Preparation method of 5-(2, 6-dimethoxybenzene)-1-(4-iodine-2-isopropyl benzene)-3-(carboxylic acid methyl ester) pyrrole
5-(2,6-dimethoxybenzene)-1-(4-iodo-2-isopropylbenzene)-3-(methyl carboxylate)pyrrole was prepared by addition reaction of methyl propargylate with phenol, halogenation reaction, deacetylation reaction, Sonogashira coupling reaction and cyclization reaction. This method solves the problems of complex synthetic routes and low yield of pyrrole derivatives in the prior art and achieves the preparation of the target product in high yield.
Patent Information
- Application Number
- CN202511050798.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-29
- Publication Date
- 2025-11-18
AI Technical Summary
In the existing technology, the synthetic routes of pyrrole derivatives are complex and the yield is low, making it difficult to prepare products with a single target configuration.
Using methyl propargyl ester as the starting material, 5-(2,6-dimethoxybenzene)-1-(4-iodo-2-isopropylbenzene)-3-(methyl carboxylate)pyrrole was prepared through addition with phenol, halogenation, deacetylation, Sonogashira coupling, substitution, and cyclization. The process is simple, using readily available raw materials and mild conditions.
The method achieves high yield of the target product, is simple to operate, operates under mild conditions, and is suitable for industrial production.
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Figure CN120965550A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, and in particular to a method for preparing 5-(2,6-dimethoxybenzene)-1-(4-iodo-2-isopropylbenzene)-3-(methyl carboxylate)pyrrole. Background Technology
[0002] Pyrrole rings and their derivatives have extremely wide applications in many fields such as pharmaceuticals, pesticides, fragrances, polymer materials and organic functional materials. They are key intermediates for many drugs, pesticides and organic functional materials and have important research and application value.
[0003] In the pharmaceutical field, pyrrole rings and their derivatives are raw materials for the synthesis of various drugs. For example, cyclopyrrole ketones have significant hypnotic and anti-anxiety effects, providing an effective means of treating related diseases. In the pesticide field, pyrrole derivatives can be used as highly effective insecticides with a broad insecticidal spectrum, showing good control effects against a variety of pests. Furthermore, pyrrole and its derivatives also play an important role in the fragrance industry, polymer materials, and organic functional materials, and their research and application in these fields are constantly expanding, demonstrating enormous development potential. For example, 2,4-dimethylpyrrole and its derivatives are important synthetic intermediates for many drugs and organic functional materials. Pyrrole derivatives can also be used as rubber vulcanization accelerators and epoxy resin curing agents; certain pyrrole-containing metal complexes can be used as catalysts in olefin polymerization reactions.
[0004] Due to their unique structure and excellent properties, pyrrole rings have broad application prospects in many fields, and their application scope continues to expand with ongoing research. Developing synthetic routes for pyrrole derivatives with unique structures will help further expand their application areas and promote the development of related industries. Summary of the Invention
[0005] To address the shortcomings of existing technologies, this invention provides a method for preparing 5-(2,6-dimethoxybenzene)-1-(4-iodo-2-isopropylbenzene)-3-(methyl carboxylate)pyrrole. The method of this invention uses readily available raw materials, is simple to operate, has a high yield, and can produce a product with a single desired configuration.
[0006] The technical solution of the present invention is as follows:
[0007] A method for preparing 5-(2,6-dimethoxybenzene)-1-(4-iodo-2-isopropylbenzene)-3-(methyl carboxylate)pyrrole, wherein the preparation method is carried out according to the following process:
[0008]
[0009] Includes the following steps:
[0010] (1) Compound 1 was dissolved in water and reacted with phenol in the presence of potassium carbonate to prepare compound 2.
[0011] (2) Compound 2 was dissolved in solvent I and subjected to a halogenation reaction with a halogenating agent to obtain compound 3;
[0012] (3) Compound 3 was dissolved in solvent II, and a basic reagent was added to carry out a deacetylation reaction to obtain compound 4;
[0013] (4) Compound 4 was dissolved in solvent III, N,N-diisopropylethylamine was added, and 2,6-dimethoxyphenylacetylene was coupled with 2,6-dimethoxyphenylacetylene via Sonogashira coupling reaction under the action of palladium and copper catalysts to obtain compound 5.
[0014] (5) Compound 5 was dissolved in solvent IV and substituted with 4-iodo-2-isopropylaniline under the catalysis of potassium tert-butoxide to obtain compound 6;
[0015] (6) Compound 6 was dissolved in solvent V and subjected to a ring-closing reaction to obtain 5-(2,6-dimethoxybenzene)-1-(4-iodo-2-isopropylbenzene)-3-(methyl carboxylate)pyrrole.
[0016] Further, in step (1), the concentration of compound 1 in water is 0.25-0.56 g / mL; the molar ratio of compound 1 to potassium carbonate is 1:1-1.1; the molar ratio of compound 1 to phenol is 1:1; the addition reaction is carried out at room temperature for 18 hours.
[0017] Further, in step (2), solvent I is a mixed solution of dichloromethane and acetic acid, and the volume ratio of dichloromethane to acetic acid is 7 to 13:1; the concentration of compound 2 in solvent I is 0.05 to 0.09 g / mL.
[0018] Further, in step (2), the halogenating agent is N-iodosuccinimide; the molar ratio of compound 2 to the halogenating agent is 1:3; the halogenation reaction is carried out at room temperature for 18 hours.
[0019] Further, in step (3), the solvent II is acetonitrile; the concentration of compound 3 in solvent II is 0.07-0.2 g / mL; the alkaline reagent is potassium carbonate; the molar ratio of compound 3 to alkaline reagent is 1:3; the deacetylation reaction temperature is room temperature and the time is 3 h.
[0020] Further, in step (4), solvent III is tetrahydrofuran; the concentration of compound 4 in solvent III is 0.04–0.17 g / mL; the molar ratio of compound 4 to 2,6-dimethoxyphenylacetylene is 1:1.1; the molar ratio of compound 4 to N,N-diisopropylethylamine is 1:1.5–1.6; the palladium catalyst is Pd(dppf)Cl2; the copper catalyst is CuI; and the Sonogashira coupling reaction is carried out at 80 °C for 18 h.
[0021] Furthermore, the molar ratio of compound 4 to palladium catalyst is 7-7.7:1; the molar ratio of compound 4 to copper catalyst is 1:0.4.
[0022] Further, in step (5), the solvent IV is N,N-dimethylformamide; the concentration of compound 5 in solvent IV is 0.01 g / mL; the molar ratio of compound 5 to 4-iodo-2-isopropylaniline is 1:1; the molar ratio of compound 5 to potassium tert-butoxide is 1:0.4 to 1.2; the substitution reaction is carried out at room temperature for 1 h.
[0023] Further, in step (6), the solvent V is N,N-dimethylformamide; the concentration of compound 6 in solvent V is 0.05 to 0.1 g / mL.
[0024] Further, in step (6), the catalyst for the ring-closing reaction is cesium carbonate and cuprous iodide; the molar ratio of compound 6 to cesium carbonate is 1:1.8-2; the molar ratio of compound 6 to cuprous iodide is 1:0.1; the temperature of the ring-closing reaction is 80°C and the time is 3h.
[0025] The beneficial technical effects of this invention are as follows:
[0026] This invention uses methyl propargyl ester as the starting material to react with phenol to obtain methyl 3-phenoxyacrylate. After halogenation, deacetylation, Sonogashira coupling, substitution, and cyclization, the target product is obtained. The entire preparation process is carried out under mild conditions, with readily available raw materials, simple operation, and high yield, and can prepare a single-configuration product. Attached Figure Description
[0027] Figure 1 The 1H NMR spectrum of 5-(2,6-dimethoxybenzene)-1-(4-iodo-2-isopropylbenzene)-3-(methyl carboxylate)pyrrole prepared in Example 1 of this invention. Detailed Implementation
[0028] The present invention will now be described in detail with reference to the accompanying drawings and embodiments.
[0029] Example 1
[0030] A method for preparing 5-(2,6-dimethoxybenzene)-1-(4-iodo-2-isopropylbenzene)-3-(methyl carboxylate)pyrrole includes the following steps:
[0031] (1) Methyl propargyl ester (1.12 g, 0.0133 mol) was dissolved in water (2 mL), and phenol (1.25 g, 0.0133 mol) and potassium carbonate (2.02 g, 0.0146 mol) were added. The mixture was reacted overnight at room temperature. TLC was used to detect the disappearance of the starting material. The system was then added to water (20 mL), and ethyl acetate was added for extraction (30 mL × 3). The organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. The crude product was purified by column chromatography (PE:EA = 10:1) to give methyl 3-phenoxyacrylate (compound 2, 0.5 g, purity 95%, yield 21%), which was a colorless oil.
[0032] (2) Compound 2 (0.45 g, 0.0025 mol) was added to anhydrous DCM / AcOH (7 mL / 1 mL), and NIS (1.7 g, 0.0075 mol) was added. The mixture was reacted overnight at room temperature. TLC was used to detect the disappearance of the starting material. The reaction was quenched with triethylamine (5 mL) and stirred at room temperature for 2 h. The system was added to water (20 mL), and extracted with ethyl acetate (20 mL × 3). The organic phase was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (PE:EA = 10:1) to give methyl 3-acetoxy-2-iodo-3-phenoxypropionate (compound 3, 0.4 g, purity 96%, yield 43%), which was a yellow oil.
[0033] (3) Compound 3 (0.38 g, 0.001 mol) was added to acetonitrile (5 mL), and potassium carbonate (0.43 g, 0.003 mol) was added. The mixture was reacted at room temperature for 3 h. TLC was used to detect the disappearance of the starting material. The reaction solution was filtered, and the filter cake was washed with ethyl acetate. The filtrate was collected, dried with anhydrous sodium sulfate to remove water, and then filtered. The filtrate was concentrated to obtain the product methyl 2-iodo-3-phenoxyacrylate (compound 4, 0.3 g, purity 95%, yield 94.6%), which was a yellow oily substance.
[0034] (4) Compound 4 (0.23 g, 0.756 mmol) and 2,6-dimethoxyphenylacetylene (0.135 g, 0.832 mmol) were dissolved in THF (5 mL), and DIEA (0.15 g, 1.16 mmol) was added. After purging with nitrogen, Pd(dppf)Cl2 (71 mg, 0.098 mmol) and CuI (57 mg, 0.299 mmol) were added. The mixture was heated to 80 °C and reacted overnight under a nitrogen atmosphere. The system was added to water (20 mL), and extracted with ethyl acetate (20 mL × 3). The organic phase was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (PE:EA = 10:1-5:1) to give methyl 4-(2,6-dimethoxyphenyl)-2-phenoxymethylenebut-3-acetylic acid (compound 5, 0.2 g, purity 97%, yield 78%), as a yellow solid.
[0035] (5) Compound 5 (0.1 g, 0.295 mmol) and 4-iodo-2-isopropylaniline (77 mg, 0.295 mmol) were dissolved in DMF (10 mL), and potassium tert-butoxide (39.8 mg, 0.35 mmol) was added. The reaction was carried out at room temperature for 1 h. The system was added to water (30 mL), and extracted with ethyl acetate (30 mL × 3). The organic phase was collected, washed with water (20 mL × 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate to remove water, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (PE:EA = 5:1) to give methyl 4-(2,6-dimethoxy-phenyl)-2-((4-iodo-2-isopropyl-phenylamino)-methylene)-but-3-acetylginate (compound 6, 0.1 g, purity 96%, yield 67%), which was a yellow solid.
[0036] (6) Compound 6 (0.1 g, 0.2 mmol) was dissolved in DMF (2 mL), and cesium carbonate (0.12 g, 0.368 mmol) and CuI (4 mg, 0.02 mmol) were added under a nitrogen atmosphere. The nitrogen atmosphere was replaced, and the mixture was heated to 80 °C and reacted for 3 h. The system was added to water (10 mL), and extracted with ethyl acetate (20 mL × 3). The organic phase was collected, washed with water (30 mL × 3), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate to remove water, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (PE:EA = 10:1-2:1) to give 5-(2,6-dimethoxybenzene)-1-(4-iodo-2-isopropylbenzene)-3-(methyl carboxylate)pyrrole (35 mg, purity 95%, yield 35%), which was a white solid.
[0037] The NMR spectrum of the product is as follows Figure 1 As shown, where, 1H NMR (400MHz, DMSO-d6) δ7.57–7.51(m,2H),7.46(d,J=1.8Hz,1H),7.21(t,J=8.4Hz,1H),6.99(d,J=8.2Hz,1H),6.60(s,1H),6.48(s ,1H),6.40(d,J=1.9Hz,1H),3.73(s,3H),3.66(s,3H),3.49(s,3H),2.57–2.53(m,1H),0.97(d,J=6.9Hz,3H),0.76(d,J=6.8Hz,3H).
[0038] Example 2
[0039] A method for preparing 5-(2,6-dimethoxybenzene)-1-(4-iodo-2-isopropylbenzene)-3-(methyl carboxylate)pyrrole, the method comprising the following steps:
[0040] (1) Methyl propargyl ester (2.5 g, 29.74 mmol) was dissolved in water (10 mL), and phenol (2.8 g, 29.74 mmol) and potassium carbonate (4.5 g, 32.56 mmol) were added. The mixture was reacted overnight at room temperature. TLC was used to detect the disappearance of the starting material. The system was then added to water (100 mL), and ethyl acetate was added for extraction (100 mL × 3). The organic phases were combined and washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. The crude product was purified by column chromatography (PE:EA = 10:1) to give methyl 3-phenoxyacrylate (2, 1.5 g, purity 96%, yield 28%), a colorless oil.
[0041] (2) Compound 2 (1.5 g, 8.42 mmol) was added to anhydrous DCM / AcOH (15 mL / 1.5 mL), and NIS (5.7 g, 25.34 mmol) was added. The reaction was allowed to proceed overnight at room temperature. TLC was used to detect the disappearance of the starting material. The reaction was quenched with triethylamine (15 mL) and stirred at room temperature for 2 h. The system was added to water (100 mL), and extracted with ethyl acetate (50 mL × 3). The organic phase was collected, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (PE:EA = 10:1) to give methyl 3-acetoxy-2-iodo-3-phenoxypropionate (compound 3, 1.3 g, purity 97%, yield 42%), which was a yellow oil.
[0042] (3) Compound 3 (1 g, 2.747 mmol) was added to acetonitrile (5 mL), and potassium carbonate (1.1 g, 7.96 mmol) was added. The reaction was carried out at room temperature for 3 h. The reaction solution was filtered until the starting material disappeared. The filter cake was washed with ethyl acetate and the filtrate was collected. After drying with anhydrous sodium sulfate, the filtrate was filtered and concentrated to obtain the product methyl 2-iodo-3-phenoxyacrylate (compound 4, 0.8 g, purity 97%, yield 95%), which was a yellow oil.
[0043] (4) Compound 4 (0.86 g, 2.83 mmol) and 2,6-dimethoxyphenylacetylene (0.5 g, 3.08 mmol) were dissolved in THF (5 mL), and DIEA (0.6 g, 4.6 mmol) was added. After purging with nitrogen, Pd(dppf)Cl2 (0.29 g, 0.4 mmol) and CuI (0.23 g, 1.21 mmol) were added. The mixture was heated to 80 °C and reacted overnight under a nitrogen atmosphere. The system was added to water (20 mL), and extracted with ethyl acetate (30 mL × 3). The organic phase was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (PE:EA = 10:1-5:1) to give methyl 4-(2,6-dimethoxyphenyl)-2-phenoxymethylenebut-3-acetylic acid (compound 5, 0.4 g, purity 98%, yield 42%), as a yellow solid.
[0044] (5) Compound 5 (0.4 g, 1.18 mmol) and 4-iodo-2-isopropylaniline (0.31 g, 1.187 mmol) were dissolved in DMF (40 mL), and potassium tert-butoxide (159 mg, 1.417 mmol) was added. The reaction was carried out at room temperature for 1 h. The system was added to water (100 mL), and extracted with ethyl acetate (100 mL × 3). The organic phase was collected, washed with water (100 mL × 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (PE:EA = 5:1) to give methyl 4-(2,6-dimethoxy-phenyl)-2-((4-iodo-2-isopropyl-phenylamino)-methylene)-but-3-acetylginate (compound 6, 0.5 g, purity 96%, yield 83%), which was a yellow solid.
[0045] (6) Compound 6 (0.5 g, 1 mmol) was dissolved in DMF (5 mL), and cesium carbonate (0.65 g, 2 mmol) and CuI (19 mg, 0.1 mmol) were added under a nitrogen atmosphere. The nitrogen atmosphere was replaced, and the mixture was heated to 80 °C and reacted for 3 h. The system was added to water (50 mL), and extracted with ethyl acetate (50 mL × 3). The organic phase was collected, washed with water (50 mL × 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate to remove water, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (PE:EA = 10:1-2:1) to give 5-(2,6-dimethoxybenzene)-1-(4-iodo-2-isopropylbenzene)-3-(methyl carboxylate)pyrrole (0.2 g, purity 96%, yield 40%), which was a white solid.
[0046] Example 3
[0047] A method for preparing 5-(2,6-dimethoxybenzene)-1-(4-iodo-2-isopropylbenzene)-3-(methyl carboxylate)pyrrole, the method comprising the following steps:
[0048] (1) Methyl propargyl ester (8.9 g, 0.106 mol) was dissolved in water (20 mL), and phenol (10 g, 0.106 mol) and potassium carbonate (18 g, 0.13 mol) were added. The mixture was reacted overnight at room temperature. TLC was used to detect the disappearance of the starting material. The system was then added to water (100 mL), and ethyl acetate was added for extraction (100 mL × 3). The organic phases were combined and washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. The crude product was purified by column chromatography (PE:EA = 10:1) to give methyl 3-phenoxyacrylate (compound 2, 5.5 g, purity 97%, yield 23%), which was a colorless oil.
[0049] (2) Compound 2 (4.5 g, 0.025 mol) was added to anhydrous DCM / AcOH (77 mL / 5.9 mL), and NIS (17 g, 0.075 mmol) was added. The reaction was allowed to proceed overnight at room temperature. TLC was used to detect the disappearance of the starting material. The reaction was quenched with triethylamine (50 mL) and stirred at room temperature for 2 h. The system was added to water (200 mL), and extracted with ethyl acetate (100 mL × 3). The organic phase was collected, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (PE:EA = 10:1) to give methyl 3-acetoxy-2-iodo-3-phenoxypropionate (compound 3, 3.8 g, purity 95%, yield 41%), which was a yellow oil.
[0050] (3) Compound 3 (3.8 g, 0.01 mol) was added to acetonitrile (38 mL), and potassium carbonate (4.3 g, 0.03 mol) was added. The mixture was reacted at room temperature for 3 h. TLC was used to detect the disappearance of the starting material. The reaction solution was filtered, and the filter cake was washed with ethyl acetate. The filtrate was collected, dried with anhydrous sodium sulfate to remove water, and then filtered. The filtrate was concentrated to obtain the product methyl 2-iodo-3-phenoxyacrylate (compound 4, 3.0 g, purity 96%, yield 94%), which was a yellow oil.
[0051] (4) Compound 4 (2.3 g, 7.56 mmol) and 2,6-dimethoxyphenylacetylene (1.35 g, 8.32 mmol) were dissolved in THF (25 mL), and DIEA (1.46 g, 11.3 mmol) was added. After purging with nitrogen, Pd(dppf)Cl2 (0.71 g, 0.98 mmol) and CuI (0.57 g, 2.99 mmol) were added. The mixture was heated to 80 °C and reacted overnight under a nitrogen atmosphere. The system was then added to water (100 mL), extracted with ethyl acetate (50 mL × 3), and the organic phase was collected. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (PE:EA = 10:1-5:1) to give methyl 4-(2,6-dimethoxyphenyl)-2-phenoxymethylenebut-3-acetylic acid (compound 5, 1.8 g, purity 97%, yield 70%), as a yellow solid.
[0052] (5) Compound 5 (1 g, 2.95 mmol) and 4-iodo-2-isopropylaniline (0.77 g, 2.95 mmol) were dissolved in DMF (100 mL), and potassium tert-butoxide (151.07 mg, 1.346 mmol) was added. The reaction was carried out at room temperature for 1 h. The system was added to water (100 mL), and extracted with ethyl acetate (50 mL × 3). The organic phase was collected, washed with water (50 mL × 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (PE:EA = 5:1) to give methyl 4-(2,6-dimethoxy-phenyl)-2-((4-iodo-2-isopropyl-phenylamino)-methylene)-but-3-acetylginate (compound 6, 1 g, purity 96%, yield 67%), which was a yellow solid.
[0053] (6) Compound 6 (1 g, 1.983 mmol) was dissolved in DMF (10 mL), and cesium carbonate (1.2 g, 3.68 mmol) and CuI (37 mg, 0.19 mmol) were added under a nitrogen atmosphere. The nitrogen atmosphere was replaced, and the mixture was heated to 80 °C and reacted for 3 h. The system was added to water (100 mL), and extracted with ethyl acetate (50 mL × 3). The organic phase was collected, washed with water (50 mL × 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate to remove water, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (PE:EA = 10:1-2:1) to give 5-(2,6-dimethoxybenzene)-1-(4-iodo-2-isopropylbenzene)-3-(methyl carboxylate)pyrrole (0.3 g, purity 96%, yield 30%), which was a white solid.
[0054] The above description is merely a preferred embodiment of the present invention, and the present invention is not limited to the above embodiments. It is understood that other improvements and variations that are directly derived or conceived by those skilled in the art without departing from the spirit and concept of the present invention should be considered to be included within the protection scope of the present invention.
Claims
1. A method for preparing 5-(2,6-dimethoxybenzene)-1-(4-iodo-2-isopropylbenzene)-3-(methyl carboxylate)pyrrole, characterized in that, The preparation method is carried out according to the following process: Includes the following steps: (1) Compound 1 was dissolved in water and reacted with phenol in the presence of potassium carbonate to prepare compound 2. (2) Compound 2 was dissolved in solvent I and subjected to a halogenation reaction with a halogenating agent to obtain compound 3; (3) Compound 3 was dissolved in solvent II, and a basic reagent was added to carry out a deacetylation reaction to obtain compound 4; (4) Compound 4 was dissolved in solvent III, N,N-diisopropylethylamine was added, and 2,6-dimethoxyphenylacetylene was coupled with 2,6-dimethoxyphenylacetylene via Sonogashira coupling reaction under the action of palladium and copper catalysts to obtain compound 5. (5) Compound 5 was dissolved in solvent IV and substituted with 4-iodo-2-isopropylaniline under the catalysis of potassium tert-butoxide to obtain compound 6; (6) Compound 6 was dissolved in solvent V and subjected to a ring-closing reaction to obtain 5-(2,6-dimethoxybenzene)-1-(4-iodo-2-isopropylbenzene)-3-(methyl carboxylate)pyrrole.
2. The preparation method according to claim 1, characterized in that, In step (1), the concentration of compound 1 in water is 0.25-0.56 g / mL; the molar ratio of compound 1 to potassium carbonate is 1:1-1.1; the molar ratio of compound 1 to phenol is 1:1; the addition reaction is carried out at room temperature for 18 hours.
3. The preparation method according to claim 1, characterized in that, In step (2), solvent I is a mixed solution of dichloromethane and acetic acid, and the volume ratio of dichloromethane to acetic acid is 7 to 13:1; the concentration of compound 2 in solvent I is 0.05 to 0.09 g / mL.
4. The preparation method according to claim 1, characterized in that, In step (2), the halogenating agent is N-iodosuccinimide; the molar ratio of compound 2 to the halogenating agent is 1:3; the halogenation reaction is carried out at room temperature for 18 hours.
5. The preparation method according to claim 1, characterized in that, In step (3), solvent II is acetonitrile; the concentration of compound 3 in solvent II is 0.07-0.2 g / mL; the alkaline reagent is potassium carbonate; the molar ratio of compound 3 to alkaline reagent is 1:3; the deacetylation reaction temperature is room temperature and the time is 3 h.
6. The preparation method according to claim 1, characterized in that, In step (4), solvent III is tetrahydrofuran; the concentration of compound 4 in solvent III is 0.04–0.17 g / mL; the molar ratio of compound 4 to 2,6-dimethoxyphenylacetylene is 1:1.1; the molar ratio of compound 4 to N,N-diisopropylethylamine is 1:1.5–1.6; the palladium catalyst is Pd(dppf)Cl2; the copper catalyst is CuI; and the Sonogashira coupling reaction is carried out at 80 °C for 18 h.
7. The preparation method according to claim 5, characterized in that, The molar ratio of compound 4 to palladium catalyst is 7-7.7:1; the molar ratio of compound 4 to copper catalyst is 1:0.
4.
8. The preparation method according to claim 1, characterized in that, In step (5), solvent IV is N,N-dimethylformamide; the concentration of compound 5 in solvent IV is 0.01 g / mL; the molar ratio of compound 5 to 4-iodo-2-isopropylaniline is 1:1; the molar ratio of compound 5 to potassium tert-butoxide is 1:0.4 to 1.2; the substitution reaction is carried out at room temperature for 1 h.
9. The preparation method according to claim 1, characterized in that, In step (6), the solvent V is N,N-dimethylformamide; the concentration of compound 6 in solvent V is 0.05 to 0.1 g / mL.
10. The preparation method according to claim 1, characterized in that, In step (6), the catalyst for the ring-closing reaction is cesium carbonate and cuprous iodide; the molar ratio of compound 6 to cesium carbonate is 1:1.8-2; the molar ratio of compound 6 to cuprous iodide is 1:0.1; the temperature of the ring-closing reaction is 80℃ and the time is 3h.