4-methoxypyrrole derivatives and their synthesis methods

Abstract

The present invention discloses a 4-methoxypyrrole derivative and a method for synthesizing the same. In step 1), m-difluorobenzene (compound (I)) as a starting material is reacted with a monoester of oxalyl chloride in a solvent using aluminum trichloride as a catalyst, and after post-treatment, compound (II) is obtained; in step 2), compound (II) is subjected to a dehydration reaction with methyl 3-aminopropionate or a salt thereof in a solvent, and after post-treatment, compound (III) is obtained; in step 3), compound (III) undergoes an intramolecular ring formation reaction under the action of an alkali in a solvent, and after post-treatment, compound (IV) is obtained; in step 4), compound (IV) is reacted with dimethyl sulfate under the action of an alkali in a solvent, and after post-treatment, the product compound (V) is obtained. The 4-methoxypyrrole derivative and the method for synthesizing the same according to the present invention have the advantages of easy availability of raw materials, high yield, good quality, and simple operation.

Description

[Technical Field]

[0001] The present invention relates to the pharmaceutical industry and the technology of synthesis of organic chemical intermediates, and more particularly to a method for synthesizing 4-methoxypyrrole derivatives. [Background technology]

[0002] Korean Patent No. 10-1613245 and International Patent Application WO28236153, among others, describe that 4-methoxypyrrole derivatives possess good anti-ulcer activity (such as proton pump inhibitory activity) and bactericidal activity against Helicobacter pylori, and can be effectively used for the prevention and treatment of gastric ulcers, gastritis, reflux esophagitis, or gastrointestinal disorders caused by H. pylori. In conclusion, 4-methoxypyrrole derivatives are widely used in the field of pharmaceutical synthesis, and their synthesis process has great development value.

[0003] The difficulty in synthesizing 4-methoxypyrrole derivatives lies in constructing the 4-methoxypyrrole structure, and the main synthetic strategies are as follows.

[0004] Patents such as WO2012236153 describe a method of producing the target product using 2,4-difluorobenzaldehyde as a raw material, via Strecker reaction, Boc protection, condensation decarboxylation, cyclization, methylation, and de-Boc protection. However, this pathway is long, yields low results, involves highly toxic sodium cyanide, and poses significant risks. Furthermore, the raw material for 2,4-difluorobenzaldehyde is relatively expensive, and the use of large amounts of ammonia and concentrated hydrochloric acid generates a large amount of highly saline wastewater, resulting in a massive amount of "three types of waste" and making it unsuitable for industrial production. [ka]

[0005] Patent CN109867617 describes preparing the target product using 2,4-difluorobenzaldehyde as a starting material by methods such as condensation addition, TosMIC synthesis, and Vanleusen pyrrole synthesis. However, this route using 2,4-difluorobenzaldehyde is costly, and the purification of the final product by column chromatography is not suitable for industrial production. [ka]

[0006] As mentioned above, existing synthesis routes have several drawbacks, including: 1) the need to use expensive raw materials, and 2) the use of hazardous reagents that produce highly toxic products or cause serious environmental pollution, making them unsuitable for large-scale industrial production.

[0007] To address the technical problems of these prior art methods, there is an urgent need in the market for a method of preparing 4-methoxypyrrole derivatives that is simple to react, inexpensive, and easily produced industrially. [Overview of the Initiative]

[0008] The technical problem that this invention aims to solve is to develop a 4-methoxypyrrole derivative and a method for synthesizing it that is readily available, yields high yields, is of good quality, is easy to operate, and is suitable for industrial production.

[0009] To achieve the above objectives, the present invention employs the following technical approach. The specific synthesis process is as follows: Starting with m-difluorobenzene (compound (I)), compound (II) is produced by oxalyl monoester chloride foucault acylation, followed by compound (III) through condensation with methyl 3-aminopropionate, compound (IV) is obtained by cyclization under alkaline conditions, and finally, compound (V) is obtained by methylation reaction preparation. [ka]

[0010] The method for synthesizing the 4-methoxypyrrole derivative of the present invention comprises the following synthesis steps: Step 1) involves reacting m-difluorobenzene (compound (I)) as a starting material with oxalyl monoester chloride using aluminum trichloride as a catalyst at a reaction temperature of -10 to 50°C, and then preparing compound (II) after post-treatment. In step 1), the solvent is one or more of tetrahydrofuran, toluene, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, and dichloromethane, and the oxalyl monoester chloride is one or more of oxalyl monomethyl chloride, oxalyl monoethyl chloride, oxalyl mono-n-propyl chloride, and oxalyl monoisopropyl chloride. Step 2) involves reacting compound (II) with methyl 3-aminopropionate or its salt in a solvent at a reaction temperature of 50-150°C, and then post-treatment to obtain compound (III). In step 2), the solvent is one or more of the following: tetrahydrofuran, toluene, n-heptane, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, methanol, acetonitrile, N,N-dimethylformamide. Step 3) involves reacting compound (III) in a solvent under the action of a base at a reaction temperature of -80 to 30°C, and then post-treatment to obtain compound (IV). In step 3), the solvent is one or more of tetrahydrofuran, toluene, 2-methyltetrahydrofuran, methyl ter-butyl ether, and dioxane, and the base is one or more of butyllithium, diisopropylammonium lithium, hexamethyldisylonylammonium lithium, sodium hydride, sodium tert-butanol, and potassium tert-butanol. Step 4) involves reacting compound (IV) with dimethyl sulfate in a solvent under the action of a base at a reaction temperature of -40 to 40°C, followed by workup to obtain product compound (V), In this step 4), the solvent is any one or more of tetrahydrofuran, methanol, 2-methyltetrahydrofuran, acetonitrile, N, N-dimethylformamide, and dioxin, and the base is any one or more of sodium methanol, sodium ethanol, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, and lithium carbonate.

[0011] In the chemical reaction formulas of the compounds (I), (II), (III), (IV), and (V) of the present invention, R represents any one of hydrogen, a linear or branched alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a linear or branched alkenyl group having 1 to 6 carbon atoms, a linear or branched alkynyl group having 1 to 6 carbon atoms, and halogen.

[0012] More preferably, R represents methyl or ethyl.

[0013] [[ID=I2]] The present invention also discloses a compound (II) having the following chemical formula, <00001OI>

Chemical formula

[0014] The present invention also discloses a compound (III) having the following chemical formula,

Chemical formula

[0015] The present invention also discloses a compound (IV) having the following chemical formula,

Chemical formula

[0016] The present invention also discloses compound (V) having the following chemical formula: [ka] Compound (V) is synthesized by steps 1) to 4) of the method for synthesizing 4-methoxypyrrole derivatives of the present invention.

[0017] Specifically, in step 1), the molar ratio of compound (I), oxalyl chloride monoester, and aluminum trichloride is 1:0.9 to 5:0.9 to 3. The oxalyl chloride monoester is one or more of monomethyl oxalyl chloride and monoethyl oxalyl chloride. Compound (II) is obtained by post-treatment preparation for the next reaction.

[0018] Specifically, in step 1), the reaction is carried out under the protection of a protective gas, which is one or more of nitrogen and argon.

[0019] Specifically, in step 2), the molar ratio of compound (II) to methyl 3-aminopropionate is 1:1 to 5. Compound (III) is obtained by post-treatment preparation for the next reaction.

[0020] Specifically, in step 2), the reaction is carried out under the protection of a protective gas, which is one or more of nitrogen or argon.

[0021] Specifically, in step 3), the molar ratio of compound (III) to base is 1:1 to 5, and the base is one or more of butyllithium, diisopropylaminolithium, and sodium hydride. Compound (IV) is obtained by post-treatment preparation for the next reaction.

[0022] Specifically, in step 3), the reaction is carried out under the protection of a protective gas, which is one or more of nitrogen or argon.

[0023] Specifically, in step 4), the molar ratio of compound (IV), dimethyl sulfate, and base is 1:0.8 to 5:1 to 5, and the base is one or more of sodium methanol, sodium hydroxide, and potassium hydroxide. Product compound (V) is obtained by post-processing.

[0024] Specifically, in step 4), the reaction is carried out under the protection of a protective gas, which is one or more of nitrogen and argon.

[0025] Specifically, in step 1), the solvent is one or more of the following: tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and dichloromethane.

[0026] Specifically, in step 2), the solvent is one or more of the following: tetrahydrofuran, toluene, methanol, dioxane, and acetonitrile.

[0027] Specifically, in step 3), the solvent is one or more of methyl tert-butyl ether, 2-methyltetrahydrofuran, and tetrahydrofuran.

[0028] Specifically, in step 4), the solvent is one or more of methanol, acetonitrile, and dioxane.

[0029] The method for synthesizing 4-methoxypyrrole derivatives provided by the present invention has the following advantages. The present invention provides a relatively simple route, using only commercially available materials. The raw materials are relatively inexpensive, safe, and controllable, without complex special operating steps, making it suitable for industrial production. It offers a novel synthetic scheme for the synthesis and preparation of 4-methoxypyrrole derivatives. [Modes for carrying out the invention]

[0030] To further clarify the object, technical solution, and advantages of the present invention, the present invention will be described by embodiments.

[0031] The method for synthesizing the 4-methoxypyrrole derivative of the present invention consists of the following steps: Step 1) involves reacting m-difluorobenzene (compound (I)) as a starting material with oxalyl monoester chloride using aluminum trichloride as a catalyst at a reaction temperature of -10 to 50°C, and then preparing compound (II) after post-treatment. In step 1), the solvent is one or more of tetrahydrofuran, toluene, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, and dichloromethane, and the oxalyl monoester chloride is one or more of oxalyl monomethyl chloride, oxalyl monoethyl chloride, oxalyl mono-n-propyl chloride, and oxalyl monoisopropyl chloride. Step 2) involves reacting compound (II) with methyl 3-aminopropionate or its salt in a solvent at a reaction temperature of 50-150°C, and then post-treatment to obtain compound (III). In step 2), the solvent is one or more of the following: tetrahydrofuran, toluene, n-heptane, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, methanol, acetonitrile, N,N-dimethylformamide. Step 3) involves reacting compound (III) in a solvent under the action of a base at a reaction temperature of -80 to 30°C, and then post-treatment to obtain compound (IV). In step 3), the solvent is one or more of tetrahydrofuran, toluene, 2-methyltetrahydrofuran, methyl ter-butyl ether, and dioxane, and the base is one or more of butyllithium, diisopropylammonium lithium, hexamethyldisylonylammonium lithium, sodium hydride, sodium tert-butanol, and potassium tert-butanol. Step 4) involves reacting compound (IV) with dimethyl sulfate in a solvent under the action of a base at a reaction temperature of -40 to 40°C, followed by workup to obtain product compound (V), In step 4), the solvent is one or more of tetrahydrofuran, methanol, 2-methyltetrahydrofuran, acetonitrile, N,N-dimethylformamide, and dioxin, and the base is one or more of sodium methanol, sodium ethanol sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, and lithium carbonate.

[0032] In one embodiment, in step 1), first, m-difluorobenzene (compound (I)) and aluminum trichloride are added to the solvent to prepare a reaction solution, and the reaction temperature of this reaction solution is controlled to -10 to 50°C before oxalyl monoester chloride is added dropwise to the reaction solution. More preferably, the reaction temperature in step 1) is 0 to 10°C.

[0033] In one embodiment, in step 1), oxalyl monoester chloride is added dropwise to the reaction solution, and the reaction is allowed to proceed sufficiently by keeping it warm for 1 to 3 hours. After the holding time, the reaction solution is quenched by adding it dropwise to ice water, and the mixture is stratified into an aqueous phase and an organic phase. The aqueous phase is extracted with an extractant, and the extractant is combined with the organic phase. Next, the organic phase is washed with water. Finally, the organic phase washed with water is evaporated to obtain compound (II). The extractant is one of dichloromethane, 2-methyltetrahydrofuran, or trichloromethane.

[0034] In one embodiment, in step 2), first, compound (II), anhydrous copper sulfate, and trimethyl orthoformate are added to the solvent to prepare the reaction solution, and after controlling the reaction temperature to 50-150°C, methyl 3-aminopropionate or its salt is added dropwise to the reaction solution. More preferably, the reaction temperature in step 2) is 70-80°C.

[0035] In one embodiment, in step 2), first, compound (II), anhydrous copper sulfate, trimethyl orthoformate, and acetonitrile are added to the solvent to prepare a reaction solution, and the reaction temperature is controlled to 50-150°C. Then, methyl 3-aminopropionate hydrochloride and acetonitrile are added to the reaction solution in another reaction vial, triethylamine is added dropwise, the mixture is stirred, the mixture is filtered, and the filtrate is slowly added dropwise to the compound (II) reaction solution. More preferably, the reaction temperature in step 2 is 60-70°C.

[0036] In one embodiment, in step 2), first, compound (II), methyl 3-aminopropionate hydrochloride, and toluene are added to the solvent to prepare the reaction solution, the reaction temperature is controlled to 50-150°C, then triethylamine is added dropwise, and after the addition is complete, the mixture is heated and refluxed to dehydrate it. More preferably, the reaction temperature in step 2) is 110-112°C.

[0037] In one embodiment, in step 2), methyl 3-aminopropionate or a salt thereof is added dropwise to the reaction solution, and the reaction is carried out thoroughly by holding the temperature for 2 to 3 hours. After the holding time, the reaction solution is evaporated, tetrahydrofuran is added and stirred, and the diatomaceous earth is filtered to obtain a mixed solution of compound (III) and tetrahydrofuran.

[0038] In one embodiment, in step 3), the temperature is lowered to a reaction temperature of -80 to 30°C, an alkali is added, the mixture is stirred for 1 to 3 hours, water is added to quench the reaction, and then the mixture is allowed to stand to stratify, yielding an aqueous phase and an organic phase. After adding petroleum ether to the organic phase, the mixture is cooled to 0 to 10°C, stirred for 1 to 3 hours, filtered, and dried to obtain compound (IV). More preferably, the reaction temperature in step 3) is -40 to 30°C. More preferably, the aqueous phase is extracted with an extractant and combined with the organic phase. The extractant is either tetrahydrofuran or methyl tert-butyl ether.

[0039] In one embodiment, in step 4), compound (IV) is first added to the solvent to prepare the reaction solution, the reaction temperature of this solution is controlled to -40 to 40°C, and then the base is added dropwise to the reaction solution. More preferably, the reaction temperature in step 4) is -10 to 0°C.

[0040] In one embodiment, in step 4), alkali is added dropwise to the reaction mixture, and after the addition is complete, the mixture is kept warm for 0.5 to 2 hours to allow the reaction to proceed sufficiently. After the warming is complete, dimethyl sulfate is added dropwise to the reaction mixture, and the mixture is held for 1 to 3 hours after the addition is complete. Then, the pH is adjusted to 7 to 8 with concentrated hydrochloric acid, and after distillation to a certain volume, water is added, the mixture is stirred at 20 to 30°C for 1 to 3 hours, filtered, and dried to obtain the crude product of compound (V).

[0041] In one embodiment, in step 4), isopropyl alcohol is added to the crude product of compound (V) obtained and dissolved, filtered, distilled to a certain volume, cooled to 0-5°C, kept warm and stirred for 1-3 hours, filtered and dried to obtain compound (V).

[0042] The solvent in step 1) is one or more of the following: tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and dichloromethane.

[0043] The solvent in step 2) is one or more of the following: tetrahydrofuran, toluene, methanol, dioxane, and acetonitrile.

[0044] The solvent in step 3) is one or more of methyl tert-butyl ether, 2-methyltetrahydrofuran, and tetrahydrofuran.

[0045] The solvent in step 4) is one or more of methanol, acetonitrile, and dioxane.

[0046] The above is a detailed description of the method for synthesizing the 4-methoxypyrrole derivative of the present invention. The present invention will be further described in detail below with reference to specific embodiments.

[0047] Example 1 [ka] Under nitrogen protection, 50.0 g (0.44 mol, 1.0 eq) of m-difluorobenzene, 81.8 g (0.6 1 mol, 1.4 eq) of aluminum trichloride, and 250.0 g of dichloromethane were added to a reaction vial. The temperature was controlled to 0-10°C, and 59.1 g (0.48 mol, 1.1 eq) of oxaloyl monomethyl chloride was slowly added dropwise to the reaction mixture. The reaction mixture was maintained at a constant temperature for 1 hour. After maintaining the temperature, the reaction mixture was slowly added dropwise to 500 mL of ice water to quench, and the layers were separated. The aqueous layer was extracted with 100 g of dichloromethane, and after combining the organic phases, the organic phase was washed with 300 g of water. The organic phase was removed and evaporated to obtain 74.6 g of compound (II) in 85.0% yield. The NMR data for the compound are as follows: 1 HNMR (400MHz, DMSO-d6) δ8.04(td, J=8.6, 6.5Hz, 1H), 7.57(ddd, J=11.6, 9.2, 2.4Hz, 1H), 7.36(tdd, J=8.2, 2.5, 0.9Hz, 1H), 3.92(s, 3H); 13CNMR (101MHz, DMSO-d6) δ182.74, 168.42, 168.29, 165.86, 165.73, 164.66, 164.52, 164.01, 162.08, 161.94, 133.91, 133 .89, 133.80, 133.77, 118.49, 118.46, 118.39, 118.36, 113.87, 113.84, 113.65, 113.62, 106.25, 105.99, 105.73, 53.72.

[0048] Under nitrogen protection, 100.0 g (0.5 mol, 1.0 eq) of compound (II), 39.9 g (0.25 mol, 0.5 eq) of anhydrous copper sulfate, 68.9 g (0.65 mol, 1.3 eq) of trimethyl orthoformate, and 800.0 g of methanol were added to a reaction vial. The temperature was maintained at 50-60°C, and a solution of 103.0 g (1.0 mol, 2.0 eq) of methyl 3-aminopropanoate and 100.0 g of methanol was added dropwise. After addition, the mixture was kept warm for 2-3 hours. After the reaction and evaporation, 400 g of tetrahydrofuran was added and the mixture was thoroughly stirred. The mixture was then filtered using diatomaceous earth filtration to obtain a mixed solution of compound (III) and tetrahydrofuran, which was then directly added to the next reaction.

[0049] Under a nitrogen atmosphere, the mixed solution of compound (III) from the previous step and tetrahydrofuran was cooled to -40 to 20°C. 375 mL of lithium diisopropylammonium tetrahydrofuran solution (0.75 mol, 1.5 eq, standard 2 mol / L) was added dropwise. After the addition was complete, the mixture was stirred for 1 hour, water was added to quench the mixture, and stratification was performed to obtain the organic phase. 200.0 g of petroleum ether was added to the organic phase, and the mixture was cooled to 0 to 10°C and stirred for 2 hours. By filtration and drying, 73.0 g of compound (IV) was obtained in a two-step reaction yield of 57.7%. The NMR data for the compound is as follows. 1 HNMR (400MHz, DMSO-d6) δ11.27(s, 1H), 8.16(s, 1H), 7.78(td, J=8.8, 6.7Hz, 1H), 7.29 (ddd, J=11.7, 9.3, 2.7Hz, 1H), 7.23(d, J=3.9Hz, 1H), 7.19-7.09(m, 1H), 3.76(s, 3H); 13CNMR (101MHz, DMSO-d6) δ165.76, 161.93, 161.81, 159.49, 159.37, 159.25, 156.90, 156.78, 142.91, 130.10, 130.04, 130.00, 129 .95, 121.37, 116.60, 116.57, 116.47, 116.43, 112.19, 112.15, 111.97, 111.94, 108.56, 104.96, 104.70, 104.44, 104.05, 51.11.

[0050] Under a nitrogen atmosphere, 100.0 g (0.39 mol, 1.0 eq) of compound (IV) and 500 g of anhydrous methanol were added to a reaction vial, and the temperature was controlled to -10 to 0°C. 142.2 g (0.79 mol, 2.0 eq) of a methanol solution of sodium methanolate (30% sodium methanolate) was added dropwise to the reaction mixture, and the mixture was incubated for 0.5 hours after the addition was complete. 149.4 g (1.18 mol, 3.0 eq) of dimethyl sulfate was added dropwise to the reaction mixture, and the mixture was incubated for 2 hours after the addition was complete. After incubation, the pH was adjusted to 7-8 with concentrated hydrochloric acid, and after distillation to a certain volume, water was added, the mixture was stirred at 20-30°C for 1 hour, filtered, and dried to obtain the crude product of compound (V). The compound (V) was dissolved by adding isopropanol, filtered, and distilled to a certain volume. The temperature was then lowered to 0-5°C, and the mixture was kept warm and stirred for 2 hours. After filtering and drying, 88 g of compound (V) was obtained, and the one-step reaction yield was 83.4%. The NMR data for the compound is as follows. 1 HNMR (400MHz, DMSO-d6) δ11.50(s, 1H), 7.64(td, J=8.7, 6.6Hz, 1H), 7.41-7.31(m, 2H), 7.23-7.13(m, 1H), 3.72(d, J=3.0Hz, 6H); 13CNMR (101MHz, DMSO-d6) δ163.65, 162.86, 162.74, 160.41, 160.29, 160.20, 160.07, 157.72, 157.60, 144.64, 131.34, 131.29, 131.24, 13 1.19, 123.46, 115.91, 115.88, 115.77, 115.73, 114.49, 112.36, 112.33, 112.15, 112.11, 107.41, 105.09, 104.83, 104.57, 62.04, 51.03.

[0051] Example 2 [ka] Under nitrogen protection, 50.0 g (0.44 mol, 1.0 eq) of m-difluorobenzene, 81.8 g (0.6 mol, 1.4 eq) of aluminum trichloride, and 250.0 g of 2-methyltetrahydrofuran were added to a reaction vial. The temperature was controlled to 0-10°C, and 64.4 g (0.53 mol, 1.2 eq) of oxaloyl monomethyl chloride was slowly added dropwise to the reaction mixture. After addition, the mixture was held at a constant temperature for 1 hour. After maintaining the temperature, the reaction mixture was quenched by slowly adding it dropwise to 500 mL of ice water and then stratified. The aqueous layer was extracted with 100 g of 2-methyltetrahydrofuran, and the organic phase was washed with 100 g of water. The organic phase was removed and evaporated to obtain 75.6 g of compound (II) in 86.2% yield. The NMR data of the compound is as follows: 1 HNMR (400MHz, DMSO-d6) δ8.04(td, J=8.6, 6.5Hz, 1H), 7.57(ddd, J=11.6, 9.2, 2.4Hz, 1H), 7.36(tdd, J=8.2, 2.5, 0.9Hz, 1H), 3.92(s, 3H); 13 CNMR (101MHz, DMSO-d6) δ182.74, 168.42, 168.29, 165.86, 165.73, 164.66, 164.52, 164.01, 162.08, 161.94, 133.91, 133 .89, 133.80, 133.77, 118.49, 118.46, 118.39, 118.36, 113.87, 113.84, 113.65, 113.62, 106.25, 105.99, 105.73, 53.72.

[0052] Under nitrogen protection, 100.0 g (0.5 mol, 1.0 eq) of compound (II), 23.9 g (0.15 mol, 0.3 eq) of anhydrous copper sulfate, 68.9 g (0.65 mol, 1.3 eq) of trimethyl orthoformate and 600 g of 1,4-dioxane were added to a reaction vial, the temperature was raised to 70 - 80 °C, and a solution prepared by mixing 103.0 g of methyl 3-aminopropionate (1.0 mol, 2.0 eq) and 100.0 g of 1,4-dioxane was added dropwise. After the dropwise addition, the mixture was kept warm for 2 - 3 hours. After the reaction was completed and evaporation occurred, 400 g of tetrahydrofuran was added, stirred well, and filtered through diatomaceous earth to obtain a tetrahydrofuran solution of compound (III), which was directly used in the next reaction.

[0053] Under a nitrogen atmosphere, the temperature of the tetrahydrofuran solution of compound (III) from the previous step was controlled at 15 - 30 °C, and solid sodium hydride was added in batches. A total of 36.0 g (0.9 mol, 1.8 eq, specification with a content of 60%) of sodium hydride was added, and the mixture was stirred and reacted for 2 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was allowed to separate into layers. The aqueous layer was extracted once with tetrahydrofuran, and the organic phases were combined. After distillation to a certain amount, 200.0 g of petroleum ether was added, the temperature was lowered to 0 - 10 °C, and the mixture was stirred for 2 hours, then filtered and dried to obtain 78 g of compound (IV). The yield of the two-step reaction was 61.5%. The NMR data of the compound is as follows: 1 HNMR(400MHz, DMSO-d6)δ11.27(s, 1H), 8.16(s, 1H), 7.78(td, J = 8.8, 6.7Hz, 1H), 7.29(ddd, J = 11.7, 9.3, 2.7Hz, 1H), 7.23(d, J = 3.9Hz, 1H), 7.19 - 7.09(m, 1H), 3.76(s, 3H); 13CNMR (101MHz, DMSO-d6) δ165.76, 161.93, 161.81, 159.49, 159.37, 159.25, 156.90, 156.78, 142.91, 130.10, 130.04, 130.00, 129 .95, 121.37, 116.60, 116.57, 116.47, 116.43, 112.19, 112.15, 111.97, 111.94, 108.56, 104.96, 104.70, 104.44, 104.05, 51.11.

[0054] Under a nitrogen atmosphere, 23.7 g (0.59 mol, 1.5 eq) of solid sodium hydroxide and 500 g of 1,4-dioxane were added to a reaction vial, and the temperature was controlled to 0-10°C. 100.0 g (0.39 mol, 1.0 eq) of compound (IV) was slowly added to the reaction mixture, and the mixture was incubated for 0.5 hours after the addition was complete. Next, 64.8 g (0.51 mol, 1.3 eq) of dimethyl sulfate was slowly added dropwise to the reaction mixture, and the mixture was incubated for 2 hours after the addition was complete. After incubation, the pH was adjusted to 7-8 with concentrated hydrochloric acid, and after distillation to a certain volume, water was added, the mixture was stirred at 20-30°C for 1 hour, filtered, and dried to obtain the crude product of compound (V). The compound (V) was dissolved by adding isopropanol, filtered, and distilled to a certain volume. The temperature was then lowered to 0-5°C, maintained, stirred for 2 hours, filtered, and dried to obtain 86.3 g of compound (V). The reaction yield for one step was 81.8%. The NMR data for the compound is as follows: 1 HNMR (400MHz, DMSO-d6) δ11.50(s, 1H), 7.64(td, J=8.7, 6.6Hz, 1H), 7.41-7.31(m, 2H), 7.23-7.13(m, 1H), 3.72(d, J=3.0Hz, 1H)J=3.0Hz, 6H); 13CNMR (101MHz, DMSO-d6) δ163.65, 162.86, 162.74, 160.41, 160.29, 160.20, 160.07, 157.72, 157.60, 144.64, 131.34, 131.29, 131.24, 13 1.19, 123.46, 115.91, 115.88, 115.77, 115.73, 114.49, 112.36, 112.33, 112.15, 112.11, 107.41, 105.09, 104.83, 104.57, 62.04, 51.03.

[0055] Example 3 [ka] Under nitrogen protection, 50.0 g (0.44 mol, 1.0 eq) of m-difluorobenzene, 64.5 g (0.48 mol, 1.1 eq) of aluminum trichloride, and 250.0 g of dichloromethane were added to a reaction vial. The temperature was controlled to 0-10°C, and 64.4 g (0.53 mol, 1.2 eq) of monomethyl oxalyl chloride was slowly added dropwise to the reaction mixture. After the addition was complete, the mixture was held at a constant temperature for 1 hour. After maintaining the temperature, the reaction mixture was slowly quenched by adding it dropwise to 500 mL of ice water, and the layers were stratified. The aqueous layer was extracted with 100 g of dichloromethane, and the organic phase was washed with 100 g of water. The organic phase was removed and evaporated to obtain 72.1 g of compound (II) in 82.2% yield. The NMR data of the compound is as follows: 1 HNMR (400MHz, DMSO-d6) δ8.04(td, J=8.6, 6.5Hz, 1H), 7.57(ddd, J=11.6, 9.2, 2.4Hz, 1H), 7.36(tdd, J=8.2, 2.5, 0.9Hz, 1H), 3.92(s, 3H); 13 CNMR (101MHz, DMSO-d6) δ182.74, 168.42, 168.29, 165.86, 165.73, 164.66, 164.52, 164.01, 162.08, 161.94, 133.91, 133 .89, 133.80, 133.77, 118.49, 118.46, 118.39, 118.36, 113.87, 113.84, 113.65, 113.62, 106.25, 105.99, 105.73, 53.72.

[0056] Under nitrogen protection, 100.0 g (0.5 mol, 1.0 eq) of compound (II), 23.9 g (0.15 mol, 0.3 eq) of anhydrous copper sulfate, 68.9 g (0.65 mol, 1.3 eq) of trimethyl orthoformate, and 600 g of acetonitrile were added to a reaction vial and the temperature was raised to 60-70°C. In another reaction vial, 125.5 g of methyl 3-aminopropionate hydrochloride (0.9 mol, 1.8 eq) and 200 g of acetonitrile were added, and 91.0 g of triethylamine (0.9 mol, 1.8 eq) was added dropwise. After the addition was complete, the mixture was stirred for 0.5 hours, filtered, and the filtrate was slowly added dropwise to the reaction solution of compound (II). After the addition was complete, the mixture was kept warm for 2-3 hours. After the reaction was complete, the mixture was evaporated, 400 g of tetrahydrofuran was added, the mixture was stirred well, and diatomaceous earth filtration was performed to obtain a tetrahydrofuran solution of compound (III), from which the reaction proceeded directly to the next step.

[0057] Under a nitrogen atmosphere, the tetrahydrofuran solution of compound (III) from the previous step was cooled to -80 to -70°C, and 340 mL of tetrahydrofuran solution of n-butyllithium (0.85 mol, 1.7 eq, standard value 2.5 mol / L) was added dropwise, and the mixture was stirred for 1 hour. After the reaction was complete, water was added to quench the mixture, and after stratification, the aqueous layer was extracted once with tetrahydrofuran to combine the organic phases. After distillation to a certain volume, 200.0 g of petroleum ether was added, the mixture was cooled to 0 to 10°C, stirred for 2 hours, filtered, and dried to obtain 81.3 g of compound (IV). The reaction yield for both steps was 64.3%. The NMR data for the compounds are as follows: 1 HNMR (400MHz, DMSO-d6) δ11.27(s, 1H), 8.16(s, 1H), 7.78(td, J=8.8, 6.7Hz, 1H), 7.29 (ddd, J=11.7, 9.3, 2.7Hz, 1H), 7.23(d, J=3.9Hz, 1H), 7.19-7.09(m, 1H), 3.76(s, 3H); 13CNMR (101MHz, DMSO-d6) δ165.76, 161.93, 161.81, 159.49, 159.37, 159.25, 156.90, 156.78, 142.91, 130.10, 130.04, 130.00, 129 .95, 121.37, 116.60, 116.57, 116.47, 116.43, 112.19, 112.15, 111.97, 111.94, 108.56, 104.96, 104.70, 104.44, 104.05, 51.11.

[0058] Under a nitrogen atmosphere, 31.6 g (0.79 mol, 2.0 eq) of solid sodium hydroxide and 500 g of anhydrous methanol were added to a reaction vial, and the temperature was controlled to 5-10°C. 100.0 g (0.39 mol, 1.0 eq) of compound (IV) was slowly added to the reaction mixture, and the temperature was maintained for 0.5 hours after the addition was complete. Next, 149.4 g (1.18 mol, 3.0 eq) of dimethyl sulfate was slowly added dropwise to the reaction mixture, and the mixture was kept warm for 2 hours after the addition was complete. After the warming period, the pH was adjusted to 7-8 with concentrated hydrochloric acid, and after distillation to a certain volume, water was added, the mixture was stirred at 20-30°C for 1 hour, filtered, and dried to obtain the crude product of compound (V). The compound (V) was dissolved by adding isopropanol, filtered, and distilled to a certain volume. The temperature was then lowered to 0-5°C, maintained, stirred for 2 hours, filtered, and dried to obtain 85.6 g of compound (V). The yield of this single-step reaction was 81.1%. The NMR data for the compound is as follows: 1 HNMR (400MHz, DMSO-d6) δ11.50(s, 1H), 7.64(td, J=8.7, 6.6Hz, 1H), 7.41-7.31(m, 2H), 7.23-7.13(m, 1H), 3.72(d, J=3.0Hz, 1H)J=3.0Hz, 6H); 13CNMR (101MHz, DMSO-d6) δ163.65, 162.86, 162.74, 160.41, 160.29, 160.20, 160.07, 157.72, 157.60, 144.64, 131.34, 131.29, 131.24, 13 1.19, 123.46, 115.91, 115.88, 115.77, 115.73, 114.49, 112.36, 112.33, 112.15, 112.11, 107.41, 105.09, 104.83, 104.57, 62.04, 51.03.

[0059] Example 4 [ka] Under nitrogen protection, 50.0 g (0.44 mol, 1.0 eq) of m-difluorobenzene, 76.3 g (0.57 mol, 1.3 eq) of aluminum trichloride, and 250.0 g of dichloromethane were added to a reaction vial. The temperature was controlled to 0-10°C, and 64.4 g (0.53 mol, 1.2 eq) of monomethyl oxalyl chloride was slowly added dropwise to the reaction mixture. After the addition was complete, the mixture was held at a constant temperature for 1 hour. After maintaining the temperature, the reaction mixture was quenched by slowly adding it dropwise to 500 mL of ice water and then stratified. The aqueous layer was extracted with 100 g of dichloromethane, and after combining with the organic phase, the organic phase was washed with 300 g of water. The organic phase was removed and evaporated to obtain 74.0 g of compound (II) in 84.4% yield. The NMR data of the compound is as follows: 1 HNMR (400MHz, DMSO-d6) δ8.04(td, J=8.6, 6.5Hz, 1H), 7.57(ddd, J=11.6, 9.2, 2.4Hz, 1H), 7.36(tdd, J=8.2, 2.5, 0.9Hz, 1H), 3.92(s, 3H); 13 CNMR (101MHz, DMSO-d6) δ182.74, 168.42, 168.29, 165.86, 165.73, 164.66, 164.52, 164.01, 162.08, 161.94, 133.91, 133 .89, 133.80, 133.77, 118.49, 118.46, 118.39, 118.36, 113.87, 113.84, 113.65, 113.62, 106.25, 105.99, 105.73, 53.72.

[0060] 100.0 g (0.5 mol, 1.0 eq) of compound (II), 125.5 g (0.9 mol, 1.8 eq) of methyl 3-aminopropanoate hydrochloride, and 1000 g of toluene were added to a reaction vial. The temperature was raised to 70-80°C, and 91.0 g (0.9 mol, 1.8 eq) of triethylamine was slowly added dropwise. After addition, the mixture was kept warm and stirred for 0.5 hours, then the temperature was raised to 110-112°C and refluxed for 2-3 hours. After the reaction was complete, the temperature was lowered to 20-30°C, water was added to quench the mixture, and the organic phase was separated by layering. After evaporation, 400 g of tetrahydrofuran was added to obtain a compound (III) tetrahydrofuran solution, which was then directly added to the next reaction.

[0061] Under a nitrogen atmosphere, the tetrahydrofuran solution of compound (III) from the previous step was cooled to -40 to 20°C, and 300 mL of n-butyllithium tetrahydrofuran solution (0.75 mol, 1.5 eq, standard 2.5 mol / L) was added dropwise. After the addition was complete, the mixture was stirred for 1 hour. After the reaction was complete, water was added to quench the mixture and stratify it. The aqueous layer was extracted with 200 g of tetrahydrofuran, and the organic phases were combined. After distillation to a certain volume, 200 g of petroleum ether was added, the mixture was cooled to 0 to 10°C, and stirred for 2 hours. By filtration and drying, 70.3 g of compound (IV) was obtained, and the reaction yield for the two steps was 55.6%. The NMR data for the compound is as follows: 1 HNMR (400MHz, DMSO-d6) δ11.27(s, 1H), 8.16(s, 1H), 7.78(td, J=8.8, 6.7Hz, 1H), 7.29 (ddd, J=11.7, 9.3, 2.7Hz, 1H), 7.23(d, J=3.9Hz, 1H), 7.19-7.09(m, 1H), 3.76(s, 3H); 13CNMR (101MHz, DMSO-d6) δ165.76, 161.93, 161.81, 159.49, 159.37, 159.25, 156.90, 156.78, 142.91, 130.10, 130.04, 130.00, 129 .95, 121.37, 116.60, 116.57, 116.47, 116.43, 112.19, 112.15, 111.97, 111.94, 108.56, 104.96, 104.70, 104.44, 104.05, 51.11.

[0062] Under a nitrogen atmosphere, 100.0 g (0.39 mol, 1.0 eq) of compound (IV) and 500 g of acetonitrile were added to a reaction vial, and the temperature was controlled to -10 to 0°C. 99.6 g of methanol solution of sodium methanolate (30% sodium methanolate) was slowly added dropwise to the reaction mixture, and after the addition was complete, the mixture was incubated for 0.5 hours. Next, 59.8 g (0.47 mol, 1.2 eq) of dimethyl sulfate was added dropwise to the reaction mixture, and after the addition was complete, the mixture was incubated for 2 hours. After incubation, the pH was adjusted to 7-8 with concentrated hydrochloric acid, and after distillation to a certain volume, water was added, the mixture was stirred at 20-30°C for 1 hour, filtered, and dried to obtain the crude product of compound (V). Isopropanol was added to dissolve the product, filtered, and after distillation to a certain volume, the temperature was lowered to 0-5°C, incubated, and stirred for 2 hours. The mixture was filtered and dried to obtain 89.5 g of compound (V), and the reaction yield for one step was 84.8%. The NMR data for the compound is as follows: 1 HNMR (400MHz, DMSO-d6) δ11.50(s, 1H), 7.64(td, J=8.7, 6.6Hz, 1H), 7.41-7.31(m, 2H), 7.23-7.13(m, 1H), 3.72(d, J=3.0Hz, 1H)J=3.0Hz, 6H); 13CNMR (101MHz, DMSO-d6) δ163.65, 162.86, 162.74, 160.41, 160.29, 160.20, 160.07, 157.72, 157.60, 144.64, 131.34, 131.29, 131.24, 13 1.19, 123.46, 115.91, 115.88, 115.77, 115.73, 114.49, 112.36, 112.33, 112.15, 112.11, 107.41, 105.09, 104.83, 104.57, 62.04, 51.03.

[0063] Example 5 [ka] Under nitrogen protection, 50.0 g (0.44 mol, 1.0 eq) of m-difluorobenzene, 81.8 g (0.61 mol, 1.4 eq) of aluminum trichloride, and 350.0 g of trichloromethane were added to a reaction vial. The temperature was controlled to 0-20°C, and 71.8 g (0.53 mol, 1.2 eq) of ethyl monooxygen oxalyl chloride was slowly added dropwise to the reaction mixture. After the addition was complete, the mixture was held at a constant temperature for 3 hours. After maintaining the temperature, the reaction mixture was quenched by slowly adding it dropwise to 500 mL of ice water and then stratified. The aqueous layer was extracted with 100 g of trichloromethane, and the organic phase was combined with the aqueous phase. The organic phase was washed with 300 g of water. The organic phase was removed and evaporated to obtain 76.7 g of compound (II) in 81.7% yield. The NMR data of the compound is as follows: 1 HNMR (400MHz, DMSO-d6) δ8.03(td, J=8.6, 6.5Hz, 1H), 7.57(dd, J=11.6, 9.2, 2.4Hz, 1H), 7.41-7.32(m, 1H), 4.40(q, J=7.1Hz, 2H), 1.31(t, J=7.1Hz, 3H); 13CNMR (101MHz, DMSO-d6) δ182.88, 168.47, 168.34, 165.90, 165.77, 164.71, 164.57, 163.74, 162.13, 162.00, 133.59, 133.5 7133.48, 133.45, 118.32, 118.29, 118.22, 118.19, 113.74, 113.71, 113.52, 113.49, 105.99, 105.73, 105.47, 62.87, 13.90.

[0064] Under a nitrogen atmosphere, 100.0 g (0.47 mol, 1.0 eq) of compound (II), 112.4 g (0.93 mol, 2.0 eq) of anhydrous magnesium sulfate, and 600 g of acetonitrile were added to a reaction vial. The temperature was raised to 60-70°C, and a mixed solution of 97.0 g (0.94 mol, 2.0 eq) of methyl 3-aminopropionate and 100.0 g of acetonitrile was slowly added dropwise. After the addition was complete, the mixture was stirred for 3-4 hours. After the reaction was complete, the mixture was evaporated, 500 g of methyl tert-butyl ether was added, and the mixture was stirred well. The mixture was then filtered through diatomaceous earth to obtain a methyl tert-butyl ether solution of compound (III), which was then directly added to the next step in the reaction.

[0065] Under a nitrogen atmosphere, the temperature of the compound (III) methyl tert-butyl ether solution from the previous step was controlled to 15-30°C. Sodium hydride solid was added in batches, totaling 33.8 g (0.85 mol, 1.8 eq, 60% content). After the addition of materials was complete, the mixture was stirred for 2 hours. After the reaction was complete, water was added to quench the mixture and stratify it. The aqueous layer was extracted with methyl tert-butyl ether, and the organic phases were combined. After distillation to a certain volume, 200.0 g of petroleum ether was added, the mixture was cooled to 0-10°C, stirred for 2 hours, filtered, and dried to obtain 72.8 g of compound (IV). The reaction yield for both steps was 61.6%. The NMR data for the compound is as follows: 1HNMR (400MHz, DMSO-d6) δ11.27(s, 1H), 8.16(s, 1H), 7.78(td, J=8.8, 6.7Hz, 1H), 7.29 (ddd, J=11.7, 9.3, 2.7Hz, 1H), 7.23(d, J=3.9Hz, 1H), 7.19-7.09(m, 1H), 3.76(s, 3H); 13 CNMR (101MHz, DMSO-d6) δ165.76, 161.93, 161.81, 159.49, 159.37, 159.25, 156.90, 156.78, 142.91, 130.10, 130.04, 130.00, 129 .95, 121.37, 116.60, 116.57, 116.47, 116.43, 112.19, 112.15, 111.97, 111.94, 108.56, 104.96, 104.70, 104.44, 104.05, 51.11.

[0066] Under a nitrogen atmosphere, 100.0 g (0.39 mol, 1.0 eq) of compound (IV) and 500 g of anhydrous methanol were added to a reaction vial. After controlling the temperature to -10 to 0°C, 128.0 g (0.71 mol, 1.8 eq) of a methanol solution of sodium methanolate (30% sodium methanolate content) was added dropwise to the reaction mixture, and the mixture was held for 0.5 hours after the addition was complete. 124.6 g (0.99 mol, 2.5 eq) of dimethyl sulfate was added dropwise to the reaction mixture, and the mixture was kept warm for 2 hours after the addition was complete. After the reaction was complete, the pH was adjusted to 7-8 with concentrated hydrochloric acid, and after distillation to a certain volume, water was added and the mixture was stirred at 20-30°C for 1 hour. The mixture was filtered and dried to obtain the crude product of compound (V). The compound (V) was dissolved by adding isopropanol, filtered, and distilled to a certain volume. The temperature was then lowered to 0-5°C, maintained, stirred for 2 hours, filtered, and dried to obtain 83.7 g of compound (V). The yield for this single-step reaction was 79.3%. The NMR data for the compound is as follows: 1 HNMR (400MHz, DMSO-d6) δ11.50(s, 1H), 7.64(td, J=8.7, 6.6Hz, 1H), 7.41-7.31(m, 2H), 7.23-7.13(m, 1H), 3.72(d, J=3.0Hz, 1H)J=3.0Hz, 6H); 13CNMR (101MHz, DMSO-d6) δ163.65, 162.86, 162.74, 160.41, 160.29, 160.20, 160.07, 157.72, 157.60, 144.64, 131.34, 131.29, 131.24, 13 1.19, 123.46, 115.91, 115.88, 115.77, 115.73, 114.49, 112.36, 112.33, 112.15, 112.11, 107.41, 105.09, 104.83, 104.57, 62.04, 51.03.

[0067] The above describes only preferred embodiments of the present invention and is not intended to limit the scope of the patent, and all equivalent modifications made using the present invention are within the scope of patent protection.

Claims

【Request Item 1】 【Chemistry 13】 Step 1) involves using m-difluorobenzene (compound (I)) as a starting material, reacting it with oxalyl chloride monoester in a solvent under the catalyst of aluminum trichloride, and then adjusting the mixture through post-treatment to obtain compound (II). Step 2) involves dehydrating compound (II) in a solvent with methyl 3-aminopropionate or a salt thereof, followed by post-treatment to obtain compound (III), Step 3) involves carrying out an intramolecular ring formation reaction of compound (III) in a solvent under the action of alkali, and then adjusting it by post-treatment to obtain compound (IV). Step 4) involves reacting compound (IV) with dimethyl sulfate in a solvent under the action of an alkali, and then preparing the product compound (V) by post-treatment. Including the above synthesis steps, R represents one of the following: hydrogen, a C1-C6 linear or branched alkyl group, a C3-C6 cycloalkyl group, a C1-C6 linear or branched alkenyl group, a C1-C6 linear or branched alkynyl group, or a halogen. A method for synthesizing a 4-methoxypyrrole derivative, characterized in that the product compound (V) is a compound represented by the following chemical formula. 【Chemistry 14】

2. The method for synthesizing a 4-methoxypyrrole derivative according to claim 1, characterized in that, in step 2), the solvent is one or more of tetrahydrofuran, toluene, n-heptane, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, methanol, acetonitrile, and N,N-dimethylformamide.

3. The method for synthesizing a 4-methoxypyrrole derivative according to claim 1, characterized in that, in step 2), the molar ratio of compound (II) to methyl 3-aminopropionate or a salt thereof is 1:1 to 5.

4. The method for synthesizing a 4-methoxypyrrole derivative according to claim 1, characterized in that in step 2), the dehydration reaction is one or more of the following: a dehydrating agent dehydration reaction and a solvent azeotropic dehydration reaction.

5. The method for synthesizing a 4-methoxypyrrole derivative according to claim 1, characterized in that, in step 3), the solvent is one or more of tetrahydrofuran, toluene, 2-methyltetrahydrofuran, methyl tert-butyl ether, and dioxane.

6. The method for synthesizing a 4-methoxypyrrole derivative according to claim 1, characterized in that in step 3), the base is one or more of butyllithium, diisopropylaminolithium, hexamethyldisilanyamolium, sodium hydride, sodium tert-butanolate, and potassium tert-butanolate.

7. The method for synthesizing a 4-methoxypyrrole derivative according to claim 1, characterized in that in step 3), the ratio of the molar amounts of compound (III) to the base is 1:1 to 5.

8. The method for synthesizing a 4-methoxypyrrole derivative according to claim 4, characterized in that, in step 2), the dehydrating agent is one or more of trimethyl orthoformate, molecular sieve, magnesium sulfate, and sodium sulfate.

9. The method for synthesizing a 4-methoxypyrrole derivative according to claim 4, characterized in that, in step 2), the solvent used for azeotropic dehydration is one or more of toluene and n-heptane.

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