3-benzyloxymethylindole-2-carboxylic acid derivatives, processes for their preparation and use

Abstract

The present application relates to the technical field of medicine, in particular to a kind of 3-benzyloxymethyl indole-2-carboxylic acid derivative and its preparation method and application.The 3-benzyloxymethyl indole-2-carboxylic acid derivative of the present application has simple synthesis method, simple procedure, first using indole-2-carboxylic acid compound as raw material, after esterification reaction protection carboxyl, introduce different substituent groups on the 2, 3, 6 position of indole ring, finally hydrolysis by alkali to release carboxyl, a series of 3-benzyloxymethyl indole-2-carboxylic acid derivatives can be obtained, the compound has significant HIV-1 integrase inhibitory activity, and has less effect on normal cells, provides new ideas and methods for the treatment of AIDS.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a 3-benzyloxymethylindole-2-carboxylic acid derivative, its preparation method, and its application. Background Technology

[0002] Since the early 1980s, when Acquired Immunodeficiency Syndrome (AIDS) spread worldwide, it has posed a tremendous threat to human health and life. To date, AIDS has caused more than one million deaths, and the number of people currently living with HIV-1 is in the tens of millions. The main strategy for treating AIDS is highly active antiretroviral therapy (HAART), also known as "cocktail therapy," which combines the use of reverse transcriptase inhibitors and protease inhibitors. Although this strategy has played an important role in AIDS treatment, both types of inhibitors have significant drug resistance, high toxicity, and high cost, making the search for new drug targets for AIDS treatment urgently needed in clinical practice.

[0003] In the AIDS life cycle, viral integration is crucial. Integration is the process by which viral DNA integrates into the human host's DNA, an indispensable part of the HIV-1 replication cycle. HIV-1 integrase participates in the entire integration process, catalyzing the entire integration reaction. It is an essential enzyme for HIV-1 replication and for stable viral infection. Furthermore, due to its different target, it is unaffected by drug resistance resulting from current chemotherapy drugs and remains effective against current drug-resistant variants. Secondly, the absence of a corresponding enzyme in human cells means that inhibitors targeting integrase have lower toxicity. Therefore, integrase has become a highly attractive new target in anti-HIV-1 research.

[0004] Although five integrase inhibitors are currently on the market, their efficacy has decreased due to the emergence of drug-resistant viral strains. Furthermore, while patent CN1560035A discloses a 5-hydroxyindole-3-carboxylic acid ester derivative with anti-HIV activity, it demonstrates anti-HIV-1 protease activity; its safety and anti-HIV-1 integrase activity are unknown. The preparation process is complex, requiring various reagents such as catalysts and oxidants, and the target product must be controlled by adjusting the oxidant ratio and reaction time, directly increasing the control requirements and making the target product difficult to control. Moreover, since this compound is a protease inhibitor, it represents a completely different antiviral target from integrase, with a completely different mechanism of action. Therefore, it is essential to explore a new generation of integrase inhibitors with a novel mode of action, high efficiency, low toxicity, and simple synthetic control. Summary of the Invention

[0005] To address the aforementioned technical problems in the prior art, this invention provides a 3-benzyloxymethylindole-2-carboxylic acid derivative, its preparation method, and its application, as detailed below:

[0006] A 3-benzyloxymethylindole-2-carboxylic acid derivative has the general structural formula shown in formula (I):

[0007]

[0008] Preferably, in the general formula (Ⅰ), R1 is a hydrogen atom, sodium atom, potassium atom, methyl, ethyl, propyl, or isopropyl; R2 and R3 are halogens, trifluoromethyl, methyl, or methoxy; X and Y are carbon and nitrogen atoms; and n is 0, 1, or 2.

[0009] A 3-benzyloxymethylindole-2-carboxylic acid derivative, including but not limited to the following compounds:

[0010]

[0011]

[0012]

[0013] Another objective of this invention is to provide a method for preparing 3-benzyloxymethylindole-2-carboxylic acid derivatives. Using indole-2-carboxylic acid compounds as raw materials, the carboxyl group is protected by esterification, and different substituents are introduced at the 2, 3, or 6 positions on the indole ring. Finally, the carboxyl group is released by alkaline hydrolysis, thus obtaining the 3-benzyloxymethylindole-2-carboxylic acid derivative.

[0014] Specifically, the preparation method of the 3-benzyloxymethylindole-2-carboxylic acid derivative includes the following steps:

[0015] (1) Synthesis of ethyl 6-bromo-1H-indole-2-carboxylic acid: 6-bromo-1H-indole-2-carboxylic acid (i.e., compound a) was dissolved in ethanol, concentrated sulfuric acid was added, and the mixture was refluxed and stirred at 80°C under oil bath conditions. The reaction was detected by thin-layer chromatography. After the reaction was complete, the reaction solution was taken out for post-processing to obtain 6-bromo-1H-indole-2-carboxylic acid (i.e., compound b).

[0016] (2) Synthesis of ethyl 3-formyl-6-bromo-1H-indole-2-carboxylic acid: 6-bromo-1H-indole-2-carboxylic acid (compound b) was dissolved in N,N-dimethylformamide, and then phosphorus oxychloride was slowly added. The reaction was carried out at room temperature and detected by thin-layer chromatography. After the reaction was complete, the reaction solution was taken out and slowly added dropwise to ice water for post-treatment to obtain ethyl 3-formyl-6-bromo-1H-indole-2-carboxylic acid (i.e., compound c).

[0017] (3) Synthesis of 3-(hydroxymethyl)-6-bromo-1H-indole-2-carboxylic acid isopropyl ester (i.e., compound d): 3-formyl-6-bromo-1H-indole-2-carboxylic acid ethyl ester (compound c) was dissolved in isopropanol, aluminum isopropoxide was added, and the reaction was carried out in an oil bath at 60°C. The reaction was detected by thin-layer chromatography. After the reaction was complete, the reaction solution was taken out, evaporated to dryness, and purified by silica gel column chromatography to obtain compound d.

[0018] (4) Synthesis of intermediate compound e: 3-(hydroxymethyl)-6-bromo-1H-indole-2-carboxylic acid isopropyl ester (compound d), substituted benzyl bromide or substituted bromomethylpyridine, and potassium carbonate were dissolved in N,N-dimethylformamide and reacted at room temperature. The reaction was detected by thin-layer chromatography. After the reaction was complete, the reaction solution was taken out, water was added, and the solution was extracted with ethyl acetate. The extract was evaporated to dryness and the intermediate compound e was separated and purified by silica gel column chromatography.

[0019] (5) Synthesis of target compound f: The intermediate compound e synthesized in step (4), substituted aniline or substituted pyridine, palladium acetate, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and cesium carbonate were dissolved in 1,4-dioxane and reacted in an oil bath at 110°C. The reaction was detected by thin-layer chromatography. After the reaction was complete, the reaction solution was taken out, filtered, and the filtrate was evaporated to dryness. The target compound f was separated and purified by silica gel column chromatography.

[0020] Furthermore, a method for preparing a 3-benzyloxymethylindole-2-carboxylic acid derivative, based on the above steps (1)-(5), further includes (6) synthesizing the target compound g, namely, dissolving the target compound f synthesized in step (5) and sodium hydroxide in a mixed solvent of methanol and water, stirring the reaction at room temperature, detecting the reaction by thin-layer chromatography, adjusting the pH to weakly acidic with acetic acid after the reaction is complete, adding water, extracting with ethyl acetate, drying the extract by rotary evaporation, packing into a column, and separating and purifying the target compound B by silica gel column chromatography; wherein the methanol:water ratio in the mixed solvent of methanol and water is 3:1.

[0021] Furthermore, a method for preparing a 3-benzyloxymethylindole-2-carboxylic acid derivative, based on the above steps (1)-(6), further includes (7) synthesizing the target compound h, namely, dissolving the target compound B synthesized in step (6) in acetone, gradually adding sodium hydroxide aqueous solution to the solution until a large amount of white solid precipitates, washing the filter cake with a small amount of cold water, and drying to obtain the target compound h.

[0022] Preferably, in steps (1) and (2), the post-processing involves first adjusting the pH of the reaction solution, and then sequentially extracting, concentrating, and purifying by thin-layer chromatography. More preferably, the operations of adjusting the pH of the reaction solution, extracting with ethyl acetate, concentrating, and separating specifically involve adjusting the pH to weakly alkaline, extracting with ethyl acetate, concentrating the extract, packing it into a column, and purifying the target product by thin-layer chromatography.

[0023] The pH of the reaction solution is adjusted to a slightly alkaline state using anhydrous sodium carbonate.

[0024] The thin-layer chromatography separation was performed using silica gel column chromatography for purification.

[0025] In step (4), the substituted benzyl bromide is either p-trifluoromethylbenzyl bromide or o-fluorobenzyl bromide; the substituted pyridine is 4-trifluoromethyl-3-hydroxymethylpyridine.

[0026] In step (5), the substituted amine is any one of 3-fluoro-4-methoxyaniline, 2,4-difluoroaniline, and p-fluorobenzylamine; the substituted pyridine is 2-methyl-5-aminopyridine.

[0027] Another aspect of the present invention is to provide the use of a 3-benzyloxymethylindole-2-carboxylic acid derivative in the preparation of an anti-HIV drug.

[0028] More preferably, the application of a 3-benzyloxymethylindole-2-carboxylic acid derivative in the preparation of HIV-1 integrase inhibitors is provided.

[0029] Furthermore, an HIV-1 integrase inhibitor comprises a compound having the general formula (I), or a stereoisomer, geometric isomer, hydrate, solvate, pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound having the general formula (I).

[0030] Beneficial effects:

[0031] The 3-benzyloxymethylindole-2-carboxylic acid derivative of the present invention has been experimentally verified to have excellent HIV-1 integrase inhibitory activity and high safety.

[0032] The preparation method of the 3-benzyloxymethylindole-2-carboxylic acid derivative of the present invention is simple, convenient, and has a novel structure; the preparation time is short, with a total reaction time of less than 24 hours; the reaction conditions are mild; the TLC method has the advantages of being simple, rapid, sensitive, and capable of real-time monitoring; the process control of the present invention is simple, without the need for complex temperature and time control. Attached Figure Description

[0033] Figure 1 Synthetic route for 3-benzyloxymethylindole-2-carboxylic acid derivatives;

[0034] Figure 2 This is a schematic diagram of the binding pattern between a 3-benzyloxymethylindole-2-carboxylic acid derivative and an integrase. Detailed Implementation

[0035] Example 1

[0036] (1) Synthesis of ethyl 6-bromo-1H-indole-2-carboxylic acid (compound b1): 100 mg of compound a1 (6-bromo-1H-indole-2-carboxylic acid) was dissolved in 10 mL of ethanol, and 0.5 mL of concentrated sulfuric acid was added. The mixture was stirred in an oil bath at 80 °C for 1.5 h. After the reaction was completed, the reaction solution was removed, and anhydrous sodium carbonate was added to adjust the pH of the reaction solution to weakly alkaline. The solution was extracted with ethyl acetate, the extract was concentrated, and the target compound b1 was separated and purified by silica gel column chromatography.

[0037]

[0038] (2) Synthesis of ethyl 3-formyl-6-bromo-1H-indole-2-carboxylic acid (compound c1): 100 mg of compound b1 was dissolved in 10 mL of N,N-dimethylformamide, and then 1.9 mL of phosphorus oxychloride was slowly added. The reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction solution was taken out, anhydrous sodium carbonate was added to adjust the pH of the reaction solution to weakly alkaline, and the solution was extracted with ethyl acetate and the extract was evaporated to dryness. The target compound c1 was separated and purified by silica gel column chromatography.

[0039]

[0040] (3) Synthesis of 3-(hydroxymethyl)-6-bromo-1H-indole-2-carboxylic acid isopropyl ester (compound d1): 100 mg of compound c1 was dissolved in 15 mL of isopropanol, 150 mg of aluminum isopropoxide was added, and the reaction was carried out in an oil bath at 60 °C for about 5 h. After the reaction was completed, the reaction solution was removed, the reaction solution was evaporated to dryness, and the target compound d1 was separated and purified by silica gel column chromatography.

[0041]

[0042] (4) Synthesis of 6-bromo-3-(4-trifluoromethylbenzyloxymethyl)-1H-indole-2-carboxylic acid isopropyl ester (compound e1): 100 mg of compound d1, 78 mg of p-trifluoromethylbenzyl bromide and 160 mg of potassium carbonate were dissolved in 10 mL of N,N-dimethylformamide and reacted at room temperature for 5 h. After the reaction was completed, the reaction solution was removed, an appropriate amount of water was added, and the solution was extracted with ethyl acetate. The extract was evaporated to dryness and purified by silica gel column chromatography to obtain the target compound e1.

[0043]

[0044] (5) Synthesis of 6-(3-fluoro-4-methoxyphenylamino)-3-(4-trifluoromethylbenzyloxymethyl)-1H-indole-2-carboxylic acid isopropyl ester (compound f1): 100 mg of compound e1, 115 mg of 3-fluoro-4-methoxyaniline, 20 mg of palladium acetate, 38 mg of 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, and 110 mg of cesium carbonate were dissolved in 10 mL of 1,4-dioxane. The reaction was carried out in an oil bath at 110 °C for about 4 h. After the reaction was completed, the reaction solution was removed, filtered, and the filtrate was evaporated to dryness. The target compound f1 was purified by silica gel column chromatography.

[0045]

[0046] Compound f1 with HIV-1 integrase inhibitory activity

[0047] (6) Synthesis of 6-((3-fluoro-4-methoxyphenylamino)-3-(4-trifluoromethylbenzyloxymethyl)-1H-indole-2-carboxylic acid (compound g1): 100 mg of compound f1 and 60 mg of sodium hydroxide were dissolved in 4 mL of a mixed solvent of methanol and water (methanol:water = 3:1), and the reaction was stirred at room temperature. After the reaction was completed, post-treatment was performed, and then the target compound g1 was separated and purified.

[0048]

[0049] Compound g1 with HIV-1 integrase inhibitory activity

[0050] (7) Synthesis of sodium 6-((3-fluoro-4-methoxyphenylamino)-3-(4-trifluoromethylbenzyloxymethyl)-1H-indole-2-carboxylate (compound h1): Dissolve 100 mg of compound g1 in 5 mL of acetone, and gradually add sodium hydroxide aqueous solution to the solution until a large amount of white solid precipitates. Filter, wash the filter cake with a small amount of cold water, and dry to obtain the target compound h1.

[0051]

[0052] Compound h1 with HIV-1 integrase inhibitory activity

[0053] Example 2

[0054] In step (4) of Example 1, p-trifluoromethylbenzyl bromide was replaced with o-fluorobenzyl bromide, and the remaining steps were the same, finally yielding intermediate e2.

[0055]

[0056] Example 3

[0057] In step (5) of Example 1, 3-fluoro-4-methoxyaniline was replaced with 2,4-difluoroaniline, and the remaining steps were the same, finally yielding compound f2 with HIV-1 integrase inhibitory activity.

[0058]

[0059] Compound f2 has HIV-1 integrase inhibitory activity.

[0060] Example 4

[0061] By replacing compound e1 in step (5) of Example 1 with e2, and keeping the other steps the same, compound f3 with HIV-1 integrase inhibitory activity was finally obtained.

[0062]

[0063] Compound f3 has HIV-1 integrase inhibitory activity.

[0064] Example 5

[0065] In step (5) of Example 1, compound e1 was replaced with e2, 3-fluoro-4-methoxyaniline was replaced with 2,4-difluoroaniline, and the remaining steps were the same, finally yielding compound f4 with HIV-1 integrase inhibitory activity.

[0066]

[0067] Compound f4, which has HIV-1 integrase inhibitory activity

[0068] Example 6

[0069] Replace compound f1 in step (6) of Example 1 with compound f2, and keep the other steps the same, and finally obtain compound g2 with HIV-1 integrase inhibitory activity.

[0070]

[0071] Compound g2 with HIV-1 integrase inhibitory activity

[0072] Example 7

[0073] Replace f1 with f3 in step (6) of Example 1, and keep the other steps the same. Finally, compound g3 with HIV-1 integrase inhibitory activity is obtained.

[0074]

[0075] Compound g3 with HIV-1 integrase inhibitory activity

[0076] Example 8

[0077] Replace f1 with f4 in step (6) of Example 1, and keep the other steps the same. Finally, compound g4 with HIV-1 integrase inhibitory activity is obtained.

[0078]

[0079] Compound g4 with HIV-1 integrase inhibitory activity

[0080] Example 9

[0081] Replace g1 with g2 in step (7) of Example 1, and keep the other steps the same, and finally obtain compound h2 with HIV-1 integrase inhibitory activity.

[0082]

[0083] Compound h2 with HIV-1 integrase inhibitory activity

[0084] Example 10

[0085] Replace g1 with g3 in step (7) of Example 1, and keep the other steps the same. Finally, compound h3 with HIV-1 integrase inhibitory activity is obtained.

[0086]

[0087] Compound h3 with HIV-1 integrase inhibitory activity

[0088] Example 11

[0089] Replace g1 with g4 in step (7) of Example 1, and keep the other steps the same. Finally, compound h4 with HIV-1 integrase inhibitory activity is obtained.

[0090]

[0091] Compound h4 with HIV-1 integrase inhibitory activity

[0092] Example 12

[0093] In step (5) of Example 1, 3-fluoro-4-methoxyaniline was replaced with 2-methylaniline, and the remaining steps were the same, finally yielding compound f5 with HIV-1 integrase inhibitory activity.

[0094]

[0095] Compound f5, which has HIV-1 integrase inhibitory activity

[0096] Example 13

[0097] Replace f1 with f5 in step (6) of Example 1, and keep the other steps the same. Finally, compound g5 with HIV-1 integrase inhibitory activity is obtained.

[0098]

[0099] Compound g5 with HIV-1 integrase inhibitory activity

[0100] Example 14

[0101] Replace g1 with g5 in step (7) of Example 1, and keep the other steps the same, and finally obtain compound h5 with HIV-1 integrase inhibitory activity.

[0102]

[0103] Compound h5 with HIV-1 integrase inhibitory activity

[0104] Example 15

[0105] In step (4) of Example 1, 3-trifluoromethylbenzyl bromide was replaced with 4-trifluoromethyl-3-bromomethylpyridine, and the remaining steps were the same, finally yielding intermediate e3.

[0106]

[0107] Example 16

[0108] In step (5) of Example 1, e1 was replaced with e3, 3-fluoro-4-methoxyaniline was replaced with 2-methyl-5-aminopyridine, and the remaining steps were the same, finally yielding compound f6 with HIV-1 integrase inhibitory activity.

[0109]

[0110] Compound f6 has HIV-1 integrase inhibitory activity.

[0111] Example 17

[0112] Replace f1 with f6 in step (6) of Example 1, and keep the other steps the same. Finally, compound g6 with HIV-1 integrase inhibitory activity is obtained.

[0113]

[0114] Compound g6 has HIV-1 integrase inhibitory activity.

[0115] Example 18

[0116] Replace g1 with g6 in step (7) of Example 1, and keep the other steps the same. Finally, compound h6 with HIV-1 integrase inhibitory activity is obtained.

[0117]

[0118] Compound h6 with HIV-1 integrase inhibitory activity

[0119] Example 19

[0120] In step (5) of Example 1, 3-fluoro-4-methoxyaniline was replaced with p-fluorobenzylamine, and the remaining steps were the same, finally yielding compound f7 with HIV-1 integrase inhibitory activity.

[0121]

[0122] Compound f7 has HIV-1 integrase inhibitory activity.

[0123] Example 20

[0124] Replace f1 with f7 in step (6) of Example 1, and keep the other steps the same. Finally, compound g7 with HIV-1 integrase inhibitory activity is obtained.

[0125]

[0126] Compound g7 with HIV-1 integrase inhibitory activity

[0127] Example 21

[0128] Replace g1 with g7 in step (7) of Example 1, and keep the other steps the same. Finally, obtain compound h7 with HIV-1 integrase inhibitory activity.

[0129]

[0130] Compound h7 with HIV-1 integrase inhibitory activity

[0131] The compounds with HIV-1 integrase inhibitory activity obtained in Examples 1-21 were subjected to the following determinations:

[0132] 1. Integrase strand transfer activity assay

[0133] The activities of the compounds with HIV-1 integrase inhibitory activity obtained in Examples 1-21 are as follows:

[0134] The main method for detecting HIV-1 integrase inhibitor activity is to use an integrase kit.

[0135] (1) Coating DS DNA: Remove any unused strips from the streptavidin-coated 96-well plate and reseal them in aluminum foil bags containing desiccant. Dilute the required DS DNA 100× solution (10 μL DS DNA 100× solution and 990 μL reaction buffer) 100-fold in the reaction buffer. Add 100 μL of 1× DS DNA solution to each well and incubate at 37°C for 30 min. Return the reaction buffer to a 37°C water bath. Draw liquid from the wells and wash 5 times with 300 μL of washing buffer. Add 200 μL of blocking buffer to each well and incubate at 37°C for 30 min.

[0136] (2) Dilute the enzyme 1:300 to prepare a reaction buffer (2 μL HIV-1 integrase and 598 μL reaction buffer). Aspirate the liquid from the wells and wash three times with 200 μL of reaction buffer. Add 100 μL of reaction buffer (negative control) or integrase solution (positive control) to each well and incubate at 37°C for 30 min.

[0137] (3) Wash three times with 200 μL of reaction buffer. Add 50 μL of reaction buffer (both positive and negative controls are reaction buffer) to each well of each test sample and incubate at room temperature for 5 min.

[0138] (4) Dilute the required TS DNA 100× solution 100-fold in the reaction buffer (10 μL of TS DNA 100× solution per mL, 990 μL of reaction buffer). Add 50 μL of 1×TS DNA solution directly to each well in a 50 μL buffer / test sample container. Gently tap the dish 3-5 times with a steady hand to mix the reactions. Incubate at 37°C for 30 minutes.

[0139] (5) Draw liquid from the wells and wash 5 times with 300 μL of washing buffer. Add 100 μL of HRP antibody solution to each well and incubate at 37°C for 30 min.

[0140] (6) Draw liquid from the wells and wash 5 times with 300 μL of washing buffer. Add 100 μL of TMB peroxidase substrate solution to each well and incubate at room temperature for 10 minutes.

[0141] (7) Add 100 μL of TMB stop solution directly to the well containing the TMB substrate. Prick any large air bubbles with the tip of a pipette. Read the absorbance of the well using a flatbed reader set to 450 nm for at least 0.1 seconds. Read the plate within 10 minutes of adding the TMB stop solution.

[0142] (8) The absorbance A value was measured using an enzyme-linked immunosorbent assay (ELISA) reader, and the inhibition rate was calculated using the formula 100×[1-(A value of drug-treated group - A value of blank control) / (A value of integrase control group - A value of blank control)].

[0143] 2. Cytotoxicity assay

[0144] Cytotoxicity assays were performed using the MTT assay. The test sample was dissolved in DMSO and then diluted with phosphate buffer to different desired concentrations. 100 μL of each concentration of the test compound was then added to MT-4 cells (5 × 10⁻⁶ cells). 4 The samples were pre-incubated together at 37°C for 5 days on a 96-well plate. Then, 150 μL of DMSO was added to each well, mixed thoroughly, and the absorbance was measured at 570 nm using a microplate reader. The CC value was calculated. 50 That is, you get it.

[0145]

[0146]

[0147] The above activity test results indicate that the compounds of this invention have very low toxicity to T cells (MT-4). Only compounds f3 and f4 showed low toxicity, while the other compounds did not show significant toxicity. On the other hand, the invented compounds exhibit very significant inhibitory activity against HIV-1 integrase strand transfer, with compound 1n IC showing the best activity. 50 At a concentration of 0.13 μM, these compounds exhibited good integrase inhibition. Furthermore, in addition to the classic integrase inhibitor mechanism of action (i.e., metal ion occlusion and π-stacking with viral nucleic acids), these compounds also added hydrophobic binding near the active site, enhancing their integrase inhibitory activity. Figure 2 ), Figure 2 This is a schematic diagram of the binding pattern of compound g1 with HIV-1 integrase. These results provide new options for the development of drugs to treat AIDS.

Claims

1. A 3-benzyloxymethylindole-2-carboxylic acid derivative, characterized in that, The general structural formula of the derivative is shown in formula (I): (Ⅰ) Where R1 is hydrogen, sodium, potassium, methyl, ethyl, propyl, or isopropyl; R2 and R3 are halogen, trifluoromethyl, methyl, or methoxy; X and Y are carbon or nitrogen; and n is 0, 1, or 2.

2. A 3-benzyloxymethylindole-2-carboxylic acid derivative, characterized in that, The specific compounds are as follows: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 3. The method for preparing a 3-benzyloxymethylindole-2-carboxylic acid derivative according to claim 1 or 2, characterized in that, Includes the following steps: (1) Synthesis of ethyl 6-bromo-1H-indole-2-carboxylic acid: 6-bromo-1H-indole-2-carboxylic acid was dissolved in ethanol, concentrated sulfuric acid was added, and the mixture was refluxed and stirred at 80°C under oil bath conditions. The reaction was detected by thin-layer chromatography. After the reaction was complete, the reaction solution was taken out for post-processing to obtain ethyl 6-bromo-1H-indole-2-carboxylic acid. (2) Synthesis of ethyl 3-formyl-6-bromo-1H-indole-2-carboxylate: ethyl 6-bromo-1H-indole-2-carboxylate was dissolved in N,N-dimethylformamide, and then phosphorus oxychloride was slowly added. The reaction was carried out at room temperature, and the reaction was detected by thin-layer chromatography. After the reaction was complete, the reaction solution was taken out and slowly added dropwise to ice water for post-treatment to obtain ethyl 3-formyl-6-bromo-1H-indole-2-carboxylate. (3) Synthesis of 3-(hydroxymethyl)-6-bromo-1H-indole-2-carboxylic acid isopropyl ester: 3-formyl-6-bromo-1H-indole-2-carboxylic acid ethyl ester was dissolved in isopropanol, aluminum isopropoxide was added, and the reaction was carried out in an oil bath at 60°C. The reaction was detected by thin-layer chromatography. After the reaction was complete, the reaction solution was taken out, evaporated to dryness, and purified by silica gel column chromatography. (4) Synthesis of intermediate compound e: 3-(hydroxymethyl)-6-bromo-1H-indole-2-carboxylic acid isopropyl ester, substituted benzyl bromide or substituted bromomethylpyridine, and potassium carbonate were dissolved in N,N-dimethylformamide and reacted at room temperature. The reaction was detected by thin-layer chromatography. After the reaction was complete, the reaction solution was taken out, water was added, and the solution was extracted with ethyl acetate. The extract was evaporated to dryness and the intermediate compound e was separated and purified by silica gel column chromatography. (5) Synthesis of target compound f: The intermediate compound synthesized in step (4), substituted aniline or substituted pyridine, palladium acetate, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and cesium carbonate were dissolved in 1,4-dioxane and reacted in an oil bath at 110°C. The reaction was detected by thin-layer chromatography. After the reaction was complete, the reaction solution was taken out, filtered, and the filtrate was dried by rotary evaporation. The target compound f was separated and purified by silica gel column chromatography.

4. The method for preparing a 3-benzyloxymethylindole-2-carboxylic acid derivative according to claim 3, characterized in that, It also includes (6) synthesizing target compound g, that is, dissolving target compound f synthesized in step (5) and sodium hydroxide in a mixed solvent of methanol and water, stirring the reaction at room temperature, detecting the reaction by thin-layer chromatography, adjusting the pH to weak acidity with acetic acid after the reaction is complete, adding water, extracting with ethyl acetate, drying the extract by rotary evaporation, packing the column, and separating and purifying target compound g by silica gel column chromatography; in the mixed solvent of methanol and water, methanol:water = 3:

1.

5. The method for preparing a 3-benzyloxymethylindole-2-carboxylic acid derivative according to claim 4, characterized in that, It also includes (7) synthesizing target compound h, that is, dissolving target compound g synthesized in step (6) in acetone, gradually adding sodium hydroxide aqueous solution to the solution until a large amount of white solid precipitates, washing the filter cake with a small amount of cold water, and drying to obtain target compound h.

6. The method for preparing a 3-benzyloxymethylindole-2-carboxylic acid derivative according to claim 3, characterized in that, In steps (1) and (2), the post-treatment involves first adjusting the pH of the reaction solution, and then sequentially extracting with ethyl acetate, concentrating, and separating and purifying by thin-layer chromatography.

7. The method for preparing a 3-benzyloxymethylindole-2-carboxylic acid derivative according to claim 3, characterized in that, In step (4), the substituted benzyl bromide is either p-trifluoromethylbenzyl bromide or o-fluorobenzyl bromide; the substituted pyridine is 4-trifluoromethyl-3-hydroxymethylpyridine.

8. The method for preparing a 3-benzyloxymethylindole-2-carboxylic acid derivative according to claim 4, characterized in that, In step (5), the substituted amine is any one of 3-fluoro-4-methoxyaniline, 2,4-difluoroaniline, and p-fluorobenzylamine; the substituted pyridine is 2-methyl-5-aminopyridine.

9. The use of a 3-benzyloxymethylindole-2-carboxylic acid derivative according to claim 1 or 2 in the preparation of an anti-HIV drug.

10. The use of a 3-benzyloxymethylindole-2-carboxylic acid derivative according to claim 1 or 2 in the preparation of a medicament as an HIV-1 integrase inhibitor.

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