A method for microwave-assisted bromination of 1,5,6,7-tetrahydro-4h-indol-4-one derivatives

Abstract

The application discloses a microwave-assisted bromination method of 1,5,6,7-tetrahydro-4H-indole-4-ketone derivative, and provides synthesis schemes of two types of compounds (II and III). The synthesis of the compound II is as follows: tetrahydroindole ketone derivative is used as a starting material, is reacted with N-bromosuccinimide under microwave conditions to obtain a bromination crystallization mother liquor of formula (II) and formula (III), the crystallization mother liquor is used as a raw material, pH is adjusted to weak alkalinity, diethyl phosphite is added under microwave conditions to perform selective debromination reaction, the dibromide by-product shown in formula (III) is converted into the target product (II), and the synthesis of the compound III is as follows: the above crystallization mother liquor is used as a raw material, N-bromosuccinimide is additionally added under higher microwave power to convert formula (II) into formula (III), and the structural formula of the compound is as follows: The application has the characteristics of simple process, mild condition, convenient operation, economy and environmental protection, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, specifically relating to a microwave-assisted bromination method for 1,5,6,7-tetrahydro-4H-indole-4-one derivatives. Background Technology

[0002] Currently, indole derivatives play an important role in pharmaceuticals, dyes, and fragrances. Notably, a significant number of studies have shown that certain indole compounds, such as 4-substituted indoles and their 5-brominated derivatives, possess unique antidepressant effects, solidifying their status as high-value-added fine chemical products. Tetrahydroindole ketones are important intermediates in the synthesis of 4-substituted indoles and their 5-brominated derivatives, typically achieved through aromatization followed by dehydrobromination.

[0003] The key intermediates for 4-substituted indole and its 5-brominated derivative are compounds II and III, with the following structural formulas:

[0004]

[0005] Currently, there are few synthetic methods for compounds (II) and (III), and copper bromide reagent is mainly used. However, these methods have drawbacks such as poor selectivity, difficult post-processing, high levels of waste, and difficulty in industrialization.

[0006] In 2009, Hansen et al., while studying the total synthesis of 1,3,4,5-tetrahydrobenzoindole β-one, provided a method for synthesizing 5-bromo-1-methylbenzenesulfonyl-1,5,6,7-tetrahydro-4H-4-one, using ethyl acetate as solvent and copper bromide as brominating agent, with bromination completed under reflux conditions. Although the procedure is simple, the atom utilization rate is low, and it easily generates compounds with dibromo substitution at the 5-position, requiring careful monitoring of the reaction and posing significant challenges for industrialization (Tetrahedron Lett., 2009, 50, 6506-6508.). The reaction route is as follows:

[0007]

[0008] In 2017, Morikawa et al., while studying the total synthesis of carbazolemycin A and B, provided a scheme for the dibromination of the α-position of a ketone, using ethyl acetate as solvent and copper bromide as the brominating agent, completing the bromination under reflux conditions. Although the yield was considerable, it suffered from drawbacks such as high copper bromide consumption, difficult post-processing, high levels of waste, and significant challenges to industrialization (Chem. Pharm. Bull., 2018, 66, 178-183). The reaction route is as follows:

[0009]

[0010] When the target compound is a monobrominated product, the dibrominated product is mixed in the product as a byproduct. Commonly used recrystallization purification methods often result in huge product losses, so debromination schemes should be considered.

[0011] In 2006, Kalicaran et al. reported a microwave-mediated ionic liquid debromination method. A mixture of 2,2-dibromo-1-phenylethyl ketone and 1-methyl-3-pentylimidazolium tetrafluoroborate was dissolved in water and heated under microwave irradiation. The product, 2-bromo-1-phenylethyl ketone, was generated after 2-3 minutes of heating, followed by further reaction for 3-4 minutes to produce acetophenone. Although the efficiency was considerable and the reaction was rapid, it was prone to removing both bromines, posing a significant risk for industrial application (Tetrahedron, 2007, 63, 155-159). The reaction route is as follows:

[0012]

[0013] In 2017, Beeraiah et al. reported a method for the monohalogenation of 2,2-dibromo-1-phenylethylone. The substrate 2,2-dibromo-1-phenylethylone was placed in a solvent of acetonitrile to water in a 1:1 ratio, and the mixture was refluxed at 100°C to obtain 2-bromo-1-phenylethylone with a conversion of 65%. Although the reaction system and conditions are easy to meet, the conversion rate is low, purification losses are significant, and the overall cost is relatively high (Advanced Synthesis & Catalysis, 2017, 360, 298-304). The reaction route is as follows:

[0014] Summary of the Invention

[0015] The purpose of this invention is to provide a microwave-assisted bromination method for 1,5,6,7-tetrahydro-4H-indole-4-one derivatives. This method is characterized by its simplicity, mild conditions, ease of operation, economic efficiency, environmental friendliness, and suitability for industrial production.

[0016] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0017] A microwave-assisted bromination method for 1,5,6,7-tetrahydro-4H-indole-4-one derivatives includes: using a tetrahydroindole ketone compound of formula (I) as a raw material, reacting it with a brominating reagent in an organic solvent under microwave conditions to obtain a brominated 1,5,6,7-tetrahydro-4H-indole-4-one derivative of formula (III) or a mixture of formulas (II) and (III); adjusting the pH of the mixture of formulas (II) and (III) to alkaline by adding alkali, and then reacting it with diethyl phosphite under microwave conditions to completely convert it into a brominated 1,5,6,7-tetrahydro-4H-indole-4-one derivative of formula (II).

[0018] The reaction equation is as follows:

[0019]

[0020] In the formula, the substituent R is a halogen-substituted C1-C2 alkyl acyl group, a C1-C2 alkyl-substituted benzenesulfonyl group, a phenyl-substituted C1-C2 alkyl group, or a phenyl-substituted C1-C2 alkoxycarbonyl group.

[0021] Preferably, the substituent R is selected from trifluoroacetyl (Tfa), p-toluenesulfonyl (Ts), benzyloxycarbonyl (Cbz), or benzyl (Bn).

[0022] Furthermore, when preparing the dibromo-1,5,6,7-tetrahydro-4H-indole-4-one derivatives of formula (III), a two-step method is preferably adopted, comprising: first, using the tetrahydroindole one compound of formula (I) as a raw material, and carrying out a bromination reaction with a brominating reagent in an organic solvent under microwave conditions I until the compound of formula (I) reacts completely; second, continuing to add a brominating reagent and carrying out the bromination reaction under microwave conditions II, finally obtaining the dibromo-1,5,6,7-tetrahydro-4H-indole-4-one derivatives of formula (III).

[0023] Preferably, in the stepwise method for preparing the dibromo-1,5,6,7-tetrahydro-4H-indole-4-one derivatives of formula (III) described above, the temperature of the first step reaction is -10°C to 30°C, preferably 5°C to 15°C. Microwave condition I is a microwave power of 100 to 900 W, preferably 200 to 400 W. The temperature of the second step reaction is -10°C to 30°C, preferably 10 to 20°C, and microwave condition II is a microwave power of 100 to 900 W, preferably 400 to 600 W.

[0024] When using the above method, the molar ratio of the brominating reagent in the first step and the compound shown in formula (I) is 1 to 1.3:1, and more preferably 1.1 to 1.3:1.

[0025] Furthermore, when preparing the monobromo-1,5,6,7-tetrahydro-4H-indole-4-one derivatives of formula (II), a two-step method is preferred. First, using the tetrahydroindole one compound of formula (I) as a raw material, a bromination reaction is carried out with a brominating reagent in an organic solvent under microwave conditions I until the compound of formula (I) reacts completely. The mixture is then filtered, and the reaction solution is washed with water. Second, the pH of the resulting reaction solution is adjusted to a weakly alkaline state, and then reacted with diethyl phosphite under microwave conditions II to finally obtain the monobromo-1,5,6,7-tetrahydro-4H-indole-4-one derivative of formula (II).

[0026] Preferably, in the stepwise method for preparing the monobrominated 1,5,6,7-tetrahydro-4H-indole-4-one derivatives of formula (II) described above, the temperature of the first step reaction is -10°C to 30°C, preferably 5°C to 15°C. Microwave condition I is a microwave power of 100 to 900 W, preferably 200 to 400 W. The temperature of the second step reaction is 20°C to 70°C, preferably 40 to 50°C, and microwave condition II is a microwave power of 100 to 900 W, preferably 200 to 400 W.

[0027] When using the above method, the molar ratio of the brominating reagent to the compound shown in formula (I) in the first step is 1 to 1.3:1, more preferably 1.1 to 1.3:1; the molar ratio of diethyl phosphite to the compound shown in formula (III) in the reaction solution in the second step is 0.9 to 4.0:1, more preferably 1.6 to 2.1:1.

[0028] The brominating reagent is N-bromosuccinimide (NBS). The brominating reagent can be added dropwise after being dissolved in an organic solvent, and the dropping temperature can be selected to be consistent with the temperature of the subsequent reaction.

[0029] As a specific implementation scheme, the process is as follows: Using the tetrahydroindolone compound represented by formula (I) as a raw material, a bromination reaction is carried out with N-bromosuccinimide (NBS) in an organic solvent under microwave conditions to obtain formulas (II) and (III). The reaction solution is divided into two batches or carried out separately under the two schemes. After removing some impurities in the first batch, the pH is adjusted to weakly alkaline, and then diethyl phosphite is added to the reaction solution under microwave conditions to selectively convert compound (III) into compound (II), followed by separation and purification to obtain the target product (II). The second batch continues to undergo a bromination reaction with N-bromosuccinimide under microwave conditions to obtain formula (III), followed by separation and purification to obtain the target product (III), specifically including the following steps:

[0030] Step 1: Under microwave conditions, the tetrahydroindolone derivative shown in formula (Ⅰ) is added to solvent A, and the solution of brominated reagent NBS in solvent A is added dropwise under controlled temperature. After the addition is completed, the reaction is kept at the temperature until the TLC detection shows no trace of formula (Ⅰ), which is the reaction endpoint. After the reaction is completed, the reaction solution is divided into two equal batches. The first batch is filtered, washed with water, and the content of each component is detected by HPLC.

[0031] Step 2: Add base B to the first batch of reaction solution to adjust the pH to weakly alkaline, then add diethyl phosphite dropwise under controlled temperature. After the addition is complete, keep the temperature and react until TLC detection shows no reaction of formula (III), which is the reaction endpoint. After the reaction is complete, concentrate to remove most of the solvent, then add water to slurry, filter and wash the filter cake with water, and dry the filter cake to obtain the compound shown in formula (II).

[0032] Step 3: The second batch of reaction solution was added dropwise with solvent A of brominated reagent NBS under microwave temperature control. After the addition was completed, the reaction was kept at the temperature until TLC detection showed no reaction of formula (II), which was the reaction endpoint. After the reaction was completed, the solution was filtered, the filtrate was concentrated to half, cooled to crystallize, filtered again, and the filter cake was dried to obtain the compound shown in formula (III).

[0033] In step 1, solvent A is one or more of dichloromethane, dichloroethane, chloroform, ethyl acetate, methyl propionate, tetrahydrofuran, and N,N-dimethylformamide, preferably dichloromethane or dichloroethane.

[0034] In step 2, the base B is one or more of triethylamine, ethylenediamine, pyridine, sodium bicarbonate, sodium carbonate, and potassium carbonate, preferably triethylamine or ethylenediamine.

[0035] In step 3, the crystallization temperature is -20 to 20°C, preferably -5 to 5°C.

[0036] As a preferred embodiment, a method for synthesizing monobromo-1,5,6,7-tetrahydro-4H-indole-4-one derivatives of formula (II) includes:

[0037] (1) Add tetrahydroindole ketone (I) and dichloroethane to a four-necked flask, stir and cool to 10°C. Simultaneously, prepare a dichloroethane solution of NBS at a molar ratio of 1:1.2 (raw material: NBS). Slowly add the NBS solution dissolved in dichloroethane to the four-necked flask at 200W microwave power while maintaining the temperature at 10°C. Continue the reaction until no raw material is detected by TLC. After the reaction is complete, filter and wash the reaction solution with water. Analyze the composition of the reaction solution using HPLC.

[0038] (2) Adjust the pH of the above-treated reaction solution to 8-9 with triethylamine. Calculate the content of compound (III) using HPLC data. Add diethyl phosphite to the reaction solution at a molar ratio of compound (III): diethyl phosphite of 1:1.8. React at 45℃ under 300W microwave power until no single impurities are detected by TLC. After the reaction is complete, concentrate under reduced pressure to a paste, add cold water to slurry, filter, and wash the filter cake with hot water and dry to obtain compound (II).

[0039] A method for synthesizing dibromo-1,5,6,7-tetrahydro-4H-indole-4-one derivatives of formula (III), comprising:

[0040] (1) Add the raw material tetrahydroindole ketone (Ⅰ) and solvent dichloroethane to the four-necked flask, stir and cool to 10°C. At the same time, take NBS according to the molar ratio of raw material to NBS of 1:1.2 and prepare it as a dichloroethane solution. Control the temperature at 10°C and slowly add the NBS reagent dissolved in dichloroethane to the four-necked flask under a microwave power of 200W. After the addition is completed, continue the reaction until no raw material is detected by TLC.

[0041] (2) Under microwave power of 500W and controlled temperature of 15℃, NBS reagent dissolved in dichloroethane was slowly added dropwise to the second batch of reaction solution. After the addition was completed, the reaction was continued until no formula (II) was found on TLC. After the reaction was completed, the solution was filtered, and the filtrate was concentrated under reduced pressure to half. The solution was stirred and cooled to -5℃ and kept at this temperature for 2 hours before being filtered again. The filter cake was dried to obtain compound (III).

[0042] The beneficial effects of this invention are as follows:

[0043] This invention introduces a microwave reactor into bromination and debromination reactions. Utilizing the ability of microwave radiation to alter the electron cloud distribution of reactants and rapidly activate reaction sites, it achieves bromination of specific carbon sites on the substrate by NBS and removal of specific bromine from intermediates by diethyl phosphite. The reactions are stable and controllable, enabling the interconversion of several compounds and significantly reducing industrialization risks. Furthermore, post-reaction processing is simple and rapid, products are easily separated, and the solvent is highly recyclable, making it a green and economical option. Detailed Implementation

[0044] The technical solution of the present invention is illustrated by the following specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0045] Example 1

[0046]

[0047] 1) Add 20 g (89 mmol) of 1-benzyl-1,5,6,7-tetrahydro-4H-indole-4-one and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant-pressure dropping funnel, and a thermometer, placed in a microwave reactor. Start stirring and slowly add 19 g (107 mmol) of NBS reagent dissolved in dichloroethane at 200 W microwave power, maintaining the temperature at 10 °C. Continue the reaction until TLC shows no reaction (I-1). After the reaction is complete, filter the solution, wash with water, and determine the composition of the reaction solution by HPLC.

[0048] 2) The above reaction solution was added to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer, which was placed in a microwave reactor. Stirring was started, and the pH was adjusted to 8-9 with triethylamine. Diethyl phosphite (4.4 g, 32 mmol) was added, and the reaction was carried out at 45 °C under 300 W microwave power until TLC showed no (Ⅲ-1). After the reaction was complete, the mixture was concentrated under reduced pressure to a paste, then mixed with cold water, filtered, and the filter cake was washed with hot water and dried to obtain 25.1 g of a white solid product (Ⅱ-1), with a yield of 93% and a purity of 99.3% as determined by HPLC.

[0049] Example 2

[0050] 1) Add 20 g (89 mmol) of 1-benzyl-1,5,6,7-tetrahydro-4H-indole-4-one and dichloromethane to a 500 mL four-necked flask equipped with a condenser, a constant-pressure dropping funnel, and a thermometer, placed in a microwave reactor. Start stirring and slowly add 19 g (107 mmol) of NBS reagent dissolved in dichloromethane at 200 W microwave power, maintaining the temperature at 10 °C. Continue the reaction until TLC shows no reaction (I-1). After the reaction is complete, filter the solution, wash with water, and determine the composition of the reaction solution by HPLC.

[0051] 2) The above reaction solution was added to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer, which was placed in a microwave reactor. Stirring was started, and the pH was adjusted to 8-9 with triethylamine. Diethyl phosphite (4.4 g, 32 mmol) was added, and the reaction was carried out at 40 °C under 300 W microwave power until TLC showed no (Ⅲ-1). After the reaction was complete, the mixture was concentrated under reduced pressure to a paste, then mixed with cold water, filtered, and the filter cake was washed with hot water and dried to obtain 25.1 g of a white solid product (Ⅱ-1), with a yield of 93% and a purity of 99.2% as determined by HPLC.

[0052] Example 3

[0053] 1) Add 20 g (89 mmol) of 1-benzyl-1,5,6,7-tetrahydro-4H-indole-4-one and ethyl acetate to a 500 mL four-necked flask equipped with a condenser, a constant-pressure dropping funnel, and a thermometer, placed in a microwave reactor. Start stirring and slowly add 19 g (107 mmol) of NBS reagent dissolved in ethyl acetate at 200 W microwave power, maintaining the temperature at 10 °C. Continue the reaction until TLC shows no reaction (I-1). After the reaction is complete, filter the solution, wash with water, and determine the composition of the reaction solution by HPLC.

[0054] 2) The above reaction solution was added to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer, which was placed in a microwave reactor. Stirring was started, and the pH was adjusted to 8-9 with triethylamine. Diethyl phosphite (4.4 g, 32 mmol) was added, and the reaction was carried out at 45 °C under 300 W microwave power until TLC showed no (Ⅲ-1). After the reaction was complete, the mixture was concentrated under reduced pressure to a paste, then mixed with cold water, filtered, and the filter cake was washed with hot water and dried to obtain 20.3 g of a white solid product (Ⅱ-1), with a yield of 75% and a purity of 98.2% as determined by HPLC.

[0055] Example 4

[0056] 1) Add 20 g (89 mmol) of 1-benzyl-1,5,6,7-tetrahydro-4H-indole-4-one and N,N-dimethylformamide to a 500 mL four-necked flask equipped with a condenser, a constant-pressure dropping funnel, and a thermometer, placed in a microwave reactor. Start stirring and slowly add 19 g (107 mmol) of NBS reagent dissolved in N,N-dimethylformamide dropwise at 200 W microwave power, maintaining the temperature at 10 °C. Continue the reaction until TLC shows no reaction (I-1). After the reaction is complete, filter the solution, quench the reaction mixture with cold water, and determine the composition of the reaction solution by HPLC.

[0057] 2) The above reaction solution was added to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer, which was placed in a microwave reactor. Stirring was started, and the pH was adjusted to 8-9 with triethylamine. Diethyl phosphite (4.4 g, 32 mmol) was added, and the reaction was carried out at 45 °C under 300 W microwave power until TLC showed no (Ⅲ-1). After the reaction was complete, the mixture was concentrated under reduced pressure to a paste, then mixed with cold water, filtered, and the filter cake was washed with hot water and dried to obtain 20.8 g of a white solid product (Ⅱ-1), with a yield of 77% and a purity of 98.4% as determined by HPLC.

[0058] Example 5

[0059] 1) Add 20 g (89 mmol) of 1-benzyl-1,5,6,7-tetrahydro-4H-indole-4-one and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant-pressure dropping funnel, and a thermometer, placed in a microwave reactor. Start stirring and slowly add 19 g (107 mmol) of NBS reagent dissolved in dichloroethane at 200 W microwave power, maintaining the temperature at 10 °C. Continue the reaction until TLC shows no reaction (I-1). After the reaction is complete, filter the solution, wash with water, and determine the composition of the reaction solution by HPLC.

[0060] 2) The above reaction solution was added to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer, which was placed in a microwave reactor. Stirring was started, and the pH was adjusted to 8-9 with ethylenediamine. Diethyl phosphite (4.4 g, 32 mmol) was added, and the reaction was carried out at 45 °C under 300 W microwave power until TLC showed no (Ⅲ-1). After the reaction was complete, the mixture was concentrated under reduced pressure to a paste, then mixed with cold water, filtered, and the filter cake was washed with hot water and dried to obtain 25.7 g of a white solid product (Ⅱ-1), with a yield of 95% and a purity of 99.5% as determined by HPLC.

[0061] Example 6

[0062] 1) Add 20 g (89 mmol) of 1-benzyl-1,5,6,7-tetrahydro-4H-indole-4-one and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant-pressure dropping funnel, and a thermometer, placed in a microwave reactor. Start stirring and slowly add 19 g (107 mmol) of NBS reagent dissolved in dichloroethane at 200 W microwave power, maintaining the temperature at 10 °C. Continue the reaction until TLC shows no reaction (I-1). After the reaction is complete, filter the solution, wash with water, and determine the composition of the reaction solution by HPLC.

[0063] 2) The above reaction solution was added to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer, which was placed in a microwave reactor. Stirring was started, and the pH was adjusted to 8-9 with potassium carbonate. Diethyl phosphite (4.4 g, 32 mmol) was added, and the reaction was carried out at 45 °C under 300 W microwave power until TLC showed no (Ⅲ-1). After the reaction was completed, the mixture was concentrated under reduced pressure to a paste, and cold water was added to make a slurry. The mixture was filtered, and the filter cake was washed with hot water and dried to obtain 22.1 g of white solid product (Ⅱ-1), with a yield of 81% and a purity of 98.7% as determined by HPLC.

[0064] Example 7

[0065] 1) Add 20 g (89 mmol) of 1-benzyl-1,5,6,7-tetrahydro-4H-indole-4-one and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant-pressure dropping funnel, and a thermometer, placed in a microwave reactor. Start stirring and slowly add 19 g (107 mmol) of NBS reagent dissolved in dichloroethane at 200 W microwave power, maintaining the temperature at 10 °C. Continue the reaction until TLC shows no reaction (I-1). After the reaction is complete, filter the solution, wash with water, and determine the composition of the reaction solution by HPLC.

[0066] 2) The above reaction solution was added to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer, which was placed in a microwave reactor. Stirring was started, and the pH was adjusted to 8-9 with triethylamine. Diethyl phosphite (4.4 g, 32 mmol) was added, and the reaction was carried out at 45 °C under 400 W microwave power until TLC showed no (Ⅲ-1). After the reaction was complete, the mixture was concentrated under reduced pressure to a paste, then mixed with cold water, filtered, and the filter cake was washed with hot water and dried to obtain 25.6 g of a white solid product (Ⅱ-1), with a yield of 94.7% and a purity of 99.7% as determined by HPLC.

[0067] Example 8

[0068] 1) Add 20 g (89 mmol) of 1-benzyl-1,5,6,7-tetrahydro-4H-indole-4-one and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant-pressure dropping funnel, and a thermometer, placed in a microwave reactor. Start stirring and slowly add 19 g (107 mmol) of NBS reagent dissolved in dichloroethane at 50 W microwave power, maintaining the temperature at 10 °C. Continue the reaction until TLC shows no reaction (I-1). After the reaction is complete, filter the solution, wash with water, and determine the composition of the reaction solution by HPLC.

[0069] 2) The above reaction solution was added to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer, which was placed in a microwave reactor. Stirring was started, and the pH was adjusted to 8-9 with triethylamine. Diethyl phosphite (4.4 g, 32 mmol) was added, and the reaction was carried out at 45 °C under 300 W microwave power until TLC showed no (Ⅲ-1). After the reaction was complete, the mixture was concentrated under reduced pressure to a paste, then mixed with cold water, filtered, and the filter cake was washed with hot water and dried to obtain 14.9 g of a white solid product (Ⅱ-1), with a yield of 55% and a purity of 97.2% as determined by HPLC.

[0070] Example 9

[0071] 1) Add 20 g (89 mmol) of 1-benzyl-1,5,6,7-tetrahydro-4H-indole-4-one and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant-pressure dropping funnel, and a thermometer, placed in a microwave reactor. Start stirring and slowly add 19 g (107 mmol) of NBS reagent dissolved in dichloroethane at 200 W microwave power, maintaining the temperature at 10 °C. Continue the reaction until TLC shows no reaction (I-1). After the reaction is complete, filter the solution, wash with water, and determine the composition of the reaction solution by HPLC.

[0072] 2) The above reaction solution was added to a 500 mL four-necked flask equipped with a condenser, a constant-pressure dropping funnel, and a thermometer, which was placed in a microwave reactor. Stirring was started, and the pH was adjusted to 8-9 with triethylamine. Diethyl phosphite (4.4 g, 32 mmol) was added, and the reaction was carried out at 45 °C under 700 W microwave power until TLC showed no (Ⅲ-1). After the reaction was complete, the mixture was concentrated under reduced pressure to a paste, then mixed with cold water, filtered, and the filter cake was washed with hot water and dried to obtain 16.2 g of a white solid product (Ⅱ-1), with a yield of 60% and a purity of 97.9% as determined by HPLC.

[0073] Example 10

[0074] 1) Add 20 g (89 mmol) of 1-benzyl-1,5,6,7-tetrahydro-4H-indole-4-one and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant-pressure dropping funnel, and a thermometer, placed in a microwave reactor. Start stirring and slowly add 19 g (107 mmol) of NBS reagent dissolved in dichloroethane at 200 W microwave power, maintaining the temperature at 5 °C. Continue the reaction until TLC shows no reaction (I-1). After the reaction is complete, filter the solution, wash with water, and determine the composition of the reaction solution by HPLC.

[0075] 2) The above reaction solution was added to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer, which was placed in a microwave reactor. Stirring was started, and the pH was adjusted to 8-9 with triethylamine. Diethyl phosphite (4.4 g, 32 mmol) was added, and the reaction was carried out at 45 °C under 300 W microwave power until TLC showed no (Ⅲ-1). After the reaction was complete, the mixture was concentrated under reduced pressure to a paste, then mixed with cold water, filtered, and the filter cake was washed with hot water and dried to obtain 24.6 g of a white solid product (Ⅱ-1), with a yield of 91% and a purity of 99.3% as determined by HPLC.

[0076] Example 11

[0077] 1) Add 20 g (89 mmol) of 1-benzyl-1,5,6,7-tetrahydro-4H-indole-4-one and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant-pressure dropping funnel, and a thermometer, placed in a microwave reactor. Start stirring and slowly add 19 g (107 mmol) of NBS reagent dissolved in dichloroethane at 200 W microwave power, maintaining the temperature at 10 °C. Continue the reaction until TLC shows no reaction (I-1). After the reaction is complete, filter the solution, wash with water, and determine the composition of the reaction solution by HPLC.

[0078] 2) The above reaction solution was added to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer, which was placed in a microwave reactor. Stirring was started, and the pH was adjusted to 8-9 with triethylamine. Diethyl phosphite (4.4 g, 32 mmol) was added, and the reaction was carried out at 50 °C under 300 W microwave power until TLC showed no (Ⅲ-1). After the reaction was complete, the mixture was concentrated under reduced pressure to a paste, then mixed with cold water, filtered, and the filter cake was washed with hot water and dried to obtain 25.2 g of a white solid product (Ⅱ-1), with a yield of 93.2% and a purity of 99.8% as determined by HPLC.

[0079] Example 12

[0080] 1) Add 20 g (89 mmol) of 1-benzyl-1,5,6,7-tetrahydro-4H-indole-4-one and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant-pressure dropping funnel, and a thermometer, placed in a microwave reactor. Start stirring and slowly add 19 g (107 mmol) of NBS reagent dissolved in dichloroethane at 200 W microwave power, maintaining the temperature at 30 °C. Continue the reaction until TLC shows no reaction (I-1). After the reaction is complete, filter the solution, wash with water, and determine the composition of the reaction solution by HPLC.

[0081] 2) The above reaction solution was added to a 500 mL four-necked flask equipped with a condenser, a constant-pressure dropping funnel, and a thermometer, which was placed in a microwave reactor. Stirring was started, and the pH was adjusted to 8-9 with triethylamine. Diethyl phosphite (4.4 g, 32 mmol) was added, and the reaction was carried out at 45 °C under 300 W microwave power until TLC showed no (Ⅲ-1). After the reaction was complete, the mixture was concentrated under reduced pressure to a paste, then mixed with cold water, filtered, and the filter cake was washed with hot water and dried to obtain 21.6 g of a white solid product (Ⅱ-1), with a yield of 80% and a purity of 99.0% as determined by HPLC.

[0082] Example 13

[0083] 1) Add 20 g (89 mmol) of 1-benzyl-1,5,6,7-tetrahydro-4H-indole-4-one and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant-pressure dropping funnel, and a thermometer, placed in a microwave reactor. Start stirring and slowly add 19 g (107 mmol) of NBS reagent dissolved in dichloroethane at 200 W microwave power, maintaining the temperature at 10 °C. Continue the reaction until TLC shows no reaction (I-1). After the reaction is complete, filter the solution, wash with water, and determine the composition of the reaction solution by HPLC.

[0084] 2) The above reaction solution was added to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer, which was placed in a microwave reactor. Stirring was started, and the pH was adjusted to 8-9 with triethylamine. Diethyl phosphite (9.7 g, 70 mmol) was added, and the reaction was carried out at 45 °C under 300 W microwave power until TLC showed no (Ⅲ-1). After the reaction was complete, the mixture was concentrated under reduced pressure to a paste, then mixed with cold water, filtered, and the filter cake was washed with hot water and dried to obtain 16.7 g of a white solid product (Ⅱ-1), with a yield of 62% and a purity of 98.1% as determined by HPLC. 1 H NMR (400MHz)

[0085] Example 14

[0086] 1-Benzyl-1,5,6,7-tetrahydro-4H-indole-4-one (20 g, 89 mmol) and dichloroethane were added to a 500 mL four-necked flask equipped with a mechanical stirrer, condenser, constant pressure dropping funnel, and thermometer. Stirring was started, and NBS reagent (19 g, 107 mmol) dissolved in dichloroethane was slowly added dropwise while maintaining the temperature at 10 °C. The reaction continued until no TLC result was obtained (I-1). After the reaction was complete, the mixture was filtered, washed with water, and no HPLC result was obtained (II-1). The reaction mixture was concentrated to a paste, then stirred with cold water, filtered, and the filter cake was washed with hot water and dried to obtain the other product, 1-benzyl-3-bromo-1,5,6,7-tetrahydro-4H-indole-4-one, with a purity of 99.1% as determined by HPLC. 1 HNMR(400MHz,DMSO-d6)δ7.76-7.67(m,2H),7.31(d,J=8.2Hz,2H),6.48(s,1H),3.02 (t,J=6.1Hz,2H),2.30(p,J=1.8Hz,1H),2.21(d,J=3.0Hz,4H),1.89(p,J=6.2Hz,2H).

[0087] Example 15

[0088] 1) Add 20 g (89 mmol) of 1-benzyl-1,5,6,7-tetrahydro-4H-indole-4-one and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant-pressure dropping funnel, and a thermometer, placed in a microwave reactor. Start stirring and slowly add 19 g (107 mmol) of NBS reagent dissolved in dichloroethane at 200 W microwave power, maintaining the temperature at 10 °C. Continue the reaction until TLC shows no reaction (I-1). After the reaction is complete, filter the solution, wash with water, and determine the composition of the reaction solution by HPLC.

[0089] 2) The above reaction solution was added to a 500 mL four-necked flask equipped with a mechanical stirrer, condenser, constant pressure dropping funnel, and thermometer. Stirring was started, and the pH was adjusted to 8-9 with triethylamine. Diethyl phosphite (4.4 g, 32 mmol) was added, and the reaction was carried out at 45 °C until TLC showed no formula (III-1). After the reaction was completed, the mixture was concentrated under reduced pressure to a paste, then mixed with cold water, filtered, and the filter cake was washed with hot water and dried to obtain 17.82 g of white solid product, with a yield of 66% and a purity of 99.1% as determined by HPLC.

[0090] Example 16

[0091]

[0092] 1) Add 20 g (69 mmol) of 1-toluenesulfonyl-1,5,6,7-tetrahydro-4H-indole-4-one and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant-pressure dropping funnel, and a thermometer, placed in a microwave reactor. Start stirring and slowly add 19 g (107 mmol) of NBS reagent dissolved in dichloroethane at 200 W microwave power, maintaining the temperature at 10 °C. Continue the reaction until TLC shows no reaction (Ⅰ-2). After the reaction is complete, filter the solution, wash with water, and determine the composition of the reaction solution by HPLC.

[0093] 2) The above reaction solution was added to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer, which was placed in a microwave reactor. Stirring was started, and the pH was adjusted to 8-9 with triethylamine. Diethyl phosphite (3.4 g, 25 mmol) was added, and the reaction was carried out at 45 °C under 300 W microwave power until TLC showed no (Ⅲ-2). After the reaction was complete, the mixture was concentrated under reduced pressure to a paste, then mixed with cold water, filtered, and the filter cake was washed with hot water and dried to obtain 24.4 g of a white solid product (Ⅱ-2), with a yield of 90% and a purity of 99.2% as determined by HPLC. 1 H NMR (400MHz, DMSO-d6) δ7.97-7.88 (m, J=3.5Hz, 2H), 7.49 (dd, J=6.1, 2.5Hz, 3H), 6.59 (d, J=3.5Hz, 1H), 4.77 (dd, J=5. 4,3.5Hz,1H),3.31(dt,J=18.1,4.7Hz,1H),2.91(ddd,J=18.1,8.9,4.9Hz,1H),2.56-2.49(m,1H),2.42-2.29(m,4H).

[0094] Example 17

[0095]

[0096] 1) In a 500 mL four-necked flask equipped with a condenser, a constant-pressure dropping funnel, and a thermometer, add 20 g (87 mmol) of 1-(2,2,2-trifluoroacetyl)-1,5,6,7-tetrahydro-4H-indole-4-one and dichloroethane. Start stirring and slowly add NBS reagent (19 g, 107 mmol) dissolved in dichloroethane at 200 W microwave power, maintaining the temperature at 10 °C. Continue the reaction until TLC shows no reaction (Ⅰ-3). After the reaction is complete, filter the solution, wash with water, and determine the composition of the reaction solution by HPLC.

[0097] 2) The above reaction solution was added to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer, which was placed in a microwave reactor. Stirring was started, and the pH was adjusted to 8-9 with triethylamine. Diethyl phosphite (4.3 g, 31 mmol) was added, and the reaction was carried out at 45 °C under 300 W microwave power until TLC showed no (Ⅲ-3). After the reaction was complete, the mixture was concentrated under reduced pressure to a paste, then mixed with cold water, filtered, and the filter cake was washed with hot water and dried to obtain 24.4 g of a white solid product (Ⅱ-3), with a yield of 91% and a purity of 99.2% as determined by HPLC.

[0098] Example 18

[0099]

[0100] 1) Add 20 g (74 mmol) of 4-oxo-4,5,6,7-tetrahydro-1H-indole-1-carboxylic acid benzyl ester and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant-pressure dropping funnel, and a thermometer, placed in a microwave reactor. Start stirring and slowly add 19 g (107 mmol) of NBS reagent dissolved in dichloroethane at 200 W microwave power, maintaining the temperature at 10 °C. Continue the reaction until TLC shows no result (I-4). After the reaction is complete, filter the solution, wash with water, and determine the composition of the reaction solution by HPLC.

[0101] 2) The above reaction solution was added to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer, which was placed in a microwave reactor. Stirring was started, and the pH was adjusted to 8-9 with triethylamine. Diethyl phosphite (3.6 g, 26 mmol) was added, and the reaction was carried out at 45 °C under 300 W microwave power until TLC showed no (Ⅲ-4). After the reaction was complete, the mixture was concentrated under reduced pressure to a paste, then mixed with cold water, filtered, and the filter cake was washed with hot water and dried to obtain 23.1 g of a white solid product (Ⅱ-4), with a yield of 89% and a purity of 99.6% as determined by HPLC.

[0102] Example 19

[0103] 1-Benzyl-1,5,6,7-tetrahydro-4H-indole-4-one (20 g, 89 mmol) and dichloroethane were added to a 500 mL four-necked flask equipped with a condenser, a constant-pressure dropping funnel, and a thermometer in a microwave reactor. Stirring was started, and the temperature was controlled at 10 °C with a microwave power of 200 W. NBS reagent dissolved in dichloroethane (19 g, 107 mmol) was slowly added dropwise. After the addition was complete, the reaction was maintained at this temperature until TLC showed no reaction (I-1). The temperature was raised to 15 °C, and the microwave power was adjusted to 500 W. NBS reagent dissolved in dichloroethane (19 g, 107 mmol) was added dropwise again. After the addition was complete, the reaction was maintained at this temperature until TLC showed no reaction (II-1). The mixture was filtered after the reaction was complete. The filtrate was concentrated under reduced pressure to half its original volume, stirred, cooled to -5 °C, and maintained at this temperature for 2 hours. The mixture was then filtered again, and the filter cake was dried to obtain 32.7 g of a white solid product, with a yield of 96%. HPLC analysis showed a purity of 99.9%.

[0104] Example 20

[0105] 1-Benzyl-1,5,6,7-tetrahydro-4H-indole-4-one (20 g, 89 mmol) and dichloroethane were added to a 500 mL four-necked flask equipped with a condenser, a constant-pressure dropping funnel, and a thermometer in a microwave reactor. Stirring was started, and the temperature was controlled at 10 °C with a microwave power of 200 W. NBS reagent dissolved in dichloroethane (19 g, 107 mmol) was slowly added dropwise. After the addition was complete, the reaction was maintained at this temperature until TLC showed no reaction (I-1). The temperature was raised to 15 °C, and the microwave power was adjusted to 350 W. NBS reagent dissolved in dichloroethane (19 g, 107 mmol) was added dropwise again. After the addition was complete, the reaction was maintained at this temperature until TLC showed no reaction (II-1). After the reaction was complete, the mixture was filtered. The filtrate was concentrated under reduced pressure to half its original volume, stirred, and cooled to -5 °C. After maintaining this temperature for 2 hours, the mixture was filtered again. The filter cake was dried to obtain 28.3 g of a white solid product, with a yield of 83%. HPLC analysis showed a purity of 99.7%.

[0106] Example 21

[0107] 1-Benzyl-1,5,6,7-tetrahydro-4H-indole-4-one (20 g, 89 mmol) and dichloroethane were added to a 500 mL four-necked flask equipped with a condenser, a constant-pressure dropping funnel, and a thermometer in a microwave reactor. Stirring was started, and the temperature was controlled at 10 °C with a microwave power of 200 W. NBS reagent dissolved in dichloroethane (19 g, 107 mmol) was slowly added dropwise. After the addition was complete, the reaction was maintained at this temperature until TLC showed no reaction (I-1). The temperature was raised to 15 °C, and the microwave power was adjusted to 250 W. NBS reagent dissolved in dichloroethane (19 g, 107 mmol) was added dropwise again. After the addition was complete, the reaction was maintained at this temperature until TLC showed no reaction (II-1). After the reaction was complete, the mixture was filtered. The filtrate was concentrated under reduced pressure to half its original volume, stirred, and cooled to -5 °C. After maintaining this temperature for 2 hours, the mixture was filtered again. The filter cake was dried to obtain 11.3 g of a white solid product, with a yield of 33%. HPLC analysis showed a purity of 97.2%.

Claims

1. A microwave-assisted bromination method for 1,5,6,7-tetrahydro-4H-indole-4-one derivatives, characterized in that, The process includes the following steps: using the tetrahydroindolone compound shown in formula (I) as a raw material, a bromination reaction is carried out with a brominating reagent in an organic solvent under microwave conditions of 200-400W and 5-15℃ to obtain a mixture shown in formula (II) and formula (III); the mixture shown in formula (II) and formula (III) is adjusted to a weakly alkaline pH by adding an alkali, and under microwave conditions of 200-400W and 40-50℃, diethyl phosphite is added to react completely to convert it into the bromo-1,5,6,7-tetrahydro-4H-indol-4-one derivative shown in formula (II); The structures corresponding to equations (Ⅰ), (Ⅱ), and (Ⅲ) are as follows: ， Wherein the substituent R is a halogen-substituted C2 alkyl acyl group, a C1~C2 alkyl-substituted benzenesulfonyl group, a phenyl-substituted C1~C2 alkyl group, or a phenyl-substituted C1~C2 alkoxycarbonyl group; The organic solvent is selected from dichloromethane or dichloroethane, and the brominating agent is N-bromosuccinimide.

2. The microwave-assisted bromination method for 1,5,6,7-tetrahydro-4H-indole-4-one derivatives according to claim 1, characterized in that, The substituent R is trifluoroacetyl, p-toluenesulfonyl, benzyloxycarbonyl, or benzyl.

3. The microwave-assisted bromination method for 1,5,6,7-tetrahydro-4H-indole-4-one derivatives according to claim 1, characterized in that, The alkali used to adjust the pH value is selected from one or more of triethylamine, ethylenediamine, pyridine, sodium bicarbonate, sodium carbonate, and potassium carbonate; the molar ratio of diethyl phosphite to the compound shown in formula (III) in the reaction solution is 0.9~4.0:1; The molar ratio of the brominating reagent to the compound shown in formula (Ⅰ) is 1.1-1.3:

1.

4. A microwave-assisted bromination method for 1,5,6,7-tetrahydro-4H-indole-4-one derivatives, characterized in that, The preparation of the compound shown in formula (III) is carried out using a two-step method, including the following steps: First, using the tetrahydroindole ketone compound shown in formula (I) as a raw material, a bromination reaction is carried out with a brominating reagent in an organic solvent under microwave conditions of 200-400W and 5-15℃ until the raw material reacts completely, yielding a mixture of formulas (II) and (III); Second, a brominating reagent is added to the reaction solution from the first step, and the bromination reaction is continued under microwave conditions of 400-600W and 10-20℃ to obtain the compound shown in formula (III). The total molar ratio of the brominating reagent consumed in the first and second steps to the compound shown in formula (I) is 2~2.6:

1. The structures corresponding to equations (Ⅰ), (Ⅱ), and (Ⅲ) are as follows: ， Wherein the substituent R is a halogen-substituted C2 alkyl acyl group, a C1~C2 alkyl-substituted benzenesulfonyl group, a phenyl-substituted C1~C2 alkyl group, or a phenyl-substituted C1~C2 alkoxycarbonyl group. The organic solvent is selected from dichloromethane or dichloroethane, and the brominating agent is N-bromosuccinimide.

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