4-Methoxypyrrole derivatives and a method for synthesizing the same

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 technical fields of the pharmaceutical industry and the synthesis of organic chemical intermediates, and relates to a method for synthesizing 4-methoxypyrrole derivatives.

Background Art

[0002] In Korean Patent No. 10-1613245, International Patent Application WO28236153, etc., it is described that 4-methoxypyrrole derivatives have good anti-ulcer activity (such as proton pump inhibitory activity) and bactericidal activity against Helicobacter pylori (H. pylori), and can be effectively used for the prevention and treatment of gastric ulcers, gastritis, reflux esophagitis or gastrointestinal disorders caused by Helicobacter 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 the synthesis of 4-methoxypyrrole derivatives lies in the construction of the 4-methoxypyrrole structure, and the main synthesis strategies are as follows.

[0004] Patents such as WO2012236153 describe using 2,4-difluorobenzaldehyde as a raw material, and generating the target product through reactions such as Strecker, Boc protection, condensation decarboxylation, cyclization, methylation, and de-Boc protection. This route is long, the yield is low, the reaction contains highly toxic sodium cyanide, the risk factors are large, the raw material of 2,4-difluorobenzaldehyde is relatively expensive, and a large amount of ammonia and concentrated hydrochloric acid are used, resulting in a large amount of high-salt wastewater, and the amount of "three wastes" is huge, which is not suitable for industrial production.

Chemical Formula

[0005] In Patent CN109867617, it is described that the target product is prepared using 2,4-difluorobenzaldehyde as a raw material by methods such as condensation addition method, TosMIC synthesis method, Vanleusen pyrrole synthesis method, etc. This route using 2,4-difluorobenzaldehyde has a high cost, and the purification of the final product by column chromatography is not suitable for industrial production.

Chemical formula

[0006] As described above, in the existing synthesis routes, there are drawbacks such as 1) the need to use expensive raw materials, and 2) the use of dangerous reagents such as highly toxic products and serious environmental pollution, which are not suitable for large-scale industrial production.

[0007] To solve the technical problems of such prior art, there is an urgent need in the market for a preparation method of 4-methoxypyrrole derivatives that is simple in reaction, low in cost, and easy for industrial production.

Summary of the Invention

[0008] The technical problem to be solved by the present invention is to develop a 4-methoxypyrrole derivative and its synthesis method that are easy to obtain raw materials, have a high yield, good quality, simple operation, and are suitable for industrial production.

[0009] To achieve the above object, the present invention adopts the following technical solutions. The specific synthesis process is as follows. Using m-difluorobenzene (Compound (I)) as a starting material, Compound (II) is prepared by oxalyl chloride monoester acylation, then Compound (III) is obtained by condensation with methyl 3-aminopropionate, cyclized under alkaline conditions to obtain Compound (IV), and finally the target Compound (V) is obtained by methylation reaction preparation.

Chemical formula

[0010] The synthetic method of the 4-methoxypyrrole derivative of the present invention comprises the following synthetic steps: Step 1) Reacting m-difluorobenzene (Compound (I)) as a starting material with oxalyl chloride monoester using aluminum trichloride as a catalyst at a reaction temperature of -10 to 50 °C, and preparing Compound (II) after post-treatment; In this Step 1), the solvent is any one or two or more of tetrahydrofuran, toluene, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, dichloromethane, and the oxalyl chloride monoester is any one or two or more of oxalyl chloride monomethyl ester, oxalyl chloride monoethyl ester, oxalyl chloride mono-n-propyl ester, oxalyl chloride monoisopropyl ester; Step 2) Reacting Compound (II) with methyl 3-aminopropionate or its salt in a solvent at a reaction temperature of 50 to 150 °C, and performing post-treatment to obtain Compound (III); In this Step 2), the solvent is any one or two or more of tetrahydrofuran, toluene, n-heptane, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, methanol, acetonitrile, N,N-dimethylformamide; Step 3) Reacting Compound (III) in a solvent under the action of a base at a reaction temperature of -80 to 30 °C, and performing post-treatment to obtain Compound (IV); In this Step 3), the solvent is any one or two or more of tetrahydrofuran, toluene, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, and the base is any one or two or more of butyllithium, diisopropylammoniumlithium, hexamethyldisilazanyllithium, sodium hydride, sodium tert-butanol, potassium tert-butanol; Step 4) Reacting Compound (IV) with dimethyl sulfate in a solvent under the action of a base at a reaction temperature of -40 to 40 °C, and performing post-treatment to obtain the product Compound (V); In this step 4), the solvent is any one or two or more of tetrahydrofuran, methanol, 2-methyltetrahydrofuran, acetonitrile, N, N-dimethylformamide, and dioxin, and the base is any one or two 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 a halogen.

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

[0013] The present invention also discloses a compound (II) having the following chemical formula,

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 a compound (V) having the following chemical formula, [Chemical Formula] Compound (V) is synthesized by Steps 1) to 4) in the method for synthesizing the 4-methoxypyrrole derivative of the present invention.

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

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

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

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

[0021] Specifically, in Step 3), the molar ratio of compound (III) and the base is 1:1 to 5, and the base mentioned above is any one or more of butyllithium, diisopropylaminolithium, and sodium hydride. For the next reaction, compound (IV) is obtained by post-treatment adjustment.

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

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

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

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

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

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

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

[0029] The synthesis method of the 4-methoxypyrrole derivative provided by the present invention has the following advantages. The route of the present invention is relatively simple, and all the raw materials used are commercially available off-the-shelf materials. The raw materials are relatively inexpensive, safe and controllable, without complicated special operation processes, and are suitable for industrial production. It provides a new synthetic scheme for the synthesis and preparation of 4-methoxypyrrole derivatives.

Embodiments for Carrying Out the Invention

[0030] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described by way of embodiments.

[0031] The synthetic method of the 4-methoxypyrrole derivative of the present invention comprises the following steps: Step 1): Using m-difluorobenzene (Compound (I)) as the starting material, reacting it with oxalyl chloride monoester using aluminum trichloride as a catalyst at a reaction temperature of -10 to 50 °C, and preparing Compound (II) after post-treatment; In this Step 1), the solvent is any one or two or more of tetrahydrofuran, toluene, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, dichloromethane, and the above-mentioned oxalyl chloride monoester is any one or two or more of oxalyl chloride monomethyl ester, oxalyl chloride monoethyl ester, oxalyl chloride mono-n-propyl ester, oxalyl chloride monoisopropyl ester; Step 2): Reacting Compound (II) with methyl 3-aminopropionate or its salt in a solvent at a reaction temperature of 50 to 150 °C, and performing post-treatment to obtain Compound (III); In this Step 2), the above-mentioned solvent is any one or two or more of tetrahydrofuran, toluene, n-heptane, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, methanol, acetonitrile, N,N-dimethylformamide; Step 3): Reacting Compound (III) under the action of a base in a solvent at a reaction temperature of -80 to 30 °C, and performing post-treatment to obtain Compound (IV); In this step 3), the solvent is any one or two or more of tetrahydrofuran, toluene, 2-methyltetrahydrofuran, methyl tert-butyl ether, and dioxane, and the base is any one or two or more of sodium hydride, sodium tert-butanol, potassium tert-butanol, butyllithium, diisopropylammonium lithium, and hexamethyldisilonylammonium lithium. Step 4) of reacting compound (IV) with dimethyl sulfate at a reaction temperature of -40 to 40 °C under the action of a base in a solvent, followed by post-treatment to obtain the product compound (V). In this step 4), the solvent is any one or more of tetrahydrofuran, methanol, 2-methyltetrahydrofuran, acetonitrile, N, N-dimethylformamide, and dioxane, and the base is any one or two 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 a solvent to prepare a reaction solution. After controlling the reaction solution to a reaction temperature of -10 to 50 °C, oxalyl chloride monoester 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), after adding oxalyl chloride monoester dropwise to the reaction solution, the mixture is kept warm for 1 to 3 hours to allow the reaction to proceed sufficiently. After the holding time ends, the reaction solution is added dropwise to ice water for quenching, and the aqueous phase and the organic phase are separated. 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 any one of dichloromethane, 2-methyltetrahydrofuran, and trichloromethane.

[0034] In one embodiment, in step 2), first, compound (II), copper sulfate anhydrous, and trimethyl orthoformate are added into a solvent to prepare a reaction solution. After controlling the reaction temperature at 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), copper sulfate anhydrous, trimethyl orthoformate, and acetonitrile are added into a solvent to prepare a reaction solution. After controlling the reaction temperature at 50 - 150°C, methyl 3-aminopropionate hydrochloride and acetonitrile are added to the reaction solution in another reaction vial, triethylamine is added dropwise. After the addition is completed, stirring is carried out, filtration is carried out, 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 into a solvent to prepare a reaction solution. After controlling the reaction temperature at 50 - 150°C, triethylamine is added dropwise. After the addition is completed, the temperature is raised to reflux for dehydration. More preferably, the reaction temperature in step 2) is 110 - 112°C.

[0037] In one embodiment, in step 2), methyl 3-aminopropionate or its salt is added dropwise to the reaction solution, and the holding temperature is set for 2 - 3 hours to fully carry out the reaction. After the holding time ends, the reaction solution is evaporated, tetrahydrofuran is added and stirred, and 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. After adding an alkali, it is stirred for 1 to 3 hours, water is added to quench it, and then it is left to stand for layering to obtain an aqueous phase and an organic phase. After adding petroleum ether to the organic phase, it 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 layer 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), first, compound (IV) is added to a solvent to prepare a reaction solution. After controlling the reaction solution to a reaction temperature of -40 to 40 °C, a base is dropped into the reaction solution. More preferably, the reaction temperature in step 4) is -10 to 0 °C.

[0040] In one embodiment, in step 4), an alkali is dropped into the reaction solution. After the dropping is completed, it is kept warm for 0.5 to 2 hours so that the reaction proceeds sufficiently. After the heat preservation is completed, dimethyl sulfate is dropped into the reaction solution. After the dropping is completed, it is held for 1 to 3 hours. Then, the pH is adjusted to 7 to 8 with concentrated hydrochloric acid. After distilling to a certain amount, water is added, and it is stirred at 20 to 30 °C for 1 to 3 hours, filtered, and dried to obtain a crude product of compound (V).

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

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

[0043] The solvent in step 2) is one or more of 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 following further describes the present invention in more detail with specific embodiments.

[0047] Example 1

Chemical formula

[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 prepared by mixing 103.0 g (1.0 mol, 2.0 eq) of methyl 3 - aminopropionate and 100.0 g of methanol was added dropwise. After the addition, the mixture was kept warm for 2 - 3 hours. After the reaction and evaporation, 400 g of tetrahydrofuran was added and stirred well, followed by filtration through diatomaceous earth to obtain a mixed solution of compound (III) and tetrahydrofuran, which was directly used in the next reaction.

[0049] Under a nitrogen atmosphere, the mixed solution of compound (III) and tetrahydrofuran from the previous step was cooled to - 40 - 20 °C, and 375 mL (0.75 mol, 1.5 eq, specification 2 mol / L) of a tetrahydrofuran solution of lithium diisopropylammonium was added dropwise. After the addition was complete, the mixture was stirred for 1 hour, water was added to quench the reaction, and the layers were separated to obtain an organic phase. 200.0 g of petroleum ether was further added to the organic phase, and the mixture was cooled to 0 - 10 °C and stirred for 2 hours. By filtration and drying, 73.0 g of compound (IV) was obtained with a two - step reaction yield of 57.7%. The NMR data of the compound are as follows. 1 HNMR (400 MHz, DMSO - d6) δ 11.27 (s, 1H), 8.16 (s, 1H), 7.78 (td, J = 8.8, 6.7 Hz, 1H), 7.29 (ddd, J = 11.7, 9.3, 2.7 Hz, 1H), 7.23 (d, J = 3.9 Hz, 1H), 7.19 - 7.09 (m, 1H), 3.76 (s, 3H); 13CNMR (101 MHz, DMSO-d6) δ 165.76, 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. The temperature was controlled at -10 to 0 °C, and 142.2 g (0.79 mol, 2.0 eq) of a methanol solution of sodium methoxide (30% sodium methoxide in methanol) was added dropwise to the reaction solution. After the addition was complete, the mixture was kept warm for 0.5 h. 149.4 g (1.18 mol, 3.0 eq) of dimethyl sulfate was added dropwise to the reaction solution. After the addition was complete, the mixture was kept warm for 2 h. After warming, the pH was adjusted to 7 - 8 with concentrated hydrochloric acid. After distilling to a certain volume, water was added, and the mixture was stirred at 20 - 30 °C for 1 h, filtered, and dried to obtain a crude product of compound (V). Isopropanol was added to dissolve it, filtered, distilled to a certain volume, then the temperature was lowered to 0 - 5 °C, kept warm and stirred for 2 h, filtered, and dried to obtain 88 g of compound (V). The reaction yield of the one-step reaction was 83.4%. The NMR data of the compound are as follows. 1 HNMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 7.64 (td, J = 8.7, 6.6 Hz, 1H), 7.41 - 7.31 (m, 2H), 7.23 - 7.13 (m, 1H), 3.72 (d, J = 3.0 Hz, 6H); 13CNMR (101 MHz, DMSO-d6) δ 163.65, 162.86, 162.74, 160.41, 160.29, 160.20, 160.07, 157.72, 157.60, 144.64, 131.34, 131.29, 131.24, 131.19, 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

Chemical formula

[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 addition, the mixture was kept warm for 2 - 3 hours. After the reaction was completed and evaporation, 400 g of tetrahydrofuran was added, stirred well, 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 for quenching, 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, filtered and dried to obtain 78 g of compound (IV). The two-step reaction yield was 61.5%. The NMR data of the compound is as follows: 1 HNMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.16 (s, 1H), 7.78 (td, J = 8.8, 6.7 Hz, 1H), 7.29 (ddd, J = 11.7, 9.3, 2.7 Hz, 1H), 7.23 (d, J = 3.9 Hz, 1H), 7.19 - 7.09 (m, 1H), 3.76 (s, 3H);13 CNMR (101 MHz, DMSO-d6) δ 165.76, 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 at 0 - 10°C. 100.0 g (0.39 mol, 1.0 eq) of compound (IV) was slowly added to the reaction solution. After the addition was completed, the mixture was kept warm for 0.5 h. Next, 64.8 g (0.51 mol, 1.3 eq) of dimethyl sulfate was slowly added dropwise to the reaction solution, and after the addition was completed, the mixture was kept warm for 2 h. After the holding was completed, the pH was adjusted to 7 - 8 with concentrated hydrochloric acid, distilled to a certain amount, water was added, stirred at 20 - 30°C for 1 h, filtered, and dried to obtain a crude product of compound (V). Isopropanol was added to dissolve it, filtered, distilled to a certain amount, then the temperature was lowered to 0 - 5°C, kept warm, stirred for 2 h, filtered, and dried to obtain 86.3 g of compound (V). The reaction yield of one step was 81.8%. The NMR data of the compound is as follows, 1 HNMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 7.64 (td, J = 8.7, 6.6 Hz, 1H), 7.41 - 7.31 (m, 2H), 7.23 - 7.13 (m, 1H), 3.72 (d, J = 3.0 Hz, 1H) J = 3.0 Hz, 6H); 13CNMR (101 MHz, DMSO-d6) δ 163.65, 162.86, 162.74, 160.41, 160.29, 160.20, 160.07, 157.72, 157.60, 144.64, 131.34, 131.29, 131.24, 131.19, 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

Chemical Structure

[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 (0.9 mol, 1.8 eq) of methyl 3-aminopropionate hydrochloride and 200 g of acetonitrile were added, 91.0 g (0.9 mol, 1.8 eq) of triethylamine was added dropwise. After the addition was complete, the mixture was stirred for 0.5 h, filtered, and the filtrate was slowly added dropwise to the reaction solution of compound (II). After the addition was complete, the temperature was maintained for 2 - 3 h. After the reaction was completed, the mixture was evaporated, 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 step of the reaction.

[0057] Under a nitrogen atmosphere, the tetrahydrofuran solution of compound (III) from the previous step was cooled to -80 - 70 °C, and 340 mL of a 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 h. After the reaction was completed, water was added to quench the reaction. After phase separation, the aqueous layer was extracted once with tetrahydrofuran, and the organic phases were combined. After distilling to a certain amount, 200.0 g of petroleum ether was added, cooled to 0 - 10 °C, stirred for 2 h, filtered, and dried to obtain 81.3 g of compound (IV). The reaction yield of the two steps was 64.3%. The NMR data of the compound is as follows: 1 HNMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.16 (s, 1H), 7.78 (td, J = 8.8, 6.7 Hz, 1H), 7.29 (ddd, J = 11.7, 9.3, 2.7 Hz, 1H), 7.23 (d, J = 3.9 Hz, 1H), 7.19 - 7.09 (m, 1H), 3.76 (s, 3H); 13CNMR (101 MHz, DMSO-d6) δ 165.76, 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 at 5 - 10 °C. 100.0 g (0.39 mol, 1.0 eq) of compound (IV) was slowly added to the reaction solution. After the dropping addition was completed, the temperature was maintained for 0.5 h. Next, 149.4 g (1.18 mol, 3.0 eq) of dimethyl sulfate was slowly added dropwise to the reaction solution, and after the dropping was completed, the temperature was kept warm for 2 h. After the heat preservation was completed, the pH was adjusted to 7 - 8 with concentrated hydrochloric acid, distilled to a certain amount, then water was added, stirred at 20 - 30 °C for 1 h, filtered, and dried to obtain a crude product of compound (V). Isopropanol was added to dissolve it, filtered, distilled to a certain amount, then the temperature was lowered to 0 - 5 °C, kept warm, stirred for 2 h, filtered, and dried to obtain 85.6 g of compound (V). The yield of one-step reaction was 81.1%. The NMR data of the compound is as follows, 1 HNMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 7.64 (td, J = 8.7, 6.6 Hz, 1H), 7.41 - 7.31 (m, 2H), 7.23 - 7.13 (m, 1H), 3.72 (d, J = 3.0 Hz, 1H) J = 3.0 Hz, 6H); 13CNMR (101 MHz, DMSO-d6) δ 163.65, 162.86, 162.74, 160.41, 160.29, 160.20, 160.07, 157.72, 157.60, 144.64, 131.34, 131.29, 131.24, 131.19, 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

Chem.

[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-aminopropionate hydrochloride and 1000 g of toluene were added to a reaction vial, and the temperature was raised to 70 - 80 °C. 91.0 g (0.9 mol, 1.8 eq) of triethylamine was slowly added dropwise. After the addition, the mixture was kept warm for 0.5 hour with stirring, then the temperature was raised to 110 - 112 °C, and reflux dehydration was carried out for 2 - 3 hours. After the reaction was completed, the temperature was lowered to 20 - 30 °C, water was added for quenching, and after layering, the organic phase was taken. After evaporation, 400 g of tetrahydrofuran was added to obtain a tetrahydrofuran solution of compound (III), which was directly charged into the next reaction.

[0061] Under a nitrogen atmosphere, the tetrahydrofuran solution of compound (III) from the previous step was cooled to -40 - 20 °C, and 300 mL (0.75 mol, 1.5 eq, specification 2.5 mol / L) of a tetrahydrofuran solution of n-butyllithium was added dropwise. After the addition was completed, the mixture was stirred for 1 hour. After the reaction was completed, water was added for quenching, and after layering, the aqueous layer was extracted with 200 g of tetrahydrofuran, and the organic phases were combined. After distillation to a certain amount, 200 g of petroleum ether was added, and the mixture was cooled to 0 - 10 °C and stirred for 2 hours. By filtration and drying, 70.3 g of compound (IV) was obtained, and the reaction yield in two steps was 55.6%. The NMR data of the compound is as follows. 1 HNMR(400 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.16 (s, 1H), 7.78 (td, J = 8.8, 6.7 Hz, 1H), 7.29 (ddd, J = 11.7, 9.3, 2.7 Hz, 1H), 7.23 (d, J = 3.9 Hz, 1H), 7.19 - 7.09 (m, 1H), 3.76 (s, 3H); 13CNMR (101 MHz, DMSO-d6) δ 165.76, 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 at -10 to 0 °C. 99.6 g (30% sodium methoxide in methanol) of a methanol solution of sodium methoxide was slowly added dropwise to the reaction solution. After the addition was complete, the mixture was kept warm for 0.5 hour. Next, 59.8 g (0.47 mol, 1.2 eq) of dimethyl sulfate was added dropwise to the reaction solution, and after the addition was complete, the mixture was kept warm for 2 hours. After the warming was complete, the pH was adjusted to 7 - 8 with concentrated hydrochloric acid, distilled to a certain volume, water was added, stirred at 20 - 30 °C for 1 hour, filtered, and dried to obtain a crude product of compound (V). Isopropanol was added to dissolve it, filtered, distilled to a certain volume, the temperature was lowered to 0 - 5 °C, kept warm, and stirred for 2 hours. Filtered and dried to obtain 89.5 g of compound (V), and the reaction yield of one step was 84.8%. The NMR data of the compound is as follows: 1 HNMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 7.64 (td, J = 8.7, 6.6 Hz, 1H), 7.41 - 7.31 (m, 2H), 7.23 - 7.13 (m, 1H), 3.72 (d, J = 3.0 Hz, 1H) J = 3.0 Hz, 6H); 13CNMR (101 MHz, DMSO-d6) δ 163.65, 162.86, 162.74, 160.41, 160.29, 160.20, 160.07, 157.72, 157.60, 144.64, 131.34, 131.29, 131.24, 131.19, 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

Chemical formula

[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 completed, it was evaporated, 500 g of methyl tert-butyl ether was added, stirred well, diatomaceous earth was spread and filtered to obtain a methyl tert-butyl ether solution of compound (III), which was directly charged into the reaction of the next step.

[0065] Under a nitrogen atmosphere, the temperature of the methyl tert-butyl ether solution of compound (III) from the previous step was controlled at 15 - 30 °C, and solid sodium hydride was added in batches, with a total of 33.8 g of sodium hydride (0.85 mol, 1.8 eq, specification with a content of 60%). After the addition of the material was completed, the mixture was stirred and reacted for 2 hours. After the reaction was completed, water was added to quench it, and it was layered. The aqueous layer was extracted with methyl tert-butyl ether, and the organic phases were combined. After distilling to a certain amount, 200.0 g of petroleum ether was added, cooled to 0 - 10 °C, stirred for 2 hours, filtered, and dried to obtain 72.8 g of compound (IV). The reaction yield of the two steps was 61.6%. The NMR data of the compound is as follows, 1HNMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.16 (s, 1H), 7.78 (td, J = 8.8, 6.7 Hz, 1H), 7.29 (ddd, J = 11.7, 9.3, 2.7 Hz, 1H), 7.23 (d, J = 3.9 Hz, 1H), 7.19 - 7.09 (m, 1H), 3.76 (s, 3H); 13 CNMR (101 MHz, DMSO-d6) δ 165.76, 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 -10~0 °C, 128.0 g (0.71 mol, 1.8 eq) of a methanol solution of sodium methoxide (sodium methoxide content 30%) was added dropwise to the reaction solution. After the addition was complete, it was held for 0.5 h. 124.6 g (0.99 mol, 2.5 eq) of dimethyl sulfate was added dropwise to the reaction solution. After the addition was complete, it was kept warm for 2 h. After the reaction was completed, the pH was adjusted to 7~8 with concentrated hydrochloric acid, distilled to a certain amount, water was added, and it was stirred at 20~30 °C for 1 h. It was filtered and dried to obtain a crude product of compound (V). Isopropanol was added to dissolve it, filtered, distilled to a certain amount, then the temperature was lowered to 0~5 °C, kept warm, stirred for 2 h, filtered, and dried to obtain 83.7 g of compound (V). The yield of the one-step reaction was 79.3%. The NMR data of the compound is as follows, 1 HNMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 7.64 (td, J = 8.7, 6.6 Hz, 1H), 7.41 - 7.31 (m, 2H), 7.23 - 7.13 (m, 1H), 3.72 (d, J = 3.0 Hz, 1H) J = 3.0 Hz, 6H); 13CNMR (101 MHz, DMSO-d6) δ 163.65, 162.86, 162.74, 160.41, 160.29, 160.20, 160.07, 157.72, 157.60, 144.64, 131.34, 131.29, 131.24, 131.19, 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 are only preferred embodiments of the present invention and are not intended to limit the patent scope of the present invention. All equivalent modifications made using the present invention are within the scope of patent protection of the present invention.

Claims

1. 【Fig. 13】 Step 1): Using m-difluorobenzene (Compound (I)) as the starting material, reacting it with a monoester of oxalyl chloride in a solvent under the catalysis of aluminum trichloride, and adjusting through post-treatment to obtain Compound (II). Step 2): After subjecting Compound (II) to a dehydration reaction with methyl 3-aminopropionate or its salt in a solvent, preparing it through post-treatment to obtain Compound (III). Step 3): Performing an intramolecular ring formation reaction on Compound (III) in a solvent under the action of a base, and adjusting through post-treatment to obtain Compound (IV). Step 4): Reacting Compound (IV) with dimethyl sulfate in a solvent under the action of a base, and preparing it through post-treatment to obtain the product Compound (V). Including the above synthetic steps A method for synthesizing a 4-methoxypyrrole derivative, characterized in that.

2. The method for synthesizing a 4-methoxypyrrole derivative according to Claim 1, characterized in that in Step 2), the solvent is any one or more of tetrahydrofuran, toluene, n-heptane, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, methanol, acetonitrile, 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 its salt 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 any one or more of 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 any one or more of tetrahydrofuran, toluene, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane.

6. The method for synthesizing a 4-methoxypyrrole derivative according to Claim 1, characterized in that in Step 3), the base is any one or more of butyllithium, diisopropylaminolithium, hexamethyldisilanylamolithium, sodium hydride, sodium tert-butoxide, potassium tert-butoxide.

7. The method for synthesizing a 4-methoxypyrrole derivative according to claim 1, characterized in that in step (3), the molar ratio of the 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 any 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 for azeotropic dehydration of the solvent is any one or more of toluene and n-heptane.

10. A 4-methoxypyrrole derivative, characterized in that it is synthesized by the method for synthesizing a 4-methoxypyrrole derivative according to any one of claims 1 to 9.

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