Fisurazan intermediate and preparation method thereof

Abstract

The invention provides a fisurazan intermediate and a preparation method thereof. Specifically, the invention provides a preparation method of a compound as shown in a formula VII, which comprises the following step: in a methylamine solution, methylamine salt and a compound as shown in a formula IV are subjected to amidation reaction to generate the compound as shown in the formula VII. The preparation method provided by the invention meets one or more of the following advantages: (1) reaction steps are short; (2) the post-treatment is simple; (3) the production cost is low; and (4) the method is suitable for commercial amplification. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a fexuprazan intermediate and a preparation method thereof. Background Art

[0002] Fexuprazan, with the chemical name 1-{5-(2,4-difluorophenyl)-1-[(3-fluorophenyl)sulfonyl]-4-methoxy-1H-pyrrol-3-yl}-N-methylmethanamine, has the molecular formula C 19 H 17 F 3 N 2 O 3 S, with a molecular weight of 410.4, is a novel potassium ion competitive acid blocker produced by Daejoon Pharmaceutical in South Korea. It is a new generation of proton pump inhibitor that can reversibly block the proton pump secreting gastric acid. Its molecular formula is as follows:

[0003]

[0004] WO2017164575 discloses a method for preparing fexuprazan. The preparation process includes a total of four reaction steps. However, the yield in the preparation process of this patent is relatively low, and the total yield of the four steps is 51.4%. Moreover, hazardous reagents (such as sodium hydride, diisobutylaluminum hydride, etc.) and environmentally polluting reagents (such as pyridinium chlorochromate) are used, which is not suitable for large-scale industrial production. Its preparation route is as follows:

[0005]

[0006] WO2020060213 does not change the route based on WO2017164575, but only optimizes the process, removes hazardous reagents (such as sodium hydride, diisobutylaluminum hydride, etc.) and environmentally polluting reagents (such as pyridinium chlorochromate), and improves the yield. This route can adapt to commercial production. However, generally speaking, there is no fundamental change, and the production operation is complex. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to overcome the defects of low yield, high cost, and complex operation of the above routes, and provide a fexuprazan intermediate and a preparation method thereof. The preparation method of the present invention satisfies one or more of the following advantages: (1) short reaction steps; (2) simple post-treatment; (3) low production cost; (4) suitable for commercial scale-up.

[0008] The present invention mainly solves the above technical problems through the following technical solutions.

[0009] The present invention provides a method for preparing a compound as shown in formula VII, which includes the following steps:

[0010] In the methylamine solution, the methylamine salt reacts with the compound shown in Formula IV to form the compound shown in Formula VII through an amidation reaction;

[0011]

[0012] In some embodiments, in the amidation reaction, the methylamine solution is an alcohol solution of methylamine, preferably a methylamine methanol solution or a methylamine ethanol solution, and more preferably a 30% methylamine methanol solution.

[0013] In some embodiments, in the amidation reaction, the molar ratio of the compound of Formula IV to methylamine in the methylamine solution is 1:10 - 15, preferably 1:12.

[0014] In some embodiments, in the amidation reaction, the methylamine salt is a salt formed by methylamine and an inorganic acid or a carboxylic acid. The inorganic acid can be hydrochloric acid, and the carboxylic acid can be a lower fatty acid or benzoic acid. The lower fatty acid is preferably acetic acid. The methylamine salt is preferably methylamine acetate and / or methylamine benzoate.

[0015] In some embodiments, in the amidation reaction, the molar ratio of the compound of Formula IV to the methylamine salt is 1:0.1 - 1:0.3, preferably 1:0.2.

[0016] In some embodiments, in the amidation reaction, the reaction temperature is 40 - 70 °C, such as 50 - 60 °C.

[0017] In some embodiments, in the amidation reaction, the progress of the reaction can be monitored by conventional detection methods in the art (such as HPLC, TLC or NMR). Generally, the reaction end point is when the compound of Formula IV disappears. The reaction time is generally 20 - 110 hours, preferably 30 - 45 hours, such as 30 - 35 hours.

[0018] In some embodiments, the amidation reaction includes the following steps: at the reaction temperature, mix the methylamine salt, the methylamine solution and the compound shown in Formula IV to obtain the compound shown in Formula VII.

[0019] In some embodiments, the amidation reaction further includes the following post-treatment steps: after the reaction ends, concentrate under reduced pressure, and add water three times the volume of the solution while controlling the temperature not exceeding 30 °C to precipitate a solid.

[0020] In some embodiments, in the amidation reaction, the reaction materials of the amidation reaction are composed of the following substances: the methylamine salt, the methylamine solution and the compound of Formula IV.

[0021] In some embodiments, the method for preparing the compound represented by Formula VII further comprises the following steps: in the presence of a solvent, a catalyst and a base, the compound represented by Formula II and the compound of Formula III undergo a Hinsberg reaction to obtain the compound of Formula IV;

[0022]

[0023] In the Hinsberg reaction, the catalyst is a conventional catalyst for this type of reaction in the art, such as pyridineamine catalysts, for example 4-dimethylaminopyridine and / or 4-pyrrolidinopyridine, preferably 4-dimethylaminopyridine.

[0024] In the Hinsberg reaction, the base is a conventional base for this type of reaction in the art, such as secondary alkylamines, for example N,N-diisopropylethylamine.

[0025] In the Hinsberg reaction, the solvent is a conventional solvent for this type of reaction in the art, such as halogenated alkane solvents, preferably chloroalkane solvents; for example, dichloromethane.

[0026] In some embodiments, in the Hinsberg reaction, the molar ratio of the compound of Formula II to the compound of Formula III is 1:1 - 1:1.2, for example 1:1.1.

[0027] In some embodiments, in the Hinsberg reaction, the molar ratio of the compound of Formula II to the catalyst is 7:1 - 9:1, for example 7.9:1.

[0028] In some embodiments, in the Hinsberg reaction, the molar ratio of the compound of Formula II to the base is 1:1 - 1:1.2, for example 1:1.1.

[0029] In some embodiments, in the Hinsberg reaction, the reaction materials are the compound represented by Formula II, the compound of Formula III, the solvent, the catalyst and the base.

[0030] In some embodiments, in the Hinsberg reaction, the reaction temperature is 15 - 35°C, for example 20 - 30°C.

[0031] In some embodiments, in the Hinsberg reaction, the progress of the reaction can be monitored by conventional detection methods in the art (such as HPLC, TLC or NMR), generally with the disappearance of the compound of Formula II as the reaction end point, and the reaction time is generally 2 - 6 hours, for example 5 - 6 hours.

[0032] In some embodiments, the Hinsberg reaction comprises the following steps: adding the compound shown in Formula II, the catalyst, and the base to the solvent, mixing with the solution of the compound shown in Formula III in the solvent, and carrying out the Hinsberg reaction to obtain the compound shown in Formula IV.

[0033] In some embodiments, the Hinsberg reaction further comprises the following post-treatment steps: after the reaction is completed, adding water for liquid separation, and adding methanol and water for liquid separation.

[0034] The present invention also provides a method for preparing a compound shown in Formula I, which comprises the following steps:

[0035] In the presence of a solvent, a reducing agent, and an acid, the compound shown in Formula VII undergoes the reduction reaction shown in the following formula to generate the compound shown in Formula I;

[0036]

[0037] In the reduction reaction, the solvent is a conventional solvent for this type of reaction in the art, such as an ether solvent, preferably a cyclic ether solvent, such as tetrahydrofuran.

[0038] In the reduction reaction, the acid is a conventional acid for this type of reaction in the art, such as an organic acid, such as trifluoroacetic acid.

[0039] In some embodiments, in the reduction reaction, the molar ratio of the compound shown in Formula VII to the acid is 1:4 - 1:5, such as 1:4.7.

[0040] In some embodiments, in the reduction reaction, the reducing agent is one or more of sodium borohydride, potassium borohydride, and lithium aluminum hydride, such as sodium borohydride.

[0041] In some embodiments, in the reduction reaction, the molar ratio of the compound shown in Formula VII to the reducing agent is 1:3 - 1:5, such as 1:4.2.

[0042] In some embodiments, in the reduction reaction, the mass-to-volume ratio of the compound shown in Formula VII to the solvent is 1 g:4 - 6 ml, such as 1 g:5 ml.

[0043] In some embodiments, in the reduction reaction, the reaction materials of the reduction reaction are composed of the following: the reducing agent, the solvent, the acid, and the compound shown in Formula VII.

[0044] In some embodiments, in the reduction reaction, the reaction temperature is 20 - 40 °C, such as 30 - 40 °C.

[0045] In some embodiments, in the reduction reaction, the progress of the reaction can be monitored by conventional detection methods in the art (such as HPLC, TLC or NMR). Generally, the end point of the reaction is when the compound of formula VII disappears, and the reaction time is generally 6-10 hours, such as 7-8 hours.

[0046] In some embodiments, in the reduction reaction, the temperature for adding the reducing agent is not higher than 35 °C.

[0047] In some embodiments, in the reduction reaction, the temperature for adding the acid is 30-40 °C, such as 30-35 °C.

[0048] In some embodiments, the reduction reaction comprises the following steps: mixing the compound of formula VII and the solvent, adding the reducing agent under the condition of not higher than 30 °C, adding the acid at 30-40 °C, and reacting at 30-40 °C to obtain the compound shown in formula I.

[0049] In some embodiments, the reduction reaction further comprises the following post-treatment steps: after the reaction is completed, adding water, adjusting the pH to about 7, separating and extracting with ethyl acetate, concentrating, and dropping 1.6-2.5 times the volume of the solution of n-heptane when the water content is not higher than 0.5%, and filtering.

[0050] In some embodiments, the method for preparing the compound shown in formula I further comprises the following steps: preparing the compound shown in formula VII by any of the above methods.

[0051] The present invention also provides a compound shown in formula VII:

[0052]

[0053] On the basis of not violating the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain the preferred examples of the present invention.

[0054] The reagents and raw materials used in the present invention are all commercially available.

[0055] The positive and progressive effects of the present invention are as follows: the reaction steps are short, the post-treatment is simple, the production cost is greatly reduced, and it is suitable for commercial scale-up. Detailed Embodiments

[0056] The present invention will be further illustrated below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods without specific conditions noted in the following examples are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0057] Example 1

[0058] Synthesis of Compound IV

[0059]

[0060] 100.0 g of Compound II (0.374 mol), 9.2 g of 4-dimethylaminopyridine (0.0473 mol), and 300 mL of dichloromethane were added to a reaction kettle, followed by 53.2 g of N,N-diisopropylethylamine (0.412 mol). The temperature was adjusted to 20 - 30 °C. While controlling the internal temperature at 20 - 30 °C, a solution of 80.1 g (0.412 mol) of Compound III dissolved in 200 mL of dichloromethane was added. After the addition was complete, the reaction was carried out under heat preservation for 3 - 4 hours. And the reaction was completed by stirring for 2 hours at a temperature of 20 to 30 °C. 500 mL of water was added, and the mixture was stirred for 1 hour, then separated. It was washed with 500 mL of 0.1 N dilute hydrochloric acid and 500 mL of 1% sodium bicarbonate. The organic layer was concentrated to dryness under reduced pressure with the external temperature not exceeding 40 °C. 500 mL of methanol was added, and the mixture was stirred for 1 - 2 hours. While controlling the temperature at 20 - 30 °C, 300 mL of water was added and stirred for 1 - 2 hours. It was filtered, and the filter cake was washed with 200 mL of water. The filter cake was dried in vacuo at 40 - 50 °C to obtain 156 g of dry product, with a yield of 98.0%. MS (M + H) + : 425.9 1 HNMR (400 MHz, MeOD) δ ppm: 7.99 (s, 1H), 7.44 - 7.41 (m, 1H), 7.31 (t, 1H), 7.24 (d, 1H), 7.17 - 7.10 (m, 2H), 6.92 (t, 1H), 6.78 (t, 1H), 3.89 (s, 3H), 2.80 (s, 3H).

[0061] Example 2

[0062] Synthesis of Compound VII

[0063]

[0064] 100 g of Compound IV (0.235 mol), 3.17 g of methylamine hydrochloride (0.0469 mol), and 300 g of 30% methylamine methanol solution were added to a reaction kettle, sealed, and heated to 50 - 60 °C. The mixture was stirred under heat preservation for 100 - 110 hours, concentrated under reduced pressure to about 150 mL, and then cooled to 20 - 30 °C. While controlling the temperature not exceeding 30 °C, 500 mL of water was added, and the mixture was stirred at 20 - 30 °C for 1 - 2 hours. It was filtered, and the filter cake was washed with 200 mL of water. The filter cake was dried in vacuo at 40 - 50 °C to obtain 99.5 g, with a yield of 99.7% and a purity of 98.9%. MS (M + H) + : 424.9 11H NMR (400 MHz, MeOD) δ ppm: 7.92 (s, 1H), 7.42 - 7.39 (m, 1H), 7.33 (t, 1H), 7.22 (d, 1H), 7.19 - 7.11 (m, 2H), 6.97 (t, 1H), 6.75 (t, 1H), 3.89 (s, 3H), 2.80 (s, 3H).

[0065] Example 3

[0066] Synthesis of Compound VII

[0067] While controlling the temperature not higher than 30 °C, 5 g of glacial acetic acid was added dropwise to 20 mL of 30% methylamine ethanol solution, and stirred for 1 - 2 hours. It was concentrated under reduced pressure to about 10 mL, and 20 - 30 mL of n - heptane was added dropwise with stirring. After the addition was completed, it was filtered under reduced pressure under nitrogen protection, and washed with 10 mL of n - heptane, and dried in vacuo for 1 - 2 hours. 4.27 g (0.0469 mol) of the above - obtained solid, 100 g of Compound IV (0.235 mol), and 300 g of 30% methylamine methanol solution were added to the reaction kettle, sealed, heated to 50 - 60 °C, and kept warm and stirred for 40 - 45 hours. It was concentrated under reduced pressure to about 150 mL, and then cooled to 20 - 30 °C. While controlling the temperature not exceeding 30 °C, 500 mL of water was added, and stirred at 20 - 30 °C for 1 - 2 hours, filtered, and the filter cake was washed with 200 mL of water. The filter cake was dried in vacuo at 40 - 50 °C to obtain 99.8 g, with a yield of 100% and a purity of 99.4%.

[0068] Example 4

[0069] Synthesis of Compound VII

[0070] 12.2 g of benzoic acid was dissolved in 30 mL of ethanol. While controlling the temperature not higher than 30 °C, it was added dropwise to 20 mL of 30% methylamine ethanol solution, and stirred for 1 - 2 hours. It was concentrated under reduced pressure to about 20 mL, and 40 - 50 mL of n - heptane was added dropwise with stirring. After the addition was completed, it was filtered under reduced pressure under nitrogen protection, and washed with 20 mL of n - heptane, and dried in vacuo for 1 - 2 hours. 7.18 g (0.0469 mol) of the above solid, 100 g of Compound III (0.235 mol), and 300 g of 30% methylamine methanol solution were added to the reaction kettle, sealed, heated to 50 - 60 °C, and kept warm and stirred for 30 - 35 hours. It was concentrated under reduced pressure to about 150 mL, and then cooled to 20 - 30 °C. While controlling the temperature not exceeding 30 °C, 500 mL of water was added, and stirred at 20 - 30 °C for 1 - 2 hours, filtered, and the filter cake was washed with 200 mL of water. The filter cake was dried in vacuo at 40 - 50 °C to obtain 99.5 g, with a yield of 99.7% and a purity of 99.3%.

[0071] Example 5

[0072] Synthesis of Compound I

[0073]

[0074] Add 100 g of Compound VII (0.236 mol) and 500 mL of tetrahydrofuran to the reaction kettle. While controlling the temperature not higher than 30 °C, add 37.1 g of sodium borohydride (0.981 mol). After addition, add trifluoroacetic acid (125 g, 1.10 mol) while controlling the temperature at 30 - 35 °C. After addition, react at 30 - 40 °C for 7 - 8 hours. TLC shows that the raw materials have completely reacted. Cool the reaction solution to 5 - 15 °C. While controlling the temperature not higher than 15 °C, add the reaction solution to 500 mL of water and stir at a temperature not higher than 15 °C for 4 - 5 hours. After the reaction is completed, adjust the pH to about 7 with 5% sodium carbonate and separate the layers. Extract the aqueous phase with 500 mL of ethyl acetate. Combine the organic phases, wash with 10% NaCl solution (200 mL * 2), and concentrate the organic phase under reduced pressure to 200 - 300 mL. Add 500 mL of ethyl acetate and stir for 10 - 20 minutes, filter, and concentrate the filtrate under reduced pressure to 200 - 300 mL. Detect that the water content is not higher than 0.5%. While controlling the temperature at 20 - 30 °C, add 800 mL of n-heptane dropwise with stirring, keep warm and stir for 2 - 3 hours, filter, wash the filter cake with 200 mL of ethyl acetate / n-heptane (V:V = 1:4) solution, and dry to obtain 86.5 g of Compound I with a yield of 89.5% and a purity of 99.2%. MS(M + H) + : 410.9. 1 HNMR(400 MHz, MeOD) δ ppm: 7.70(s, 1H), 7.60 - 7.54(m, 1H), 7.47(t, 1H), 7.31(d, 1H), 7.21 - 7.16(m, 2H), 7.04 - 6.95(m, 2H), 4.08(d, 2H), 3.47(s, 3H), 2.72(s, 3H).

Claims

1. A method for preparing a compound represented by Formula VII, characterized in that, it comprises the following steps: In a methylamine solution and in the presence of a methylamine salt, the compound represented by Formula IV undergoes an amidation reaction to form the compound represented by Formula VII; 2. The preparation method according to claim 1, characterized in that, it satisfies one or more of the following conditions: (1) In the amidation reaction, the methylamine solution is an alcohol solution of methylamine; (2) In the amidation reaction, the molar ratio of the compound of Formula IV to methylamine in the methylamine solution is 1:10 - 15; (3) In the amidation reaction, the methylamine salt is a salt formed by methylamine and an inorganic acid or a carboxylic acid; (4) In the amidation reaction, the molar ratio of the compound of Formula IV to the methylamine salt is 1:0.1 - 1:0.3; (5) In the amidation reaction, the reaction temperature is 40 - 70 °C; (6) In the amidation reaction, the reaction time is 20 - 110 hours; (7) After the amidation reaction, it further comprises the following post-treatment steps: After the reaction, concentrate under reduced pressure, and add water three times the volume of the solution while controlling the temperature not exceeding 30 °C to precipitate a solid.

3. The preparation method according to claim 2, characterized in that, it satisfies one or more of the following conditions: (1) In the amidation reaction, the methylamine solution is a methylamine methanol solution or a methylamine ethanol solution; (2) In the amidation reaction, the molar ratio of the compound of Formula IV to methylamine in the methylamine solution is 1:12; (3) In the amidation reaction, the inorganic acid is hydrochloric acid; (4) In the amidation reaction, the carboxylic acid is a lower fatty acid or benzoic acid; (5) In the amidation reaction, the molar ratio of the compound of Formula IV to the methylamine salt is 1:0.2; (6) In the amidation reaction, the reaction temperature is 50 - 60 °C; (7) In the amidation reaction, the reaction time is 30 - 45 hours.

4. The preparation method according to claim 3, characterized in that, it satisfies one or more of the following conditions: (1) In the amidation reaction, the methylamine solution is a 30% methylamine methanol solution; (2) In the amidation reaction, the lower fatty acid is acetic acid; (3) In the amidation reaction, the reaction time is 30 - 35 hours; Preferably, the methylamine salt is methylamine acetate and / or methylamine benzoate.

5. The preparation method according to claim 1, characterized in that, it further comprises the following steps: In the presence of a solvent, a catalyst and a base, the compound represented by Formula II and the compound represented by Formula III undergo a Hinsberg reaction to obtain the compound represented by Formula IV; 6. The preparation method according to claim 5, characterized in that, it satisfies one or more of the following conditions: (1) In the Hinsberg reaction, the catalyst is a pyridineamine catalyst, such as 4-dimethylaminopyridine and / or 4-pyrrolidinopyridine, preferably 4-dimethylaminopyridine; (2) In the Hinsberg reaction, the base is an alkyl secondary amine, such as N,N-diisopropylethylamine; (3) In the Hinsberg reaction, the solvent is a halogenated alkane solvent, preferably a chloroalkane solvent; such as dichloromethane; (4) In the Hinsberg reaction, the molar ratio of the compound of Formula II to the compound of Formula III is 1:1 - 1:1.2, such as 1:1.1; (5) In the Hinsberg reaction, the molar ratio of the compound of Formula II to the catalyst is 7:1 - 9:1, such as 7.9:1; (6) In the Hinsberg reaction, the molar ratio of the compound of Formula II to the base is 1:1 - 1:1.2, such as 1:1.1; (7) In the Hinsberg reaction, the reaction materials are the compound shown in Formula II, the compound of Formula III, the solvent, the catalyst and the base; (8) In the Hinsberg reaction, the reaction temperature is 15 - 35 °C, such as 20 - 30 °C; (9) In the Hinsberg reaction, the reaction time is 2 - 6 hours, such as 5 - 6 hours; (10) After the Hinsberg reaction, the following post-treatment steps are further included: after the reaction is completed, water is added for liquid separation, and then methanol and water are added for liquid separation.

7. A method for preparing a compound shown in Formula I, characterized in that, it comprises the following steps: In the presence of a solvent, a reducing agent and an acid, the compound of Formula VII undergoes the following reduction reaction to form the compound shown in Formula I; 8. The preparation method according to claim 7, characterized in that, it satisfies one or more of the following conditions: (1) In the reduction reaction, the solvent is an ether solvent, preferably a cyclic ether solvent, such as tetrahydrofuran; (2) In the reduction reaction, the acid is an organic acid, such as trifluoroacetic acid; (3) In the reduction reaction, the molar ratio of the compound of Formula VII to the acid is 1:4 - 1:5, such as 1:4.7; (4) In the reduction reaction, the reducing agent is one or more of sodium borohydride, potassium borohydride and lithium aluminum hydride, such as sodium borohydride; (5) In the reduction reaction, the molar ratio of the compound of Formula VII to the reducing agent is 1:3 - 1:5, such as 1:4.2; (6) In the reduction reaction, the mass-to-volume ratio of the compound of Formula VII to the solvent is 1 g:4 - 6 ml, such as 1 g:5 ml; (7) In the reduction reaction, the reaction materials of the reduction reaction are composed of the following: the reducing agent, the solvent, the acid and the compound of Formula VII; (8) In the reduction reaction, the reaction temperature is 20 - 40 °C, such as 30 - 40 °C; (9) In the reduction reaction, the reaction time is 6 - 10 hours, such as 7 - 8 hours; (10) In the reduction reaction, the temperature for adding the reducing agent is not higher than 35 °C; (11) In the reduction reaction, the temperature for adding the acid is 30 - 40 °C, such as 30 - 35 °C; (12) After the reduction reaction, the following post-treatment steps are further included: after the reaction is completed, water is added, the pH is adjusted to about 7, extracted by liquid separation with ethyl acetate, concentrated, and when the water content is not higher than 0.5%, 1.6 - 2.5 times the volume of the solution of n-heptane is added dropwise, and then filtered; Preferably, the reduction reaction comprises the following steps: mixing the compound of formula VII and the solvent, adding the reducing agent under the condition of not higher than 30 °C, adding the acid at 30-35 °C, and reacting at 30-40 °C to obtain the compound shown in formula I.

9. The preparation method according to claim 7, characterized in that it comprises the following steps: The compound of formula VII is prepared by the preparation method of the compound of formula VII according to any one of claims 1-6.

10. A compound of formula VII;

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