A method for preparing phenyl-substituted 2-methyl-1h-indene derivatives by stille coupling reaction

Abstract

This invention provides a method for preparing phenyl-substituted 2-methyl-1H-indene derivatives via Stille coupling reaction, comprising: reacting brominated 2-methyl-1H-indene, trialkylphenyltin, palladium catalyst, and additives in an organic solvent; and after post-treatment following reaction to obtain the phenyl-substituted 2-methyl-1H-indene derivatives; wherein the trialkylphenyltin is at least one of trimethylphenyltin and tributylphenyltin; the palladium catalyst is at least one of Pd(PPh3)4, Pd2(dba)3, and Pd(dba)2; the additive is at least one of lithium chloride, cesium fluoride, and potassium fluoride; and the organic solvent is at least one of DMF, 1,4-dioxane, and NMP. This invention uses brominated 2-methyl-1H-indene and trialkylphenyltin as raw materials, and prepares the target product by reaction in an organic solvent in the presence of a palladium catalyst and additives. It exhibits good substrate adaptability and is simple to operate.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for preparing phenyl-substituted 2-methyl-1H-indene derivatives via Stille coupling reaction. Background Technology

[0002] Indene and its derivatives are an important class of aromatic fused-ring compounds, playing an indispensable role in organic functional materials, medicinal chemistry, and coordination chemistry. Particularly in the polyolefin industry, substituted indene structures are crucial ligand frameworks for metallocene catalysts. Metallocene catalysts, as a new generation of olefin polymerization catalysts, possess superior properties such as single active sites, mild polymerization conditions, and the ability to precisely control polymer microstructure, and are widely used in the production of high-performance polyolefin materials. Even minor changes in ligand structure directly affect the spatial environment and electronic effects of the catalyst's active sites.

[0003] Studies have shown that 2-methyl-4-aryl-substituted indene ligands are key structural units constituting so-called "advanced metallocene catalysts," providing unique steric hindrance and electronic effects to the metal center (Spaleck et al., Organometallics 1994, 13, 954). However, the synthesis of such ligand precursors often faces the challenge of positional isomerism. Voskoboynikov et al. (Organometallics 2006, 25, 25-36) reported a synthetic method for 4-bromo-2-methyl-1H-indene, noting that the product obtained by this method was a mixture of 4-bromo and 7-bromo isomers (in a ratio of approximately 29:71).

[0004] Based on this, the authors prepared the corresponding phenyl-substituted indene mixtures via Suzuki coupling reaction and characterized them.

[0005] Stille coupling reaction, as a reliable method for constructing carbon-carbon bonds, has advantages such as good functional group tolerance and mild reaction conditions. Therefore, it is proposed to develop a new method to prepare phenyl-substituted 2-methyl-1H-indene derivatives, namely the mixed isomers 2-methyl-7-phenyl-1H-indene and 2-methyl-4-phenyl-1H-indene, by using bromo-2-methyl-1H-indene (and its isomer mixture) as substrates and undergoing Stille cross-coupling reaction with trialkylphenyltin reagents under palladium catalysis. Summary of the Invention

[0006] The purpose of this invention is to provide a method for preparing phenyl-substituted 2-methyl-1H-indene derivatives by Stille coupling reaction, using bromo-2-methyl-1H-indene and trialkylphenyltin as raw materials, and reacting them in an organic solvent in the presence of a palladium catalyst and additives to prepare the target product.

[0007] To achieve the above objectives, the present invention provides the following technical solution: A method for preparing phenyl-substituted 2-methyl-1H-indene derivatives via Stille coupling reaction includes the following steps: Under inert gas protection, bromo-2-methyl-1H-indene, trialkylphenyltin, palladium catalyst, and additives were placed in an organic solvent for reaction. After the reaction was completed, post-treatment was performed to obtain phenyl-substituted 2-methyl-1H-indene derivatives. The trialkylphenyltin is at least one of trimethylphenyltin and tributylphenyltin; the palladium catalyst is at least one of Pd(PPh3)4, Pd2(dba)3, and Pd(dba)2; the additive is at least one of lithium chloride, cesium fluoride, and potassium fluoride; and the organic solvent is at least one of DMF, 1,4-dioxane, and NMP.

[0008] The reaction synthesis route is shown in equation (1).

[0009] Equation (1)

[0010] As a preferred embodiment, the molar ratio of bromo-2-methyl-1H-indene to trialkylphenyltin is 1:1.2-2.0; the amount of palladium catalyst is 3-10% of the molar amount of bromo-2-methyl-1H-indene; and the amount of additive is 2-4 times the molar amount of bromo-2-methyl-1H-indene.

[0011] As a preferred embodiment, the molar ratio of bromo-2-methyl-1H-indene to trialkylphenyltin is 1:1.5; the amount of palladium catalyst used is 5% of the molar amount of bromo-2-methyl-1H-indene; and the amount of additive used is 3 times the molar amount of bromo-2-methyl-1H-indene.

[0012] As a preferred embodiment, the trialkylphenyltin is tributylphenyltin; the palladium catalyst is Pd(PPh3)4; and the additive is lithium chloride.

[0013] As a preferred embodiment, the phenyl-substituted 2-methyl-1H-indene derivative is a mixture of isomers of 2-methyl-4-phenyl-1H-indene and 2-methyl-7-phenyl-1H-indene.

[0014] As a preferred embodiment, the method for preparing phenyl-substituted 2-methyl-1H-indene derivatives by Stille coupling reaction includes the following steps: under inert gas protection, adding brominated 2-methyl-1H-indene, trialkylphenyltin, palladium catalyst, additives and organic solvent to a reactor, heating and stirring the reaction, and after the reaction is completed, obtaining phenyl-substituted 2-methyl-1H-indene derivatives through post-treatment; the reaction temperature is 80-120℃, and the reaction time is 4-8 hours.

[0015] As a preferred embodiment, the reaction temperature is 100-110℃ and the reaction time is 6-8 hours; the organic solvent is DMF or 1,4-dioxane.

[0016] As a preferred embodiment, the ratio of bromo-2-methyl-1H-indene to the organic solvent is 1.0 mmol: 4-8 mL.

[0017] As a preferred embodiment, the method for preparing phenyl-substituted 2-methyl-1H-indene derivatives via the Stille coupling reaction includes the following steps: S1: Add bromo-2-methyl-1H-indene, palladium catalyst, and additives to an organic solvent and stir to obtain mixed solution A; S2: Trialkylphenyltin is added to an organic solvent and stirred to obtain mixed solution B; S3: Under inert gas protection, the mixed solution A and mixed solution B are injected into the microchannel reactor through a metering pump for reaction. The reaction temperature is 60-70℃ and the residence time is 10-15 minutes. The resulting reaction solution flows out continuously from the outlet and is then post-processed to obtain a phenyl-substituted 2-methyl-1H-indene derivative.

[0018] In the above technical solution, by feeding the palladium catalyst / additive and the organotin reagent separately, premature contact between the two before entering the reactor avoids catalyst deactivation or unnecessary transmetallization side reactions. This method allows the reaction to proceed under milder conditions of 60-70℃, with a residence time of only 10-15 minutes, far shorter than stirred reactions, enabling rapid and continuous production while improving the purity and yield of the target product.

[0019] As a preferred embodiment, the ratio of the amount of bromo-2-methyl-1H-indene to the organic solvent in step S1 and the organic solvent in step S2 is 1.0 mmol: 2.5-4 mL: 2.5-4 mL.

[0020] As a preferred embodiment, the organic solvents in steps S1 and S2 are DMF or a mixture of DMF and 1,4-dioxane, wherein the volume ratio of DMF to 1,4-dioxane in the mixed solvent is 1:0.2-0.4. When DMF is used as the solvent, it exhibits good solubility for bromo-2-methyl-1H-indene, palladium catalysts (such as Pd(PPh3)4), and inorganic salt additives (LiCl / CsF / KF), forming a homogeneous reaction system. Combined with the excellent heat transfer characteristics of the microchannel reactor, the reaction temperature can be stably maintained, reducing the decomposition of DMF or the occurrence of side reactions at high temperatures. Furthermore, extensive experimental research has shown that adding an appropriate amount of 1,4-dioxane to DMF during the reaction in a microchannel reactor further enhances the reaction efficiency.

[0021] The bromo-2-methyl-1H-indene described in this invention can be prepared by methods known in the art. Referring to the method reported by Voskoboynikov et al. (Organometallics 2006, 25, 25-36), bromo-2-methyl-1H-indene can be prepared from 2-bromobenzyl bromide via malonic esterification, Friedel-Crafts cyclization, NaBH4 reduction, and p-toluenesulfonic acid-catalyzed dehydration. It can then be directly used in subsequent coupling reactions without further separation.

[0022] The post-processing described in this invention includes: after the reaction is completed, adding potassium fluoride aqueous solution to the reaction solution and stirring overnight to convert tin salt into tin fluoride precipitate, filtering, extracting, drying and concentrating the filtrate, and finally purifying it by column chromatography to obtain the target product, a mixture of phenyl-substituted 2-methyl-1H-indene derivatives.

[0023] The beneficial effects of this invention are: This invention provides a novel method for preparing phenyl-substituted 2-methyl-1H-indene derivatives. The method employs Stille coupling reaction, exhibiting good substrate adaptability and simple operation. The resulting product is a mixture of isomers of 2-methyl-4-phenyl-1H-indene and 2-methyl-7-phenyl-1H-indene, which can be directly used for the subsequent synthesis of metallocene catalyst ligands without the need for cumbersome isomer separation. This simplifies the operation process, reduces production costs, and demonstrates promising prospects for industrial application. Attached Figure Description

[0024] Figure 1 This is a high-performance liquid chromatography (HPLC) chromatogram of the product in Example 1. Detailed Implementation

[0025] The present invention will be further described below with reference to specific embodiments, but the present invention is not limited to the following embodiments. Unless otherwise specified, the methods described are conventional methods. Unless otherwise specified, the materials described are commercially available. The raw material preparation refers to the method described on pages 3-5 of the supporting information of Voskoboynikov et al. (Organometallics 2006, 25, 25-36), which is to prepare bromo-2-methyl-1H-indene from 2-bromobenzyl bromide via malonic ester method, Friedel-Crafts cyclization, NaBH4 reduction and p-toluenesulfonic acid catalytic dehydration. The molecular weight of this mixed isomer is calculated according to C 10 The calculated value of H9Br is 209.07 g / mol.

[0026] Example 1: Under nitrogen protection, a mixture of the prepared brominated 2-methyl-1H-indene isomers (209.1 mg, 1.0 mmol on a mixture basis), tributylphenyltin (550.7 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium Pd(PPh3)4 (57.8 mg, 0.05 mmol), lithium chloride LiCl (127.2 mg, 3.0 mmol), and DMF (5 mL) were added to a 100 mL reaction flask. The mixture was heated to 100 °C and stirred for 6 hours. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 20:1, Rf value approximately 0.3). After the reaction was completed, the mixture was cooled to room temperature. A saturated potassium fluoride aqueous solution (10 mL) was added to the reaction solution, and the mixture was stirred overnight at room temperature to convert the tin salt into tin fluoride precipitate. The precipitate was removed by filtration, and the filtrate was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 40 °C to remove the solvent. The residue was purified by silica gel column chromatography (30-60℃, petroleum ether / ethyl acetate = 20:1) to give a pale yellow oily phenyl-substituted 2-methyl-1H-indene derivative. Product characterization: The 1H NMR spectrum (¹H NMR, 400 MHz, CDCl3) of the obtained product showed characteristic signals at δ 7.47-7.51 (m), 7.36-7.42 (m), 7.31 (m), 7.27 (d, J=7.5 Hz), 7.21 (dd, J=7.5, 1.2 Hz), 7.10 (dd, J=7.5, 1.2 Hz), 6.50 (hex, J=1.6 Hz), 3.33 (m), 2.08 (m) ppm. The above data are consistent with those reported in the literature (Voskoboynikov et al., Organometallics 2006, 25, 25-36) for a mixture of 2-methyl-4-phenyl-1H-indene and 2-methyl-7-phenyl-1H-indene, confirming that the product is a mixture of the target isomers. The isomer mixture does not require further isomer separation and can be directly used for the subsequent synthesis of metallocene catalyst ligands. Total mass yield: 189.8 mg (in C1). 16 H 14 The molecular weight was 206.27 g / mol, the theoretical yield was 206.3 mg, and the yield was 92.0%. The purity was 99.5% (purity determined by HPLC).

[0027] The obtained product was analyzed by high-performance liquid chromatography (HPLC). The chromatographic conditions were: Syergi 4μ HydroRP80A column (250×4.6 mm), column temperature 25°C, detection wavelength 254 nm, mobile phase 80% acetonitrile / 20% water, flow rate 1.0 mL / min. Chromatogram ( Figure 1The results show that the product in Example 1 exhibits a single peak at a retention time of approximately 11.9 minutes, and the purity calculated by area normalization is 99.5%.

[0028] Isomer analysis: Since the product is a mixture of 2-methyl-4-phenyl-1H-indene and 2-methyl-7-phenyl-1H-indene, and the two are isomers with very similar polarities, baseline separation was not achieved under the above HPLC conditions; both isomers eluted to a single chromatographic peak. This result confirms that the product does not contain any other significant impurities.

[0029] Example 2: Under argon protection, a mixture of bromo-2-methyl-1H-indene isomers (209.1 mg, 1.0 mmol), trimethylphenyltin (289.1 mg, 1.2 mmol), tris(dibenzylacetone)dipalladium Pd2(dba)3 (31.1 mg, 0.03 mmol), cesium fluoride CsF (303.8 mg, 2.0 mmol), and 1,4-dioxane (5 mL) were added to a 100 mL reaction flask. The mixture was heated to 80 °C and stirred for 8 hours, with TLC monitoring of the reaction progress. The post-treatment was the same as in Example 1, yielding 182.6 mg of a pale yellow oily phenyl-substituted 2-methyl-1H-indene derivative, with a yield of 88.5% and a purity of 98.3%. The 1H NMR spectral characteristics of the product were essentially consistent with those of Example 1.

[0030] Example 3: Under nitrogen protection, a mixture of bromo-2-methyl-1H-indene isomers (209.1 mg, 1.0 mmol), tributylphenyltin (550.7 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium Pd(PPh3)4 (57.8 mg, 0.05 mmol), potassium fluoride KF (174.3 mg, 3.0 mmol), and N-methylpyrrolidone NMP (5 mL) were added to a 100 mL reaction flask. The mixture was heated to 110 °C and stirred for 6 hours, with TLC monitoring of the reaction progress. The post-treatment was the same as in Example 1, yielding 184.2 mg of a phenyl-substituted 2-methyl-1H-indene derivative, with a yield of 89.3% and a purity of 99.0%. The 1H NMR spectral characteristics of the product were essentially consistent with those of Example 1.

[0031] Example 4: Under nitrogen protection, a mixture of bromo-2-methyl-1H-indene isomers (209.1 mg, 1.0 mmol), tributylphenyltin (550.7 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium Pd(PPh3)4 (57.8 mg, 0.05 mmol), lithium chloride LiCl (127.2 mg, 3.0 mmol), and 1,4-dioxane (5 mL) were added to a 100 mL reaction flask. The mixture was heated to 100 °C and stirred for 8 hours, with TLC monitoring of the reaction progress. The post-treatment was the same as in Example 1, yielding 186.1 mg of a phenyl-substituted 2-methyl-1H-indene derivative, with a yield of 90.2% and a purity of 99.1%. The 1H NMR spectral characteristics of the product were essentially consistent with those of Example 1.

[0032] Example 5: Unlike Example 1, the temperature was raised to 120°C and the reaction was stirred for 6 hours, while other conditions remained the same as in Example 1. 184.2 mg of a phenyl-substituted 2-methyl-1H-indene derivative was obtained, with a yield of 89.3% and a purity of 99.2%. The 1H NMR spectrum characteristics of the product were essentially consistent with those of Example 1.

[0033] Example 6: Unlike Example 1, the temperature was raised to 100°C and the reaction was stirred for 4 hours, while other conditions remained the same as in Example 1. 183.6 mg of a phenyl-substituted 2-methyl-1H-indene derivative was obtained, with a yield of 89.0% and a purity of 99.0%. The 1H NMR spectrum characteristics of the product were essentially consistent with those of Example 1.

[0034] Example 7: Unlike Example 1, tetrakis(triphenylphosphine)palladium Pd(PPh3)4 was replaced with bis(dibenzylacetone)palladium Pd(dba)2, while other conditions remained the same as in Example 1. 183.4 mg of a phenyl-substituted 2-methyl-1H-indene derivative was obtained, with a yield of 88.9% and a purity of 98.9%. The 1H NMR spectrum characteristics of the product were essentially consistent with those of Example 1.

[0035] Example 8: Unlike Example 1, the amount of tetrakis(triphenylphosphine)palladium Pd(PPh3)4 added was 115.6 mg (0.10 mmol), while other conditions were the same as in Example 1. 190.0 mg of a phenyl-substituted 2-methyl-1H-indene derivative was obtained, with a yield of 92.1% and a purity of 99.4%. The 1H NMR spectrum characteristics of the product were essentially consistent with those of Example 1.

[0036] Example 9: Unlike Example 1, the amount of tributylphenyltin added was 734.3 mg (2.0 mmol), while other conditions were the same as in Example 1. 189.4 mg of a phenyl-substituted 2-methyl-1H-indene derivative was obtained, with a yield of 91.8% and a purity of 99.3%. The 1H NMR spectrum characteristics of the product were essentially consistent with those of Example 1.

[0037] Example 10: Unlike Example 1, the amount of lithium chloride (LiCl) added was 169.6 mg (4.0 mmol), while other conditions were the same as in Example 1. 189.1 mg of a phenyl-substituted 2-methyl-1H-indene derivative was obtained, with a yield of 91.7% and a purity of 99.4%. The 1H NMR spectrum characteristics of the product were essentially consistent with those of Example 1.

[0038] Example 11: The prepared mixture of bromo-2-methyl-1H-indene isomers (209.1 mg, 1.0 mmol on a mixture basis), tetrakis(triphenylphosphine)palladium Pd(PPh3)4 (57.8 mg, 0.05 mmol), and lithium chloride LiCl (127.2 mg, 3.0 mmol) were added to DMF (2.5 mL) and stirred to obtain mixed solution A. Tributylphenyltin (550.7 mg, 1.5 mmol) was added to DMF (2.5 mL) and stirred to obtain mixed solution B; Under nitrogen protection, mixed solutions A and B were injected into a microchannel reactor via a metering pump for reaction at 65°C for 15 minutes. The resulting reaction solution flowed continuously from the outlet and was then post-processed as in Example 1, yielding 192.3 mg of a phenyl-substituted 2-methyl-1H-indene derivative with a yield of 93.2% and a purity of 99.6%. The 1H NMR spectrum characteristics of the product were essentially consistent with those of Example 1.

[0039] Example 12: The prepared mixture of bromo-2-methyl-1H-indene isomers (209.1 mg, 1.0 mmol on a mixture basis), tetrakis(triphenylphosphine)palladium Pd(PPh3)4 (57.8 mg, 0.05 mmol), and lithium chloride LiCl (127.2 mg, 3.0 mmol) were added to DMF (4 mL) and stirred to obtain mixed solution A; Tributylphenyltin (550.7 mg, 1.5 mmol) was added to DMF (4 mL) and stirred to obtain mixed solution B; Under nitrogen protection, mixed solutions A and B were injected into a microchannel reactor via a metering pump for reaction at 70°C for 10 minutes. The resulting reaction solution flowed continuously from the outlet and was then post-processed as in Example 1, yielding 192.9 mg of a phenyl-substituted 2-methyl-1H-indene derivative with a yield of 93.5% and a purity of 99.7%. The 1H NMR spectrum characteristics of the product were essentially consistent with those of Example 1.

[0040] Example 13: Unlike Example 11, the reaction temperature was 60°C, while other conditions remained the same as in Example 11. 191.9 mg of a phenyl-substituted 2-methyl-1H-indene derivative was obtained, with a yield of 93.0% and a purity of 99.5%. The 1H NMR spectrum characteristics of the product were essentially consistent with those of Example 11.

[0041] Example 14: Unlike Example 11, the solvent DMF was replaced with a mixed solvent of DMF and 1,4-dioxane, with a volume ratio of DMF to 1,4-dioxane of 1:0.2. Other conditions remained the same as in Example 11. 196.6 mg of a phenyl-substituted 2-methyl-1H-indene derivative was obtained, with a yield of 95.3% and a purity of 99.8%. The 1H NMR spectrum characteristics of the product were essentially consistent with those of Example 11.

[0042] Example 15: Unlike Example 11, the solvent DMF was replaced with a mixed solvent of DMF and 1,4-dioxane, with a volume ratio of DMF to 1,4-dioxane of 1:0.4. Other conditions remained the same as in Example 11. 194.3 mg of a phenyl-substituted 2-methyl-1H-indene derivative was obtained, with a yield of 94.2% and a purity of 99.5%. The 1H NMR spectrum characteristics of the product were essentially consistent with those of Example 11.

[0043] Example 16: Unlike Example 11, the solvent DMF was replaced with a mixed solvent of DMF and 1,4-dioxane, with a volume ratio of DMF to 1,4-dioxane of 1:0.3. Other conditions remained the same as in Example 11. 196.2 mg of a phenyl-substituted 2-methyl-1H-indene derivative was obtained, with a yield of 95.1% and a purity of 99.7%. The 1H NMR spectrum characteristics of the product were essentially consistent with those of Example 11.

[0044] Comparative Example 1: Unlike Example 1, the amount of tributylphenyltin used was 1 mmol, while other conditions were the same as in Example 1. 179.5 mg of a phenyl-substituted 2-methyl-1H-indene derivative was obtained, with a yield of 87.0% and a purity of 98.4%. The 1H NMR spectrum characteristics of the product were essentially consistent with those of Example 1.

[0045] Comparative Example 2: Unlike Example 1, the amount of tributylphenyltin used was 2.5 mmol, while other conditions were the same as in Example 1. 189.6 mg of a phenyl-substituted 2-methyl-1H-indene derivative was obtained, with a yield of 91.9% and a purity of 97.6%. The 1H NMR spectrum characteristics of the product were essentially consistent with those of Example 1.

[0046] Comparative Example 3: Unlike Example 1, the amount of tetrakis(triphenylphosphine)palladium Pd(PPh3)4 used was 0.01 mmol, while other conditions were the same as in Example 1. 178.0 mg of a phenyl-substituted 2-methyl-1H-indene derivative was obtained, with a yield of 86.3% and a purity of 98.0%. The 1H NMR spectrum characteristics of the product were essentially consistent with those of Example 1.

[0047] Comparative Example 4: Unlike Example 1, the amount of tetrakis(triphenylphosphine)palladium Pd(PPh3)4 used was 0.15 mmol, while other conditions were the same as in Example 1. 190.0 mg of a phenyl-substituted 2-methyl-1H-indene derivative was obtained, with a yield of 92.1% and a purity of 98.1%. The 1H NMR spectrum characteristics of the product were essentially consistent with those of Example 1.

[0048] Comparative Example 5: Unlike Example 1, the amount of lithium chloride (LiCl) used was 1 mmol, while other conditions were the same as in Example 1. 180.7 mg of a phenyl-substituted 2-methyl-1H-indene derivative was obtained, with a yield of 87.6% and a purity of 95.9%. The 1H NMR spectrum characteristics of the product were essentially consistent with those of Example 1.

[0049] Comparative Example 6: Unlike Example 1, the amount of lithium chloride (LiCl) used was 5 mmol, while other conditions were the same as in Example 1. 182.0 mg of a phenyl-substituted 2-methyl-1H-indene derivative was obtained, with a yield of 88.2% and a purity of 97.6%. The 1H NMR spectrum characteristics of the product were essentially consistent with those of Example 1.

[0050] The results of the examples and comparative examples are shown in Table 1.

[0051] Table 1:

[0052] A comparison of the data from the above examples and comparative examples shows that the Stille coupling reaction of bromo-2-methyl-1H-indene with tributylphenyltin, under the optimized heating and stirring conditions of Example 1, achieved a yield of approximately 92% and a purity exceeding 99%. Both yield and purity decreased when deviating from the optimal conditions. In Example 2, using trimethylphenyltin in combination with Pd2(dba)3 and CsF, the yield decreased to 88.5%, while the purity remained at 98.3%, indicating that the tributylphenyltin and Pd(PPh3)4 system in Example 1 was more advantageous. In Example 3, replacing LiCl with KF and DMF with NMP resulted in a yield of 89.3%, demonstrating that the conditions in Example 1 were superior. In Example 4, replacing DMF with dioxane resulted in a yield of 90.2%, slightly lower than the DMF system. In Example 5, heating to 120°C yielded 89.3%, and in Example 6, shortening the reaction time to 4 hours resulted in a yield of 89.0%, proving that 100°C and 6 hours were the optimal combination. Example 7 showed an 88.9% yield when Pd(dba)2 replaced Pd(PPh3)4, indicating that Pd(PPh3)4 has higher activity. Example 8 doubled the amount of Pd(PPh3)4 to 0.1 mmol, increasing the yield only slightly to 92.1%, suggesting that 5 mol% is sufficient. Example 9 increased the yield to 2.0 mmol, resulting in a 91.8% yield, and Example 10 increased the yield to 4.0 mmol, resulting in a 91.7% yield. Both yields did not exceed the conditions of Example 1, but the decrease was not significant. Comparative Examples 1-6 further confirmed that insufficient or excessive Tributylphenyltin, Pd(PPh3)4, or LiCl all lead to a decrease in yield and purity. Excessive Tributylphenyltin or Pd(PPh3)4 does not further improve the yield but instead reduces product purity and increases cost.

[0053] Examples 11-16 demonstrate that microchannel reactor technology further improves process efficiency. Example 11 achieved a 93.2% yield and 99.6% purity after a 15-minute residence time at 65°C. Example 12 achieved a 93.5% yield after a 10-minute residence time at 70°C, a 36-fold reduction in time and a 30°C decrease in temperature compared to batch reactors. Example 13 achieved a 93.0% yield at 60°C. Example 14, using a DMF to dioxane volume ratio of 1:0.2, saw a significant increase in yield to 95.3% and purity to 99.8%; Example 15, with a ratio of 1:0.4, achieved a 94.2% yield; and Example 16, with a ratio of 1:0.3, achieved a 95.1% yield. The composite solvent systems in these three examples were significantly superior to the pure DMF system, indicating that the addition of an appropriate amount of dioxane may improve substrate solubility or the microenvironment of the palladium catalytic cycle.

[0054] 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 preparing phenyl-substituted 2-methyl-1H-indene derivatives via Stille coupling reaction, characterized in that, Includes the following steps: Under inert gas protection, bromo-2-methyl-1H-indene, trialkylphenyltin, palladium catalyst, and additives were placed in an organic solvent for reaction. After the reaction was completed, post-treatment was performed to obtain phenyl-substituted 2-methyl-1H-indene derivatives. The trialkylphenyltin is at least one of trimethylphenyltin and tributylphenyltin; the palladium catalyst is at least one of Pd(PPh3)4, Pd2(dba)3, and Pd(dba)2; the additive is at least one of lithium chloride, cesium fluoride, and potassium fluoride; and the organic solvent is at least one of DMF, 1,4-dioxane, and NMP.

2. The method for preparing phenyl-substituted 2-methyl-1H-indene derivatives via Stille coupling reaction according to claim 1, characterized in that, The molar ratio of bromo-2-methyl-1H-indene to trialkylphenyltin is 1:1.2-2.0; the amount of palladium catalyst used is 3-10% of the molar amount of bromo-2-methyl-1H-indene; and the amount of additive used is 2-4 times the molar amount of bromo-2-methyl-1H-indene.

3. The method for preparing phenyl-substituted 2-methyl-1H-indene derivatives via Stille coupling reaction according to claim 1, characterized in that, The trialkylphenyltin is tributylphenyltin; the palladium catalyst is Pd(PPh3)4; and the additive is lithium chloride.

4. The method for preparing phenyl-substituted 2-methyl-1H-indene derivatives via Stille coupling reaction according to claim 1, characterized in that, The phenyl-substituted 2-methyl-1H-indene derivative is a mixture of isomers of 2-methyl-4-phenyl-1H-indene and 2-methyl-7-phenyl-1H-indene.

5. The method for preparing phenyl-substituted 2-methyl-1H-indene derivatives by Stille coupling reaction according to any one of claims 1-4, characterized in that, Includes the following steps: Under inert gas protection, bromo-2-methyl-1H-indene, trialkylphenyltin, palladium catalyst, additives and organic solvent are added to the reactor, and the mixture is heated and stirred to react. After the reaction is completed, the phenyl-substituted 2-methyl-1H-indene derivative is obtained through post-treatment. The reaction temperature is 80-120℃ and the reaction time is 4-8 hours.

6. The method for preparing phenyl-substituted 2-methyl-1H-indene derivatives via Stille coupling reaction according to claim 5, characterized in that, The reaction temperature is 100-110℃, and the reaction time is 6-8 hours; the organic solvent is DMF or 1,4-dioxane.

7. The method for preparing phenyl-substituted 2-methyl-1H-indene derivatives via Stille coupling reaction according to claim 5, characterized in that, The ratio of bromo-2-methyl-1H-indene to organic solvent is 1.0 mmol: 4-8 mL.

8. The method for preparing phenyl-substituted 2-methyl-1H-indene derivatives by Stille coupling reaction according to any one of claims 1-4, characterized in that, Includes the following steps: S1: Add bromo-2-methyl-1H-indene, palladium catalyst, and additives to an organic solvent and stir to obtain mixed solution A; S2: Trialkylphenyltin is added to an organic solvent and stirred to obtain mixed solution B; S3: Under inert gas protection, the mixed solution A and mixed solution B are injected into the microchannel reactor through a metering pump for reaction. The reaction temperature is 60-70℃ and the residence time is 10-15 minutes. The resulting reaction solution flows out continuously from the outlet and is then post-processed to obtain a phenyl-substituted 2-methyl-1H-indene derivative.

9. The method for preparing phenyl-substituted 2-methyl-1H-indene derivatives via Stille coupling reaction according to claim 8, characterized in that, The ratio of the amount of bromo-2-methyl-1H-indene to the organic solvent in step S1 and the organic solvent in step S2 is 1.0 mmol: 2.5-4 mL: 2.5-4 mL.

10. The method for preparing phenyl-substituted 2-methyl-1H-indene derivatives via Stille coupling reaction according to claim 8, characterized in that, The organic solvents used in steps S1 and S2 are DMF or a mixture of DMF and 1,4-dioxane, wherein the volume ratio of DMF to 1,4-dioxane in the mixture is 1:0.2-0.4.

Images