A series of methods for producing vonoprazan intermediates using isonitrile and Michael receptors
A single-step reaction using isonitrile and Michael acceptors simplifies the synthesis of 3-substituted 5-(2-fluorophenyl)pyrrole derivatives, addressing the complexity and cost issues of existing methods by enhancing yield and simplifying purification in vonoprazan production.
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Patents
- Current Assignee / Owner
- SHANGHAI BIOS TECH CO LTD
- Filing Date
- 2024-04-02
- Publication Date
- 2026-07-03
AI Technical Summary
Existing methods for producing 3-substituted 5-(2-fluorophenyl)pyrrole derivatives in vonoprazan synthesis are lengthy, complex, and difficult to control, leading to high costs and low yields.
A method utilizing isonitrile and Michael acceptors in a single-step reaction to synthesize 3-substituted 5-(2-fluorophenyl)pyrrole derivatives, employing α-(p-toluenesulfonyl)-2-fluorobenzylisonitrile and a base in specific solvents at controlled temperatures, resulting in high yield and simplified purification.
The method achieves a high yield and simplifies the synthesis process with fewer steps, offering easier separation and purification of vonoprazan intermediates.
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Abstract
Description
[Technical Field]
[0001] The present invention relates to a method for producing a series of vonoprazan intermediates using isonitrile and Michael receptor, and belongs to the field of organic synthesis. [Background technology]
[0002] Vonoprazan (TAK-438) is a potassium-competitive acid blocker (also known as a P-CAB) that suppresses acid secretion by competitively inhibiting the activity of potassium ions in the HK-ATP enzyme. Conventional PPI inhibitors primarily suppress gastric acid secretion induced by various stimuli by inhibiting the activity of the H+ / K+-ATP enzyme. However, PPIs do not always provide sufficient therapeutic effect, and the effect of suppressing gastric acid secretion always varies from person to person. Potassium-competitive acid blockers (P-CABs) are a new type of proton pump inhibitor that has a rapid, potent, and sustained effect of suppressing gastric acid secretion. Vonoprazan is jointly researched and developed by Takeda Pharmaceutical Company and Otsuka Pharmaceutical Co., Ltd. It received manufacturing and marketing approval from the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on December 26, 2014, and from the National Medical Products Administration (NMPA) of China on December 18, 2019. Its trade name is Takecab (registered trademark), and it is used for the treatment of gastric and duodenal ulcers, the treatment and prevention of recurrence of reflux esophagitis, and as primary and secondary eradication therapy for Helicobacter pylori, and it has excellent resistance and safety.
[0003] The structure of vonoprazan is as follows: [ka]
[0004] Numerous methods for manufacturing vonoprazan have been reported in the literature, including the following:
[0005] Takeda Pharmaceutical Company, the pioneering pharmaceutical company, has reported the following pathway in its compound patent CN101300229B. [ka]
[0006] In the precursor compound pathway, 2-fluoroacetophenone is used as the starting material and undergoes six reactions—bromination, alkylation, cyclization, hydrogenation, and oxidation—to produce the intermediate 5-(2-fluorophenyl)pyrrole-3-carbaldehyde. Furthermore, the target product is obtained by subjecting this intermediate to a total of ten reactions: condensation, imination, reduction, and salt formation.
[0007] Takeda Pharmaceutical Company subsequently disclosed the following process pathway in CN105524046B. [ka]
[0008] In this process pathway, similar to the compound patent, Takeda Pharmaceutical Company still uses 2-fluoroacetophenone as a starting material and produces the intermediate 5-(2-fluorophenyl)pyrrole-3-carbaldehyde through five reaction steps: bromination, alkylation, cyclization, hydrogenation, and reduction. Furthermore, the product is produced by four reaction steps: condensation, imine formation, reduction, and salt production. The main difference is the use of malononitrile instead of ethyl cyanoethyl acetate, which avoids the reduction of the ester group after cyclization and shortens the reaction by one step.
[0009] In patent CN109232537A, Disha Pharmaceutical reports the production of the core intermediate 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate ethyl by attacking bromoacetophenone with ethyl 3-oxopropionate and then closing the pyrrole ring. [ka]
[0010] Lunan Pharmaceutical Co., Ltd., in CN113549054, discloses a method for synthesizing vonoprazan, starting with 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile as the starting material, hydrolyzing it with a cyano group to obtain 5-(2-fluorophenyl)-1H-pyrrole-3-carboxamide, and then obtaining the target product vonoprazan through a multi-step process. The synthesis route is as follows: [ka]
[0011] Currently, as can be seen from the above-mentioned patent documents, 3-substituted 5-(2-fluorophenyl)pyrrole is a core component in the synthesis of vonoprazan. Intermediates I, II, III, and IV for the synthesis of vonoprazan can be summarized and listed below from the above-mentioned patent documents. [ka]
[0012] Furthermore, from the perspective of the synthetic methods for producing these intermediates, the method for synthesizing 3-substituted 5-(2-fluorophenyl)pyrrole is relatively simple, mainly using a method developed by Takeda Pharmaceutical Company, which involves 4 to 6 steps of synthesis using 2-fluoroacetophenone as a starting material. However, this method has drawbacks such as a long reaction pathway, complicated procedures, and difficulty in quality control. Therefore, there is significant importance in developing a method for producing 3-substituted 5-(2-fluorophenyl)pyrrole derivatives that has the advantages of fewer reaction steps, simpler operation, lower cost, and higher yield. [Overview of the Initiative] [Problems that the invention aims to solve]
[0013] The object of the present invention is as follows. In view of the defects existing in the conventional method for producing 3-substituted 5-(2-fluorophenyl)pyrrole derivatives, the present invention provides a new method for synthesizing 3-substituted 5-(2-fluorophenyl)pyrrole, thereby providing more options for the synthesis of such core intermediates. The method of the present invention has the advantages of fewer reaction steps, simple operation, low cost, and high yield.
Means for Solving the Problems
[0014] To achieve the above object, the present invention provides a method for producing a series of Bonoprazan intermediates using isonitrile and Michael acceptor. The general formula of the synthetic route of the method is as follows.
Chemical formula
[0015] Specifically, the method includes the step of dissolving α-(p-toluenesulfonyl)-2-fluorobenzyl isonitrile and a Michael acceptor in a solvent, adding a base and reacting to produce 3-substituted 5-(2-fluorophenyl)pyrrole.
[0016] Preferably, as is known in the art, the Michael acceptor is an α,β-unsaturated carbonyl compound, including but not limited to α,β-unsaturated amide, α,β-unsaturated ketone, α,β-unsaturated ester, conjugated alkynyl carbonyl, and α,β-unsaturated nitrile. Z is an electron-withdrawing group, including but not limited to CHO, COOR, CONRCH3, CONROR’, CN, NO2. R may be H, alkyl or aryl. R’ is alkyl, alkenyl, alkoxy or aryl.
[0017] Preferably, the solvent is at least one selected from tetrahydrofuran, 2-methyltetrahydrofuran, methyl-tert-butyl ether, isopropyl ether, ethyl ether, 1,4-dioxane, diphenyl ether, dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), cyclohexane, n-hexane, n-heptane, toluene, acetonitrile, N,N-dimethylacetamide, and N,N-dimethylformamide.
[0018] More preferably, the solvent is at least one of tetrahydrofuran, isopropyl ether, and dimethyl sulfoxide.
[0019] Preferably, the base is at least one selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, sodium hydride, potassium carbonate, sodium carbonate, lithium diisopropylamide (LDA), and lithium hexamethyldisilazide (LiHMDS).
[0020] Preferably, the reaction temperature is -78 to 60°C, and the duration is 0.5 to 6 hours.
[0021] More preferably, the reaction temperature is -20 to 30°C, and the duration is 0.5 to 2 hours. [Effects of the Invention]
[0022] The present invention has the following beneficial effects compared to the prior art.
[0023] The present invention allows for the synthesis of a series of vonoprazan intermediates, specifically 3-substituted 5-(2-fluorophenyl)pyrrole, via a single-step reaction using α-(p-toluenesulfonyl)-2-fluorobenzylisonitrile and different Michael acceptors. This method has the advantages of mild reaction conditions, simple workup, easy separation and purification, and high yield. The method of the present invention is of significant importance for the subsequent production of vonoprazan. [Modes for carrying out the invention]
[0024] To provide a clearer understanding of the present invention, preferred embodiments will be described in detail with reference to the drawings.
[0025] In the following examples, the production and characterization of α-(p-toluenesulfonyl)-2-fluorobenzylisonitrile are as follows.
[0026] For the preparation of α-(p-toluenesulfonyl)-2-fluorobenzylisonitrile, please refer to the reference "Fallarini; Massarotti; Gesu; Giovarruscio. MedChemComm, 2016(7), 409-419". In the examples of this invention, the synthesis is not described in detail, and the product is a yellowish-white solid. Characterization data by nuclear magnetic resonance and mass spectrometry are as follows.
[0027] 1 H NMR (300 MHz; CDCl3) δ 7.71-7.75 (m, 2H), 7.44-7.50 (m, 1H), 7.35-7.41 (m, 3H), 7.21 (t, J= 7.7 Hz, 1H), 7.12 (t, J = 9.6 Hz, 1H), 5.97 (s, 1H), 2.49 (s, 3H); ESI-MS:290[M+H + ].
[0028] (Example 1) Production of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate ethyl ethyl acrylate using ethyl acrylate as a Michael acceptor. [ka]
[0029] In a 500 mL three-necked flask equipped with a dropping funnel and thermometer, under a nitrogen gas atmosphere, 200 mL of DMSO and sodium hydride (4.8 g, 120 mmol) were added, and the system was cooled to 10-15°C. α-(p-toluenesulfonyl)-2-fluorobenzylisonitrile (29 g, 100 mmol) and ethyl acrylate (13 g, 130 mmol) were dissolved in 100 mL of DMSO. This solution was then transferred to a constant-pressure dropping funnel and slowly added dropwise to the NaH DMSO solution. After the addition was complete, the system was heated to 20-30°C and allowed to react until the conversion of the starting materials was confirmed by monitoring with TLC. Subsequently, the system was cooled to 10-15°C, 100 mL of water was slowly added dropwise to quench the reaction, and after the addition was complete, the mixture was kept warm for 2-3 hours, filtered, the filtered cake was washed with 20 mL of purified water, and dried at 55-70°C for 12 hours to obtain 19.1 g of yellow solid, with a yield of 82%. The characterization data is as follows.
[0030] 1 H-NMR (CDCl3) δ:1.67 (3H, t, J=7.2 Hz), 4.31 (2H, q, J=7.2 Hz), 7.03-7.05 (1H, m), 7.08-7.25 (3H, m), 7.49-7.50 (1H, m), 7.58-7.66 (1H, m), 9.22 (1H, brs);ESI-MS:234[M+H + ].
[0031] (Example 2) Production of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde using acrolein as a Michael receptor [ka]
[0032] In a 250 mL three-necked flask equipped with a dropping funnel and thermometer, under a nitrogen gas atmosphere, 50 mL of DMSO and sodium hydride (0.88 g, 22 mmol) were added, and the system was cooled to 10-15°C. α-(p-toluenesulfonyl)-2-fluorobenzylisonitrile (5.8 g, 20 mmol) and acrolein (1.2 g, 22 mmol) were dissolved in 25 mL of DMSO. This solution was then transferred to a constant-pressure dropping funnel and slowly added dropwise to the NaH DMSO solution. After the addition was complete, the system was heated to 20-30°C and the reaction was allowed to proceed while monitoring with TLC until the conversion of the starting materials was confirmed to be complete. Subsequently, the system was cooled to 10-15°C, and the reaction was quenched by slowly adding 30 mL of water dropwise. After the addition was complete, 100 mL of ethyl acetate was added for extraction, and the solution was separated. The aqueous phase was extracted with 30 mL of ethyl acetate, and the ethyl acetate layers were combined and dried over anhydrous sodium sulfate. The solution was vacuum concentrated at 40°C until no more solvent leached out. The resulting crude product was purified by flash column chromatography (PE:EA=5:1) to obtain 2.5 g of a yellow solid, with a yield of 65%. The characterization data is as follows.
[0033] 1 H-NMR (CDCl3) δ:7.02-7.28 (4H, m), 7.49-7.55 (1H, m), 7.59-7.67 (1H, m), 9.53 (1H, brs), 9.85 (1H, s); ESI-MS:190[M+H + ].
[0034] (Example 3) Production of 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile using acrylonitrile as a Michael receptor [ka]
[0035] In a 250 mL three-necked flask equipped with a dropping funnel and thermometer, under a nitrogen gas atmosphere, 50 mL of DMSO and sodium hydride (0.88 g, 22 mmol) were added, and the system was cooled to 10-15°C. α-(p-toluenesulfonyl)-2-fluorobenzylisonitrile (5.8 g, 20 mmol) and acrylonitrile (1.2 g, 22 mmol) were dissolved in 25 mL of DMSO. This solution was then transferred to a constant-pressure dropping funnel and slowly added dropwise to the NaH DMSO solution. After the addition was complete, the system was heated to 20-30°C and the reaction was allowed to proceed while monitoring with TLC to confirm the completion of the starting material conversion. Subsequently, the system was cooled to 10-15°C, and the reaction was quenched by slowly adding 30 mL of water dropwise. After the addition was complete, 100 mL of ethyl acetate was added for extraction, and the solution was separated. The aqueous phase was extracted with 30 mL of ethyl acetate, and the ethyl acetate layers were combined and dried over anhydrous sodium sulfate. The solution was vacuum concentrated at 40°C until no more solvent leached out. The resulting crude product was purified by flash column chromatography (PE:EA=5:1) to obtain 2.6 g of a yellow solid, with a yield of 69%. The characterization data is as follows.
[0036] 1 H-NMR (500 MHz, CDCl3) δ (ppm):6.78-6.85 (m, 1H), 7.09-7.30 (m, 3H), 7.34-7.41 (m, 1H), 7.53-7.61 (m, 1H), 9.38 (brs, 1H);ESI-MS:187[M+H + ].
[0037] (Example 4) Preparation of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxamide using acrylamide as a Michael receptor. [ka]
[0038] In a 250 mL three-necked flask equipped with a dropping funnel and a thermometer under a nitrogen gas atmosphere, 50 mL of DMSO and sodium hydride (1.2 g, 30 mmol) were added, and the system was cooled to 10 - 15 °C. α-(p-Toluenesulfonyl)-2-fluorobenzyl isocyanide (5.8 g, 20 mmol) and acrylamide (2 g, 28 mmol) were dissolved in 25 mL of DMSO, and then this solution was transferred to a constant-pressure dropping funnel and slowly dropped into the DMSO solution of NaH. After the dropping was completed, the system was heated to 20 - 30 °C and reacted until the conversion of the raw materials was confirmed by TLC monitoring. Then, the system was cooled to 10 - 15 °C, 30 mL of water was slowly dropped to quench the reaction. After the dropping was completed, 100 mL of ethyl acetate was added for extraction, and the layers were separated. The aqueous phase was extracted with 30 mL of ethyl acetate, and the ethyl acetate layers were combined and dried over anhydrous sodium sulfate. It was concentrated under vacuum at 40 °C until the solvent stopped flowing out, and the obtained crude product was purified by flash column chromatography (eluted with pure EA) to obtain 2.9 g of a yellow solid with a yield of 71%. The characteristic evaluation data are as follows.
[0039] 1 H-NMR (500 MHz, DMSO-d6) δ (ppm): 6.76 (brs, 1H), 6.91 (s, 1H), 7.16 - 7.24 (m, 3H), 7.40 (brs, 1H), 7.48 (s, 1H), 7.61 - 7.70 (m, 1H), 11.61(s, 1H); ESI-MS: 204[M+].
[0040] (Example 5) Substitution of the base during the reaction with potassium tert-butoxide (taking ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate as an example) [Chemical formula]
[0041] In a 250 mL three-necked flask equipped with a dropping funnel and thermometer, 100 mL of THF and sodium hydride (2.4 g, 60 mmol) were added under a nitrogen gas atmosphere, and the system was cooled to 10-15°C. α-(p-toluenesulfonyl)-2-fluorobenzylisonitrile (14.5 g, 50 mmol) and ethyl acrylate (6.5 g, 65 mmol) were dissolved in 100 mL of THF. This solution was then transferred to a constant-pressure dropping funnel and slowly added dropwise to the potassium-tert-butoxide THF solution. After the addition was complete, the system was heated to 20-30°C and the reaction was allowed to proceed while monitoring with TLC until the conversion of the starting materials was confirmed to be complete. Subsequently, the system was cooled to 10-15°C, and 50 mL of water was slowly added dropwise to quench the reaction. After the addition was complete, the THF was recovered by concentrating under reduced pressure at <40°C. After the liquid stopped flowing out, the system was cooled to 10-15°C, kept warm for 2-3 hours, and filtered. The filtered cake was washed with 20 mL of purified water and dried at 55-70°C for 12 hours to obtain 9.0 g of yellow solid, with a yield of 77%. The characterization data was the same as in Example 1.
Claims
1. A method for producing a series of vonoprazan intermediates using isonitrile and a Michael receptor, wherein the general formula of the synthesis route is as follows: 【Chemistry 1】 Specifically, the process includes the step of dissolving α-(p-toluenesulfonyl)-2-fluorobenzylisonitrile and ethyl acrylate, acrolein, acrylonitrile, or acrylamide as a Michael acceptor in a solvent, then adding a base and reacting to produce 3-substituted 5-(2-fluorophenyl)pyrrole. A method characterized by the following:
2. The Michael receptor is an ethyl acrylate, and the resulting 3-substituted 5-(2-fluorophenyl)pyrrole is ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate. The method according to feature 1.
3. The Michael receptor is acrolein, and the resulting 3-substituted 5-(2-fluorophenyl)pyrrole is 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde. The method according to feature 1.
4. The Michael receptor is acrylonitrile, and the resulting 3-substituted 5-(2-fluorophenyl)pyrrole is 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile. The method according to feature 1.
5. The Michael receptor is an acrylamide, and the resulting 3-substituted 5-(2-fluorophenyl)pyrrole is 5-(2-fluorophenyl)-1H-pyrrole-3-carboxamide. The method according to feature 1.
6. The solvent is dimethyl sulfoxide or tetrahydrofuran. The method according to feature 1.
7. The base is potassium-tert-butoxide or sodium hydride, the reaction temperature is -20 to 30°C, and the reaction time is 0.5 to 2 hours. The method according to feature 1.