Preparation method of fumaric acid Vonoprazan impurity

Abstract

The preparation method comprises the following steps: mixing 5-(2-fluorophenyl)-1-[(pyridine-3-yl) sulfonyl]-1H-pyrrole-3-formaldehyde with an organic solvent, adding a methanol solution of dimethylamine, carrying out an amination reaction, adding a reducing agent, and carrying out a reduction reaction to obtain a compound B in a free state; and after the reaction is finished, adjusting the pH value of the reaction solution to 2-3 by using hydrochloric acid, cooling and crystallizing to obtain a compound B. The purity of the compound B prepared by the method reaches 99% or above, the yield reaches 85% or above, and the method is suitable for industrial production. The method has mild and simple reaction conditions, and is convenient for reaction reproduction and enlarged production.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis and relates to a method for preparing a vonoprazan fumarate impurity, and specifically relates to a method for preparing a vonoprazan fumarate dimethylamine impurity (referred to as dimethylamine impurity, chemical name: 1-[5-(2-fluorophenyl)-1-(pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl]-N,N-dimethylmethylamine, code U-9 in the import registration standard) hydrochloride. Background Art

[0002] Vonoprazan fumarate (TAK-438, Takecab) is a potassium ion competitive acid blocker (P-CAB) developed by Takeda Pharmaceutical Company (Takeda). It was first approved for marketing in Japan in December 2014 for the treatment of gastric acid-related diseases (ARDs) such as Helicobacter pylori infection, gastroesophageal reflux, peptic ulcer, duodenal ulcer, esophagitis, and gastric ulcer.

[0003] In the supplementary materials for the first pharmaceutical professional review opinion in the application for international multi-center clinical trials (JXHL1200409, 410), Takeda Pharmaceutical proposed that dimethylamine impurities (structure as shown in Formula I) are by-products in the production process of vonoprazan fumarate API. In addition, the National Drug Administration's imported drug registration standards (standard number: JX20190049) also clearly stated that dimethylamine impurities are known impurities. The structure and properties of dimethylamine impurities are very similar to those of vonoprazan fumarate. It is difficult to remove them during the refining process, and multiple refinings are required to obtain qualified products.

[0004]

[0005] The inventors found that during the coating process of the preparation of vonoprazan fumarate tablets, the dimethylamine impurity in the preparation tablets had an obvious growth trend under light conditions, indicating that it is very necessary to study and prepare the dimethylamine impurity.

[0006] At present, CN113214223A and CN117964604A disclose methods for synthesizing dimethylamine impurities. However, the method reported in CN113214223A uses a metal-organic skeleton coordination compound formed by metal iron, aluminum or chromium and 1,3,5-tri(4-carboxyphenyl)benzene as a catalyst. The preparation method of the complex is cumbersome, and the reaction also requires the addition of an acid binding agent, a variety of solvents, and heating (methylation reaction temperature 60-110°C, salt formation reaction temperature 40-50°C), and the reaction conditions are strict; the method reported in CN117964604A uses formaldehyde, methyl bromide, methyl iodide, polyformaldehyde, etc. as methylating agents, at a temperature of 70-80°C, in a slightly acidic reaction In the reaction system, vonoprazan fumarate is subjected to a methylation reaction to obtain an imine transition state, and the transition state is reduced by a reducing agent, formic acid, to obtain a dimethylamine impurity, and then a free dimethylamine impurity is obtained under the action of a base, and then the dimethylamine impurity is salified with fumaric acid to obtain a fumarate of the dimethylamine impurity of vonoprazan fumarate; although a higher yield and a higher purity can be obtained, the following disadvantages exist: many reaction steps and complicated operation; the methylation reagent is highly toxic, such as formaldehyde, which is a primary carcinogen and requires special protection during the production process; the raw material vonoprazan fumarate has a high cost; it is difficult to expand the scale, which is not conducive to the industrial preparation of impurities. Summary of the invention

[0007] To solve the above problems, the purpose of the present invention is to provide a method for preparing vonoprazan fumarate impurities. The prepared vonoprazan fumarate impurities can be used as an impurity reference substance, which is of great significance for effectively controlling the quality of vonoprazan fumarate.

[0008] The vonoprazan fumarate impurity described in the present invention is the hydrochloride of the vonoprazan fumarate dimethylamine impurity (compound B), and its structural formula is as follows:

[0009]

[0010] The chemical name is: 1-[5-(2-fluorophenyl)-1-(pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl]-N,N-dimethylmethanamine hydrochloride.

[0011] The hydrochloride of the dimethylamine impurity of vonoprazan fumarate has better stability, which can increase the shelf life of the impurity and avoid deterioration due to long storage time. Compared with the fumarate of the dimethylamine impurity, the water solubility of the dimethylamine impurity after being converted into hydrochloride is significantly increased, and it can be accurately measured in the later analysis process. It can be seen that the hydrochloride of the dimethylamine impurity has more advantages than the free state and the fumarate of the dimethylamine impurity.

[0012] A method for preparing vonoprazan fumarate impurities, the synthetic route is as follows:

[0013]

[0014] Reaction mechanism: Using the vonoprazan fumarate intermediate (compound A, chemical name: 5-(2-fluorophenyl)-1-[(pyridin-3-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde) as the starting material, the vonoprazan fumarate intermediate is subjected to an imidization reaction with dimethylamine to obtain an imine intermediate state, and then a reduction reaction is carried out to reduce the double bond to obtain the free state of compound B, and then a salt-forming reaction is carried out to purify the impurities while forming the salt, and finally a C1-C4 alcohol is used as a recrystallization solvent for recrystallization to obtain compound B.

[0015] The following steps are involved:

[0016] Step (1), preparing the free state of compound B by one-step reaction: Compound A is mixed with an organic solvent, a methanol solution of dimethylamine is added, compound A and dimethylamine undergo an amination reaction to obtain an imine intermediate, and then a reducing agent is added to carry out a reduction reaction to obtain the free state of compound B;

[0017] Step (2): After the reaction is completed, the pH value of the reaction solution is adjusted to 2-3 with hydrochloric acid, and the temperature is lowered to crystallize to obtain compound B.

[0018] In step (1), the organic solvent is one or a mixed solvent selected from DMAC (N,N-dimethylacetamide), DMF or chloroform, preferably DMAC or DMF.

[0019] The mass ratio of the compound A to the organic solvent is 1:3 to 1:10, preferably 1:5.

[0020] The molar ratio of the compound A to dimethylamine is 1:2.0 to 1:3.0, preferably 1:2.5.

[0021] The temperature of the amination reaction is 0 to 30° C., preferably 0 to 25° C., and the time of the amination reaction after adding dimethylamine is 1 to 5 hours.

[0022] The reducing agent is sodium borohydride, potassium borohydride or lithium aluminum hydride. Compared with sodium borohydride, lithium aluminum hydride and potassium borohydride have stronger reducing properties, but the inventors found that compared with sodium borohydride as a reducing agent, when potassium borohydride and lithium aluminum hydride are used as reducing agents, the purity of dimethylamine impurities obtained is lower. Therefore, preferably, the reducing agent is sodium borohydride.

[0023] The molar ratio of the compound A to the reducing agent is 1:0.4-0.6, preferably 1:0.5.

[0024] The temperature of the reduction reaction is 0 to 30° C., preferably 0 to 25° C., and the time of the reduction reaction is 1 to 3 hours.

[0025] In step (2), the hydrochloric acid is concentrated hydrochloric acid, and the mass fraction of the concentrated hydrochloric acid is 31-38%.

[0026] The crystallization temperature is -10 to 10°C, preferably -10 to 0°C.

[0027] As a further preferred embodiment of the method for preparing the dimethylamine impurity of vonoprazan fumarate according to the present invention, it also includes: filtering after crystallization to obtain a crude compound B, and recrystallizing the crude compound B using a C1-C4 alcohol as a recrystallization solvent to obtain a finished compound B.

[0028] Preferably, the recrystallization solvent is at least one of methanol, ethanol, isopropanol and n-butanol.

[0029] The mass ratio of the compound A to the recrystallization solvent is 1:5 to 1:10.

[0030] The recrystallization temperature is 0-5°C.

[0031] Specifically, a method for preparing vonoprazan fumarate impurities comprises the following steps:

[0032] Step (1), preparing the free state of compound B by one-step reaction: Compound A is mixed with an organic solvent, and a methanol solution of dimethylamine is added dropwise, compound A and dimethylamine undergo an amination reaction to obtain an imine intermediate state, and then a reducing agent is added, and the imine intermediate state undergoes a reduction reaction to obtain the free state of compound B;

[0033] Step (2), after the reaction is completed, the pH value of the reaction solution is adjusted to 2-3 with hydrochloric acid, the temperature is lowered for crystallization, and the mixture is filtered to obtain a crude compound B;

[0034] Step (3), the crude compound B is recrystallized using a C1-C4 alcohol as a recrystallization solvent to obtain a finished compound B.

[0035] Beneficial effects of the present invention:

[0036] 1. Based on the necessity of studying the impurities of vonoprazan fumarate, the present invention proposes a simple synthesis method to prepare the hydrochloride of dimethylamine impurity, which has high yield and can provide a high-purity product with good stability.

[0037] 2. The present invention does not require the preparation of corresponding catalysts, and does not require the use of toxic and harmful reagents to provide methylation reactions. The starting material compound A of vonoprazan fumarate is used as the starting material. In an alkaline reaction system, under mild reaction conditions, only one step of reaction is required to obtain the free state of compound B, and then concentrated hydrochloric acid is added to quench the excess reducing agent in the system and form a hydrochloride with the free state of compound B. The reaction by-products may not be able to form a hydrochloride during the salt formation process, and the product is then purified.

[0038] 3. The purity of compound B prepared by the method of the present invention reaches more than 99%, and the yield reaches more than 85%, which is suitable for industrial production. The reaction conditions of the method of the present invention are mild and simple, which is convenient for reproducing the reaction and scaling up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 This is the liquid chromatogram of compound B prepared in Example 1.

[0040] Figure 2 is the mass spectrum of compound B.

[0041] Figure 3 is the infrared spectrum of compound B. DETAILED DESCRIPTION

[0042] The technical scheme of the present invention is further illustrated by the following examples, but these examples do not constitute any limitation to the present invention.

[0043] Example 1

[0044] Add 5-(2-fluorophenyl)-1-[(pyridin-3-yl)sulfonyl]-1H-pyrrole-3-carboxaldehyde (Compound A, 150.0 g, 0.454 mol) and DMAC (750 g) to the reaction bottle, stir and dissolve; control the temperature at 0-5°C, add methanol solution of dimethylamine (dimethylamine content 30%, 170 g, 1.133 mol), continue to control the temperature at 0-5°C after the addition is complete, continue to react for 3.0 h; continue to control the temperature at 0-5°C, add sodium borohydride (8.59 g, 0.227 mol), keep the temperature at 0-5°C after the addition is complete, perform reduction reaction, react for 2.0 h, and stop the reaction. Add concentrated hydrochloric acid (mass fraction 31%, the same below) to adjust the pH of the reaction solution to 2, cool to -10°C for crystallization, filter, and obtain a crude compound B.

[0045] Add methanol (1500 g) to the crude compound B, raise the temperature to 60°C, stir to dissolve, cool to 0°C, crystallize for 2 hours, filter, and dry to obtain the finished compound B (158.2 g, yield 88.0%, purity 99.46%).

[0046] 1H NMR (500MHz, DMSO) δ10.82(s,1H),8.91(d,J=5.0Hz,1H),8.60(d,J=5.0Hz,1H),7.97-7.91(m,2H),7.68-7.61(m,1H),7.6 0-7.52(m,1H),7.28-7.20(m,2H),7.19-7.12(m,1H),6.66(d,J=5.0Hz,1H),4.16(d,J=5.0Hz,2H),2.69(d,J=5.0Hz,6H).

[0047] LCMS (m / z): 360.0 [M+H] + .

[0048] Example 2

[0049] Add 5-(2-fluorophenyl)-1-[(pyridin-3-yl)sulfonyl]-1H-pyrrole-3-carboxaldehyde (50.0 g, 0.151 mol) and DMF (500 g) to the reaction bottle, stir and dissolve; control the temperature at 20-25°C, add methanol solution of dimethylamine (dimethylamine content 30%, 56.7 g, 0.377 mol), and continue to control the temperature at 20-25°C after the addition is complete, and continue to react for 5.0 h; control the temperature at 20-25°C, add sodium borohydride (2.86 g, 0.0775 mol), and maintain the temperature at 20-25°C after the addition is complete for reduction reaction, react for 3.0 h, and stop the reaction. Add concentrated hydrochloric acid to adjust the pH of the reaction solution to 3, cool to 0°C for crystallization, and filter to obtain a crude compound B.

[0050] Add n-butanol (250 g) to the crude compound B, raise the temperature to 80°C, stir to dissolve, cool to 5°C, crystallize for 2 hours, filter, and dry to obtain the finished compound B (54.0 g, yield 90.3%, purity 99.11%).

[0051] Example 3

[0052] Referring to Example 1, only the amount of DMAC was adjusted to 450 g, and the rest was the same as Example 1. The purity and yield of compound B are shown in Table 1.

[0053] Example 4

[0054] Referring to Example 2, only DMF was replaced with an equal amount of DMAC, and the rest was the same as Example 2. The purity and yield of compound B are shown in Table 1.

[0055] Example 5

[0056] Referring to Example 1, only DMAC was replaced with an equal amount of DMF, and the rest was the same as Example 1. The purity and yield of compound B are shown in Table 1.

[0057] Table 1. Effect of reaction solvent type and dosage on compound purity and yield

[0058]

[0059] Example 6

[0060] The crude compound B prepared in Example 1 was recrystallized according to Table 2.

[0061] Table 2. Effect of different recrystallization solvents on recrystallization effect

[0062]

[0063] Note: Serial number 1 is Example 1; Serial number 4 is Example 2.

Claims

1. A method for preparing vonoprazan fumarate impurities, characterized in that: The following steps are involved: Step (1), preparing compound B in free form by one-step reaction: Compound A is mixed with an organic solvent, a methanol solution of dimethylamine is added to cause an amination reaction, and then a reducing agent is added to carry out a reduction reaction to obtain compound B in free form; Step (2): After the reaction is completed, the pH value of the reaction solution is adjusted to 2-3 with hydrochloric acid, and the temperature is lowered to crystallize to obtain compound B.

2. The method for preparing vonoprazan fumarate impurities according to claim 1, characterized in that: In step (1), the organic solvent is one or a mixed solvent of DMAC, DMF or chloroform, preferably DMAC or DMF.

3. The method for preparing vonoprazan fumarate impurities according to claim 1 or 2, characterized in that: In step (1), the mass ratio of compound A to organic solvent is 1:3 to 1:10, preferably 1:

5.

4. The method for preparing vonoprazan fumarate impurities according to claim 1, characterized in that: In step (1), the molar ratio of compound A to dimethylamine is 1:2.0 to 1:3.0, preferably 1:2.

5.

5. The method for preparing vonoprazan fumarate impurities according to claim 1, characterized in that: In step (1), the reducing agent is sodium borohydride, potassium borohydride or lithium aluminum hydride, preferably sodium borohydride.

6. The method for preparing vonoprazan fumarate impurities according to claim 1 or 5, characterized in that: In step (1), the molar ratio of compound A to reducing agent is 1:0.4-0.6, preferably 1:0.

5.

7. The method for preparing vonoprazan fumarate impurities according to claim 1, characterized in that: In step (1), the temperature of the amination reaction is 0-30° C., and the time of the amination reaction is 1-5 hours; the temperature of the reduction reaction is 0-30° C., and the time of the reduction reaction is 1-3 hours.

8. The method for preparing vonoprazan fumarate impurities according to claim 1, characterized in that: In step (2), the crystallization temperature is -10 to 10°C, preferably -10 to 0°C.

9. The method for preparing vonoprazan fumarate impurities according to claim 1, characterized in that: include: After crystallization, the crude compound B is filtered to obtain the crude compound B, and the crude compound B is recrystallized using C1-C4 alcohol as a recrystallization solvent to obtain a finished compound B; wherein the mass ratio of the compound A to the recrystallization solvent is 1:5 to 1:10; and the recrystallization temperature is 0 to 5°C.

10. The method for preparing vonoprazan fumarate impurities according to claim 9, characterized in that: The recrystallization solvent is at least one of methanol, ethanol, isopropanol and n-butanol.

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