A method for synthesizing 4-methoxypyrrole derivatives

Abstract

This invention provides a method for synthesizing 4-methoxypyrrole derivatives, relating to the field of organic chemical intermediate synthesis technology. The 4-methoxypyrrole derivative is prepared by first reacting m-difluorobenzene as a starting material with oxaloyl chloride monoester under Lewis acid catalysis. The reaction product then undergoes cyclization with aminopropionitrile under alkaline conditions. The subsequent product reacts with methanol in a boron trifluoride complex, followed by methylation with a methylating agent under alkaline conditions. This invention overcomes the shortcomings of existing technologies, providing a simple, low-cost, and easily industrialized method for preparing 4-methoxypyrrole derivatives. It offers advantages such as readily available raw materials, high yield, good quality, simple operation, and suitability for industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic chemical intermediate synthesis technology, specifically to a method for synthesizing a 4-methoxypyrrole derivative. Background Technology

[0002] Korean Patent No. 10-1613245 and World Patent WO2018236153 both report that 4-methoxypyrrole derivatives possess good anti-ulcer activity (i.e., proton pump inhibitory activity, etc.) and disinfectant activity against Helicobacter pylori. Therefore, they can be effectively used to prevent and treat gastrointestinal damage caused by gastrointestinal ulcers, gastritis, reflux esophagitis, or Helicobacter pylori. In other words, 4-methoxypyrrole derivatives currently have wide applications in the field of pharmaceutical synthesis, and their synthetic processes have significant development potential.

[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 WO2018236153 report the synthesis of the target product from 2,4-difluorobenzaldehyde via Strecker, Boc protection, condensation decarboxylation, cyclization, methylation, and deBoc protection reactions. The relevant synthetic route is as follows:

[0005]

[0006] The process is lengthy, has a low yield, involves the highly toxic substance sodium cyanide, and is extremely dangerous. The raw material, 2,4-difluorobenzaldehyde, is also expensive. Furthermore, the process uses large amounts of ammonia and concentrated hydrochloric acid, generating a large amount of high-salt wastewater, resulting in a huge volume of waste and making it unsuitable for industrial production.

[0007] Patent CN109867617 reports the preparation of the target product using 2,4-difluorobenzaldehyde as a raw material through reactions including condensation addition, TosMIC synthesis, and Van leusen pyrrole synthesis. The specific synthetic route is as follows:

[0008]

[0009] This route uses 2,4-difluorobenzaldehyde, which is expensive, and the final product purification is done by column chromatography, making it unsuitable for large-scale industrial production.

[0010] In summary, the existing synthetic routes have the following drawbacks: 1. They require expensive raw materials; 2. They involve long steps, low yields, and low atom economy; 3. They involve dangerous reagents such as highly toxic substances and cause serious environmental pollution, which is not conducive to large-scale industrial production. Summary of the Invention

[0011] To address the shortcomings of existing technologies, this invention provides a method for preparing 4-methoxypyrrole derivatives that is simple to react, low in cost, and easy to industrialize. It has the advantages of readily available raw materials, high yield, good quality, simple operation, and suitability for industrial production.

[0012] To achieve the above objectives, the present invention provides the following technical solution:

[0013] A method for synthesizing a 4-methoxypyrrole derivative, the method comprising the following steps:

[0014] S1. Compound II was prepared by Friedel-Crafts acylation of m-difluorobenzene (designated as compound I) with oxaloyl chloride monoester under Lewis acid catalysis.

[0015] S2. Compound II was cyclized with aminopropionitrile under the action of alkaline reagent I to prepare compound III;

[0016] S3. Compound III was reacted with methanol in the presence of a boron trifluoride complex to obtain compound IV;

[0017] S4. Compound IV was reacted with a methylating agent in the presence of a basic reagent II to prepare compound V, which is a 4-methoxypyrrole derivative. The specific synthetic route is as follows:

[0018]

[0019] Preferably, the chemical structural formula of oxaloyl chloride monoester in step S1 is:

[0020]

[0021] Where R represents an ester formed from a carbon chain with a length of 1 to 20.

[0022] Preferably, the Lewis acid in step S1 is any one or more of aluminum trichloride, ferric trichloride, and boron trifluoride complex.

[0023] Preferably, the alkaline reagent in step S2 is one or more of the following: n-butyllithium, potassium tert-butoxide, sodium tert-butoxide, lithium di(trimethylsilyl)amino, sodium di(trimethylsilyl)amino, potassium di(trimethylsilyl)amino, lithium diisopropylamino, and sodium diisopropylamino.

[0024] Preferably, the molar ratio of compound II, aminopropionitrile, and alkaline reagent in step S2 is 1:1.0 to 5.0:1.0 to 10.0.

[0025] Preferably, in step S3, the molar ratio of compound III, methanol, and boron trifluoride complex is 1:2.0 to 100.0:1.0 to 20.0; and the reaction is carried out under the protection of at least one gas, nitrogen and argon, at a reaction temperature of 0 to 100°C.

[0026] Preferably, the boron trifluoride complex in step S3 is any one or more of boron trifluoride diethyl ether, boron trifluoride dimethyl ether, boron trifluoride acetonitrile, boron trifluoride methanol, boron trifluoride acetic acid, boron trifluoride tetrahydrofuran, boron trifluoride anisole, and boron trifluoride phenol.

[0027] Preferably, the methylating agent in step S4 is selected from at least one of iodomethane, dimethyl sulfate, and (trimethylsilyl)diazomethane.

[0028] Preferably, in step S4, the molar ratio of compound IV, methylating agent, and basic reagent II is 1:1.0 to 5.0:1.0 to 10.0; and the reaction temperature is -40 to 100°C.

[0029] Preferably, the alkaline reagent 2 in step S4 is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N-methylmorpholine, tetramethylethylenediamine, and pyridine.

[0030] This invention provides a method for synthesizing 4-methoxypyrrole derivatives, which has the following advantages compared with the prior art:

[0031] The route of this invention is relatively simple, and the raw materials used are all commercially available materials. The raw materials are relatively cheap and safe and controllable. There are no complicated special operation steps, which is suitable for industrial production. It provides a new synthetic scheme for the synthesis and preparation of 4-methoxypyrrole derivatives. Detailed Implementation

[0032] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0033] Example 1:

[0034] The synthetic route for 4-methoxypyrrole derivatives is as follows:

[0035]

[0036] The specific synthesis method is as follows:

[0037] (1) Under nitrogen protection, 50.0 g (0.44 mol, 1.0 equiv.) of compound I (m-difluorobenzene), 70.7 g (0.53 mol, 1.2 equiv.) of aluminum trichloride and 100.0 g (2.0 w / w) of dichloromethane were added to the reaction flask. The temperature was controlled at 8℃. 75.6 g (0.62 mol, 1.4 equiv.) of monomethyl oxalate was slowly added dropwise to the reaction flask. After the addition was completed, the temperature was kept at 8℃ for 3 h.

[0038] After the incubation period, the reaction solution was slowly added dropwise to 200.0 g of ice water to quench the reaction, resulting in two layers. The aqueous layer was extracted with 100.0 g of dichloromethane, and the organic phases were combined and washed with 200.0 g of water. The organic phase was then collected and distilled to give compound II-1 in 68.3% yield. The NMR data of the compound are as follows: 1 H NMR (600MHz, DMSO-d6) δ7.99-7.93(m,1H),7.44-7.39(m,1H),7.28-7.23(m,1H),3.88(s,3H); 13 C NMR (600MHz, DMSO-d6) δ182.6,168.4,168.3,165.8,165.7,164.6,164.5,164.0,162.0,161.9,133.74,133.72 ,133.63,133.61,118.39,118.35,118.29,118.25,113.71,113.68,113.49,113.46,106.1,105.8,105.5,53.5.

[0039] (2) 17.5 g (0.25 mol, 1.0 equiv.) of 3-aminopropionitrile and 150.0 g (3.0 w / w) of tetrahydrofuran were purged with nitrogen three times. The reaction flask was placed in a cold trap and cooled to -78 °C. 45.8 g (0.25 mol, 1.0 equiv.) of sodium di(trimethylsilyl)aminoacetate was slowly added dropwise, and the mixture was kept at this temperature and stirred for 1 h. The internal temperature was controlled below -70 °C, and 50.0 g (1.0 w / w) of a tetrahydrofuran solution of 150.0 g (0.25 mol, 1.0 equiv.) of the above compound II was added dropwise, and the reaction mixture was kept at this temperature for 2 h. At -78 °C, the reaction mixture was added dropwise in three batches to an AcOH-MeOH solution, and the internal temperature was controlled at -30 °C, and the mixture was stirred overnight. The solid was filtered through a Buchner funnel under vacuum, washed with toluene (200 mL × 2), and dried under vacuum at 50 °C for 16 h to obtain compound III, which was then added to the next reaction step.

[0040] (3) Under nitrogen protection, 50.0 g (0.23 mol, 1.0 equiv.) of compound III, 73.7 g (2.30 mol, 10.0 equiv.) of methanol, and 128.9 g (0.91 mol, 4.0 equiv.) of boron trifluoride diethyl ether were added to a reaction flask. The mixture was stirred and heated to 65 °C, and the reaction was maintained at this temperature with stirring for 72 h. After the reaction was completed, the temperature was lowered to 25 °C, and 250.0 g of water was added dropwise to quench the reaction mixture. The mixture was filtered, and the filter cake was rinsed with 50.0 g of water. After drying the filter cake, 40.5 g of compound IV was obtained, with a yield of 70.0%.

[0041] The NMR data for compound IV are as follows: 1 H NMR (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); 13 C NMR(101MHz,DMSO-d6)δ163.65,162.86,162.74,160.41,160.29,160.20,160.07,157.72,157.60,144.64,131.34,131.29,131.24,131 .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.

[0042] (4) Under a nitrogen atmosphere, 40.0 g (0.16 mol, 1.0 equiv.) of compound IV and 500 g of anhydrous methanol were added to a reaction flask. The temperature was controlled at -5℃. 56.9 g (0.32 mol, 2.0 equiv.) of a methanol solution of sodium methoxide (sodium methoxide content 30%) was slowly added dropwise to the reaction solution. After the addition was complete, the temperature was maintained for 0.5 h. Then, 59.8 g (0.47 mol, 3.0 equiv.) of dimethyl sulfate was slowly added dropwise to the reaction solution. After the addition was complete, the temperature was maintained for 2 h. After the temperature was maintained, the pH was adjusted to 7-8 with concentrated hydrochloric acid. After distillation to a certain volume, water was added and stirred at 25℃ for 1 h. The mixture was filtered and dried to obtain crude compound V. Isopropanol was added to dissolve the crude compound V. After filtration and distillation to a certain volume, the temperature was lowered to 0℃ and stirred for 2 h. After filtration and drying, 88 g of compound V was obtained. The single-step reaction yield was 83.4%.

[0043] The NMR data for compound V are as follows: 1H NMR (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); 13 C NMR(101MHz,DMSO-d6)δ163.65,162.86,162.74,160.41,160.29,160.20,160.07,157.72,157.60,144.64,131.34,131.29,131.24,131 .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.

[0044] Example 2:

[0045] The synthetic route for 4-methoxypyrrole derivatives is as follows:

[0046]

[0047] The specific synthesis method is as follows:

[0048] (1) Under nitrogen protection, 50.0 g (0.44 mol, 1.0 equiv.) of compound I (m-difluorobenzene), 70.7 g (0.53 mol, 1.2 equiv.) of aluminum trichloride, and 100.0 g (2 w / w) of dichloromethane were added to a reaction flask. The temperature was controlled at 12 °C. 95.2 g (0.69 mol, 1.6 equiv.) of monoethyl oxalate was slowly added dropwise to the reaction flask. After the addition was complete, the mixture was kept at this temperature for 3 h. After the temperature was complete, the reaction solution was slowly added dropwise to 200.0 g of ice water to quench the reaction and separate the layers. The aqueous layer was extracted with 100.0 g of dichloromethane, and the organic phases were combined and washed with 200.0 g of water. The organic phase was collected and distilled to obtain compound II-2.

[0049] (2) 3-Aminopropionitrile (0.66 mol, 1.5 equiv.) and tetrahydrofuran (3.0 w / w) were purged with nitrogen three times. The reaction flask was placed in a cold trap and cooled to -70 °C. Sodium di(trimethylsilyl)aminoacetate (0.66 mol, 1.5 equiv.) was slowly added dropwise, and the mixture was stirred at this temperature for 1 h. The internal temperature was maintained below -70 °C, and a tetrahydrofuran solution (1.0 w / w) of compound II-2 (0.44 mol, 1.0 equiv.) was added dropwise, and the reaction was maintained at this temperature for 2 h. At -70 °C, the reaction mixture was added dropwise in three batches to an AcOH-MeOH solution, and the internal temperature was maintained at -25 °C, with stirring overnight. The solid was filtered through a Buchner funnel under vacuum and washed with toluene (200 mL × 2) to obtain compound III.

[0050] (3) Under nitrogen protection, compound III (0.44 mol, 1.0 equiv.), methanol (417.6 g, 13.20 mol, 30.0 equiv.), and boron trifluoride diethyl ether (246.6 g, 1.76 mol, 4.0 equiv.) were added to the reaction flask. The mixture was stirred and heated to 63 °C, and maintained at 63 °C with stirring for 96 h. After the reaction was complete, the temperature was lowered to 20 °C, and 500.0 g of water was added dropwise to quench the reaction mixture. The mixture was filtered, and the filter cake was rinsed with 50.0 g of water. After drying the filter cake, 75.9 g of compound IV was obtained, with a yield of 68.2%. The NMR data of compound IV are as follows: 1 H NMR (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); 13 C NMR(101MHz,DMSO-d6)δ163.65,162.86,162.74,160.41,160.29,160.20,160.07,157.72,157.60,144.64,131.34,131.29,131.24,131 .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] (4) Under a nitrogen atmosphere, 18.0 g (0.45 mol, 1.5 equiv.) of sodium hydroxide and 400 g of 1,4-dioxane were added to a reaction flask. The temperature was controlled at 5 °C. 75.0 g (0.30 mol, 1.0 equiv.) of compound IV was slowly added to the reaction solution. After the addition was complete, the temperature was maintained for 0.5 h. Then, 49.5 g (0.39 mol, 1.3 equiv.) of dimethyl sulfate was slowly added dropwise to the reaction solution. After the addition was complete, the temperature was maintained for 2 h. After the temperature was maintained, the pH was adjusted to 7-8 with concentrated hydrochloric acid. After distillation to a certain volume, water was added and stirred at 20 °C for 1 h. The mixture was filtered and dried to obtain crude compound (V). Isopropanol was added to dissolve the crude compound (V). After filtration and distillation to a certain volume, the temperature was lowered to 2 °C and stirred for 2 h. After filtration and drying, 86.3 g of compound (V) was obtained. The single-step reaction yield was 81.8%. The NMR data of the compound are as follows: 1 H NMR (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); 13 C NMR(101MHz,DMSO-d6)δ163.65,162.86,162.74,160.41,160.29,160.20,160.07,157.72,157.60,144.64,131.34,131.29,131.24,131 .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.

[0052] Example 3:

[0053] The synthetic route for 4-methoxypyrrole derivatives is as follows:

[0054]

[0055] The specific synthesis method is as follows:

[0056] (1) Under nitrogen protection, 50.0 g of compound I (m-difluorobenzene) (0.44 mol, 1.0 equiv.), 70.7 g of aluminum trichloride (0.53 mol, 1.2 equiv.), and 100 mL of dichloromethane (2 w / w) were added to the reaction flask. The temperature was controlled at 10 °C. 64.6 g of monomethyl oxalate (0.53 mol, 1.2 equiv.) was slowly added dropwise to the reaction flask. After the addition was complete, the mixture was kept at this temperature for 3 h. After the temperature was complete, the reaction solution was slowly added dropwise to 200.0 g of ice water to quench the reaction and separate the layers. The aqueous layer was extracted with 100.0 g of dichloromethane. The organic phases were combined and then washed with 200.0 g of water to obtain a mixed solution of compound II-1 and dichloromethane. After distillation, compound II-1 was obtained and added to the next reaction step.

[0057] (2) 3-Aminopropionitrile (0.66 mol, 1.5 equiv.) and tetrahydrofuran (3.0 w / w) were purged with nitrogen three times. The reaction flask was placed in a cold trap and cooled to -80 °C. Sodium di(trimethylsilyl)aminoacetate (0.53 mol, 1.2 equiv.) was slowly added dropwise, and the mixture was stirred for 1 h. The internal temperature was controlled below -70 °C, and a tetrahydrofuran solution (1.0 w / w) of compound II-1 from step one was added dropwise, and the reaction was maintained for 2 h. At -80 °C, the reaction mixture was added dropwise in three batches to an AcOH-MeOH solution, and the internal temperature was controlled at -30 °C, with stirring overnight. The solid was filtered through a Buchner funnel under vacuum, washed with toluene (200 mL × 2), and dried under vacuum at 50 °C for 16 h to obtain 49.7 g of compound III. The two-step yield was 51.3%. The NMR data of the compound are as follows: 1 H NMR (600MHz, DMSO-d6) δ11.42(s,1H),9.19(s,1H),7.72-7.65(m,1H),7.37(d,J=5.40,1H),7.27-7.21(m,1H),7.12-7.07(m,1H); 13 C NMR(600MHz,DMSO-d6)δ162.5,162.4,160.05,159.95,159.92,159.8,157.5,157.4,142.9,130.95,130.90,130.86, 130.80,124.1,116.4,116.0,115.90,115.87,112.11,112.08,111.90,111.87,109.9,104.9,104.7,104.4,85.5ppm.

[0058] (3) Under nitrogen protection, add the compound from the previous step to the reaction flask.

[0059] Compound III (30.0 g, 0.14 mol, 1.0 eq) was reacted with 131.0 g of methanol (4.08 mol, 30.0 equiv.) and 204.8 g of boron trifluoride acetic acid (1.09 mol, 8.0 eq). The mixture was stirred and heated to 72 °C, and maintained at 72 °C with stirring for 60 h. After the reaction was complete, the reaction solution was distilled under reduced pressure to 75.3 g. The concentrate was cooled to 20 °C and quenched dropwise with 300.0 g of water. The solution was filtered, and the filter cake was washed with 30.0 g of water. After drying the filter cake, 25.6 g of compound IV was obtained, with a yield of 73.3%. The NMR data of compound IV are as follows: 1 H NMR (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); 13 C NMR(101MHz,DMSO-d6)δ163.65,162.86,162.74,160.41,160.29,160.20,160.07,157.72,157.60,144.64,131.34,131.29,131.24,131 .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.

[0060] (4) Under a nitrogen atmosphere, 4.0 g (0.10 mol, 1.0 eq) of sodium hydroxide and 150 g of anhydrous methanol were added to a reaction flask. The temperature was controlled at 5–10 °C. 25.0 g of compound IV (0.10 mol, 1.0 eq) was slowly added to the reaction solution. After the addition was complete, the temperature was maintained for 0.5 h. Then, 14.2 g (0.10 mol, 1.0 eq) of iodomethane was slowly added dropwise to the reaction solution. After the addition was complete, the temperature was maintained for 2 h. After the temperature was maintained, the pH was adjusted to 7–8 with concentrated hydrochloric acid. After distillation to a certain volume, water was added and stirred at 25 °C for 1 h. The mixture was filtered and dried to obtain crude compound V. Isopropanol was added to dissolve the crude compound V. After filtration and distillation to a certain volume, the temperature was lowered to 0 °C and stirred for 2 h. After filtration and drying, 85.6 g of compound V was obtained, with a single-step reaction yield of 81.1%. The NMR data of the compound are as follows: 1 H NMR (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);13 C NMR (101MHz, DMSO-d6) δ163.65,162.86,162.74,160.41,160.29,160.20,160.07,157.72,157.60,144.64,131.34,131.29,131.24,131. 19,123.46,115.91,115.88,115.77,115.73,114.49,112.36,112.33,112.15,112.11,107.41,105.09,104.83,104.57,62.04,51.03ppm.

[0061] Example 4:

[0062] The synthetic route for 4-methoxypyrrole derivatives is as follows:

[0063]

[0064] The specific synthesis method is as follows:

[0065] (1) Under nitrogen protection, 100.0 g of compound I (0.88 mol, 1.0 equiv.), 164.0 g of aluminum trichloride (1.23 mol, 1.4 equiv.), and 200.0 g of dichloromethane (2 w / w) were added to a reaction flask. The temperature was controlled at 15 °C. 107.3 g of monomethyl oxalate (0.88 mol, 1.0 equiv.) was slowly added dropwise to the reaction flask. After the addition was complete, the mixture was kept at this temperature for 4 h. After the temperature was complete, the reaction solution was slowly added dropwise to 400.0 g of ice water to quench the reaction and separate the layers. The aqueous layer was extracted with 200.0 g of dichloromethane, and the organic phases were combined and washed with 300.0 g of water. The organic phase was taken and distilled to obtain compound II-1.

[0066] (2) 3-Aminopropionitrile (1.76 mol, 2.0 equiv.) and tetrahydrofuran (3.0 w / w) were purged with nitrogen three times. The reaction flask was placed in a cold trap and cooled to -80 °C. Sodium di(trimethylsilyl)aminoacetate (1.76 mol, 2.0 equiv.) was slowly added dropwise, and the mixture was stirred at this temperature for 1 h. The internal temperature was controlled below -70 °C, and a tetrahydrofuran solution (1.5 w / w) of compound II-1 from step one was added dropwise, and the reaction was maintained at this temperature for 2 h. At -80 °C, the reaction mixture was added dropwise in three batches to an AcOH-MeOH solution, and the internal temperature was controlled at -20 °C, and the mixture was stirred overnight. The solid was filtered through a Buchner funnel under vacuum and washed with toluene (300 mL × 2) to obtain compound (III).

[0067] (3) Under nitrogen protection, 0.88 mol (1.0 equiv.) of the previous batch of compound (III), 845.9 g (26.4 mol, 30.0 equiv.) of methanol, and 694.2 g (5.28 mol, 6.0 equiv.) of boron trifluoride methanol complex were added to the reaction flask. The mixture was stirred and heated to 70 °C, and the reaction was maintained at 70 °C with stirring for 64 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to 88.6 g. The concentrate was cooled to 20–30 °C and quenched dropwise with 1800.0 g of water. The solution was filtered, and the filter cake was washed with 180.0 g of water. After drying the filter cake, 128.2 g of compound IV was obtained, with a three-step yield of 57.6%. The NMR data of compound IV are as follows: 1 H NMR (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); 13 C NMR(101MHz,DMSO-d6)δ163.65,162.86,162.74,160.41,160.29,160.20,160.07,157.72,157.60,144.64,131.34,131.29,131.24,131 .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.

[0068] (4) Under a nitrogen atmosphere, 100.0 g (0.39 mol, 1.0 equiv.) of compound IV and 500 g of anhydrous methanol were added to a reaction flask. The temperature was controlled at -5℃. 128.0 g (0.71 mol, 1.8 equiv.) of a methanol solution of sodium methoxide (sodium methoxide content 30%) was slowly added dropwise to the reaction solution. After the addition was complete, the temperature was maintained for 0.5 h. Then, 124.6 g (0.99 mol, 2.5 equiv.) of dimethyl sulfate was slowly added dropwise to the reaction solution. After the addition was complete, the temperature was maintained for 2 h. After the temperature was maintained, the pH was adjusted to 7-8 with concentrated hydrochloric acid. After distillation to a certain volume, water was added and stirred at 26℃ for 1 h. The mixture was filtered and dried to obtain crude compound V. Isopropanol was added to dissolve the crude compound V. After filtration and distillation to a certain volume, the temperature was lowered to 2℃ and stirred for 2 h. After filtration and drying, 83.7 g of compound V was obtained, with a single-step reaction yield of 79.3%. The NMR data of the compound are as follows: 1H NMR (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); 13 C NMR(101MHz,DMSO-d6)δ163.65,162.86,162.74,160.41,160.29,160.20,160.07,157.72,157.60,144.64,131.34,131.29,131.24,131 .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.

[0069] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing a 4-methoxypyrrole derivative, characterized in that: The synthesis method includes the following steps: S1. Compound II was prepared by Friedel-Crafts acylation of m-difluorobenzene with oxaloyl chloride monoester under Lewis acid catalysis. S2. Compound II was cyclized with aminopropionitrile under the action of alkaline reagent I to prepare compound III; S3. Compound III was reacted with methanol in the presence of a boron trifluoride complex to obtain compound IV; S4. Compound IV was prepared by reacting it with a methylating agent under the action of a basic reagent II to obtain compound V, which is a 4-methoxypyrrole derivative.

2. The synthesis method according to claim 1, characterized in that: The chemical structural formula of oxaloyl chloride monoester in step S1 is: Where R represents an ester formed from a carbon chain with a length of 1 to 20.

3. The synthesis method according to claim 1, characterized in that: In step S1, the Lewis acid is any one or more of aluminum trichloride, ferric trichloride, and boron trifluoride complex.

4. The synthesis method according to claim 1, characterized in that: In step S2, the alkaline reagent is one or more of the following: n-butyllithium, potassium tert-butoxide, sodium tert-butoxide, lithium di(trimethylsilyl)amino, sodium di(trimethylsilyl)amino, potassium di(trimethylsilyl)amino, lithium diisopropylamino, and sodium diisopropylamino.

5. The synthesis method according to claim 1, characterized in that: In step S2, the molar ratio of compound II, aminopropionitrile, and alkaline reagent is 1:1.0 to 5.0:1.0 to 10.

0.

6. The synthesis method according to claim 1, characterized in that: In step S3, the molar ratio of compound III, methanol, and boron trifluoride complex is 1:2.0 to 100.0:1.0 to 20.0; and the reaction is carried out under the protection of at least one gas, nitrogen and argon, at a reaction temperature of 0 to 100°C.

7. The synthesis method according to claim 1, characterized in that: In step S3, the boron trifluoride complex is any one or more of boron trifluoride diethyl ether, boron trifluoride dimethyl ether, boron trifluoride acetonitrile, boron trifluoride methanol, boron trifluoride acetic acid, boron trifluoride tetrahydrofuran, boron trifluoride anisole, and boron trifluoride phenol.

8. The synthesis method according to claim 1, characterized in that: In step S4, the methylating agent is selected from at least one of iodomethane, dimethyl sulfate, and (trimethylsilyl)diazomethane.

9. The synthesis method according to claim 1, characterized in that: In step S4, the molar ratio of compound IV, methylating agent, and basic reagent II is 1:1.0 to 5.0:1.0 to 10.0; and the reaction temperature is -40 to 100°C.

10. The synthesis method according to claim 1, characterized in that: In step S4, the alkaline reagent 2 is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N-methylmorpholine, tetramethylethylenediamine, and pyridine.

Images