Method for preparing series of vonoprazan intermediates from isonitrile and michael receptor

Abstract

Disclosed in the present invention is a method for preparing a series of vonoprazan intermediates from isonitrile and a Michael receptor. The method of the present invention comprises: using α-(tosyl)-2-fluorobenzyl isonitrile as a raw material, attacking a series of Michael receptors under an alkaline condition, and forming by cyclization a series of 3-substituted 5-(2-fluorophenyl)-1H-pyrroles. Moreover, these 3-substituted pyrrole intermediates can be further subjected to chemical conversion for the preparation of vonoprazan. Compared with the prior art, the technical solution of the present invention has the characteristics of short synthetic route, high comprehensive yield, simple post-treatment, and low cost.

Description

Method for preparing a series of vonoprazan intermediates using isonitrile and Michael acceptor Technical Field

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

[0002] Vonoprazan (TAK-438) is a potassium-competitive acid blocker, also known as P-CAB, which inhibits acid secretion by competitively blocking the activity of potassium ions in HK-ATPase. Traditional PPIs inhibitors mainly block gastric acid secretion caused by any stimulation by inhibiting the activity of H+ / K+-ATPase. However, PPIs do not always provide sufficient therapeutic effect, and the effect of inhibiting gastric acid secretion often varies from person to person. Potassium-competitive acid blockers (P-CABs) are a new type of proton pump inhibitors with fast-acting, strong and long-lasting gastric acid secretion inhibitory effects; Vonoprazan was jointly developed by Takeda Pharmaceuticals (Takeda) and Otsuka Pharmaceuticals (Otsuka), and was approved for marketing by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on December 26, 2014, and was approved for marketing by the National Medical Products Administration (NMPA) on December 18, 2019. The trade name It is used to treat gastric and duodenal ulcers, treat reflux esophagitis and prevent recurrence, and is used for first-line and second-line Helicobacter pylori eradication therapy with good tolerability and safety.

[0003] The structure of vonoprazan fumarate is as follows:

[0004] There are many methods for preparing vonoprazan fumarate reported in the literature, among which:

[0005] The original research company Takeda Pharmaceuticals reported the following route in compound patent CN101300229B:

[0006] In the original research compound route, 2-fluoroacetophenone was used as the starting material, and the intermediate 5-(2-fluorophenyl)pyrrole-3-carboxaldehyde was prepared through six steps of bromination, alkylation, cyclization, hydrogenation and dechlorination, and oxidation. The intermediate was then subjected to condensation, imination, reduction, and salt formation, a total of 10 steps, to obtain the target product.

[0007] Takeda Pharmaceutical subsequently disclosed its process route in CN105524046B:

[0008] Similar to the patented compound, Takeda Pharmaceutical uses 2-fluoroacetophenone as the starting material and produces the intermediate 5-(2-fluorophenyl)pyrrole-3-carboxaldehyde through a five-step reaction process: bromination, alkylation, cyclization, hydrodechlorination, and reduction. This intermediate is then converted to the product through a four-step reaction process: condensation, imidization, reduction, and salt formation. The main difference is the use of malononitrile instead of ethyl cyanoacetate, which avoids the reduction of the ester group after cyclization and shortens the reaction process by one step.

[0009] Disa Pharmaceuticals reported in its patent CN109232537A that the core intermediate 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylic acid ethyl ester was prepared by attacking bromoacetophenone with ethyl 3-oxopropionate and then closing the pyrrole ring:

[0010] Lunan Pharmaceutical published its method for synthesizing vonoprazan in CN113549054. The method uses 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile as the starting material, hydrolyzes the cyanide group to obtain 5-(2-fluorophenyl)-1H-pyrrole-3-carboxamide, and then obtains the target product vonoprazan through multiple steps. The synthetic route is as follows:

[0011] At present, it is not difficult to see from the above patent application that 3-substituted 5-(2-fluorophenyl)pyrrole is the core of the synthesis process of vonoprazan. The intermediates I, II, III, and IV for the synthesis of vonoprazan are summarized and listed as follows from the above patent application:

[0012] The synthesis methods for preparing these intermediates are relatively simple, primarily developed by Takeda Pharmaceuticals using 2-fluoroacetophenone as the starting material and proceeding through a 4-6-step synthesis reaction. However, this method presents challenges such as a long reaction route, cumbersome operation, and difficult quality control. Therefore, developing a method for preparing 3-substituted 5-(2-fluorophenyl)pyrrole derivatives with a short process, simple operation, low cost, and high yield is of great significance.

[0013] Summary of the Invention

[0014] The purpose of the present invention is to address the defects of the existing preparation methods of 3-substituted 5-(2-fluorophenyl)pyrrole derivatives and provide a new synthesis method of 3-substituted 5-(2-fluorophenyl)pyrrole, thereby providing more method options for synthesizing this type of core intermediate. The method of the present invention has the advantages of short steps, simple operation, low cost and high yield.

[0015] In order to achieve the above object, the present invention provides a method for preparing a series of vonoprazan intermediates using isonitrile and Michael acceptor. The general synthetic route of the method is as follows:

[0016] The method specifically comprises: dissolving α-(p-toluenesulfonyl)-2-fluorobenzyl isonitrile and a Michael acceptor in a solvent, and then adding a base to react to generate 3-substituted 5-(2-fluorophenyl)pyrrole.

[0017] Preferably, the Michael acceptor, as known in the art, is an α-β unsaturated carbonyl compound, 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. Wherein Z is an electron withdrawing group, including but not limited to CHO, COOR, CONRCH3, CONROR', CN, NO2. R can be H, alkyl or aryl; R' is alkyl, alkenyl, alkoxy or aryl.

[0018] Preferably, the solvent is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, diethyl 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.

[0019] More preferably, the solvent is at least one of tetrahydrofuran, isopropyl ether and dimethyl sulfoxide.

[0020] Preferably, the base is selected from at least one of 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).

[0021] Preferably, the reaction temperature is -78 to 60° C., and the reaction time is 0.5 to 6 hours.

[0022] More preferably, the reaction temperature is -20 to 30°C, and the reaction time is 0.5 to 2 hours.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The present invention uses α-(p-toluenesulfonyl)-2-fluorobenzyl isonitrile and different Michael acceptors to synthesize a series of 3-substituted 5-(2-fluorophenyl)pyrroles of vonoprazan intermediates through a one-step reaction. The method has the advantages of mild reaction conditions, simple post-treatment, easy separation and purification, and high yield. The method of the present invention is of great significance for the subsequent preparation of vonoprazan. DETAILED DESCRIPTION

[0025] To make the present invention more clearly understood, preferred embodiments are described in detail below with reference to the accompanying drawings.

[0026] In the following examples, the preparation and characterization of α-(p-toluenesulfonyl)-2-fluorobenzyl isocyanide are as follows:

[0027] The preparation of α-(p-toluenesulfonyl)-2-fluorobenzyl isocyanide is described in the literature [Fallarini; Massarotti; Gesù; Giovarruscio. MedChemComm, 2016(7), 409-419]. The synthesis of this product is omitted in the examples of the present invention. The product is a yellow-white solid. The NMR and mass spectrometry characterization data are as follows:

[0028] 1 H NMR (300MHz; CDCl3) δ7.71-7.75(m, 2H), 7.44-7.50(m, 1H), 7.35-7.41(m, 3 H), 7.21 (t, J=7.7Hz, 1H), 7.12 (t, J=9.6Hz, 1H), 5.97 (s, 1H), 2.49 (s, 3H);

[0029] ESI-MS: 290 [M+H + ].

[0030] Example 1: Preparation of ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate using ethyl acrylate as a Michael acceptor

[0031] In a 500mL three-necked glass flask equipped with a dropping funnel, thermometer, and nitrogen atmosphere, add 200mL of DMSO and sodium hydride (4.8g, 120mmol). Cool the system to 10-15°C. Dissolve α-(p-toluenesulfonyl)-2-fluorobenzyl isocyanide (29g, 100mmol) and ethyl acrylate (13g, 130mmol) in 100mL of DMSO. Transfer this solution to a constant pressure dropping funnel and slowly add it dropwise to the NaH solution in DMSO. After the addition is complete, warm the system to 20-30°C and react until the conversion of the starting material is complete as monitored by TLC. Then cool the system to 10-15°C and slowly add 100mL of water dropwise to quench the reaction. After the addition is complete, incubate for 2-3h, filter, and wash the filter cake with 20mL of purified water. Dry at 55-70°C for 12h to obtain 19.1g of a yellow solid with a yield of 82%. Characterization data are as follows:

[0032] 1H-NMR (CDCl3) δ: 1.67 (3H, t, J=7.2Hz), 4.31 (2H, q, J=7.2Hz), 7.03-7.05 (1H, m), 7.0 8-7.25(3H, m), 7.49-7.50(1H, m), 7.58-7.66(1H, m), 9.22(1H, brs); ESI-MS: 234[M+H + ].

[0033] Example 2: Preparation of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde using acrolein as a Michael acceptor

[0034] To a 250 mL three-necked glass flask equipped with a dropping funnel, thermometer, and nitrogen atmosphere, add 50 mL of DMSO and sodium hydride (0.88 g, 22 mmol). Cool the mixture to 10-15°C. Dissolve α-(p-toluenesulfonyl)-2-fluorobenzyl isocyanide (5.8 g, 20 mmol) and acrolein (1.2 g, 22 mmol) in 25 mL of DMSO. Transfer this solution to a constant pressure dropping funnel and slowly add it dropwise to the NaH solution in DMSO. After the addition is complete, warm the mixture to 20-30°C and allow the reaction to proceed until complete conversion of the starting material is monitored by TLC. Cool the mixture to 10-15°C and slowly add 30 mL of water dropwise to quench the reaction. After the addition is complete, extract the mixture with 100 mL of ethyl acetate. Separate the layers, extract the aqueous phase with another 30 mL of ethyl acetate, combine the ethyl acetate layers, and dry over anhydrous sodium sulfate. The crude product was concentrated in vacuo at 40°C until no solvent was released. Flash column chromatography (PE:EA=5:1) afforded 2.5 g of a yellow solid, yielding 65%. Characterization data are as follows:

[0035] 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 + ].

[0036] Example 3: Preparation of 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile using acrylonitrile as a Michael acceptor

[0037] To a 250 mL three-necked glass flask equipped with a dropping funnel, thermometer, and nitrogen atmosphere, add 50 mL of DMSO and sodium hydride (0.88 g, 22 mmol). Cool the mixture to 10-15°C. Dissolve α-(p-toluenesulfonyl)-2-fluorobenzyl isocyanide (5.8 g, 20 mmol) and acrylonitrile (1.2 g, 22 mmol) in 25 mL of DMSO. Transfer this solution to a constant pressure dropping funnel and slowly add it dropwise to the NaH solution in DMSO. After the addition is complete, warm the mixture to 20-30°C and allow the reaction to proceed until complete conversion of the starting material is monitored by TLC. Cool the mixture to 10-15°C and slowly add 30 mL of water dropwise to quench the reaction. After the addition is complete, extract the mixture with 100 mL of ethyl acetate. Separate the layers, extract the aqueous phase with another 30 mL of ethyl acetate, combine the ethyl acetate layers, and dry over anhydrous sodium sulfate. The crude product was concentrated in vacuo at 40°C until no solvent was released. Flash column chromatography (PE:EA=5:1) afforded 2.6 g of a yellow solid, yielding 69%. Characterization data are as follows:

[0038] 1 H-NMR (500MHz, 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 + ].

[0039] Example 4: Preparation of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxamide using acrylamide as a Michael acceptor

[0040] To a 250 mL three-necked glass flask equipped with a dropping funnel, thermometer, and nitrogen atmosphere, add 50 mL of DMSO and sodium hydride (1.2 g, 30 mmol). Cool the mixture to 10-15°C. Dissolve α-(p-toluenesulfonyl)-2-fluorobenzyl isocyanide (5.8 g, 20 mmol) and acrylamide (2 g, 28 mmol) in 25 mL of DMSO. Transfer this solution to a constant pressure dropping funnel and slowly add it dropwise to the NaH solution in DMSO. After the addition is complete, warm the mixture to 20-30°C and allow the reaction to proceed until complete conversion of the starting material is confirmed by TLC. Cool the mixture to 10-15°C and slowly add 30 mL of water dropwise to quench the reaction. After the addition is complete, extract the mixture with 100 mL of ethyl acetate. Separate the layers, extract the aqueous phase with another 30 mL of ethyl acetate, combine the ethyl acetate layers, and dry over anhydrous sodium sulfate. The crude product was concentrated in vacuo at 40°C until no solvent was released. Flash column chromatography (eluted with pure EA) afforded 2.9 g of a yellow solid, yielding 71%. Characterization data are as follows:

[0041] 1H-NMR (500MHz, 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+].

[0042] Example 5: The base in the reaction is replaced by potassium tert-butoxide (taking 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylic acid ethyl ester as an example)

[0043] To a 250 mL three-necked glass flask equipped with a dropping funnel, thermometer, and nitrogen protection, add 100 mL of THF and sodium hydride (2.4 g, 60 mmol), and cool the system to 10-15°C. Dissolve α-(p-toluenesulfonyl)-2-fluorobenzyl isocyanide (14.5 g, 50 mmol) and ethyl acrylate (6.5 g, 65 mmol) in 100 mL of THF. Transfer this solution to a constant pressure dropping funnel and slowly add it dropwise to the THF solution of potassium tert-butoxide. After the addition is complete, heat the system to 20-30°C and react until the conversion of the raw material is 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 mixture was concentrated under reduced pressure at <40°C to recover THF. After no liquid flowed out, the system was cooled to 10-15°C and kept warm for 2-3 hours. The mixture was filtered, and 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, with a yield of 77%. Characterization data were the same as in Example 1.

Claims

1. A method for preparing a series of vonoprazan intermediates using isonitrile and Michael acceptor, characterized in that: The general formula of the synthesis route of this method is as follows: The method specifically comprises: dissolving α-(p-toluenesulfonyl)-2-fluorobenzyl isonitrile and Michael acceptor in a solvent, and then adding a base to react to generate 3-substituted 5-(2-fluorophenyl)pyrrole.

2. The method according to claim 1, characterized in that: The Michael acceptor is an α-β unsaturated carbonyl compound, Z is an electron withdrawing group CHO, COOR, CONRCH3, CONROR', CN or NO2; wherein R is H, alkyl or aryl, and R' is alkyl, alkenyl, alkoxy or aryl.

3. The method according to claim 1, characterized in that The solvent is selected from at least one of 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.

4. The method according to claim 3, characterized in that The solvent is at least one of tetrahydrofuran, isopropyl ether and dimethyl sulfoxide.

5. The method according to claim 1, characterized in that The base is selected from at least one of 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.

6. The method according to claim 1, characterized in that The reaction temperature is -78 to 60°C and the reaction time is 0.5 to 6 hours.

7. The method according to claim 6, characterized in that The reaction temperature is -20 to 30°C and the reaction time is 0.5 to 2 hours.

Images