. The reaction pressure was 10 MPa and the reaction temperature was 100 °C. The effluent was collected. Step 3: Add 5 kg of fumaric acid to 60 kg of the effluent obtained in step 2, control the temperature at 40℃, stir to crystallize, stir at 100 rpm for 1 h, filter (filter cloth with 800 μm pore size), and dry (drying temperature 50℃ for 10 h) to obtain 20 kg of vonoprazan fumaric acid, with a total yield of 82.0% and a purity of 99.76%.
[0021] Reaction formula:
[0022] The above description of the disclosed embodiments enables those skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims
1. A method for continuous production of vonoprazan fumarate, characterized in that, Includes the following steps: Step 1: Preparation of solution A: Add 5-(2-fluorophenyl)-1 H Pyrrole-3-carboxaldehyde was dissolved in an organic solvent by stirring and set aside. Preparation of solution B: Add pyridine-3-sulfonyl chloride to an organic solvent and stir to dissolve. Set aside for later use. Preparation of solution C: N,N - Diisopropylethylamine was dissolved in an organic solvent by stirring and set aside. Solution A, solution B and solution C are mixed and reacted in a tubular reactor. The effluent is collected and pumped into a centrifugal extractor for centrifugation. The heavy phase is collected. Step 2: Using a fully automated hydrogenation reactor with an immobilized palladium-carbon catalyst, the heavy phase, hydrogen gas, and monomethylamine gas obtained in Step 1 are mixed and reacted, and the effluent is collected. Step 3: Add fumaric acid to the effluent obtained in step 2, stir to crystallize, filter, and dry to obtain vonoprazan fumaric acid.
2. The method for continuous production of vonoprazan fumarate according to claim 1, characterized in that, The reaction solvent in step 1 is one or more of dichloromethane, chloroform, or 1,2-dichloroethane.
3. The method for continuous production of vonoprazan fumarate according to claim 1, characterized in that, Step 1: Preparation of solution A, 5-(2-fluorophenyl)-1 H The mass ratio of pyrrole-3-carboxaldehyde to the organic solvent is 1:2; For the preparation of solution B, the mass ratio of pyridine-3-sulfonyl chloride to organic solvent is 6:5; Preparation of solution C, N,N The mass ratio of diisopropylethylamine to organic solvent is 1:
1.
4. The method for continuous production of vonoprazan fumarate according to claim 1, characterized in that, Step 1: Mix solutions A, B, and C in a tubular reactor at a flow rate of 20-100 g / min for solution A, 40-100 g / min for solution B, and 20-100 g / min for solution C, at a reaction temperature of 10-100℃.
5. The method for continuous production of vonoprazan fumarate according to claim 1, characterized in that, Step 1: Centrifuge at 800-1000 rpm for 0.5-1 hour.
6. The method for continuous production of vonoprazan fumarate according to claim 1, characterized in that, In step 2, the heavy phase, hydrogen gas and monomethylamine gas obtained in step 1 are mixed and reacted at a flow rate of 50-100 g / min for the heavy phase, 100-500 mL / min for the hydrogen gas, and 10-100 mL / min for the monomethylamine gas. The reaction pressure is 2-10 MPa and the reaction temperature is 10-100℃.
7. The method for continuous production of vonoprazan fumarate according to claim 1, characterized in that, In step 3, the mass ratio of the effluent obtained in step 2 to fumaric acid is 1:0.
5.
8. The method for continuous production of vonoprazan fumarate according to claim 1, characterized in that, In step 3, fumaric acid is added to the effluent obtained in step 2, the temperature is controlled at 30-40℃, the stirring speed is 80-100 rpm, the stirring time is 1 hour, the filter cloth has a pore size of 800 μm, the drying temperature is 40-50℃, and the drying time is 8-10 hours.