Potassium ion competitive blocker intermediates and methods for their preparation

Abstract

The application belongs to the field of organic synthesis and particularly relates to a kind of synthesis potassium ion competitive blocker intermediates and its preparation method, including the following steps: R is C1~C6 alkyl;Including the following steps: (1) in solvent, compound of formula III is reacted with methylamine under the action of trimethylaluminum to obtain compound of formula IV by amine ester exchange reaction;(2) in non-aqueous solvent, compound of formula IV is reacted with reducing agent to obtain compound 1.The application takes 5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylic acid methyl ester as raw material, and sequentially passes through sulfurylation, amine ester exchange, reduction reaction three steps to synthesize potassium ion competitive blocker compound 1;The route is simple, reaction condition is mild, three wastes are less, cost is low, purification is simple, and product purity is as high as 99.88%, total yield is as high as 85.5%, and industrialized mass production is easy to realize.

Description

Technical Field

[0001] This invention relates to a potassium ion competitive inhibitor intermediate and its preparation method, belonging to the fields of pharmaceutical and chemical technology. Background Technology

[0002] The molecular structure of potassium ion competitive inhibitor compound 1 is as follows:

[0003]

[0004] Compound 1 received marketing authorization from the Korean Ministry of Food and Drug Safety in December 2021 and was included in the medical insurance reimbursement list in July 2022, officially commencing sales. It demonstrated superiority in terms of rapid efficacy, rapid and excellent symptom improvement, excellent nighttime symptom improvement, ease of administration, low drug interactions, and consistent efficacy.

[0005] WO2020060213A1 is an improvement on the preparation route of WO2016175555A1, with the overall yield increased to 70%. However, it increases the number of steps and uses the expensive high-valent iodine reagent iodobenzene acetate as the oxidant in the subsequent oxidation process, further increasing the route cost and making it unsuitable for industrial production.

[0006]

[0007] Therefore, there is an urgent need to develop a new method for preparing potassium ion competitive inhibitor intermediates. Summary of the Invention

[0008] To address the technical problems mentioned above, this invention provides a novel method for synthesizing a potassium ion competitive inhibitor compound 1, as well as a novel intermediate for compound 1 and its preparation method.

[0009] To overcome the shortcomings of existing technologies and meet the requirements of commercial scale-up production, the present invention adopts the following preferred technical solution:

[0010] The first aspect of this invention provides a method for preparing a potassium ion competitive inhibitor intermediate of formula IV, the reaction formula of which is shown below:

[0011]

[0012] Wherein, R is a C1 to C6 alkyl group, preferably methyl or ethyl;

[0013] Includes the following steps:

[0014] In a solvent, compound III is subjected to an amino-ester exchange reaction with methylamine in the presence of trimethylaluminum to yield compound IV.

[0015] As a further improvement of the present invention, the methylamine is selected from one or more of methylamine gas, methylamine aqueous solution, methylamine alcohol solution, and methylamine hydrochloride, preferably methylamine gas or methylamine hydrochloride.

[0016] As a further improvement of the present invention, the molar ratio of the amine ester exchange reaction compound III to methylamine is 1:(1-5), preferably 1:(2-4), and more preferably 1:3.

[0017] As a further improvement of the present invention, the molar ratio of the amine-ester exchange reaction compound III to trimethylaluminum is 1:(1-5), preferably 1:(1-4), and more preferably 1:1.5.

[0018] As a further improvement of the present invention, the solvent for the amine-ester exchange reaction is preferably an aprotic solvent, more preferably one or more of 1,2-xylene, 1,3-xylene, 1,4-xylene, toluene, benzene, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, or dichloromethane.

[0019] As a further improvement of the present invention, the temperature of the amine-ester exchange reaction is 30-70°C, preferably 40-60°C, and more preferably 50-55°C.

[0020] As a further improvement of the present invention, the volume (mL) of the organic solvent used in the amine-ester exchange reaction is 2 to 15 times the mass (g) of the compound of formula III, preferably 5 to 10 times.

[0021] A second aspect of this invention provides a method for preparing a potassium ion competitive inhibitor compound 1, the reaction formula of which is shown below:

[0022]

[0023] Wherein, R is a C1 to C6 alkyl group, preferably methyl or ethyl;

[0024] Includes the following steps:

[0025] (1) In a solvent, compound III is subjected to an amino-ester exchange reaction with methylamine in the presence of trimethylaluminum to obtain compound IV;

[0026] (2) In a non-aqueous solvent, the compound of formula IV is reduced with a reducing agent to obtain compound 1.

[0027] The method for preparing compound IV by reacting compound III with methylamine in step (1) is the same as that described in the first aspect of the present invention.

[0028] As a further improvement of the present invention, the reducing agent in step (2) is selected from one or more of sodium borohydride, potassium borohydride, lithium borohydride, borane, diisobutylaluminum hydride or lithium aluminum hydride, preferably one or more of sodium borohydride, potassium borohydride or lithium borohydride.

[0029] As a further improvement of the present invention, the molar ratio of the IV compound to the reducing agent in step (2) is 1:(1-5), preferably 1:(1.2-2.0), and more preferably 1:1.5.

[0030] As a further improvement of the present invention, the non-aqueous solvent in step (2) is selected from one or more of ethers, alcohols or aromatic hydrocarbons, preferably one or more of tetrahydrofuran, methanol, ethanol, isopropanol, butanol, diethyl ether, dioxane, and toluene, and more preferably ethanol.

[0031] As a further improvement of the present invention, the volume of the non-aqueous solvent in step (2) is 4 to 20 times the mass of the compound of formula IV in g, preferably 5 to 10 times, and more preferably 6 times.

[0032] As a further improvement of the present invention, the temperature of the reduction reaction in step (2) is 20-50°C, preferably 25-40°C, and more preferably 30-35°C.

[0033] As a further improvement of the present invention, the preparation of the compound of formula III can be carried out with reference to the preparation method of compound 4 in Example 1 of CN112739684A.

[0034] A third aspect of this invention provides a novel key potassium ion competitive inhibitor intermediate compound of formula IV, with the following structure:

[0035]

[0036] The fourth aspect of the present invention provides a method for preparing a potassium ion competitive blocker compound 1, comprising the method for preparing compound IV of the first aspect described above or preparing compound 1 using a novel key potassium ion competitive blocker intermediate compound IV.

[0037] Compared with the prior art, the present invention has the following beneficial effects:

[0038] (1) The present invention uses methyl 5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylic acid as raw material, and synthesizes compound 1 in three steps through sulfonation, amine ester exchange and reduction reaction. The route is short, the purity is high, and the total yield is high at 85.5%.

[0039] (2) Compared with the original research WO2016175555A1, this invention has a simpler route, milder reaction conditions, avoids the use of hazardous reagents (such as sodium hydride, diisobutylaluminum hydride, etc.) and environmentally polluting oxidizing reagents (such as pyridine chlorochromate), and produces less waste.

[0040] It is low in cost, simple to purify, only requires recrystallization or pulping, and the yield is more than 30% higher than that of 51.4%, with a product purity of up to 99.88%.

[0041] (3) Compared with the original improved route WO2020060213A1, the total yield of this invention is increased by 15.6%, and the maximum impurity content is reduced, making it easier to achieve large-scale industrial production.

[0042] (4) This invention provides a new key intermediate IV compound, which is used to prepare potassium ion competitive blocker compound 1 with high yield and good purity, with a yield of over 90% and HPLC purity of 99.88%. The preparation of potassium ion competitive blocker compound 1 by the new key intermediate IV compound reduces the labor intensity of personnel and the cost, and is competitive.

[0043] (5) According to the present invention, when compound 1 is prepared using a 5-ton reaction apparatus according to the embodiments of this application, 240 kg can be produced, which is about 1.4 times more than the comparative example which can produce 167 kg. In addition, according to Example 1, the shortened process route is expected to reduce the material cost per kg by about 2 times compared with Comparative Example 1, which is more conducive to the large-scale industrial production of compound 1. Attached Figure Description

[0044] Figure 1 This is the HPLC purity spectrum of the product obtained in Example 1 of the present invention. Detailed Implementation

[0045] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

[0046] Example 1

[0047] Preparation of methyl 5-(2,4-difluorophenyl)-4-methoxy-1-((3-fluorophenyl)sulfonyl)-1H-pyrrole-3-carboxylic acid of formula III-1:

[0048]

[0049] In a three-necked flask, compound I-1, methyl 5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylic acid (100 g, 374.21 mmol), was added and dissolved in acetonitrile (500 mL). The mixture was stirred at 20–30 °C for 30 min, then cooled to -10–-5 °C and DIPEA (53.2 g, 411.63 mmol) and DMAP (9.2 g, 74.84 mmol) were added. Subsequently, compound II, 3-fluorobenzenesulfonyl chloride (80.2 g, 411.63 mmol), was added dropwise. The mixture was heated to 20–25 °C and stirred for 30 min. A sample was taken from the reaction vessel and analyzed by HPLC. The starting material concentration was ≤1.0%. The reaction mixture was kept at 20–30 °C and reacted for 12–15 h. The mixture was concentrated to dryness under reduced pressure at 45 °C, and ethyl acetate (500 mL) was added. Then, 600 mL of [the solution / concentration mixture] was added. HCl (1 mol / L), stirred for 5 min, allowed to stand for 10 min, separated, the upper aqueous phase was extracted three times with ethyl acetate (100 mL), the organic phases were combined and concentrated to dryness at 50 °C to obtain a yellow solid, the solid was washed with ethyl acetate, filtered, and the filter cake was dried at 60 °C for 12 h to obtain a grayish-white solid III-1 (159 g, yield 99.9%).

[0050] 1 H NMR(400MHz,d6-DMSO)δ8.07(s,1H),7.70-7.62(m,2H),7.45-7.43(m,1H),7.39-7. 37(m,1H),7.31-7.19(m,2H),7.16(td,J=8.4,2.4Hz,1H),3.82(s,3H),3.55(s,3H).

[0051] Preparation of compound IV, 5-(2,4-difluorophenyl)-4-methoxy-1-((3-fluorophenyl)sulfonyl)-1H-pyrrole-3-carboxamide:

[0052]

[0053] Toluene (50 mL) and methylamine hydrochloride (4.76 g, 70.53 mmol) were added to a 500 mL reaction flask. The temperature was maintained at 0–5 °C. 35.3 mL of trimethylaluminum (35.26 mL, 2 mol / L toluene solution, 70.53 mmol) was added dropwise. After the addition was complete, the mixture was stirred at 0–5 °C for 1 hour. Then, compound III-1 (10 g, 23.51 mmol, dissolved in 50 mL toluene) was added dropwise to the mixture. The temperature was then raised to 50–55 °C and the reaction was carried out for 16 hours. Wash with 100 mL of water and 100 mL of ethyl acetate, extract, separate into layers, wash the organic phase twice with 100 mL x 2 of water, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure until the solvent remains at 20 mL, add 100 mL of n-heptane and recrystallize to give an off-white solid, dry under vacuum at 40-45 °C to give an off-white solid of compound IV 5-(2,4-difluorophenyl)-4-methoxy-1-((3-fluorophenyl)sulfonyl)-1H-pyrrole-3-carboxamide (9.1 g, yield 91.2%).

[0054] 1 H NMR (400MHz, Acetone) δ7.87 (s, 1H), 7.71-7.63 (m, 1H), 7.56 (td, J = 8.4, 2.4Hz, 1H), 7.41 ( d,J=8.0Hz,1H),7.33-7.23(m,3H),7.11-7.03(m,2H),3.51(s,3H),2.85(d,J=4.4Hz,3H).

[0055] Preparation of compound 1:

[0056]

[0057] Compound IV, 5-(2,4-difluorophenyl)-4-methoxy-1-((3-fluorophenyl)sulfonyl)-1H-pyrrole-3-carboxamide (40 g, 94 mmol), ethanol (240 mL), and sodium borohydride (5.33 g, 141 mmol), were added to a 1 L reaction flask. The mixture was heated to 30–35 °C and reacted for 2–3 h. Subsequently, the mixture was distilled under reduced pressure at 45–50 °C to remove the ethanol. After the ethanol removal was complete, 100 mL of water and 100 mL of ethyl acetate were added. The aqueous layer was washed with 80 mL × 2 ethyl acetates. The layers were separated, and the organic phases were combined. The solvent was evaporated to dryness, and a white solid precipitated. The solid was slurried with ethanol, filtered, and the filter cake was washed with ethanol and dried under reduced pressure at 40–45 °C to obtain compound 1 (36.3 g, yield 93.8%, HPLC purity 99.80%, retention time RT = 13.780 min). The HPLC purity chromatogram is attached. Figure 1 As shown.

[0058] Comparative Example 1

[0059]

[0060] Compound 1-1 was prepared according to the method in Example 2 of CN112739684A, wherein compound 2 reacted with compound 3 to obtain 154.4 g of compound 4 (yield: 97.0%), compound 4 was reduced to obtain compound 5, which was directly used for the next step of oxidation to obtain 83.9 g of compound 6 (yield: 90.0%), and compound 6 was reduced and amination and then purified to obtain 90.7 g of compound 1 hydrochloride (yield: 80.2%).

[0061] Comparison of Implementation Examples and Comparative Examples

[0062] The yield, quality results, etc. of compound 1 obtained according to the preparation methods of Example 1 and Comparative Example 1 were evaluated and are shown in Table 1 below.

[0063] Yield of Compound 1: The weight of Compound 1 recovered after the reaction and the weight of methyl 5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylic acid before the reaction were substituted into the following formula for calculation:

[0064] Yield (%) of Compound 1 = 100% * {moles of Compound 1 recovered after the reaction} / {moles of methyl 5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylate before the reaction}

[0065] Table 1

[0066]

[0067] Referring to Table 1, it is confirmed that the present invention not only reduces the maximum single impurity compared to the comparative embodiment, but also increases the yield by approximately 1.22 times.

Claims

1. A method for preparing a potassium ion competitive inhibitor intermediate compound of formula IV, wherein the reaction formula is shown below: in, R is a C1~C6 alkyl group; Includes the following steps: (1) In a solvent, compound III is subjected to an amino-ester exchange reaction with methylamine in the presence of trimethylaluminum to obtain compound IV.

2. A method for preparing a potassium ion competitive inhibitor compound 1, the reaction formula of which is shown below: in, R is a C1~C6 alkyl group; Includes the following steps: (1) In a solvent, compound III is subjected to an amino-ester exchange reaction with methylamine in the presence of trimethylaluminum to obtain compound IV; (2) In a non-aqueous solvent, the compound of formula IV is reduced with a reducing agent to obtain compound 1.

3. The preparation method according to claim 1 or 2, characterized in that, In the compound of formula III, R is methyl or ethyl.

4. The preparation method according to claim 1 or 2, characterized in that, In step (1), methylamine is selected from one or more of methylamine gas, methylamine aqueous solution, methylamine alcohol solution, and methylamine hydrochloride.

5. The preparation method according to claim 4, characterized in that, In step (1), the molar ratio of compound III to methylamine is 1: (1~5).

6. The preparation method according to claim 5, characterized in that, In step (1), the molar ratio of compound III to methylamine is 1:(2~4).

7. The preparation method according to claim 1 or 2, characterized in that, In step (1), the molar ratio of compound III to trimethylaluminum is 1:(1~5).

8. The preparation method according to claim 7, characterized in that, In step (1), the molar ratio of compound III to trimethylaluminum is 1:(1~4).

9. The preparation method according to claim 1 or 2, characterized in that, The solvent in step (1) is an aprotic solvent; And / or, the reaction temperature in step (1) is 30~70℃; And / or, the volume of the reaction solvent used in step (1) is 2 to 15 times the mass of the compound of formula III in g.

10. The preparation method according to claim 9, characterized in that, The solvent in step (1) is one or more of 1,2-xylene, 1,3-xylene, 1,4-xylene, toluene, benzene, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, or dichloromethane; And / or, the reaction temperature in step (1) is 40~60℃; And / or, the volume of the reaction solvent used in step (1) is 5 to 10 times the mass of the compound of formula III in g.

11. The preparation method according to claim 2, characterized in that, The reducing agent in step (2) is selected from one or more of sodium borohydride, potassium borohydride, lithium borohydride, borane, diisobutylaluminum hydride or lithium aluminum hydride. And / or, in step (2), the molar ratio of compound IV to reducing agent is 1: (1~5).

12. The preparation method according to claim 11, characterized in that, In step (2), the molar ratio of compound IV to reducing agent is 1: (1.2~2.0).

13. The preparation method according to claim 2, characterized in that, The non-aqueous solvent in step (2) is selected from one or more of ethers, alcohols, or aromatic hydrocarbons; And / or, the volume of the non-aqueous solvent in step (2) is 4 to 20 times the mass of the compound of formula IV in g; And / or, the temperature of the reduction reaction in step (2) is 20~50℃.

14. The preparation method according to claim 13, characterized in that, The non-aqueous solvent in step (2) is selected from one or more of tetrahydrofuran, methanol, ethanol, isopropanol, butanol, diethyl ether, dioxane, and toluene; And / or, the volume of the non-aqueous solvent in step (2) is 5 to 10 times the mass of the compound of formula IV in g; And / or, the temperature of the reduction reaction in step (2) is 25~40℃.

15. A method for preparing a potassium ion competitive inhibitor compound 1, comprising the method for preparing the compound of formula IV as described in claim 1, wherein compound 1 is as follows: 。

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