Methods for preparing a series of vonoprazan intermediates using isonitriles and Michael acceptors

Abstract

The present invention discloses a method for preparing a series of vonoprazan intermediates using an isonitrile and a Michael acceptor. In the method of the present invention, α-(p-toluenesulfonyl)-2-fluorobenzylisonitrile is used as the starting material, which attacks a series of Michael acceptors under basic conditions and undergoes cyclization to form a series of 3-substituted 5-(2-fluorophenyl)-1H-pyrroles. These 3-substituted pyrrole intermediates can be further chemically transformed to prepare vonoprazan. Compared with the prior art, the technical means of the present invention are characterized by a short synthetic route, high overall yield, simple post-treatment, and low cost.

Description

[Technical Field]

[0001] The present invention relates to a method for preparing a series of vonoprazan intermediates using an isonitrile and a Michael acceptor, and belongs to the technical field of organic synthesis. [Background technology]

[0002] Vonoprazan (TAK-438) is a potassium ion-competitive acid blocker (P-CAB) that inhibits gastric acid secretion by competitively inhibiting the activity of potassium ions in the HK-ATP enzyme. Conventional PPI inhibitors primarily inhibit gastric acid secretion induced by any stimulus by inhibiting the activity of the H / K-ATP enzyme. However, PPIs do not always provide sufficient therapeutic effects, and the effectiveness of gastric acid secretion suppression varies from person to person. Potassium ion-competitive acid blockers (P-CABs) are a new type of proton pump inhibitor that exhibits rapid, potent, and sustained gastric acid secretion suppression. Vonoprazan was jointly researched and developed by Takeda Pharmaceutical Company Limited (Takeda) and Otsuka Pharmaceutical Co., Ltd., and obtained 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. Under the trade name Takecab (registered trademark), vonoprazan is used in the treatment of gastric and duodenal ulcers, the treatment and prevention of recurrence of reflux esophagitis, and first- and second-line eradication therapy for Helicobacter pylori, and has excellent tolerability and safety.

[0003] The structure of vonoprazan is: [ka]

[0004] Numerous methods for preparing vonoprazan have been reported in the literature, including the following:

[0005] Takeda Pharmaceutical, a pioneering pharmaceutical company, has reported the following route in compound patent CN101300229B: [ka]

[0006] In the starting compound route, 2-fluoroacetophenone is used as the starting material and undergoes six reaction steps, including bromination, alkylation, cyclization, hydrodechlorination, and oxidation, to produce the intermediate 5-(2-fluorophenyl)pyrrole-3-carbaldehyde. This intermediate then undergoes a total of 10 reaction steps, including condensation, iminization, reduction, and salt formation, to obtain the target product.

[0007] Takeda Pharmaceutical Company subsequently disclosed the following process route in CN105524046B: [ka]

[0008] In this process, similar to the compound patent, Takeda Pharmaceutical still uses 2-fluoroacetophenone as the starting material, undergoing five steps of bromination, alkylation, cyclization, hydrodechlorination, and reduction to produce the intermediate 5-(2-fluorophenyl)pyrrole-3-carbaldehyde, which then undergoes four steps of condensation, imine formation, reduction, and salt formation to produce the product. The main difference is the use of malononitrile instead of ethyl cyanoacetate, which avoids the need for reduction of the ester group after cyclization and shortens one reaction step.

[0009] In patent CN109232537A, Disha Pharmaceutical reported the preparation of the core intermediate ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate by attacking bromoacetophenone with ethyl 3-oxopropionate and then closing the pyrrole ring. [ka]

[0010] Lunan Pharmaceutical discloses in CN113549054 a method for synthesizing vonoprazan, which uses 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile as a starting material, which is hydrolyzed with a cyano group to obtain 5-(2-fluorophenyl)-1H-pyrrole-3-carboxamide, and then undergoes multiple steps to obtain the target product, vonoprazan. The synthetic route is as follows: [ka]

[0011] Currently, as can be seen from the above patent documents, 3-substituted 5-(2-fluorophenyl)pyrrole is the core in the synthesis of vonoprazan. From the above patent documents, intermediates I, II, III, and IV for synthesizing vonoprazan are summarized as follows: [ka]

[0012] Furthermore, in terms of the synthetic methods for producing these intermediates, the method for synthesizing 3-substituted 5-(2-fluorophenyl)pyrrole is relatively simple and is mainly produced using a method developed by Takeda Pharmaceutical Company Limited, which involves 4 to 6 synthetic reaction steps using 2-fluoroacetophenone as a starting material. However, this method has problems such as a long reaction path, complicated operation procedures, and difficulty in quality control. Therefore, it is of great significance to develop a method for producing 3-substituted 5-(2-fluorophenyl)pyrrole derivatives that has the advantages of fewer reaction steps, simple operation, low cost, and high yield. Summary of the Invention [Problem to be solved by the invention]

[0013] The objectives of the present invention are as follows: In response to the deficiencies in the conventional methods 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 method 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 problem]

[0014] To achieve the above object, the present invention provides a method for preparing a series of vonoprazan intermediates using an isonitrile and a Michael acceptor, the general formula of the synthetic route of which is as follows: [ka]

[0015] Specifically, the method includes the steps of dissolving α-(p-toluenesulfonyl)-2-fluorobenzylisonitrile and a Michael acceptor in a solvent, and then adding a base to react them to produce 3-substituted 5-(2-fluorophenyl)pyrrole.

[0016] Preferably, the Michael acceptor is an α,β-unsaturated carbonyl compound, as known in the art, including, but not limited to, α,β-unsaturated amides, α,β-unsaturated ketones, α,β-unsaturated esters, conjugated alkynyl carbonyls, and α,β-unsaturated nitriles. Z is an electron-withdrawing group, including, but not limited to, CHO, COOR, CONRCH3, CONROR', CN, and NO2. R can 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 reaction time is 0.5 to 6 hours.

[0021] More preferably, the reaction temperature is −20 to 30° C. and the reaction time is 0.5 to 2 hours. [Effects of the Invention]

[0022] The present invention has the following advantageous effects compared to the prior art.

[0023] The present invention uses α-(p-toluenesulfonyl)-2-fluorobenzylisonitrile and different Michael acceptors to synthesize a series of 3-substituted 5-(2-fluorophenyl)pyrroles, which are intermediates of Vonoprazan, through a single reaction step. This method has the advantages of mild reaction conditions, simple workup, easy separation and purification, and high yields. The method of the present invention is of great significance for the subsequent preparation of Vonoprazan. DETAILED DESCRIPTION OF THE INVENTION

[0024] For a clearer understanding of the present invention, a preferred embodiment will now be described in detail with reference to the accompanying drawings.

[0025] In the following examples, the preparation and characterization of α-(p-toluenesulfonyl)-2-fluorobenzylisonitrile is 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", and the synthesis is not described in detail in the examples of the present invention. The product is a pale yellow 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 Preparation of ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate using ethyl acrylate as a Michael acceptor [ka]

[0029] A 500 mL three-neck flask equipped with a dropping funnel and a thermometer was charged with 200 mL of DMSO and sodium hydride (4.8 g, 120 mmol) under a nitrogen gas atmosphere, and the mixture 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, and the solution was transferred to a constant-pressure dropping funnel and slowly added dropwise to the DMSO solution of NaH. After the addition was complete, the mixture was heated to 20-30°C and reacted until the conversion of the raw materials was complete, as monitored by TLC. The system was then cooled to 10-15°C, and 100 mL of water was slowly added dropwise to quench the reaction. After the addition was complete, the mixture was kept at room temperature for 2-3 hours, filtered, and the filter cake was washed with 20 mL of purified water and dried at 55-70°C for 12 hours to obtain 19.1 g of a yellow solid in a yield of 82%. The characterization data are 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 Preparation of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde using acrolein as a Michael acceptor [ka]

[0032] A 250 mL three-neck flask equipped with a dropping funnel and a thermometer was charged with 50 mL of DMSO and sodium hydride (0.88 g, 22 mmol) under a nitrogen gas atmosphere, and the mixture 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, and the solution was transferred to a constant-pressure dropping funnel and slowly added dropwise to the DMSO solution of NaH. After the addition was complete, the mixture was heated to 20-30 °C and reacted until the conversion of the starting material was confirmed by TLC. The mixture was then cooled to 10-15 °C, and 30 mL of water was slowly added dropwise to quench the reaction. After the addition was complete, 100 mL of ethyl acetate was added, followed by extraction. The mixture was separated, and the aqueous phase was extracted with 30 mL of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate. The mixture was concentrated under vacuum at 40°C until no further solvent was released, and the resulting crude product was purified by flash column chromatography (PE:EA=5:1) to give 2.5 g of a yellow solid in a 65% yield. The characterization data are 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 Preparation of 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile using acrylonitrile as a Michael acceptor [ka]

[0035] A 250 mL three-neck flask equipped with a dropping funnel and a thermometer was charged with 50 mL of DMSO and sodium hydride (0.88 g, 22 mmol) under a nitrogen atmosphere, and the mixture 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, and the solution was transferred to a constant-pressure dropping funnel and slowly added dropwise to the DMSO solution of NaH. After the addition was complete, the mixture was heated to 20-30 °C and reacted until the conversion of the starting material was confirmed by TLC. The mixture was then cooled to 10-15 °C, and 30 mL of water was slowly added dropwise to quench the reaction. After the addition was complete, 100 mL of ethyl acetate was added, followed by extraction and separation. The aqueous phase was extracted with 30 mL of ethyl acetate, and the combined ethyl acetate layers were dried over anhydrous sodium sulfate. The mixture was concentrated under vacuum at 40°C until no further solvent was released, and the resulting crude product was purified by flash column chromatography (PE:EA=5:1) to give 2.6 g of a yellow solid in a 69% yield. The characterization data are 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 acceptor [ka]

[0038] A 250 mL three-neck flask equipped with a dropping funnel and a thermometer was charged with 50 mL of DMSO and sodium hydride (1.2 g, 30 mmol) under a nitrogen gas atmosphere, and the mixture was cooled to 10-15 °C. α-(p-toluenesulfonyl)-2-fluorobenzylisonitrile (5.8 g, 20 mmol) and acrylamide (2 g, 28 mmol) were dissolved in 25 mL of DMSO, and the solution was transferred to a constant-pressure dropping funnel and slowly added dropwise to the DMSO solution of NaH. After the addition was complete, the mixture was heated to 20-30 °C and reacted until the conversion of the starting material was confirmed by TLC. The mixture was then cooled to 10-15 °C, and 30 mL of water was slowly added dropwise to quench the reaction. After the addition was complete, 100 mL of ethyl acetate was added, followed by extraction and separation. The aqueous phase was extracted with 30 mL of ethyl acetate, and the combined ethyl acetate layers were dried over anhydrous sodium sulfate. The solvent was concentrated under vacuum at 40°C until no further solvent flowed out, and the resulting crude product was purified by flash column chromatography (eluted with pure EA) to give 2.9 g of a yellow solid in 71% yield. Characterization 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 with potassium tert-butoxide during the reaction (e.g., ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate) [ka]

[0041] A 250 mL three-neck flask equipped with a dropping funnel and a thermometer was charged with 100 mL of THF and sodium hydride (2.4 g, 60 mmol) under a nitrogen gas atmosphere, and the mixture 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, and the resulting solution was transferred to a constant-pressure dropping funnel and slowly added dropwise to the potassium tert-butoxide THF solution. After the addition was complete, the mixture was heated to 20-30°C and reacted until the conversion of the raw materials was complete, as monitored by TLC. The system was then cooled to 10-15°C, and 50 mL of water was slowly added dropwise to quench the reaction. After the addition was complete, the system was concentrated under reduced pressure at <40°C to recover THF. After the liquid stopped flowing, the system was cooled to 10-15°C, kept at this temperature for 2-3 hours, and then filtered. The filter cake was washed with 20 mL of purified water and dried at 55-70°C for 12 hours to obtain 9.0 g of a yellow solid in a 77% yield. Characterization data were the same as in Example 1.

Claims

1. A method for preparing a series of vonoprazan intermediates using an isonitrile and a Michael acceptor, the general formula of the synthetic pathway is as follows: 【Chemistry 1】 Specifically, the method includes the steps of dissolving α-(p-toluenesulfonyl)-2-fluorobenzylisonitrile and a Michael acceptor in a solvent, and then adding a base to react them to produce 3-substituted 5-(2-fluorophenyl)pyrrole. A method characterized by:

2. The Michael acceptor is an α,β-unsaturated carbonyl compound, and Z is an electron-withdrawing group such as CHO, COOR, CONRCH, or the like. ３ , CONROR', CN or NO ２ wherein R is H, alkyl or aryl, and R′ is alkyl, alkenyl, alkoxy or aryl; 2. The method of claim 1 .

3. 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, N-methylpyrrolidone, cyclohexane, n-hexane, n-heptane, toluene, acetonitrile, N,N-dimethylacetamide, and N,N-dimethylformamide; 2. The method of claim 1 .

4. the solvent is at least one of tetrahydrofuran, isopropyl ether, and dimethyl sulfoxide; 4. The method of claim 3.

5. 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, and lithium hexamethyldisilazide; 2. The method of claim 1 .

6. The reaction temperature is −78 to 60° C., and the reaction time is 0.5 to 6 hours.

2. The method of claim 1 .

7. The reaction temperature is −20 to 30° C., and the reaction time is 0.5 to 2 hours.

7. The method of claim 6.

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