Potassium ion competitive blocker intermediate and preparation method thereof

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a synthetic potassium ion competitive blocker intermediate and a preparation method thereof, and the preparation method comprises the following steps: # imgabs0 # R is C1-C6 alkyl; comprising the following steps: (1) in a solvent, carrying out amine ester exchange reaction on a compound as shown in a formula III and methylamine under the action of trimethylaluminum to obtain a compound as shown in a formula IV; and (2) in a non-aqueous solvent, carrying out reduction reaction on the compound as shown in the formula IV and a reducing agent to obtain a compound 1. The preparation method comprises the following steps: taking 5-(2, 4-difluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylic acid methyl ester as a raw material, and sequentially carrying out sulfonylation, amine ester exchange and reduction reaction to synthesize a potassium ion competitive retardant compound 1; the method is simple in route, mild in reaction condition, few in three wastes, low in cost and simple and convenient to purify, the product purity is up to 99.88%, the total yield is up to 85.5%, and industrial mass production is easy to realize.

Description

Technical Field

[0001] The invention relates to a potassium ion competitive blocker intermediate and a preparation method thereof, belonging to the technical field of medicine and chemistry. Background Art

[0002] Potassium ion competitive blocker compound 1, its molecular structure formula is as follows:

[0003]

[0004] The compound 1 obtained marketing authorization from the Korean Food and Drug Safety Administration in December 2021, and was included in the medical insurance payment catalog in July 2022 and officially began to be sold. It has achieved superiority in rapid efficacy, rapid and excellent symptom improvement, excellent night symptom improvement, convenience of taking, low drug interactions and consistency of efficacy.

[0005] WO2020060213A1 is an improvement on the preparation route of WO2016175555A1, and the total yield is increased to 70%, but the number of steps is increased, and in the subsequent oxidation process, the expensive high-valent iodine reagent iodobenzene acetate is used as an oxidant, which further increases the route cost and is not suitable for industrial production.

[0006]

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

[0008] In order to solve the technical problems in the above reports, the present invention provides a new method for synthesizing a potassium ion competitive blocker compound 1, as well as a new intermediate of compound 1 and a preparation method thereof.

[0009] In order to overcome the defects of the prior art and achieve the requirements of commercial scale-up production, the present invention adopts the following preferred technical solutions:

[0010] The first aspect of the present invention provides a method for preparing a potassium ion competitive blocker intermediate compound of formula IV, the reaction formula of which is shown as follows:

[0011]

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

[0013] The steps include:

[0014] In a solvent, the compound of formula III is subjected to an amine ester exchange reaction with methylamine under the action of trimethylaluminum to obtain a compound of formula 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 compound of the amine ester exchange reaction formula 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 compound of the amine ester exchange reaction formula 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 transesterification 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 amount mL of the organic solvent for the amine transesterification reaction is 2 to 15 times the mass amount g of the compound of formula III, preferably 5 to 10 times.

[0021] The second aspect of the present invention provides a method for preparing a potassium ion competitive blocker compound 1, and the reaction formula is as follows:

[0022]

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

[0024] The steps include:

[0025] (1) in a solvent, subjecting the compound of formula III to an amine ester exchange reaction with methylamine under the action of trimethylaluminum to obtain a compound of formula IV;

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

[0027] The method for preparing the compound of formula IV by conducting amine ester exchange reaction between the compound of formula III and 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 tetrahydride, 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 compound of formula IV 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, ether, dioxane, toluene, more preferably ethanol.

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

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

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

[0034] The third aspect of the present invention provides a novel key potassium ion competitive blocker intermediate compound of formula IV, the structure of which is as follows:

[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 the compound of formula IV of the first aspect or using a new key potassium ion competitive blocker intermediate compound of formula IV to prepare compound 1.

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

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

[0039] (2) Compared with the original research WO2016175555A1, the present invention has a simple route, mild reaction conditions, avoids the use of dangerous reagents (such as sodium hydride, diisobutylaluminum hydride, etc.) and environmentally polluting oxidizing reagents (such as pyridinium chlorochromate), and produces less waste.

[0040] Low cost, simple purification, only using recrystallization or beating, and the yield is increased by more than 30% compared with 51.4%, and the product purity is as high as 99.88%;

[0041] (3) Compared with the original improved route WO2020060213A1, the total yield of the present invention is increased by 15.6%, and the maximum impurity content is reduced, which is easy to realize large-scale industrial production.

[0042] (4) The present invention provides a new key intermediate compound of formula IV, which is used to prepare a potassium ion competitive blocker compound 1 with high yield and good purity, with a yield of more than 90% and an HPLC purity of 99.88%. The present invention prepares a potassium ion competitive blocker compound 1 through a new key intermediate compound of formula IV, which reduces labor intensity and costs and is competitive.

[0043] (5) According to the present invention, when a 5-ton reaction device is used to prepare compound 1 according to the embodiment of the present application, 240 kg can be produced, which is about 1.4 times higher than the comparative example that can produce 167 kg. In addition, according to Example 1, the shortening of the 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 industrial large-scale production of compound 1. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 The HPLC purity spectrum of the product obtained in Example 1 of the present invention is shown in FIG. DETAILED DESCRIPTION

[0045] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0046] Example 1

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

[0048]

[0049] Add the compound of formula I-1 5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylic acid methyl ester (100 g, 374.21 mmol) into a three-necked flask, dissolve it in acetonitrile (500 mL), control the temperature at 20-30°C, stir for 30 min, then cool to -10--5°C, add DIPEA (53.2 g, 411.63 mmol), DMAP (9.2 g, 74.84 mmol), then dropwise add the compound of formula II 3-fluorobenzenesulfonyl chloride (80.2 g, 411.63 mmol), raise the temperature to 20-25°C, stir for 30 min, sample the reactor, detect the raw material ≤1.0%, control the temperature at 20-30°C, react for 12-15 h, concentrate to dryness under reduced pressure at 45°C, add ethyl acetate (500 mL), add 600 mL 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) respectively, the organic phases were combined, concentrated at 50°C to give a yellow solid, the solid was washed with ethyl acetate, filtered, and the filter cake was dried at 60°C for 12 h to give an off-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 Formula IV compound 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 bottle, the temperature was controlled at 0-5 ° C, 35.3 mL of trimethylaluminum (35.26 mL, 2 mol / L toluene solution, 70.53 mmol) was added dropwise, the temperature was controlled at 0-5 ° C and stirred for 1 hour, then the compound of formula III-1 (10 g, 23.51 mmol, dissolved in 50 mL toluene) was added dropwise to the mixed system, and then the temperature was raised to 50-55 ° C for 16 h, and then the mixture was added. The mixture was washed with 100 mL of water and 100 mL of ethyl acetate, extracted, and separated. The organic phase was washed twice with 100 mL x 2 of water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure until 20 mL of solvent remained. 100 mL of n-heptane was added for recrystallization to obtain an off-white solid. The mixture was dried under vacuum at 40-45 ° C to obtain an off-white solid compound of formula 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] A 1L reaction bottle was added with the compound of formula IV 5-(2,4-difluorophenyl)-4-methoxy-1-((3-fluorophenyl)sulfonyl)-1H-pyrrole-3-carboxamide (40 g, 94 mmol), ethanol (240 mL), sodium borohydride (5.33 g, 141 mmol), and the temperature was raised to 30-35 ° C for reaction for 2-3 h, followed by vacuum distillation at 45-50 ° C to remove ethanol. After the removal, 100 mL of water and 100 mL of ethyl acetate were added, and the aqueous layer was washed with 80 mL of ethyl acetate × 2. The layers were separated, and the organic phases were combined. The solvent was spin-dried to precipitate a white solid. The solid was slurried with ethanol and filtered. The filter cake was rinsed 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 spectrum is shown in the attached figure. Figure 1 shown.

[0058] Comparative Example 1

[0059]

[0060] Compound 1-1 was prepared by referring to the method of Example 2 in CN112739684A, wherein compound 2 was 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 in the next step of oxidation to obtain 83.9 g of compound 6 (yield: 90.0%), and compound 6 was reductively aminized and then refined to obtain 90.7 g of compound 1 hydrochloride (yield: 80.2%).

[0061] Comparison of Examples and Comparative Examples

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

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

[0064] Yield of compound 1 (%) = 100% * {the number of moles of compound 1 recovered after the reaction is completed} / {the number of moles of 5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylic acid methyl ester 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 but also increases the yield by about 1.22 times compared with the comparative example.

Claims

1. A method for preparing a potassium ion competitive blocker intermediate compound of formula IV, the reaction formula is as follows: in, R is a C1-C6 alkyl group, preferably a methyl group or an ethyl group; The steps include: In a solvent, the compound of formula III is subjected to an amine ester exchange reaction with methylamine under the action of trimethylaluminum to obtain a compound of formula IV.

2. A method for preparing a potassium ion competitive blocker compound 1, the reaction formula is as follows: in, R is a C1-C6 alkyl group, preferably a methyl group or an ethyl group; The steps include: (1) in a solvent, subjecting the compound of formula III to an amine ester exchange reaction with methylamine under the action of trimethylaluminum to obtain a compound of formula IV; (2) In a non-aqueous solvent, the compound of formula IV is subjected to a reduction reaction with a reducing agent to obtain compound 1.

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

4. The preparation method according to claim 3, characterized in that: In the step (1), the molar ratio of the compound of formula III to methylamine is 1:(1-5), preferably 1:(2-4).

5. The preparation method according to claim 3, characterized in that: In the step (1), the molar ratio of the compound of formula III to trimethylaluminum is 1:(1-5), preferably 1:(1-4).

6. The preparation method according to claim 1 or 2, characterized in that: The solvent in step (1) 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; And / or, preferably, the reaction temperature in step (1) is 30 to 70°C, preferably 40 to 60°C; And / or, preferably, the volume of the reaction solvent in step (1) is 2 to 15 times, preferably 5 to 10 times, the mass of the compound of formula III.

7. 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 tetrahydride; And / or, in step (2), the molar ratio of the compound of formula IV to the reducing agent is 1:(1-5), preferably 1:(1.2-2.0).

8. 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, preferably one or more of tetrahydrofuran, methanol, ethanol, isopropanol, butanol, ether, dioxane and toluene; And / or, preferably, the volume of the non-aqueous solvent in step (2) is 4 to 20 times, preferably 5 to 10 times, the mass of the compound of formula IV in g; And / or, preferably, the temperature of the reduction reaction in step (2) is 20 to 50°C, preferably 25 to 40°C.

9. A potassium ion competitive blocker intermediate compound of formula IV, having the following structure:

10. A method for preparing a potassium ion competitive blocker compound 1, comprising the method for preparing the compound of formula IV according to claim 1 or using the compound of formula IV according to claim 9 to prepare compound 1.

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