Preparation method of vonoprazan

Abstract

The present invention belongs to the technical field of pharmaceutical chemistry, and specifically provides a method for preparing vonoprazan and vonoprazan fumarate with efficient reaction and short route. The method uses a novel intermediate compound (5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-yl)-pyridine-3-sulfonic acid methyl ester to obtain vonoprazan by amination; vonoprazan fumarate can be obtained by salt-forming reaction, which can avoid dangerous redox operation and the introduction of toxic impurities, thereby improving the yield and product quality, thereby overcoming the problem of complicated operation process of existing process, and being suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a preparation method of vonoprazan and vonoprazan fumarate. Background Art

[0002] Vonoprazan fumarate is a new type of gastric acid secretion inhibitor developed by Takeda Pharmaceuticals of Japan. It submitted an application for marketing approval in Japan in February 2014. In China, it was approved for clinical use in May 2014. The drug is a new type of PPI-potassium ion competitive acid blocker, which works by competitively inhibiting potassium ions in hydrogen ion / potassium ion-ATPase and is a reversible potassium ion antagonist. Compared with traditional PPIs, the acid suppression effect of this type of drug is unrelated to the activation of the proton pump, and can significantly reduce the production of nocturnal acid breakthrough clinically. It can be used to treat non-erosive gastroesophageal reflux disease, duodenal ulcers, gastric ulcers, erosive esophagitis, etc. The structure of Vonoprazan fumarate is shown below:

[0003]

[0004] There are many reports on the preparation methods of vonoprazan fumarate in the literature. For example, the synthesis route reported in patent CN101300229A is as follows:

[0005]

[0006] This route has a long process step and is complicated to handle. In addition, the starting material 1H-pyrrole-3-carboxylic acid methyl ester is not easy to purchase. During the reaction, the ester group is reduced to a hydroxyl group, and the hydroxyl group is oxidized to an aldehyde group. The reaction conditions are relatively harsh, making the reaction difficult to control and post-processing difficult. Therefore, it is not suitable for large-scale production.

[0007] Patent CN105085484A reports the following synthesis route:

[0008]

[0009] Similarly, this synthetic route is long and requires the amino group to be protected by tert-butyloxycarbonyl and then deprotected. The operation steps are cumbersome and the atom economy is poor, making it unsuitable for industrial production.

[0010] The synthesis route reported in patent CN104860923A is as follows:

[0011]

[0012] The steps of this route are relatively simple, but the process of reducing the nitrile group to the amine group requires the use of heavy metal catalytic hydrogenation such as palladium, platinum, and rhodium. The catalyst is expensive and the operation is somewhat dangerous. The subsequent amine methylation is achieved using formaldehyde compounds, which are too toxic and have the risk of introducing genotoxic substances, and are also not suitable for industrial production.

[0013] Therefore, it is very necessary to develop a new method for preparing vonoprazan fumarate. Summary of the invention

[0014] In the methods for preparing vonoprazan fumarate disclosed in the existing literature, the synthetic route is generally long, and the reaction process mostly requires oxidation-reduction to be realized, the operation is dangerous, and it is not conducive to the realization of industrialization. The present invention provides a method for preparing vonoprazan fumarate with efficient reaction and short route. The method uses a novel intermediate compound, can avoid dangerous oxidation-reduction operations, avoid the introduction of toxic impurities, improve the yield, and improve the product quality, thereby overcoming the problem of complex operation process of the existing process, and is suitable for industrial production.

[0015] The present invention provides a method for preparing vonoprazan, which comprises the following specific steps:

[0016]

[0017] Preferably, the method for preparing vonoprazan comprises the following specific steps:

[0018] (5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl)-pyridine-3-sulfonic acid methyl ester is added to organic solvent A, stirred and cooled, methylamine reagent is slowly added, and then the temperature is raised, and the reaction is stirred and kept warm; after the reaction is completed, purified water is added, the extractant is extracted, the organic phase is washed, and concentrated to obtain Vonoprazan.

[0019] Further preferably, the vonoprazan obtained by the method can be further subjected to a salt-forming reaction to obtain vonoprazan fumarate, and the specific steps include: adding vonoprazan to an organic solvent B, heating and stirring to dissolve, adding fumaric acid, cooling and continuing to stir the reaction, filtering, washing, collecting the solid, and drying to obtain vonoprazan fumarate.

[0020] Preferably, the organic solvent A is methanol, ethyl acetate, dichloromethane, chloroform, acetonitrile; preferably methanol.

[0021] Preferably, the mass volume ratio of the (5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl)-pyridine-3-sulfonic acid methyl ester to the organic solvent A is 1:6-15, g / mL; the preferred mass volume ratio is 1:8-10, g / mL.

[0022] Preferably, the molar ratio of the (5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl)-pyridine-3-sulfonic acid methyl ester to the methylamine reagent (calculated as methylamine) is 1:2-2.6; the preferred molar ratio is 1:2.1-2.3.

[0023] Preferably, the methylamine reagent is methylamine, methylamine methanol solution, methylamine aqueous solution, methylamine ethanol solution; preferably methylamine methanol solution.

[0024] Preferably, the stirring and cooling temperature is -10 to 10°C; preferably, the temperature is -5 to 0°C.

[0025] Preferably, the heating temperature is 25-40°C; the preferred temperature is 35°C.

[0026] Preferably, the time of heat preservation and stirring is 5 to 20 hours; preferably, the time is 8 to 10 hours.

[0027] Preferably, the extraction agent used in the extraction is dichloromethane, chloroform, ethyl acetate; preferably dichloromethane.

[0028] Preferably, the organic solvent B is ethyl acetate, isopropanol, N,N-dimethylformamide; preferably ethyl acetate.

[0029] Preferably, the mass volume ratio of vonoprazan to organic solvent B is 1:5-10, g / mL; the preferred mass volume ratio is 1:6-8, g / mL.

[0030] Preferably, the temperature for heating and dissolving is 40-60°C; preferably, the temperature is 50-55°C.

[0031] Preferably, the temperature during cooling and continued stirring is -10°C to 10°C, and the preferred temperature is -5°C to 0°C.

[0032] Preferably, the molar ratio of vonoprazan to fumaric acid is 1:1-2; the preferred molar ratio is 1:1.05-1.2.

[0033] Preferably, the stirring reaction time is 1 to 4 hours; preferably, the time is 2 to 3 hours.

[0034] Further preferably, the (5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-pyridine-3-sulfonic acid methyl ester can be prepared by the following method, the specific steps are:

[0035]

[0036] 5-(2-Fluorophenyl)-1H-pyrrole-3-methanol and 3-pyridinesulfonyl chloride react in an organic solvent to obtain (5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-pyridine-3-sulfonic acid methyl ester.

[0037] Preferably, 5-(2-fluorophenyl)-1H-pyrrole-3-methanol, a catalyst and an acidifying agent are added to an organic solvent, stirred and cooled, and then the 3-pyridinesulfonyl chloride solution is slowly added dropwise. After the addition is completed, the temperature is increased, and the mixture is kept warm and stirred; ice water is added to control the temperature, and then acid is added to adjust the pH, stirring is continued, and suction filtration is performed to obtain (5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl)-pyridine-3-sulfonic acid methyl ester.

[0038] Preferably, the organic solvent is acetonitrile, tetrahydrofuran, or dioxane; preferably acetonitrile.

[0039] Preferably, the mass volume ratio of the 5-(2-fluorophenyl)-1H-pyrrole-3-methanol to the organic solvent is 1:6-15, g / mL; the preferred mass volume ratio is 1:8-10, g / mL.

[0040] Preferably, the molar ratio of 5-(2-fluorophenyl)-1H-pyrrole-3-methanol to 3-pyridinesulfonyl chloride is 1:2-3; the preferred molar ratio is 1:2.2-2.5.

[0041] Preferably, the catalyst is 4-dimethylaminopyridine (DMAP) or pyridine.

[0042] Preferably, the acid dressing agent is triethylamine, N-methylpyrrolidine or tetramethylethylenediamine; preferably triethylamine.

[0043] Preferably, the molar ratio of 5-(2-fluorophenyl)-1H-pyrrole-3-methanol to the catalyst is 1:0.3-1.0; the preferred molar ratio is 0.5-0.7.

[0044] Preferably, the molar ratio of the 5-(2-fluorophenyl)-1H-pyrrole-3-methanol to the acid dressing agent is 1:2-3; the preferred molar ratio is 2.2-2.4.

[0045] Preferably, the stirring and cooling temperature is -10 to 10°C; preferably, the temperature is -5 to 0°C.

[0046] Preferably, the temperature of the heating is 10-30°C; preferably, the temperature is 10-15°C.

[0047] Preferably, the time of heat preservation and stirring is 2 to 10 hours; preferably, the time is 4 to 6 hours.

[0048] Preferably, the temperature control temperature is 0-15°C; preferably 5-10°C.

[0049] Preferably, the acid is hydrochloric acid, sulfuric acid or glacial acetic acid.

[0050] Preferably, the pH is 5-7.

[0051] Preferably, the stirring time is continued for 2 to 4 hours.

[0052] Compared with the prior art, the technical effects achieved by the present invention are:

[0053] The present invention provides a new vonoprazan intermediate compound, which can be used to prepare vonoprazan fumarate, and the method is simple and the reaction is efficient; the present invention also provides a new route for preparing vonoprazan fumarate, which has shorter reaction steps than the routes reported in the existing literature, and the raw materials are easily available, thus avoiding the use of a large number of toxic and harmful reagents, having a higher reaction yield and better safety, and being suitable for industrial application. DETAILED DESCRIPTION

[0054] The present invention is further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention based on the method of the present invention are all within the scope of protection required by the present invention.

[0055] Example 1 (5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl)-pyridine-3-sulfonic acid methyl ester

[0056] Weigh 100g of 5-(2-fluorophenyl)-1H-pyrrole-3-methanol, 19.1g of 4-dimethylaminopyridine, and 115.7g of triethylamine, add them to 100mL of acetonitrile, stir and cool to -5°C, then slowly drop 230g of 3-pyridinesulfonyl chloride solution, after the dropwise addition is complete, heat to 15°C, keep stirring for 6h, add 200g of ice water, control the temperature at 5-10°C, then slowly drop 0.5mol / L of hydrochloric acid, adjust the pH to 6, and continue stirring for 3h. Collect the solid by suction filtration, wash, and dry to obtain 223.3g of (5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl)-pyridine-3-sulfonic acid methyl ester.

[0057] Structural confirmation: ESI-MS (m / z): 474.05 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ: 8.86~8.98(m,2H), 8.81~8.83(m,1H), 8.76~8.79(m,1H), 8.65~8.69(d,J=2.0Hz,2H), 7. 79~7.83(m,2H), 7.43~7.45(m,1H), 7.32~7.36(m,1H), 7.11~7.18(m,2H), 6.52(s,1H), 6.05(s,1H); 4.59(s,2H).

[0058] Example 2 Preparation of Vonoprazan Fumarate

[0059] Weigh 100g of (5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl)-pyridine-3-sulfonic acid methyl ester, add it to 800mL methanol, stir and cool to -5°C, slowly drop 45.6g of 30% methylamine methanol solution; after the dropwise addition is completed, heat to 35°C, keep warm and stir for 10h; after the reaction is completed, add 400mL of purified water, then extract with 500mL of dichloromethane, wash with 150mL of brine × 2 times, dry with anhydrous sodium sulfate, filter, and concentrate to dryness to obtain vonoprazan. Then add 420mL of ethyl acetate, heat to 50°C and stir to dissolve, add 25.6g of fumaric acid, cool to 0°C and continue stirring for 2h, filter, wash with 20mL of ethyl acetate, and dry to obtain 91.5g of white solid, HPLC: 99.68%. ESI-MS m / z: 462.12[M+H] + .

[0060] Example 3 Preparation of Vonoprazan Fumarate

[0061] Weigh 100g of (5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl)-pyridine-3-sulfonic acid methyl ester, add it to 1000mL methanol, stir and cool to 0°C, slowly drop 49.7g of 30% methylamine methanol solution; after the dropwise addition is completed, heat to 40°C and stir for 8h. After the reaction is completed, add 300mL of purified water, then extract with 400mL of dichloromethane, wash with 100mL of brine × 2 times, dry with anhydrous sodium sulfate, filter, and concentrate to dryness to obtain vonoprazan. Then add 560mL of ethyl acetate, heat to 50°C and stir to dissolve, add 29.2g of fumaric acid, cool to 30°C and continue stirring for 4h, filter, wash with 30mL of ethyl acetate, and dry to obtain 90.6g of white solid, HPLC: 99.74%. ESI-MS m / z: 462.12[M+H] + .

[0062] Example 4 Preparation of Vonoprazan Fumarate

[0063] Weigh 100g of (5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl)-pyridine-3-sulfonic acid methyl ester, add it to 600mL acetonitrile, stir and cool to -10°C, slowly add 56.5g of 30% methylamine ethanol solution to the reaction solution; after the addition is complete, heat to 25°C and stir for 12h. After the reaction is completed, add 200mL of purified water, then extract with 600mL of dichloromethane, wash with 200mL of brine × 2 times, dry with anhydrous sodium sulfate, filter, and concentrate to dryness to obtain vonoprazan. Then add 350mL of isopropanol, heat to 60°C and stir to dissolve, add 24.3g of fumaric acid, cool to 10°C and continue stirring for 4h, filter, wash with 30mL of methanol, and dry to obtain 84.3g of white solid, HPLC: 99.26%. ESI-MS m / z: 462.12[M+H] + .

[0064] Example 5 Preparation of Vonoprazan Fumarate

[0065] Weigh 100g of (5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl)-pyridine-3-sulfonic acid methyl ester, add it to 1500mL of dichloromethane, stir and cool to 10°C, slowly drop 43.5g of 30% methylamine methanol solution; after the dropwise addition is completed, heat to 40°C, keep warm and stir for 10h; after the reaction is completed, add 400mL of purified water, then extract with 500mL of ethyl acetate, wash 150mL of brine × 2 times, dry with anhydrous sodium sulfate, filter, and concentrate to dryness to obtain vonoprazan. Then add 700mL of N,N-dimethylformamide, heat to 40°C and stir to dissolve, add 48.8g of fumaric acid, cool to 0°C and continue stirring for 2h, filter, wash with 20mL of ethyl acetate, and dry to obtain 80.6g of white solid, HPLC: 98.62%. ESI-MS m / z: 462.12[M+H] + .

Claims

1. A method for preparing vonoprazan, characterized in that: The specific steps include: .

2. The preparation method according to claim 1, characterized in that The specific preparation steps include: (5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl)-pyridine-3-sulfonic acid methyl ester is added to organic solvent A, stirred and cooled, methylamine reagent is slowly added, and then the temperature is raised, and the reaction is stirred and kept warm; after the reaction is completed, purified water is added, the extractant is extracted, the organic phase is washed, and concentrated to obtain Vonoprazan.

3. The preparation method according to claim 2, characterized in that: The molar ratio of the (5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl)-pyridine-3-sulfonic acid methyl ester to the methylamine reagent is 1:2-2.

6.

4. The preparation method according to claim 2, characterized in that: The organic solvent A in step 1 is methanol, ethyl acetate, dichloromethane, chloroform or acetonitrile.

5. The preparation method according to claim 2, characterized in that: The stirring and cooling temperature is -10 to 10°C; the heating temperature is 25 to 40°C.

6. The preparation method according to claim 2, characterized in that: The prepared vonoprazan can be further subjected to a salt-forming reaction to obtain vonoprazan fumarate, and the specific steps include: adding vonoprazan to an organic solvent B, heating and stirring to dissolve, adding fumaric acid, cooling and continuing to stir and react, filtering after the reaction, washing, collecting the solid, and drying to obtain vonoprazan fumarate.

7. The preparation method according to claim 6, characterized in that: The organic solvent B is selected from ethyl acetate, isopropanol or N,N-dimethylformamide.

8. The preparation method according to claim 7, characterized in that: The mass volume ratio of the vonoprazan to the organic solvent B is 1:5-10, g / mL.

9. The preparation method according to claim 2, characterized in that: The (5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-pyridine-3-sulfonic acid methyl ester can be prepared by the following method, the specific steps are: ， 5-(2-Fluorophenyl)-1H-pyrrole-3-methanol and 3-pyridinesulfonyl chloride react in an organic solvent to obtain (5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-pyridine-3-sulfonic acid methyl ester.

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