A method for the synthesis of a key intermediate of iprocampus, 5-methoxy-7-methylindole

Abstract

This invention relates to a method for synthesizing 5-methoxy-7-methylindole, a key intermediate in iprodione, belonging to the field of organic synthesis. The method comprises: methylation of m-cresol to generate m-methyl anisole; bromination of m-methyl anisole to generate 2-bromo-5-methoxytoluene; and a Ullmann reaction of 2-bromo-5-methoxytoluene with aminoacetaldehyde diacetate in the presence of a copper catalyst, ligands, and a base to generate N-(2,2-dimethoxyethyl)-4-methoxy-2-methylaniline; followed by acid-catalyzed cyclization to generate 5-methoxy-7-methylindole. The method of this invention features mild reaction conditions, low cost, safe operation, and an overall yield exceeding 70%, making it suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically a method for synthesizing 5-methoxy-7-methylindole, a key intermediate of iprocoprine. Background Technology

[0002] Iptacopan (trade name: FABHALTA) is Novartis' first oral inhibitor targeting factor B in the alternative complement pathway. It has been approved by the FDA for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) in adults and was approved in China in 2024. Furthermore, this drug is also the first complement inhibitor used to treat primary IgA nephropathy in adults, demonstrating significant clinical value.

[0003] 5-Methoxy-7-methylindole is a key high-value intermediate in the synthesis of iprocoprine hydrochloride, and its quality directly affects the process feasibility, quality controllability, and supply chain security of the active pharmaceutical ingredient.

[0004] In the prior art, the synthesis of 5-methoxy-7-methylindole mainly involves the following methods:

[0005] Leimgruber-Batcho indole synthesis method: Publication No. CN112457235B discloses a method using 3,5-dimethyl-4-nitrobenzene ether as a raw material, reacting it with DMF-DMA and pyrrolidine in toluene to generate an intermediate, followed by reduction of the nitro group by palladium on carbon under a hydrogen atmosphere, and intramolecular cyclization to obtain the target product. The limitations of this route are: (1) it requires the use of an expensive palladium on carbon catalyst, resulting in high cost, and heavy metal removal is required in the later stage; (2) post-processing requires purification by silica gel column chromatography, making it difficult to achieve large-scale industrial production.

[0006]

[0007] Therefore, developing a method for preparing 5-methoxy-7-methylindole that has mild reaction conditions, low cost, safe operation, and is suitable for industrial production has important practical application value. Summary of the Invention

[0008] To address the shortcomings of existing technologies, this invention provides a method for synthesizing 5-methoxy-7-methylindole, a key intermediate in iprodione, as follows:

[0009] A method for synthesizing 5-methoxy-7-methylindole, a key intermediate in iprodione, includes the following steps:

[0010] Step 1: In the first solvent, add the first base, m-cresol and methylating agent to react and generate m-methyl anisole;

[0011] Step 2: Add m-methyl anisole to the second solvent, add a brominating agent to react, and generate 2-bromo-5-methoxytoluene;

[0012] Step 3: Add 2-bromo-5-methoxytoluene, aminoacetaldehyde dimethyl acetal, copper catalyst, ligand and second base to the third solvent, and heat to react and generate N-(2,2-dimethoxyethyl)-4-methoxy-2-methylaniline;

[0013] Step 4: Dissolve N-(2,2-dimethoxyethyl)-4-methoxy-2-methylaniline in a fourth solvent and perform a cyclization reaction under acid catalysis to generate 5-methoxy-7-methylindole.

[0014] As a further embodiment of the present invention, in step 1, the reaction temperature is 40-120℃;

[0015] The methylating agent is dimethyl sulfate or iodomethane;

[0016] The first alkali is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate;

[0017] The molar ratio of m-cresol to the first base is 1:(1.05-2.5);

[0018] The first solvent is one or more of water, dichloromethane, toluene, methanol, and ethanol.

[0019] As a further embodiment of the present invention, in step 2, the reaction temperature is 10~40℃;

[0020] The brominating agent is one or more of liquid bromine, N-bromosuccinimide, and dibromohydantoin;

[0021] The molar ratio of m-methyl anisole to the brominated reagent is 1:(1.05-1.2);

[0022] The second solvent is one or more of acetone, toluene, and acetonitrile.

[0023] As a further embodiment of the present invention, in step 3, the reaction temperature is 80-110℃;

[0024] The molar ratio of 2-bromo-5-methoxytoluene, aminoacetaldehyde dimethyl acetal, copper catalyst, ligand, and second base is 1:(1.2-3):(0.05-0.2):(0.1-0.3):(1.5-4);

[0025] The copper catalyst is one of cuprous iodide, cuprous chloride, copper bromide, and copper acetate;

[0026] The ligand is one of N,N,N',N'-tetramethylethylenediamine, N,N'-dimethylethylenediamine, L-proline, and triphenylphosphine;

[0027] The second alkali is one or more of potassium phosphate, potassium hydroxide, potassium carbonate, and sodium carbonate;

[0028] The third solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, toluene, and isopropanol.

[0029] As a further embodiment of the present invention, in step 4, the acid used for acid catalysis is one or more of the following: zinc chloride, aluminum trichloride, polyphosphoric acid, trifluoromethanesulfonic acid, trifluoroacetic anhydride and trifluoroacetic acid.

[0030] The fourth solvent is one or more of trifluoroacetic acid, toluene, dichloromethane, and methyl tert-butyl ether.

[0031] As a further aspect of the present invention, after the reaction in step 1 is completed, water is added at room temperature for post-treatment.

[0032] As a further embodiment of the present invention, the molar ratio of the copper catalyst to 2-bromo-5-methoxytoluene in step 3 is 0.05-0.15:1.

[0033] As a further embodiment of the present invention, the copper catalyst in step 3 is cuprous iodide, the ligand is L-proline, the second base is potassium carbonate, and the third solvent is dimethyl sulfoxide.

[0034] As a further embodiment of the present invention, the acid used for acid catalysis in step 4 is a combination of trifluoroacetic anhydride and trifluoroacetic acid, and the fourth solvent is trifluoroacetic acid.

[0035] As a further embodiment of the present invention, the acid used for acid catalysis in step 4 is anhydrous zinc chloride, and the fourth solvent is methyl tert-butyl ether.

[0036] The reaction equation of this invention is as follows:

[0037]

[0038] Compared with the prior art, the beneficial effects of the present invention are:

[0039] This invention uses readily available and inexpensive m-cresol as a starting material to synthesize 5-methoxy-7-methylindole through a four-step reaction involving methylation, bromination, Ullmann reaction, and acid-catalyzed cyclization, achieving an overall yield of 71.0%, with the purified product purity exceeding 99%. This method employs mild reaction conditions, uses substrates that meet economic and environmental requirements, and features safe and simple reaction operations and post-processing. The purification steps are straightforward, with few byproducts and high yield. It also exhibits low corrosivity to equipment, requires no special equipment, and has significant application value. Attached Figure Description

[0040] Figure 1 This is the NMR spectrum of the product obtained in Example 3 according to condition 1.

[0041] Figure 2 This is the NMR spectrum of the product obtained in Example 4 according to condition 9. Detailed Implementation

[0042] The present invention will be described in detail below with reference to specific embodiments. These embodiments are merely some, not all, implementations of the present invention. All other implementations obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0043] Example 1: Synthesis of m-methyl anisole

[0044] At room temperature, 400 mL of 3 mol / L sodium hydroxide aqueous solution and m-cresol (108.1 g, 1.0 mol) were added sequentially to a three-necked flask, followed by the slow addition of dimethyl sulfate (126.1 g, 1.0 mol). After the addition was complete, the mixture was stirred at 40 °C for 3 hours, and TLC showed no significant residue of the raw material. 17 mL of concentrated hydrochloric acid (36%–38% by mass) was added to adjust the pH to 6–7. The mixture was extracted twice with methyl tert-butyl ether, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated by rotary evaporation to obtain a colorless and transparent liquid m-methyl anisole (120.0 g, yield: 98.2%).

[0045] Example 2: Synthesis of 2-bromo-5-methoxytoluene

[0046] At room temperature, 300 mL of acetonitrile and m-methyl anisole (100.0 g, 818.6 mmol) were added sequentially to a three-necked flask. NBS (N-bromosuccinimide, 160.3 g, 900.5 mmol, 1.1 Eq) was added in portions at room temperature. After the addition was complete, the mixture was stirred at room temperature for 6 hours. TLC showed no significant residue of the starting material. The mixture was concentrated and then added to 300 mL of distilled water and 200 mL of methyl tert-butyl ether. The mixture was separated, and the aqueous phase was extracted twice with methyl tert-butyl ether. The organic phase was collected, washed with saturated brine (room temperature), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated by rotary evaporation to obtain a yellow liquid, 2-bromo-5-methoxytoluene (160.5 g, yield: 97.5%).

[0047] Example 3: Synthesis of N-(2,2-dimethoxyethyl)-4-methoxy-2-methylaniline

[0048] Condition 1: At room temperature, 450 mL of DMSO (dimethyl sulfoxide), 2-bromo-5-methoxytoluene (150.0 g, 746.0 mmol), aminoacetaldehyde dimethyl acetal (156.9 g, 1.49 mol, 2.0 eq), cuprous iodide (14.2 g, 74.6 mmol, 0.1 eq), L-proline (17.2 g, 149 mmol, 0.2 eq), and potassium carbonate (309 g, 2.24 mol, 3.0 eq) were added sequentially to a three-necked flask. After purging with nitrogen, the mixture was heated to 110 °C and stirred for 12 hours. TLC showed no significant residue of the starting material. After cooling to room temperature, ethyl acetate (450 mL) and water (1500 mL) were added and separated. The aqueous phase was extracted twice with ethyl acetate. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated by rotary evaporation to obtain reddish-brown oily N-(2,2-dimethoxyethyl)-4-methoxy-2-methylaniline (168.3 g, yield: 95.8%).

[0049] ¹H NMR (300MHz, Chloroform-d) δ 6.71–6.68 (m, 2H), 6.58–6.56 (m, 1H), 4.63–4.60 (t, J=6.0Hz, 1H), 3.75 (s, 3H), 3.42 (s, 6H), 3.25–3.23 (d, J=6.0Hz, 2H), 2.15 (s, 3H). See NMR spectrum for details. Figure 1 .

[0050] Condition 2: At room temperature, 10 mL of DMSO, 1.0 g (4.97 mmol) of 2-bromo-5-methoxytoluene, 1.05 g (9.95 mmol, 2.0 eq) of aminoacetaldehyde dimethyl acetal, and 2.06 g (14.91 mmol, 3.0 eq) of potassium carbonate were added sequentially to a three-necked flask. After purging with nitrogen, the temperature was raised to 110 °C and stirred for 12 hours. TLC showed that all components were from the starting material, with no obvious new spots formed.

[0051] Condition 3: At room temperature, 10 mL of DMSO, 1.0 g (4.97 mmol) of 2-bromo-5-methoxytoluene, 1.05 g (9.95 mmol, 2.0 eq) of aminoacetaldehyde dimethyl acetal, and 2.06 g (14.91 mmol, 3.0 eq) of potassium carbonate were added sequentially to a three-necked flask. After purging with nitrogen, the temperature was raised to 150 °C and stirred for 12 hours. TLC showed that all components were from the starting material, with no obvious new spots formed.

[0052] Condition 4: At room temperature, 10 mL of DMF, 1.0 g (4.97 mmol) of 2-bromo-5-methoxytoluene, 1.05 g (9.95 mmol, 2.0 eq) of aminoacetaldehyde dimethyl acetal, and 2.06 g (14.91 mmol, 3.0 eq) of potassium carbonate were added sequentially to a three-necked flask. After purging with nitrogen, the temperature was raised to 150 °C and stirred for 12 hours. TLC showed that all the reactants were the starting materials, and no obvious new spots were formed.

[0053] Condition 5: At room temperature, 10 mL of DMSO, 2-bromo-5-methoxytoluene (1.0 g, 4.97 mmol), aminoacetaldehyde dimethyl acetal (1.05 g, 9.95 mmol, 2.0 eq), cuprous iodide (95.2 mg, 0.5 mmol, 0.1 eq), L-proline (115 mg, 1.0 mmol, 0.2 eq), sodium iodide (150 mg, 1.0 mmol, 0.2 eq), and potassium carbonate (2.06 g, 14.91 mmol, 3.0 eq) were added sequentially to a three-necked flask. After purging with nitrogen, the mixture was heated to 110 °C and stirred for 12 hours. TLC showed no significant residue of the starting material. After cooling to room temperature, ethyl acetate (15 mL) and water (50 mL) were added and separated. The aqueous phase was extracted twice with ethyl acetate. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated by rotary evaporation to obtain reddish-brown oily N-(2,2-dimethoxyethyl)-4-methoxy-2-methylaniline (1.06 g, yield: 94.6%).

[0054] Condition 6: At room temperature, 10 mL of DMSO, 2-bromo-5-methoxytoluene (1.0 g, 4.97 mmol), aminoacetaldehyde dimethyl acetal (1.05 g, 9.95 mmol, 2.0 eq), cuprous iodide (95.2 mg, 0.5 mmol, 0.1 eq), sodium iodide (150 mg, 1.0 mmol, 0.2 eq), and potassium carbonate (2.06 g, 14.91 mmol, 3.0 eq) were added sequentially to a three-necked flask. After purging with nitrogen, the temperature was raised to 150 °C and stirred for 12 hours. TLC showed that all components were from the starting material, with no obvious new spots formed.

[0055] Condition 7: At room temperature, 10 mL of DMSO, 2-bromo-5-methoxytoluene (1.0 g, 4.97 mmol), aminoacetaldehyde dimethyl acetal (1.05 g, 9.95 mmol, 2.0 eq), cuprous iodide (95.2 mg, 0.5 mmol, 0.1 eq), TMEDA (N,N,N',N'-tetramethylethylenediamine, 116 mg, 1.0 mmol, 0.2 eq), sodium iodide (150 mg, 1.0 mmol, 0.2 eq), and potassium carbonate (2.06 g, 14.91 mmol, 3.0 eq) were added sequentially to a three-necked flask. After purging with nitrogen, the mixture was heated to 110 °C and stirred for 12 hours. TLC showed no significant residue of the starting material. After cooling to room temperature, ethyl acetate (15 mL) and water (50 mL) were added and separated. The aqueous phase was extracted twice with ethyl acetate. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated by rotary evaporation to obtain reddish-brown oily N-(2,2-dimethoxyethyl)-4-methoxy-2-methylaniline (0.97 g, yield: 86.6%).

[0056] Condition 8: At room temperature, 10 mL of DMSO, 2-bromo-5-methoxytoluene (1.0 g, 4.97 mmol), aminoacetaldehyde dimethyl acetal (1.05 g, 9.95 mmol, 2.0 eq), cuprous iodide (95.2 mg, 0.5 mmol, 0.1 eq), L-proline (115 mg, 1.0 mmol, 0.2 eq), sodium iodide (150 mg, 1.0 mmol, 0.2 eq), and tripotassium phosphate (3.16 g, 14.91 mmol, 3.0 eq) were added sequentially to a three-necked flask. After purging with nitrogen, the mixture was heated to 110 °C and stirred for 12 hours. TLC showed no significant residue of the starting material. After cooling to room temperature, ethyl acetate (15 mL) and water (50 mL) were added and separated. The aqueous phase was extracted twice with ethyl acetate. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated by rotary evaporation to obtain reddish-brown oily N-(2,2-dimethoxyethyl)-4-methoxy-2-methylaniline (0.89 g, yield: 79.5%).

[0057] Example 4: Synthesis of 5-methoxy-7-methylindole

[0058] Condition 9: N-(2,2-dimethoxyethyl)-4-methoxy-2-methylaniline (150.0 g, 665.8 mmol) was mixed with trifluoroacetic anhydride (TFAA, 250 mL) and trifluoroacetic acid (TFA, 500 mL) and heated under reflux for 24 hours. TLC showed no significant residue of the starting material. The mixture was cooled to room temperature and quenched with ice water. The precipitate was collected by filtration and washed with water. The precipitate was dissolved in 10% potassium hydroxide aqueous solution (500 mL) and methanol (300 mL) and stirred at room temperature for 2 hours. The methanol was removed by vacuum distillation, and the resulting aqueous phase was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried, filtered, and the solvent was removed by vacuum distillation. The crude product was dissolved in 400 mL of toluene, 15 g of activated carbon was added, and the mixture was heated to 60 °C and stirred for 1 hour. The mixture was filtered while hot, and the mother liquor was cooled to crystallize. The solid was collected by filtration and dried to give a brown solid 5-methoxy-7-methylindole (82.3 g, yield: 76.7%).

[0059] ¹H NMR (300MHz, Chloroform-d) δ 7.98 (br, 1H), 7.26–7.18 (m, 1H), 6.96 (s, 1H), 6.69 (s, 1H), 6.50–6.49 (m, 1H), 3.85 (s, 3H), 2.47 (s, 3H). See NMR spectrum for details. Figure 2 .

[0060] Condition 10: N-(2,2-dimethoxyethyl)-4-methoxy-2-methylaniline (5.0 g, 22.2 mmol) and trifluoroacetic acid (TFA, 50 mL) were mixed and heated under reflux for 24 hours. TLC showed that the mixture was all raw material and no obvious new spots were formed.

[0061] Condition 11: At room temperature, 10 mL of methyl tert-butyl ether and anhydrous zinc chloride (18.15 g, 133 mmol, 6.0 eq) were added sequentially to a three-necked flask, and the mixture was heated to 60-65 °C. While stirring, a solution of N-(2,2-dimethoxyethyl)-4-methoxy-2-methylaniline (5.0 g, 22.2 mmol) in methyl tert-butyl ether (10 mL) was added dropwise. After the addition was complete, the reaction mixture was stirred at 60-65 °C for 20 hours, and TLC showed no significant residue of the starting material. The mixture was cooled to room temperature and quenched with ice water. The precipitate was collected by filtration and washed with water. The precipitate was dissolved in 10% potassium hydroxide aqueous solution (15 mL) and methanol (10 mL), and stirred at room temperature for 2 hours. The methanol was removed by vacuum distillation, the resulting aqueous phase was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water, dried, filtered, and the solvent was removed by vacuum distillation. The crude product was dissolved in 12 mL of toluene, 1 g of activated carbon was added, the mixture was heated to 60 °C and stirred for 1 hour. The mixture was filtered while hot, and the mother liquor was cooled to crystallize. The solid was collected by filtration and dried to obtain a brown solid 5-methoxy-7-methylindole (2.61 g, yield: 72.9%).

[0062] Condition 12: N-(2,2-dimethoxyethyl)-4-methoxy-2-methylaniline (5.0 g, 22.2 mmol) was mixed with acetic anhydride (Ac2O, 10 mL) and trifluoroacetic acid (TFA, 25 mL) and heated under reflux for 24 hours. TLC showed that the mixture was all raw material and no obvious new spots were formed.

[0063] The optimal overall yield for the four steps was calculated to be 98.2% × 97.5% × 95.8% × 76.7% = 70.4% (based on m-cresol).

[0064] In the above embodiments, the inventors conducted multiple sets of comparative experiments on the selectivity of the catalyst, ligand, base, and solvent in Example 3 (Step 3) of the present invention, as shown in Table 1:

[0065] Table 1

[0066]

[0067] The following conclusions can be drawn from Table 1:

[0068] (1) The synergistic effect of the catalyst and ligand is a necessary condition for the reaction to occur. As shown in conditions 2-4, without the addition of copper catalyst and ligand, even if the temperature is raised to 150°C or the solvent is changed to DMF, the reactants do not react at all. This indicates that for the specific substrate 2-bromo-5-methoxytoluene of this invention, the Ullmann reaction is not a conventionally expected reaction in the art, and a specific catalytic system is required to achieve the efficient construction of CN bonds. The CuI / L-proline catalytic combination used in this invention is the key to overcoming this technical obstacle.

[0069] (2) The choice of ligand has a significant impact on the reaction yield. Comparing condition 1 (L-proline, yield 95.8%) with condition 7 (TMEDA, yield 86.6%), it can be seen that, under the same amount of catalyst, the yield difference caused by different ligands is nearly 10 percentage points. L-proline is far superior to TMEDA, which is also a commonly used ligand in the Ullmann reaction.

[0070] (3) The addition of additives did not produce a substantial promoting effect. Condition 5, based on condition 1, added NaI, and the yield was 94.6%, which is basically equivalent to the 95.8% of condition 1, indicating that NaI has no significant promoting effect on the reaction. This finding simplifies the reaction system, avoids the use of unnecessary additives, and reflects the simplicity and economy of the technical solution of this invention.

[0071] (4) The type of base has a decisive influence on the reaction effect. Comparing condition 1 (K2CO3, yield 95.8%) and condition 8 (K3PO4, yield 79.5%), it can be seen that, as inorganic bases, potassium carbonate is far more effective than tripotassium phosphate, with a yield difference of more than 16 percentage points.

[0072] In summary, the "CuI / L-proline / K2CO3 / DMSO / 110℃" catalytic system determined in step 3 (Example 3) of this invention is the optimal scheme for the Ullmann coupling reaction of 2-bromo-5-methoxytoluene and aminoacetaldehyde dimethyl acetal. Furthermore, this scheme achieves a high yield of 95.8% even under mild conditions.

[0073] To illustrate the selectivity of the acid catalytic system in step 4 (Example 4), the inventors conducted comparative experiments, the results of which are shown in Table 2:

[0074] Table 2

[0075]

[0076] The following conclusions can be drawn from Table 2:

[0077] (1) The choice of a strong acid system is crucial for the success of the ring-closing reaction. As shown in condition 10, when trifluoroacetic acid (TFA) is used alone as an acid catalyst, the starting material does not undergo a ring-closing reaction even after prolonged reflux heating. However, in condition 9, the combination of trifluoroacetic anhydride (TFAA) and trifluoroacetic acid (TFA) successfully yields the target product 5-methoxy-7-methylindole in 76.7%. This indicates that the acidity of TFA alone is insufficient to drive the ring-closing process, and the addition of TFAA plays a key role. The mechanism of action may be that TFAA first reacts with the dimethoxyethylamine side chain of the substrate to form a more reactive intermediate (such as an imine or acylated product), thereby lowering the energy barrier of the ring-closing reaction and allowing the subsequent Friedel-Crafts cyclization to occur smoothly.

[0078] (2) Lewis acid systems can serve as an effective alternative. Condition 11 uses anhydrous zinc chloride (ZnCl2) as a Lewis acid catalyst, reacting in methyl tert-butyl ether solvent at 60-65°C, and the target product can still be obtained in 72.9% yield. This approach avoids the use of highly corrosive trifluoroacetic acid, has a lower reaction temperature, and is safer to operate, providing another feasible technical route for industrial production.

[0079] (3) Condition 12 shows that the combination of acetic anhydride (Ac2O) and TFA cannot promote the reaction. This indicates that not any combination of acid anhydride and TFA can achieve this ring-closure reaction, and TFAA plays an irreplaceable role in it due to its special reactivity and structural characteristics.

[0080] (4) As can be seen from conditions 9-12, the substrate N-(2,2-dimethoxyethyl)-4-methoxy-2-methylaniline of this invention exhibits high selectivity for acid systems during acid-catalyzed cyclization. Conventional acidic conditions (such as TFA alone) cannot achieve the conversion, while the TFAA / TFA combination or ZnCl2 / methyl tert-butyl ether system screened in this invention can effectively complete the cyclization with ideal yields.

[0081] Compared to existing technologies that require expensive palladium hydrogenation reduction on carbon and column chromatography purification, the cyclization reaction in step 4 of this invention can be completed under conventional reflux or 60-65°C conditions with a common acid catalyst. The post-processing only involves quenching, extraction, and activated carbon decolorization and crystallization, without the need for chromatographic purification.

[0082] Furthermore, it should be understood that those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other implementation methods that can be understood by those skilled in the art.

Claims

1. A method for synthesizing 5-methoxy-7-methylindole, a key intermediate in iprodione, characterized in that, Includes the following steps: Step 1: In the first solvent, add the first base, m-cresol and methylating agent to react and generate m-methyl anisole; Step 2: Add m-methyl anisole to the second solvent, add a brominating agent to react, and generate 2-bromo-5-methoxytoluene; Step 3: Add 2-bromo-5-methoxytoluene, aminoacetaldehyde dimethyl acetal, copper catalyst, ligand and second base to the third solvent, and heat to react and generate N-(2,2-dimethoxyethyl)-4-methoxy-2-methylaniline; Step 4: Dissolve N-(2,2-dimethoxyethyl)-4-methoxy-2-methylaniline in a fourth solvent and perform a cyclization reaction under acid catalysis to generate 5-methoxy-7-methylindole.

2. The method for synthesizing 5-methoxy-7-methylindole, a key intermediate of iprocoprine, according to claim 1, is characterized in that: In step 1, the reaction temperature is 40-120℃; And / or, The methylating agent is dimethyl sulfate or iodomethane; And / or, The first alkali is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate; And / or, The molar ratio of m-cresol to the first base is 1:(1.05-2.5); And / or, The first solvent is one or more of water, dichloromethane, toluene, methanol, and ethanol.

3. The method for synthesizing 5-methoxy-7-methylindole, a key intermediate of iprocoprine, according to claim 1, is characterized in that: In step 2, the reaction temperature is 10~40℃; And / or, The brominating agent is one or more of liquid bromine, N-bromosuccinimide, and dibromohydantoin; And / or, The molar ratio of m-methyl anisole to the brominated reagent is 1:(1.05-1.2); And / or, The second solvent is one or more of acetone, toluene, and acetonitrile.

4. The method for synthesizing 5-methoxy-7-methylindole, a key intermediate of iprocoprine, according to claim 1, is characterized in that: In step 3, the reaction temperature is 80-110℃; And / or, The molar ratio of 2-bromo-5-methoxytoluene, aminoacetaldehyde dimethyl acetal, copper catalyst, ligand, and second base is 1:(1.2-3):(0.05-0.2):(0.1-0.3):(1.5-4); And / or, The copper catalyst is one of cuprous iodide, cuprous chloride, copper bromide, and copper acetate; And / or, The ligand is one of N,N,N',N'-tetramethylethylenediamine, N,N'-dimethylethylenediamine, L-proline, and triphenylphosphine; And / or, The second alkali is one or more of potassium phosphate, potassium hydroxide, potassium carbonate, and sodium carbonate; And / or, The third solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, toluene, and isopropanol.

5. The method for synthesizing 5-methoxy-7-methylindole, a key intermediate of iprodione, according to claim 1, is characterized in that: In step 4, the acid used for acid catalysis is one or more of the following: zinc chloride, aluminum trichloride, polyphosphoric acid, trifluoromethanesulfonic acid, trifluoroacetic anhydride and trifluoroacetic acid. And / or, The fourth solvent is one or more of trifluoroacetic acid, toluene, dichloromethane, and methyl tert-butyl ether.

6. The method for synthesizing 5-methoxy-7-methylindole, a key intermediate of iprocoprine, according to claim 1, is characterized in that: After the reaction in step 1 is completed, water is added at room temperature for post-treatment.

7. The method for synthesizing 5-methoxy-7-methylindole, a key intermediate of iprodione, according to claim 1, is characterized in that: The molar ratio of the copper catalyst to 2-bromo-5-methoxytoluene in step 3 is 0.05-0.15:

1.

8. The method for synthesizing 5-methoxy-7-methylindole, a key intermediate of iprodione, according to claim 4, is characterized in that: The copper catalyst in step 3 is cuprous iodide, the ligand is L-proline, the second base is potassium carbonate, and the third solvent is dimethyl sulfoxide.

9. The method for synthesizing 5-methoxy-7-methylindole, a key intermediate of iprodione, according to claim 5, is characterized in that: In step 4, the acid used for acid catalysis is a combination of trifluoroacetic anhydride and trifluoroacetic acid, and the fourth solvent is trifluoroacetic acid.

10. The method for synthesizing 5-methoxy-7-methylindole, a key intermediate of iprocoprine, according to claim 5, characterized in that: In step 4, the acid used for acid catalysis is anhydrous zinc chloride, and the fourth solvent is methyl tert-butyl ether.

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