Microwave-assisted bromination method of 1, 5, 6, 7-tetrahydro-4H-indole-4-one derivative

Abstract

The invention discloses a microwave-assisted bromination method of a 1, 5, 6, 7-tetrahydro-4H-indole-4-ketone derivative, and provides a synthesis scheme of two types of compounds (II and III). The synthesis of the compound II comprises the following steps: taking a tetrahydroindolone derivative as an initial raw material, reacting with N-bromosuccinimide under a microwave condition to obtain brominated crystallization mother liquor shown in a formula (II) and a formula (III), taking the crystallization mother liquor as a raw material, adjusting the pH value to alkalescence, and carrying out a reaction to obtain the compound II. Diethyl phosphite is added under the microwave condition for a selective debromination reaction, a dibromo byproduct shown in the formula (III) is converted into a target product (II), the crystallization mother liquor is also used as a raw material for synthesis of a compound III, N-bromosuccinimide is added under the higher microwave power, and the formula (II) is converted into the formula (III); the compound has the characteristics of simple process, mild conditions, convenience in operation, economy, environment friendliness, suitability for industrial production and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediate synthesis, and particularly relates to a microwave-assisted bromination method of 1,5,6,7-tetrahydro-4H-indol-4-one derivatives. Background Art

[0002] At present, indole derivatives play an important role in the fields of medicine, dyes and fragrances. It is worth mentioning that a considerable number of studies have shown that certain indole compounds such as 4-substituted indoles and their 5-brominated derivatives have unique antidepressant effects, which has established their status as high-value-added fine chemical products. Tetrahydroindole ketone compounds are important intermediates for the synthesis of 4-substituted indoles and their 5-brominated derivatives, and aromatization is usually completed by the strategy of bromination followed by dehydrobromination.

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

[0004]

[0005] Currently, there are few methods for synthesizing compounds (II) and (III), and copper bromide reagents are mainly used, which have the disadvantages of poor selectivity, difficult post-treatment, high levels of three wastes, and difficulty in industrialization.

[0006] In 2009, Hansen et al. provided a method for synthesizing 5-bromo-1-methylbenzenesulfonyl-1,5,6,7-tetrahydro-4H-4-one while studying the total synthesis of 1,3,4,5-tetrahydrobenzindole β-one. Ethyl acetate was used as solvent and copper bromide was used as bromination reagent. Bromination was completed under reflux conditions. Although the steps are simple, the atomic utilization rate is low, and compounds with dibromo substitution at the 5th position are easily generated. The reaction needs to be carefully monitored, and industrialization is difficult (Tetrahedron Lett., 2009, 50, 6506-6508.). The reaction route is as follows:

[0007]

[0008] In 2017, Morikawa et al. provided a dibromination scheme for the α-position of ketone when studying the total synthesis of carbazolylmycin A and B. The bromination was completed under reflux conditions using ethyl acetate as solvent and copper bromide as bromination reagent. Although the yield was considerable, the consumption of copper bromide was large, and there were shortcomings such as difficulty in post-treatment, high waste, and difficulty in 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 by-product. The commonly used recrystallization purification method often results in huge product losses, so a debromination scheme is considered.

[0011] In 2006, Kalicharan et al. reported a microwave-mediated ionic liquid debromination method, where a mixture of 2,2-dibromo-1-phenylethanone and 1-methyl-3-pentyl imidazole tetrafluoroborate was dissolved in water and heated under microwave irradiation to generate a monobrominated product, 2-bromo-1-phenylethanone, in 2-3 minutes, and acetophenone was generated after 3-4 minutes of reaction. Although the efficiency is considerable and the reaction is rapid, it is easy to remove both bromines, and the industrialization risk is high (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-phenylethanone, in which the substrate 2,2-dibromo-1-phenylethanone was placed in a solvent of acetonitrile to water in a ratio of 1:1, heated to 100°C for reflux reaction, and 2-bromo-1-phenylethanone was obtained with a conversion rate of 65%. Although the reaction system and conditions are easy to meet, the conversion rate is low, the refining loss is large, and the overall cost is high (Advanced Synthesis & Catalysis, 2017, 360, 298-304). The reaction route is as follows:

[0014] Summary of the invention

[0015] The purpose of the present invention is to provide a microwave-assisted bromination method for 1,5,6,7-tetrahydro-4H-indol-4-one derivatives. The method has the characteristics of simple process, mild conditions, convenient operation, economic and environmental protection, and suitability for industrial production.

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

[0017] A microwave-assisted bromination method for 1,5,6,7-tetrahydro-4H-indol-4-one derivatives comprises: using a tetrahydroindole ketone compound represented by formula (I) as a raw material, and carrying out a bromination reaction with a brominating agent in an organic solvent under microwave conditions to obtain a brominated 1,5,6,7-tetrahydro-4H-indol-4-one derivative represented by formula (III) or a mixture represented by formula (II) and formula (III); adding a base to the mixture represented by formula (II) and formula (III) to adjust the pH to alkaline, and then adding diethyl phosphite under microwave conditions to react and completely convert it into the brominated 1,5,6,7-tetrahydro-4H-indol-4-one derivative represented by formula (II).

[0018] The reaction equation is as follows:

[0019]

[0020] In the formula, the substituent R is a halogen-substituted C1-C2 alkanoyl 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-indol-4-one derivatives shown in formula (III), preferably, a two-step method can be adopted, comprising: a first step, using the tetrahydroindolinone compound shown in formula (I) as a raw material, and carrying out a bromination reaction with a brominating agent in an organic solvent under microwave condition I until the compound shown in formula (I) reacts completely; a second step, continuing to add the brominating agent, and continuing the bromination reaction under microwave condition II, and finally obtaining the dibromo-1,5,6,7-tetrahydro-4H-indol-4-one derivatives shown in formula (III).

[0023] Preferably, in the technical solution for preparing the dibromo-1,5,6,7-tetrahydro-4H-indol-4-one derivatives of formula (III) by the above-mentioned stepwise method, the temperature of the first step reaction is -10°C to 30°C, preferably 5 to 15°C. The microwave condition I is that the microwave power is 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 the microwave condition II is that the microwave power is 100 to 900 W, preferably 400 to 600 W.

[0024] When the above method is used, the molar ratio of the bromination reagent in the first step and the second step to the compound represented by formula (I) is 1 to 1.3:1, more preferably 1.1 to 1.3:1.

[0025] Furthermore, when preparing the monobrominated 1,5,6,7-tetrahydro-4H-indol-4-one derivatives shown in formula (II), preferably, a two-step method can be used. In the first step, the tetrahydroindolinone compound shown in formula (I) is used as a raw material, and a bromination reaction is carried out with a brominating agent in an organic solvent under microwave condition I until the compound shown in formula (I) reacts completely, and the reaction liquid is filtered and washed with water; in the second step, the pH value of the obtained reaction liquid is adjusted to weak alkalinity, and then reacted with diethyl phosphite under microwave condition II to finally obtain the monobrominated 1,5,6,7-tetrahydro-4H-indol-4-one derivatives shown in formula (II).

[0026] Preferably, in the technical solution for preparing the monobrominated 1,5,6,7-tetrahydro-4H-indol-4-one derivatives of formula (II) by the above-mentioned stepwise method, the temperature of the first step reaction is -10°C to 30°C, preferably 5 to 15°C. The microwave condition I is that the microwave power is 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 the microwave condition II is that the microwave power is 100 to 900 W, preferably 200 to 400 W.

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

[0028] The bromination reagent is N-bromosuccinimide (NBS), and the bromination reagent can be added by dissolving in an organic solvent and then adding dropwise, 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: the tetrahydroindolinone compound shown in formula (I) is used as a raw material, and a bromination reaction is carried out with N-bromosuccinimide (NBS) in an organic solvent under microwave conditions to obtain formula (II) and formula (III). The reaction solution is divided into two equal batches or two schemes are carried out separately. After removing some impurities in the first batch, the pH is adjusted to weak alkalinity, and then diethyl phosphite is added to the reaction solution under microwave conditions to selectively convert compound (III) into compound (II), and then separated and purified 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), and then separated and purified to obtain the target product (III), which specifically includes the following steps:

[0030] Step 1: under microwave conditions, the tetrahydroindolinone derivative represented by formula (I) is added to solvent A, and a solution of the bromination reagent NBS in solvent A is added dropwise at a controlled temperature. After the addition is completed, the reaction is kept warm until the absence of formula (I) is detected by TLC, which is the reaction end point. After the reaction is completed, the reaction solution is divided into two batches, the first batch is filtered and 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 weak alkalinity, then control the temperature and add diethyl phosphite dropwise. After the addition is completed, keep the temperature to react until TLC detection shows no formula (III), which is the reaction end point. After the reaction is completed, 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 represented by formula (II).

[0032] Step 3: The second batch of reaction liquid is continuously temperature-controlled to add the bromination reagent NBS solvent A solution under microwave conditions. After the addition is completed, the reaction is kept warm until TLC detects the absence of formula (II), i.e., the reaction end point. After the reaction is completed, the filtrate is filtered, and the filtrate is concentrated to half, cooled and crystallized, and then filtered. The filter cake is dried to obtain the compound represented by formula (III).

[0033] In step 1, the 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, 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 specific preferred embodiment, a method for synthesizing a monobrominated 1,5,6,7-tetrahydro-4H-indol-4-one derivative represented by formula (II) comprises:

[0037] (1) Add the raw material tetrahydroindolinone compound (I) and the solvent dichloroethane into a four-necked bottle, stir and cool to 10°C, and at the same time, take NBS according to the molar ratio of raw material to NBS of 1:1.2 and prepare its dichloroethane solution, control the temperature at 10°C, slowly drop the NBS reagent dissolved in dichloroethane into the four-necked bottle under a microwave power of 200W, and continue the reaction until there is no raw material on TLC. After the reaction is completed, filter and wash the reaction solution with water, and determine the components of the reaction solution by HPLC.

[0038] (2) The pH of the reaction solution after the above treatment is adjusted to 8-9 with triethylamine, and the content of compound (III) is calculated based on HPLC data. Diethyl phosphite is added to the reaction solution at a molar ratio of compound (III) to diethyl phosphite of 1:1.8, and the temperature is controlled at 45°C and the reaction is carried out under a microwave power of 300W until there is no single impurity on TLC. After the reaction is completed, the mixture is concentrated under reduced pressure to a paste, and cold water is added to make a pulp, filtered, and the filter cake is rinsed with hot water and then dried to obtain compound (II).

[0039] A method for synthesizing dibromo-1,5,6,7-tetrahydro-4H-indol-4-one derivatives represented by formula (III) comprises:

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

[0041] (2) The temperature was controlled at 15°C and the microwave power was 500W. The 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 by TLC. After the reaction was completed, the filtrate was filtered, and the filtrate was concentrated to half under reduced pressure. The mixture was stirred, cooled to -5°C, and kept warm for 2 hours before filtering. The filter cake was dried to obtain compound (III).

[0042] The beneficial effects of the present invention are:

[0043] The present invention introduces a microwave reactor into the bromination and debromination reactions, and utilizes the characteristics of microwave radiation that can change the electron cloud distribution of the reactants and quickly activate the reaction sites, thereby realizing the bromination of a specific carbon position of the substrate by NBS and the removal of specific bromine of the intermediate by diethyl phosphite. The reaction is stable and controllable, and the mutual conversion of several compounds is realized, which significantly reduces the industrialization risk. At the same time, the post-reaction treatment is simple and rapid, and the product is easy to separate; the solvent is highly recyclable, and it is green and economical. DETAILED DESCRIPTION

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

[0045] Example 1

[0046]

[0047] 1) Add 1-benzyl-1,5,6,7-tetrahydro-4H-indol-4-one (20 g, 89 mmol) and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor. Start stirring, control the temperature at 10°C, and slowly drop NBS reagent (19 g, 107 mmol) dissolved in dichloroethane under a microwave power of 200 W. After the dropwise addition, continue the reaction until there is no formula (I-1) on TLC. After the reaction is completed, filter and wash the reaction solution with water, and determine the components of the reaction solution by HPLC.

[0048] 2) Add the above reaction solution to a 500mL four-necked bottle equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor, start stirring, adjust the pH to 8-9 with triethylamine, add diethyl phosphite (4.4g, 32mmol), control the temperature at 45°C and react at 300W microwave power until TLC shows no formula (III-1). After the reaction is completed, reduce the pressure and concentrate to a paste, add cold water to slurry, filter, rinse the filter cake with hot water and dry to obtain 25.1g of a white solid product (II-1), with a yield of 93%, and a content of 99.3% detected by HPLC.

[0049] Example 2

[0050] 1) Add 1-benzyl-1,5,6,7-tetrahydro-4H-indol-4-one (20 g, 89 mmol) and dichloromethane to a 500 mL four-necked bottle equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor. Start stirring, control the temperature at 10°C, and slowly drop NBS reagent (19 g, 107 mmol) dissolved in dichloromethane under a microwave power of 200 W. After the dropwise addition, continue the reaction until there is no formula (I-1) on TLC. After the reaction is completed, filter and wash the reaction solution with water, and determine the components of the reaction solution by HPLC.

[0051] 2) Add the above reaction solution to a 500mL four-necked bottle equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor, start stirring, adjust the pH to 8-9 with triethylamine, add diethyl phosphite (4.4g, 32mmol), control the temperature at 40°C and react at 300W microwave power until TLC shows no formula (III-1). After the reaction is completed, reduce the pressure and concentrate to a paste, add cold water to slurry, filter, rinse the filter cake with hot water and dry to obtain 25.1g of a white solid product (II-1), with a yield of 93%, and a content of 99.2% detected by HPLC.

[0052] Example 3

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

[0054] 2) Add the above reaction solution to a 500mL four-necked bottle equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor, start stirring, adjust the pH to 8-9 with triethylamine, add diethyl phosphite (4.4g, 32mmol), control the temperature at 45°C and react at 300W microwave power until TLC shows no formula (III-1). After the reaction is completed, reduce the pressure and concentrate to a paste, add cold water to slurry, filter, rinse the filter cake with hot water and dry to obtain 20.3g of a white solid product (II-1), with a yield of 75%, and a content of 98.2% detected by HPLC.

[0055] Example 4

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

[0057] 2) Add the above reaction solution to a 500mL four-necked bottle equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor, start stirring, adjust the pH to 8-9 with triethylamine, add diethyl phosphite (4.4g, 32mmol), control the temperature at 45°C and react at 300W microwave power until TLC shows no formula (III-1). After the reaction is completed, reduce the pressure and concentrate to a paste, add cold water to slurry, filter, rinse the filter cake with hot water and dry to obtain 20.8g of a white solid product (II-1), with a yield of 77%, and a content of 98.4% detected by HPLC.

[0058] Example 5

[0059] 1) Add 1-benzyl-1,5,6,7-tetrahydro-4H-indol-4-one (20 g, 89 mmol) and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor. Start stirring, control the temperature at 10°C, and slowly drop NBS reagent (19 g, 107 mmol) dissolved in dichloroethane under a microwave power of 200 W. After the dropwise addition, continue the reaction until there is no formula (I-1) on TLC. After the reaction is completed, filter and wash the reaction solution with water, and determine the components of the reaction solution by HPLC.

[0060] 2) Add the above reaction solution to a 500mL four-necked bottle equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor, start stirring, adjust the pH to 8-9 with ethylenediamine, add diethyl phosphite (4.4g, 32mmol), control the temperature to 45°C and react at 300W microwave power until TLC shows no formula (III-1). After the reaction is completed, reduce the pressure and concentrate to a paste, add cold water to slurry, filter, rinse the filter cake with hot water and dry to obtain 25.7g of a white solid product (II-1), with a yield of 95%, and a content of 99.5% detected by HPLC.

[0061] Example 6

[0062] 1) Add 1-benzyl-1,5,6,7-tetrahydro-4H-indol-4-one (20 g, 89 mmol) and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor. Start stirring, control the temperature at 10°C, and slowly drop NBS reagent (19 g, 107 mmol) dissolved in dichloroethane under a microwave power of 200 W. After the dropwise addition, continue the reaction until there is no formula (I-1) on TLC. After the reaction is completed, filter and wash the reaction solution with water, and determine the components of the reaction solution by HPLC.

[0063] 2) Add the above reaction solution to a 500mL four-necked bottle equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor, start stirring, adjust the pH to 8-9 with potassium carbonate, add diethyl phosphite (4.4g, 32mmol), control the temperature at 45°C and react at 300W microwave power until TLC shows no formula (III-1). After the reaction is completed, reduce the pressure and concentrate to a paste, add cold water to slurry, filter, rinse the filter cake with hot water and dry to obtain 22.1g of a white solid product (II-1), with a yield of 81%, and a content of 98.7% detected by HPLC.

[0064] Example 7

[0065] 1) Add 1-benzyl-1,5,6,7-tetrahydro-4H-indol-4-one (20 g, 89 mmol) and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor. Start stirring, control the temperature at 10°C, and slowly drop NBS reagent (19 g, 107 mmol) dissolved in dichloroethane under a microwave power of 200 W. After the dropwise addition, continue the reaction until there is no formula (I-1) on TLC. After the reaction is completed, filter and wash the reaction solution with water, and determine the components of the reaction solution by HPLC.

[0066] 2) Add the above reaction solution to a 500mL four-necked bottle equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor, start stirring, adjust the pH to 8-9 with triethylamine, add diethyl phosphite (4.4g, 32mmol), control the temperature at 45°C and react at 400W microwave power until TLC shows no formula (III-1). After the reaction is completed, reduce the pressure and concentrate to a paste, add cold water to slurry, filter, rinse the filter cake with hot water and dry to obtain 25.6g of a white solid product (II-1), with a yield of 94.7%, and a content of 99.7% detected by HPLC.

[0067] Example 8

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

[0069] 2) Add the above reaction solution to a 500mL four-necked bottle equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor, start stirring, adjust the pH to 8-9 with triethylamine, add diethyl phosphite (4.4g, 32mmol), control the temperature at 45°C and react at 300W microwave power until TLC shows no formula (III-1). After the reaction is completed, reduce the pressure and concentrate to a paste, add cold water to slurry, filter, rinse the filter cake with hot water and dry to obtain 14.9g of a white solid product (II-1), with a yield of 55%, and a content of 97.2% detected by HPLC.

[0070] Example 9

[0071] 1) Add 1-benzyl-1,5,6,7-tetrahydro-4H-indol-4-one (20 g, 89 mmol) and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor. Start stirring, control the temperature at 10°C, and slowly drop NBS reagent (19 g, 107 mmol) dissolved in dichloroethane under a microwave power of 200 W. After the dropwise addition, continue the reaction until there is no formula (I-1) on TLC. After the reaction is completed, filter and wash the reaction solution with water, and determine the components of the reaction solution by HPLC.

[0072] 2) Add the above reaction solution to a 500mL four-necked bottle equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor, start stirring, adjust the pH to 8-9 with triethylamine, add diethyl phosphite (4.4g, 32mmol), control the temperature to 45°C and react at 700W microwave power until TLC shows no formula (III-1). After the reaction is completed, reduce the pressure and concentrate to a paste, add cold water to slurry, filter, rinse the filter cake with hot water and dry to obtain 16.2g of a white solid product (II-1), with a yield of 60%, and a content of 97.9% detected by HPLC.

[0073] Example 10

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

[0075] 2) Add the above reaction solution to a 500mL four-necked bottle equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor, start stirring, adjust the pH to 8-9 with triethylamine, add diethyl phosphite (4.4g, 32mmol), control the temperature at 45°C and react at 300W microwave power until TLC shows no formula (III-1). After the reaction is completed, reduce the pressure and concentrate to a paste, add cold water to slurry, filter, rinse the filter cake with hot water and dry to obtain 24.6g of a white solid product (II-1), with a yield of 91%, and a content of 99.3% detected by HPLC.

[0076] Embodiment 11

[0077] 1) Add 1-benzyl-1,5,6,7-tetrahydro-4H-indol-4-one (20 g, 89 mmol) and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor. Start stirring, control the temperature at 10°C, and slowly drop NBS reagent (19 g, 107 mmol) dissolved in dichloroethane under a microwave power of 200 W. After the dropwise addition, continue the reaction until there is no formula (I-1) on TLC. After the reaction is completed, filter and wash the reaction solution with water, and determine the components of the reaction solution by HPLC.

[0078] 2) Add the above reaction solution to a 500mL four-necked bottle equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor, start stirring, adjust the pH to 8-9 with triethylamine, add diethyl phosphite (4.4g, 32mmol), control the temperature to 50°C and react at 300W microwave power until TLC shows no formula (III-1). After the reaction is completed, reduce the pressure and concentrate to a paste, add cold water to slurry, filter, rinse the filter cake with hot water and dry to obtain 25.2g of a white solid product (II-1), with a yield of 93.2%, and a content of 99.8% detected by HPLC.

[0079] Example 12

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

[0081] 2) Add the above reaction solution to a 500mL four-necked bottle equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor, start stirring, adjust the pH to 8-9 with triethylamine, add diethyl phosphite (4.4g, 32mmol), control the temperature at 45°C and react at 300W microwave power until TLC shows no formula (III-1). After the reaction is completed, reduce the pressure and concentrate to a paste, add cold water to slurry, filter, rinse the filter cake with hot water and dry to obtain 21.6g of a white solid product (II-1), with a yield of 80%, and a content of 99.0% detected by HPLC.

[0082] Example 13

[0083] 1) Add 1-benzyl-1,5,6,7-tetrahydro-4H-indol-4-one (20 g, 89 mmol) and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor. Start stirring, control the temperature at 10°C, and slowly drop NBS reagent (19 g, 107 mmol) dissolved in dichloroethane under a microwave power of 200 W. After the dropwise addition, continue the reaction until there is no formula (I-1) on TLC. After the reaction is completed, filter and wash the reaction solution with water, and determine the components of the reaction solution by HPLC.

[0084] 2) Add the above reaction solution to a 500mL four-necked bottle equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor, start stirring, adjust the pH to 8-9 with triethylamine, add diethyl phosphite (9.7g, 70mmol), control the temperature at 45°C and react at 300W microwave power until TLC shows no formula (III-1). After the reaction is completed, reduce the pressure and concentrate to a paste, add cold water to slurry, filter, rinse the filter cake with hot water and dry to obtain 16.7g of a white solid product (II-1), with a yield of 62%, and a content of 98.1% detected by HPLC. 1 H NMR (400MHz)

[0085] Embodiment 14

[0086] 1-Benzyl-1,5,6,7-tetrahydro-4H-indol-4-one (20g, 89mmol) and dichloroethane were added to a 500mL four-necked flask equipped with a mechanical stirrer, a condenser, a constant pressure dropping funnel, and a thermometer. Stirring was started, and the NBS reagent (19g, 107mmol) dissolved in dichloroethane was slowly added dropwise at a temperature of 10°C. After the addition was completed, the reaction was continued until there was no formula (Ⅰ-1) on TLC. After the reaction was completed, the reaction solution was filtered and washed with water. There was no formula (Ⅱ-1) on HPLC. The reaction solution was concentrated to a paste, and then cold water was added to make a pulp, filtered, and the filter cake was rinsed with hot water and dried to obtain the other product 1-benzyl-3-bromo-1,5,6,7-tetrahydro-4H-indol-4-one. The content was 99.1% when detected 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] Embodiment 15

[0088] 1) Add 1-benzyl-1,5,6,7-tetrahydro-4H-indol-4-one (20 g, 89 mmol) and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor. Start stirring, control the temperature at 10°C, and slowly drop NBS reagent (19 g, 107 mmol) dissolved in dichloroethane under a microwave power of 200 W. After the dropwise addition, continue the reaction until there is no formula (I-1) on TLC. After the reaction is completed, filter and wash the reaction solution with water, and determine the components of the reaction solution by HPLC.

[0089] 2) Add the above reaction solution to a 500mL four-necked bottle equipped with mechanical stirring, condenser, constant pressure dropping funnel, and thermometer, start stirring, adjust the pH to 8-9 with triethylamine, add diethyl phosphite (4.4g, 32mmol), control the temperature at 45°C to react until TLC shows no formula (III-1). After the reaction is completed, reduce the pressure and concentrate to a paste, add cold water to pulp, filter, rinse the filter cake with hot water and dry it to obtain 17.82g of a white solid product, with a yield of 66%, and a content of 99.1% detected by HPLC.

[0090] Example 16

[0091]

[0092] 1) Add 1-toluenesulfonyl-1,5,6,7-tetrahydro-4H-indol-4-one (20 g, 69 mmol) and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor. Start stirring, control the temperature at 10°C, and slowly drop NBS reagent (19 g, 107 mmol) dissolved in dichloroethane under 200 W microwave power. After the dropwise addition, continue the reaction until there is no formula (I-2) on TLC. After the reaction is completed, filter and wash the reaction solution with water, and determine the components of the reaction solution by HPLC.

[0093] 2) Add the above reaction solution to a 500mL four-necked bottle equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor, start stirring, adjust the pH to 8-9 with triethylamine, add diethyl phosphite (3.4g, 25mmol), control the temperature at 45°C and react at 300W microwave power until TLC shows no formula (III-2). After the reaction is completed, reduce the pressure and concentrate to a paste, add cold water to make a pulp, filter, rinse the filter cake with hot water and dry it to obtain 24.4g of a white solid product (II-2), with a yield of 90%, and a content of 99.2% detected 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] Embodiment 17

[0095]

[0096] 1) Add 1-(2,2,2-trifluoroacetyl)-1,5,6,7-tetrahydro-4H-indol-4-one (20 g, 87 mmol) and dichloroethane to a 500 mL four-necked flask equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor. Start stirring, control the temperature at 10°C, and slowly drop NBS reagent (19 g, 107 mmol) dissolved in dichloroethane under a microwave power of 200 W. After the dropwise addition, continue the reaction until there is no formula (I-3) on TLC. After the reaction is completed, filter and wash the reaction solution with water, and determine the composition of the reaction solution by HPLC.

[0097] 2) Add the above reaction solution to a 500mL four-necked bottle equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor, start stirring, adjust the pH to 8-9 with triethylamine, add diethyl phosphite (4.3g, 31mmol), control the temperature at 45°C and react at 300W microwave power until TLC shows no formula (III-3). After the reaction is completed, reduce the pressure and concentrate to a paste, add cold water to make a pulp, filter, rinse the filter cake with hot water and dry it to obtain 24.4g of a white solid product (II-3), with a yield of 91%, and a content of 99.2% detected by HPLC.

[0098] Embodiment 18

[0099]

[0100] 1) Add 4-oxo-4,5,6,7-tetrahydro-1H-indole-1-carboxylic acid benzyl ester (20g, 74mmol) and dichloroethane to a 500mL four-necked bottle equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor. Start stirring, control the temperature at 10°C, and slowly drop NBS reagent (19g, 107mmol) dissolved in dichloroethane under 200W microwave power. After the dropwise addition, continue the reaction until there is no formula (Ⅰ-4) on TLC. After the reaction is completed, filter and wash the reaction solution with water, and determine the components of the reaction solution by HPLC.

[0101] 2) Add the above reaction solution to a 500mL four-necked bottle equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor, start stirring, adjust the pH to 8-9 with triethylamine, add diethyl phosphite (3.6g, 26mmol), control the temperature at 45°C and react at 300W microwave power until TLC shows no formula (III-4). After the reaction is completed, reduce the pressure and concentrate to a paste, add cold water to make a pulp, filter, rinse the filter cake with hot water and dry it to obtain 23.1g of a white solid product (II-4), with a yield of 89%, and a content of 99.6% detected by HPLC.

[0102] Embodiment 19

[0103] Add 1-benzyl-1,5,6,7-tetrahydro-4H-indol-4-one (20g, 89mmol) and dichloroethane to a 500mL four-necked bottle equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor. Start stirring, control the temperature at 10°C, and slowly drop NBS reagent (19g, 107mmol) dissolved in dichloroethane at 200W microwave power. After the addition is complete, keep warm and react until TLC shows no formula (I-1). Raise the temperature to 15°C and adjust the microwave power to 500W to continue dropping NBS reagent (19g, 107mmol) dissolved in dichloroethane. After the addition is complete, keep warm and react until TLC shows no formula (II-1). After the reaction is completed, filter, and the filtrate is concentrated to half under reduced pressure. Stir and cool to -5°C for 2h before filtering. The filter cake is dried to obtain 32.7g of a white solid product with a yield of 96%. The content detected by HPLC is 99.9%.

[0104] Embodiment 20

[0105] Add 1-benzyl-1,5,6,7-tetrahydro-4H-indol-4-one (20g, 89mmol) and dichloroethane to a 500mL four-necked bottle equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor. Start stirring, control the temperature at 10°C, and slowly drop NBS reagent (19g, 107mmol) dissolved in dichloroethane at 200W microwave power. After the addition is complete, keep warm and react until TLC shows no formula (I-1). Raise the temperature to 15°C and adjust the microwave power to 350W to continue to drop NBS reagent (19g, 107mmol) dissolved in dichloroethane. After the addition is complete, keep warm and react until TLC shows no formula (II-1). After the reaction is completed, filter, concentrate the filtrate under reduced pressure to half, stir and cool to -5°C, keep warm for 2h, and filter. Dry the filter cake to obtain 28.3g of a white solid product with a yield of 83%. The content detected by HPLC is 99.7%.

[0106] Embodiment 21

[0107] Add 1-benzyl-1,5,6,7-tetrahydro-4H-indol-4-one (20g, 89mmol) and dichloroethane to a 500mL four-necked bottle equipped with a condenser, a constant pressure dropping funnel, and a thermometer in a microwave reactor. Start stirring, control the temperature at 10℃, and slowly drop NBS reagent (19g, 107mmol) dissolved in dichloroethane at 200W microwave power. After the addition is complete, keep warm and react until TLC shows no formula (I-1). Raise the temperature to 15℃ and adjust the microwave power to 250W to continue to drop NBS reagent (19g, 107mmol) dissolved in dichloroethane. After the addition is complete, keep warm and react until TLC shows no formula (II-1). After the reaction is completed, filter, concentrate the filtrate under reduced pressure to half, stir and cool to -5℃, keep warm for 2h, filter, and dry the filter cake to obtain 11.3g of white solid product, with a yield of 33%, and a content of 97.2% detected by HPLC.

Claims

1. A microwave-assisted bromination method of 1,5,6,7-tetrahydro-4H-indol-4-one derivatives, characterized in that: The method comprises the following steps: using a tetrahydroindolinone compound represented by formula (I) as a raw material, carrying out a bromination reaction with a brominating agent in an organic solvent under microwave conditions to obtain a brominated 1,5,6,7-tetrahydro-4H-indol-4-one derivative represented by formula (III) or a mixture represented by formula (II) and formula (III); adding a base to the mixture represented by formula (II) and formula (III) to adjust the pH to alkaline, adding diethyl phosphite to react and completely converting it into the brominated 1,5,6,7-tetrahydro-4H-indol-4-one derivative represented by formula (II); The structures corresponding to the formula (I), formula (II) and formula (III) are as follows: The substituent R is a halogen-substituted C1-C2 alkanoyl group, a C1-C2 alkyl-substituted benzenesulfonyl group, a phenyl-substituted C1-C2 alkyl group or a phenyl-substituted C1-C2 alkoxycarbonyl group.

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

3. A microwave-assisted bromination method of 1,5,6,7-tetrahydro-4H-indol-4-one derivative according to claim 1 or 2, characterized in that: The organic solvent is selected from one or more of dichloromethane, dichloroethane, chloroform, ethyl acetate, methyl propionate, tetrahydrofuran and N,N-dimethylformamide, and the bromination reagent is N-bromosuccinimide.

4. A microwave-assisted bromination method of 1,5,6,7-tetrahydro-4H-indol-4-one derivative according to claim 1 or 2, characterized in that: When preparing the compound represented by formula (III), a two-step method is adopted, comprising the following steps: a first step, using the tetrahydroindolinone compound represented by formula (I) as a raw material, carrying out a bromination reaction with a brominating agent in an organic solvent under the conditions of microwave 100-900W and -10-30°C until the raw material reacts completely, thereby obtaining a mixture represented by formula (II) and formula (III); a second step, continuing to add the brominating agent to the reaction solution of the first step, continuing the bromination reaction under microwave 100-900W and -10 to 30°C, thereby obtaining the compound represented by formula (III), wherein the total amount of brominating agent consumed in the first step and the second step to the compound represented by formula (I) is 2 to 2.6:

1.

5. A microwave-assisted bromination method of 1,5,6,7-tetrahydro-4H-indol-4-one derivative according to claim 4, characterized in that: The first step is carried out under the condition of microwave 200-400W and 5-15°C, and the second step is carried out under the condition of microwave 400-600W and 10-20°C.

6. A microwave-assisted bromination method for the derivatization of 1,5,6,7-tetrahydro-4H-indol-4-one according to claim 1 or 2, characterized in that: When preparing the compound represented by formula (II), a two-step method is adopted. In the first step, a tetrahydroindolinone compound represented by formula (I) is used as a raw material, and a bromination reaction is carried out with a bromination reagent in an organic solvent under the conditions of microwave 100-900W and -10-30°C until the raw material reacts completely to obtain a mixture represented by formula (II) and formula (III); in the second step, the pH value of the obtained reaction solution is adjusted to weak alkalinity, and then it is reacted with diethyl phosphite under the conditions of microwave 100-900W and 20-70°C to obtain the compound represented by formula (II).

7. A microwave-assisted bromination method for the derivatization of 1,5,6,7-tetrahydro-4H-indol-4-one according to claim 6, characterized in that: The first step is carried out under the condition of microwave 200-400W and 5-15°C, and the second step is carried out under the condition of microwave 200-400W and 40-50°C.

8. A microwave-assisted bromination method of 1,5,6,7-tetrahydro-4H-indol-4-one derivative according to claim 7, characterized in that: The base 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 represented by formula (III) in the reaction solution is 0.9 to 4.0:1; The molar ratio of the bromination reagent to the compound represented by formula (I) is 1 to 1.3:1.

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