Method for preparing series of vonoprazan intermediates from isocyanide and Michael receptor

Abstract

The invention discloses a method for preparing a series of vonoprazan intermediates from isonitrile and a Michael receptor. According to the method, alpha-(p-toluenesulfonyl)-2-fluorobenzyl isocyanide is used as a raw material, attacks a series of Michael receptors under an alkaline condition, and forms a series of 3-substituted 5-(2-fluorophenyl)-1H-pyrrole through cyclization. The 3-substituted pyrrole intermediates can be used for preparing vonoprazan through further chemical conversion. Compared with the prior art, the technical scheme provided by the invention has the characteristics of short synthesis route, high comprehensive yield, simple post-treatment and low cost.

Description

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 class of proton pump inhibitors with rapid, strong and long-lasting inhibitory effects on gastric acid secretion. 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]

[0005] There are many methods for preparing vonoprazan fumarate reported in the literature, among which:

[0006] The original research Takeda Pharmaceutical reported the following route in compound patent CN101300229B:

[0007]

[0008] 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 10 steps of condensation, imination, reduction, and salt formation to obtain the target product.

[0009] Takeda Pharmaceutical subsequently disclosed its process route in CN105524046B:

[0010]

[0011] In the process route, similar to the compound patent, Takeda Pharmaceutical still uses 2-fluoroacetophenone as the starting material, and prepares the intermediate 5-(2-fluorophenyl)pyrrole-3-carboxaldehyde through bromination, alkylation, cyclization, hydrogenation dechlorination, and reduction. The intermediate is then prepared into the product through condensation, imine, reduction, and salt formation. The main difference is that malononitrile is used instead of ethyl cyanoacetate, which avoids the reduction of the ester group after cyclization and shortens the reaction by one step.

[0012] 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:

[0013]

[0014] Lunan Pharmaceutical published its method for synthesizing vonoprazan in CN113549054, using 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile as the starting material, hydrolyzing the cyanide to obtain 5-(2-fluorophenyl)-1H-pyrrole-3-carboxamide, and then obtaining the target product vonoprazan through multiple steps. The synthetic route is as follows:

[0015]

[0016] 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 synthesizing vonoprazan are summarized and listed from the above patent as follows:

[0017]

[0018] From the perspective of the synthetic methods for preparing these intermediates, the method for synthesizing 3-substituted 5-(2-fluorophenyl)pyrrole is relatively simple, and is mainly developed by Takeda Pharmaceuticals using 2-fluoroacetophenone as the starting material and undergoing 4-6 steps of synthetic reactions. However, this method has the challenges of a long reaction route, a cumbersome operation process, and difficult quality control. Therefore, it is of great significance to develop a method for preparing 3-substituted 5-(2-fluorophenyl)pyrrole derivatives with short steps, simple operation, low cost, and high yield. Summary of the invention

[0019] The purpose of the present invention is to provide a novel method for synthesizing 3-substituted 5-(2-fluorophenyl)pyrrole derivatives in view of the defects of the existing methods for preparing 3-substituted 5-(2-fluorophenyl)pyrrole derivatives, so as to provide 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.

[0020] 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, and the general synthesis route of the method is as follows:

[0021]

[0022] 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.

[0023] 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.

[0024] Preferably, 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 (DMSO), N-methylpyrrolidone (NMP), cyclohexane, n-hexane, n-heptane, toluene, acetonitrile, N,N-dimethylacetamide and N,N-dimethylformamide.

[0025] More preferably, the solvent is at least one of tetrahydrofuran, isopropyl ether and dimethyl sulfoxide.

[0026] 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).

[0027] Preferably, the reaction temperature is -78 to 60°C and the reaction time is 0.5 to 6 hours.

[0028] More preferably, the reaction temperature is -20 to 30°C and the reaction time is 0.5 to 2 hours.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] The 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 invention is of great significance for the subsequent preparation of vonoprazan. DETAILED DESCRIPTION

[0031] In order to make the present invention more clearly understood, preferred embodiments are described in detail as follows.

[0032] In the following examples, the preparation and characterization of α-(p-toluenesulfonyl)-2-fluorobenzyl isocyanide are as follows:

[0033] Preparation of α-(p-toluenesulfonyl)-2-fluorobenzyl isonitrile Reference: [Fallarini; Massarotti; Gesù; Giovarruscio. MedChemComm, 2016 (7), 409-419] Preparation, the synthesis thereof will not be described in detail in the present embodiment, and the product is a yellow-white solid. NMR and mass spectrometry characterization data are as follows:

[0034] 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);

[0035] ESI-MS: 290[M+H + ].

[0036] Example 1: Preparation of ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate using ethyl acrylate as Michael acceptor

[0037]

[0038] In a 500mL three-necked glass bottle with a dropping funnel, a thermometer, and nitrogen protection, add 200mL DMSO and sodium hydride (4.8g, 120mmol), and cool the system to 10-15℃. Dissolve α-(p-toluenesulfonyl)-2-fluorobenzyl isonitrile (29g, 100mmol) and ethyl acrylate (13g, 130mmol) in 100mL DMSO, and then transfer the solution to a constant pressure dropping funnel and slowly drop it into the DMSO solution of NaH. After the addition is complete, the system is heated to 20-30℃ and reacted until the conversion of the raw material is completed by TLC monitoring. Then the system is cooled to 10-15℃, and 100mL of water is slowly added to quench the reaction. After the addition is complete, keep warm for 2-3h, filter, wash the filter cake with 20mL purified water, and dry it at 55-70℃ for 12h to obtain 19.1g of yellow solid with a yield of 82%. Characterization data are as follows:

[0039] 1 H-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 + ].

[0040] Example 2: Preparation of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde using acrolein as Michael acceptor

[0041]

[0042] In a 250mL three-necked glass bottle with a dropping funnel, a thermometer and nitrogen protection, add 50mL DMSO and sodium hydride (0.88g, 22mmol), and cool the system to 10-15°C. Dissolve α-(p-toluenesulfonyl)-2-fluorobenzyl isonitrile (5.8g, 20mmol) and acrolein (1.2g, 22mmol) in 25mL DMSO, and then transfer the solution to a constant pressure dropping funnel and slowly drop it into the DMSO solution of NaH. After the addition is complete, the system is heated to 20-30°C to react until the conversion of the raw material is completed as monitored by TLC. Then the system is cooled to 10-15°C, and 30mL of water is slowly added to quench the reaction. After the addition is complete, 100mL of ethyl acetate is added for extraction, and the liquid is separated. The aqueous phase is extracted with 30mL of ethyl acetate again, and the ethyl acetate layers are combined and dried over anhydrous sodium sulfate. The mixture was concentrated in vacuo at 40°C until no solvent flowed out, and the crude product was purified by flash column chromatography (PE:EA=5:1) to obtain 2.5 g of yellow solid with a yield of 65%. The characterization data are as follows:

[0043] 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 + ].

[0044] Example 3: Preparation of 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile using acrylonitrile as Michael acceptor

[0045]

[0046] In a 250mL three-necked glass bottle with a dropping funnel, a thermometer and nitrogen protection, add 50mL DMSO and sodium hydride (0.88g, 22mmol), and cool the system to 10-15℃. Dissolve α-(p-toluenesulfonyl)-2-fluorobenzyl isonitrile (5.8g, 20mmol) and acrylonitrile (1.2g, 22mmol) in 25mL DMSO, and then transfer the solution to a constant pressure dropping funnel and slowly drop it into the DMSO solution of NaH. After the addition is complete, the system is heated to 20-30℃ to react until the conversion of the raw material is completed as monitored by TLC. Then the system is cooled to 10-15℃, and 30mL water is slowly added to quench the reaction. After the addition is complete, 100mL ethyl acetate is added for extraction, and the liquid is separated. The aqueous phase is extracted with 30mL ethyl acetate again, and the ethyl acetate layers are combined and dried over anhydrous sodium sulfate. The mixture was concentrated in vacuo at 40°C until no solvent was discharged, and the crude product was purified by flash column chromatography (PE:EA=5:1) to obtain 2.6 g of yellow solid with a yield of 69%. Characterization data are as follows:

[0047] 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 + ].

[0048] Example 4: Preparation of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxamide using acrylamide as a Michael acceptor

[0049]

[0050] In a 250mL three-necked glass bottle with a dropping funnel, a thermometer and nitrogen protection, add 50mL DMSO and sodium hydride (1.2g, 30mmol), and cool the system to 10-15℃. Dissolve α-(p-toluenesulfonyl)-2-fluorobenzyl isonitrile (5.8g, 20mmol) and acrylamide (2g, 28mmol) in 25mL DMSO, and then transfer the solution to a constant pressure dropping funnel and slowly drop it into the DMSO solution of NaH. After the addition is complete, the system is heated to 20-30℃ to react until the conversion of the raw material is completed as monitored by TLC. Then the system is cooled to 10-15℃, and 30mL water is slowly added to quench the reaction. After the addition is complete, 100mL ethyl acetate is added for extraction, and the liquid is separated. The aqueous phase is extracted with 30mL ethyl acetate again, and the ethyl acetate layers are combined and dried over anhydrous sodium sulfate. The mixture was concentrated in vacuo at 40°C until no solvent was discharged, and the crude product was subjected to flash column chromatography (eluted with pure EA) to obtain 2.9 g of a yellow solid with a yield of 71%. The characterization data are as follows:

[0051] 1 H-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+].

[0052] 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)

[0053]

[0054] In a 250mL three-necked glass bottle with a dropping funnel, a thermometer and nitrogen protection, add 100mL THF and sodium hydride (2.4g, 60mmol), and cool the system to 10-15°C. Dissolve α-(p-toluenesulfonyl)-2-fluorobenzyl isonitrile (14.5g, 50mmol) and ethyl acrylate (6.5g, 65mmol) in 100mL THF, and then transfer the solution to a constant pressure dropping funnel and slowly drop it into the THF solution of potassium tert-butoxide. After the dropwise addition is completed, the system is heated to 20-30°C and reacted until the conversion of the raw materials is completed as monitored by TLC. Then the system was cooled to 10-15°C, 50 mL of water was slowly added dropwise to quench the reaction, and after the addition was complete, THF was recovered by concentration under reduced pressure at <40°C. After no liquid flowed out, the system was cooled to 10-15°C and kept warm 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 9.0 g of a yellow solid with a yield of 77%. Characterization data are 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.

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