CN109810044B - Compound with HIV-1 integrase inhibitory activity and preparation and application thereof - Google Patents
Compound with HIV-1 integrase inhibitory activity and preparation and application thereof Download PDFInfo
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Abstract
The invention relates to the technical field of medicines, in particular to a compound with HIV-1 integrase inhibitory activity and a preparation method thereof. The invention takes p-methylaniline as raw material, and is synthesized through a series of steps, finally a compound which has obvious antiviral activity and less influence on normal cells and has HIV-1 integrase inhibitory activity is obtained, and the compound is represented by the following general formula (I):
in the general formula (I), R1 and R2 are hydroxyl, alkoxy, amino and hydrogen atoms; r3 is hydrogen atom, halogen atom, alkyl, nitro, hydroxyl or amino.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a compound with HIV-1 integrase inhibitory activity and preparation and application thereof.
Background
AIDS, also known as acquired immunodeficiency syndrome (AIDS), is an infectious disease characterized by severe damage to the systemic immune system caused by infection with Human Immunodeficiency Virus (HIV). Since the first AIDS case was reported in the United states in 1981, it has spread worldwide and has been widely abused worldwide, posing serious harm to human life health and social development, and has attracted general government and social attention of various countries. HIV-1 resistance is caused by the mutation of viral genes, which changes the biochemical or structural characteristics of the action target of drugs, and leads to the insensitivity or the reduced sensitivity of viruses to drugs.
HIV-1 Integrase (Integrase) is one of three key enzymes in the viral replication process and mediates the integration of retroviral DNA into host genomic DNA. If the integration process is blocked, the replication of the virus is interrupted, so the integration process is the last key step for the HIV-1 virus to invade target cells and finally form irreversible infection, and the integrase becomes an important target for inhibiting the virus transmission.
However, the integrase chain transfer inhibitors currently on the market present resistance problems. Therefore, the problem to be solved is to find an HIV-1 integrase inhibitor with novel structure, low toxicity and high antiviral activity.
Disclosure of Invention
In order to solve the above technical problems in the prior art, the present invention provides a compound having HIV-1 integrase inhibitory activity, specifically as follows:
a compound having HIV-1 integrase inhibitory activity, which is represented by the following general formula (I):
preferably, in the general formula (I), R1 and R2 are hydroxyl, alkoxy, amino and hydrogen atoms. The compound has better antiviral activity.
Preferably, in the general formula (I), R3 is a hydrogen atom, a halogen atom, an alkyl group, a nitro group, a hydroxyl group, or an amino group. The compound has better antiviral activity.
More preferably, in the general formula (I), R1 is OH, R2 is OCH2CH3And R3 is H. The compound has better antiviral activity, lower cytotoxicity and better overall effect.
The preparation method of the compound with HIV-1 integrase inhibitory activity comprises the following steps:
(1) synthesis of p-methoxybenzenediazobenzene hydrochloride (compound b): completely dissolving 1 time equivalent of the compound a (p-methylaniline) by using concentrated hydrochloric acid, and stirring for 2 hours at room temperature; moving the mixture into a reaction system at the temperature of between 0 and 10 ℃ below zero, slowly adding 2 times of equivalent of sodium nitrite when the temperature is constant, stirring the mixture for reaction, and reacting the mixture for 2 to 5 hours at the temperature to obtain a compound b;
(2) synthesis of diethyl (Z) -2-acetyl-2- ((4-methoxyphenyl) diazenyl) glutarate (Compound c): dissolving 1.2 times of raw material diethyl 2-acetylglutamate with absolute ethyl alcohol completely, adding excessive concentrated H2SO4Fully and uniformly mixing the raw materials, slowly adding a compound b at a constant speed, reacting at room temperature for 2-3h, and carrying out experimental post-treatment after the reaction is finished: adjusting pH to weak alkaline, extracting with Ethyl Acetate (EA), concentrating the extractive solution, and separating and purifying the target product by silica gel column chromatography to obtain compoundAn object c;
(3) synthesis of (Z) -diethyl 2- (2- (4-methoxyphenyl) hydrazono) glutarate (Compound d): completely dissolving the separated compound c with absolute ethyl alcohol, adding excessive concentrated HCl, stirring at room temperature for 2-5h, and separating and purifying to obtain a compound d after the reaction is finished;
(4) synthesis of ethyl 3- (2-ethoxy-2-oxoethyl) -5-methoxy-1H-indole-2-carboxylate (Compound e): and (3) completely dissolving the compound d by using absolute ethyl alcohol, introducing dry HCl gas, stirring at room temperature for 2-7h, carrying out experimental post-treatment after the reaction is finished, and then separating and purifying to obtain a compound e, wherein the compound e is a compound with HIV-1 integrase inhibitory activity.
Preferably, during the reaction of the steps (1) to (4), Thin Layer Chromatography (TLC) is performed to monitor the progress of the reaction, and if the reaction is not complete, the reaction is continued until the reaction is complete. TLC is a common method in chemical synthesis and has the advantages of simplicity, rapidness, sensitivity and real-time monitoring.
Preferably, the post-experimental treatment is performed by adjusting the pH of the reaction solution, extracting with Ethyl Acetate (EA), concentrating, separating, and the like. More preferably, the operations of adjusting the pH of the reaction solution, extracting with EA, concentrating, separating and the like are specifically adjusting the pH to be alkalescent, extracting with EA, concentrating the extract, filling into a column, and separating and purifying the target product by using thin-layer chromatography.
Preferably, the pH is adjusted to be alkalescent by using anhydrous sodium carbonate.
The application of the compound with HIV-1 integrase inhibitory activity in preparing anti-HIV drugs. In particular to the application of the compound in HIV-1 type integrase inhibitors.
Compared with the prior art, the invention has the technical effects that:
the invention discovers that the 2-indole carboxylic acid mother nucleus of the compound containing the 2-indole carboxylic acid is not reported in HIV-1 integrase inhibitors through earlier researches. Meanwhile, the indole has the most obvious antiviral activity, is an important structure, can imitate the structure of peptide to be combined with target protein, and can reach an integrase activity area more easily, so that the antiviral effect of the indole is improved. Therefore, the inventor considers that the novel 2-indole carboxylic acid integrase inhibitor can be easily combined with the active site region of integrase to achieve a more obvious antiviral effect, p-methylaniline is used as a raw material and is synthesized through a series of steps to finally obtain a compound and a derivative thereof which have obvious antiviral activity and small influence on normal cells and have HIV-1 integrase inhibitory activity.
Drawings
FIG. 1 is a schematic diagram of a synthetic process for compounds having HIV-1 integrase inhibitory activity and derivatives thereof;
FIG. 2 is a schematic structural diagram of a compound having HIV-1 integrase inhibitory activity of the present invention;
Detailed Description
The technical solution of the present invention is further defined below with reference to the specific embodiments, but the scope of the claims is not limited to the description.
Example 1
(1) Synthesis of p-methoxybenzenediazobenzene hydrochloride (compound b): completely dissolving 1.00g of compound a (p-methylaniline) by using concentrated hydrochloric acid, and stirring at room temperature for 2 hours; transferring into a reaction system at 0-10 ℃, slowly adding 0.8404g of sodium nitrite when the temperature is constant, stirring for reaction, and reacting for 3.5h at the temperature to obtain a compound b
(2) Synthesis of diethyl (Z) -2-acetyl-2- ((4-methoxyphenyl) diazenyl) glutarate (Compound c): 2.24g of diethyl 2-acetylglutamate are completely dissolved in absolute ethanol and excess concentrated H is added2SO4Fully and uniformly mixing the mixture, slowly and constantly dropping 1.7g of ethanol solution of the compound b, reacting at room temperature for 2.5 hours after the dropping is finished, and carrying out experimental post-treatment after the reaction is finished, namely separating and purifying to obtain a compound c;
(3) synthesis of (Z) -diethyl 2- (2- (4-methoxyphenyl) hydrazono) glutarate (Compound d): completely dissolving 1g of compound c by absolute ethyl alcohol, adding excessive concentrated HCl, stirring at room temperature for 3.5h, carrying out experimental post-treatment after the reaction is finished, and then separating and purifying to obtain a compound d;
(4) synthesis of ethyl 3- (2-ethoxy-2-oxoethyl) -5-methoxy-1H-indole-2-carboxylate (Compound e): and (3) completely dissolving 1g of the compound d by using absolute ethyl alcohol, introducing dry HCl gas, stirring at room temperature for 4.5h, carrying out experimental post-treatment after the reaction is finished, and then separating and purifying to obtain a compound e, wherein the compound e is the compound e with HIV-1 integrase inhibitory activity.
During the reaction of the steps (1) to (4), Thin Layer Chromatography (TLC) is carried out to monitor the progress of the reaction, and if the reaction is not complete, the reaction is continued until the reaction is complete.
The post-treatment of the experiment is to adjust the pH to be alkalescent, extract the mixture for 3 times by Ethyl Acetate (EA), concentrate the extract, pack the column and separate and purify the target product by thin-layer chromatography.
The pH value is adjusted to be alkalescent, and the pH value is adjusted by using anhydrous sodium carbonate.
Compound e with HIV-1 integrase inhibitory activity
Example 2
(1) Synthesis of p-methoxybenzenediazobenzene hydrochloride (compound b): completely dissolving 1.00g of compound a (p-methylaniline) by using concentrated hydrochloric acid, and stirring at room temperature for 2 hours; transferring into a reaction system at 0-10 ℃, slowly adding 0.8404g of sodium nitrite when the temperature is constant, stirring for reaction, and reacting for 2h at the temperature to obtain a compound b
(2) Synthesis of diethyl (Z) -2-acetyl-2- ((4-methoxyphenyl) diazenyl) glutarate (Compound c): 2.24g of diethyl 2-acetylglutamate are completely dissolved in absolute ethanol and excess concentrated H is added2SO4Fully and uniformly mixing the mixture, slowly and constantly dropping 1.7g of ethanol solution of the compound b, reacting at room temperature for 2 hours after the dropping is finished, and carrying out experimental post-treatment after the reaction is finished, namely separating and purifying to obtain a compound c;
(3) synthesis of (Z) -diethyl 2- (2- (4-methoxyphenyl) hydrazono) glutarate (Compound d): completely dissolving 1g of compound c by absolute ethyl alcohol, adding excessive concentrated HCl, stirring at room temperature for 2 hours, carrying out experimental post-treatment after the reaction is finished, and then separating and purifying to obtain a compound d;
(4) synthesis of ethyl 3- (2-ethoxy-2-oxoethyl) -5-methoxy-1H-indole-2-carboxylate (Compound e): and (3) completely dissolving 1g of the compound d by using absolute ethyl alcohol, introducing dry HCl gas, stirring at room temperature for 2h, carrying out experimental post-treatment after the reaction is finished, and then separating and purifying to obtain a compound e, wherein the compound e is the compound e with HIV-1 integrase inhibitory activity.
During the reaction of the steps (1) to (4), Thin Layer Chromatography (TLC) is carried out to monitor the progress of the reaction, and if the reaction is not complete, the reaction is continued until the reaction is complete.
The post-treatment of the experiment is to adjust the pH to be alkalescent, extract the mixture for 3 times by Ethyl Acetate (EA), concentrate the extract, pack the column and separate and purify the target product by thin-layer chromatography.
The pH value is adjusted to be alkalescent, and the pH value is adjusted by using anhydrous sodium carbonate.
Compound e with HIV-1 integrase inhibitory activity
Example 3
(1) Synthesis of p-methoxybenzenediazobenzene hydrochloride (compound b): completely dissolving 1.00g of compound a (p-methylaniline) by using concentrated hydrochloric acid, and stirring at room temperature for 2 hours; transferring into a reaction system at 0-10 ℃, slowly adding 0.8404g of sodium nitrite when the temperature is constant, stirring for reaction, and reacting for 5 hours at the temperature to obtain a compound b
(2) Synthesis of diethyl (Z) -2-acetyl-2- ((4-methoxyphenyl) diazenyl) glutarate (Compound c): 2.24g of diethyl 2-acetylglutamate are completely dissolved in absolute ethanol and excess concentrated H is added2SO4Fully and uniformly mixing the mixture, slowly and constantly dropping 1.7g of ethanol solution of the compound b, reacting at room temperature for 3 hours after the dropping is finished, and carrying out experimental post-treatment after the reaction is finished, namely separating and purifying to obtain a compound c;
(3) synthesis of (Z) -diethyl 2- (2- (4-methoxyphenyl) hydrazono) glutarate (Compound d): completely dissolving 1g of compound c by absolute ethyl alcohol, adding excessive concentrated HCl, stirring at room temperature for 5 hours, carrying out experimental post-treatment after the reaction is finished, and then separating and purifying to obtain a compound d;
(4) synthesis of ethyl 3- (2-ethoxy-2-oxoethyl) -5-methoxy-1H-indole-2-carboxylate (Compound e): and (3) completely dissolving 1g of the compound d by using absolute ethyl alcohol, introducing dry HCl gas, stirring at room temperature for 7h, carrying out experimental post-treatment after the reaction is finished, and then separating and purifying to obtain a compound e, wherein the compound e is the compound e with HIV-1 integrase inhibitory activity.
During the reaction of the steps (1) to (4), Thin Layer Chromatography (TLC) is carried out to monitor the progress of the reaction, and if the reaction is not complete, the reaction is continued until the reaction is complete.
The post-treatment of the experiment is to adjust the pH to be alkalescent, extract the mixture for 3 times by Ethyl Acetate (EA), concentrate the extract, pack the column and separate and purify the target product by thin-layer chromatography.
The pH value is adjusted to be alkalescent, and the pH value is adjusted by using anhydrous sodium carbonate.
Compound e with HIV-1 integrase inhibitory activity
Example 4
(1) Synthesis of p-methoxybenzenediazobenzene hydrochloride (compound b): completely dissolving 1.00g (1.00eq.) of the compound a (p-methylaniline) by using concentrated hydrochloric acid, and stirring at room temperature for 2 hours; transferring into a reaction system at 0-10 ℃, slowly adding 0.8404g of sodium nitrite when the temperature is constant, stirring for reaction, and reacting for 3.5h at the temperature to obtain a compound b
(2) Synthesis of diethyl (Z) -2-acetyl-2- ((4-methoxyphenyl) diazenyl) glutarate (Compound c): 2.24g of diethyl 2-acetylglutamate are completely dissolved in absolute ethanol and excess concentrated H is added2SO4Fully and uniformly mixing the mixture, slowly and constantly dropping the solution of the compound b, reacting at room temperature for 2.5 hours after the dropping is finished, and carrying out experimental post-treatment after the reaction is finished, namely separating and purifying to obtain a compound c;
(3) synthesis of (Z) -diethyl 2- (2- (4-methoxyphenyl) hydrazono) glutarate (Compound d): completely dissolving 1g of compound c by absolute ethyl alcohol, adding excessive concentrated HCl, stirring at room temperature for 3.5h, carrying out experimental post-treatment after the reaction is finished, and then separating and purifying to obtain a compound d;
(4) synthesis of ethyl 3- (2-ethoxy-2-oxoethyl) -5-methoxy-1H-indole-2-carboxylate (Compound e): completely dissolving 1g of compound d by absolute ethyl alcohol, introducing dry HCl gas, stirring at room temperature for 4.5h, carrying out experimental post-treatment after the reaction is finished, and then separating and purifying to obtain a compound e, wherein the compound e is a compound e with HIV-1 integrase inhibitory activity;
(5) synthesis of 3- (carboxymethyl) -5-methoxy-1H-indole-2-carboxylic acid (Compound f having HIV-1 integrase inhibitory Activity): to a reactor containing acetone: the water content is 2: 1 and a substance e 100.00mg, adding 78.60mg of sodium hydroxide into a reactor, stirring at room temperature, reacting, and treating the reaction when the reaction of the raw materials is finished, namely pouring the reaction solution into a beaker, adjusting the pH value to be alkalescent, extracting for 4 times by ethyl acetate, concentrating, and separating by silica gel column chromatography to obtain the compound f with the HIV-1 integrase inhibitory activity.
During the reaction of the steps (1) to (4), Thin Layer Chromatography (TLC) is carried out to monitor the progress of the reaction, and if the reaction is not complete, the reaction is continued until the reaction is complete.
The post-treatment of the experiment is to adjust the pH to be alkalescent, extract the mixture for 3 times by Ethyl Acetate (EA), concentrate the extract, pack the column and separate and purify the target product by thin-layer chromatography.
The pH value is adjusted to be alkalescent, and the pH value is adjusted by using anhydrous sodium carbonate.
Compound f having HIV-1 integrase inhibitory activity
Example 5
Taking the compound f with HIV-1 integrase inhibitory activity obtained in example 4, mixing the compound f with HIV-1 integrase inhibitory activity with 15mL of distilled water in a 100 mL reactor, magnetically stirring, heating to 40 ℃ in an oil bath, then adding 30% sodium hydroxide solution to control the pH value to be 11-11.5, heating to 85-95 ℃ to dissolve, adding a small amount of activated carbon, decoloring for 15min, carrying out suction filtration, cooling the filtrate to 25 ℃, filtering, cooling the filtrate to room temperature to naturally crystallize, washing the crystals with a small amount of ice water, and drying at 80 ℃ to obtain the compound g with HIV-1 integrase inhibitory activity.
Compound g with HIV-1 integrase inhibitory activity
Example 6
The p-methylaniline which is the raw material a in the example 4 is replaced by 3-hydroxy-4-methoxyaniline, and the rest steps are the same, so that the compound h with HIV-1 integrase inhibitory activity is finally obtained.
Compound h having HIV-1 integrase inhibitory activity
Example 7
The raw material diethyl 2-acylglutarate in example 4 was changed to 2-acetyl-5-methoxy-4-oxoglutarate, and the same procedure was followed to finally obtain compound i having an HIV-1 integrase inhibitory activity.
Compound i having HIV-1 integrase inhibitory activity
Example 8
The raw material diethyl 2-acylglutarate in example 4 was changed to 2-acetyl-5-ethoxy-4-oxoglutarate, and the same procedure was followed to finally obtain compound j having an HIV-1 integrase inhibitory activity.
Compound j having HIV-1 integrase inhibitory activity
Example 9
The p-methylaniline which is the raw material a in the example 4 is replaced by 3-fluoro-4-methoxyaniline, and the rest steps are the same, so that the compound k with HIV-1 integrase inhibitory activity is finally obtained.
Compound k having HIV-1 integrase inhibitory activity
Example 10
The p-methylaniline serving as the raw material a in the example 4 is replaced by 3-chloro-4-methoxyaniline, and the rest steps are the same, so that the compound l with the HIV-1 integrase inhibitory activity is finally obtained.
Compound I with HIV-1 integrase inhibitory activity
The compounds having HIV-1 integrase inhibitory activity obtained in examples 1 to 10 were assayed as follows:
(1) assay for the transfer Activity of the integrase chain
The experiment was carried out in a black polystyrene 96-well microplate protected from light, and the reaction system was 50. mu.L. First 1 Xreaction buffer (25mM PIPES, 10 mM. beta. -mercaptoethanol, 0.1 g/LBSA, 10mM MnCl) was used25% Glycerol, pH 7.0) plate wash, then add 25. mu.L of MnCl-free solution per well2The reaction buffer 2 Xthe purified integrase recombinant protein 550nM and 5. mu.L of the test compound dissolved in DMSO were mixed well and incubated at 37 ℃ for 20min, the positive control group was DTG. Then adding MnCl with the final concentration of 10mM230nM donor DNA and 300nM target DNA, sterile double distilled water to make up the volume to 50 μ L, mixing well and incubating at 37 deg.C for 1 h. Then, 1.5. mu.L of 10mg/mL streptavidin magnetic beads and 51.5. mu.L of magnetic bead binding buffer (10mM Tris-HCl, 2M NaCl, 20mM EDTA, 0.1% Tween-20, pH 7.6) were added, incubated at 20 ℃ for 15min after thorough shaking and mixing, the microplate was shaken and mixed once every 5min, placed in a magnetic bead collector and left to stand for 90s, the supernatant was discarded, and the magnetic beads were washed three times with PBS containing 0.05% Tween-20. And finally, detecting the relative fluorescence value (RFU) of each hole by using a fluorescence analyzer, selecting the excitation wavelength of 485nm and the emission wavelength of 528nm, and calculating the inhibition rate of the sample to be detected.
(2) Cytotoxicity test of compound on C8166 and PBMC
The test compound was diluted 5-fold in RPMI-1640 complete medium (containing 10% FBS) in a total of 6 dilutions, each dilution setting 3 wells, 100. mu.L per well, in 96-well microplate. Control wells containing no drug were also set. Adding 4X 10 of the mixture into each hole5C8166 cells/mL, or 5X 106PBMC 100. mu.L/mL. 37 ℃ and 5% CO2Culturing for 3 days, and detecting cytotoxicity by MTT colorimetric method. Measuring OD value with enzyme-labeling instrument at 595nm, and calculating to obtain CC50The value is obtained.
(3) Compound p HIV-1IIIBCytopathic (CPE) inhibitionExperiment of
The test compound was diluted 5-fold in RPMI-1640 complete medium (initial final concentration 20 μ M) in 96-well microplates, with 3 replicate wells per dilution, 100 μ L per well, and a drug-free control well. Adding 8X 10 of the mixture into each hole550. mu.L/mL of C8166 cells, then 50. mu.L of HIV-1 was addedIIIBThe supernatant was diluted 1300 TCID 50/well. 37 ℃ and 5% CO2After 3 days of culture, the formation of syncytia was counted under an inverted microscope (100X). EC (EC)50Is the concentration of compound that inhibits syncytial formation by 50%.
The activities of the compounds having HIV-1 integrase inhibitory activity obtained in examples 1-10 were as follows:
the activity test results show that the compound with HIV-1 integrase inhibitory activity has obvious antiviral activity and low cytotoxicity, and provides a new choice for the development of drugs for treating AIDS.
Finally, it should be noted that the above embodiments are merely representative examples of the present invention. Obviously, the technical solution of the present invention is not limited to the above-described embodiments, and many variations are possible. All modifications which can be derived or suggested by a person skilled in the art from the disclosure of the present invention are to be considered within the scope of the invention.
Claims (6)
1. The application of a compound with HIV-1 integrase inhibitory activity in preparing anti-HIV drugs is characterized in that the compound is represented by the following general formula (I):
in the general formula (I), R1 is OH, R2 is OCH2CH3And R3 is H.
2. The process for the preparation of a compound having HIV-1 integrase inhibitory activity according to claim 1 comprising the steps of:
(1) synthesizing p-methoxy diazobenzene hydrochloride: dissolving 1 time equivalent p-methylaniline with concentrated hydrochloric acid completely, stirring for 2h at room temperature, transferring into a reaction system at 0-10 ℃, slowly adding 2 times equivalent sodium nitrite when the temperature is constant, stirring for reaction, and reacting for 2-5h at the temperature to obtain p-methoxy diazobenzene hydrochloride;
(2) synthesis of diethyl (Z) -2-acetyl-2- ((4-methoxyphenyl) diazenyl) glutarate: dissolving 1.2 times of raw material diethyl 2-acetylglutamate with absolute ethyl alcohol completely, adding excessive concentrated H2SO4Fully and uniformly mixing the raw materials, slowly and constantly dropping a solution of 1-time equivalent of p-methoxy diazobenzene hydrochloride, reacting at room temperature for 2-3h after the dropping is finished, and carrying out experimental post-treatment after the reaction is finished, namely separating and purifying to obtain (Z) -2-acetyl-2- ((4-methoxyphenyl) diazenyl) diethyl glutarate;
(3) synthesis of (Z) -2- (2- (4-methoxyphenyl) hydrazono) glutaric acid diethyl ester: completely dissolving the separated diethyl (Z) -2-acetyl-2- ((4-methoxyphenyl) diazenyl) glutarate by using absolute ethyl alcohol, adding excessive concentrated HCl, stirring at room temperature for 2-5h, carrying out experimental post-treatment after the reaction is finished, and then separating and purifying to obtain diethyl (Z) -2- (2- (4-methoxyphenyl) hydrazono) glutarate;
(4) synthesis of 3- (2-ethoxy-2-oxoethyl) -5-methoxy-1H-indole-2-carboxylic acid ethyl ester: and (Z) -2- (2- (4-methoxyphenyl) hydrazono) diethyl glutarate is completely dissolved by absolute ethyl alcohol, dried HCl gas is introduced, the mixture is stirred for 2 to 7 hours at room temperature, after the reaction is finished, experimental post-treatment is carried out, and then the ethyl 3- (2-ethoxy-2-oxoethyl) -5-methoxy-1H-indole-2-carboxylate is separated and purified.
3. The method for preparing a compound having HIV-1 integrase inhibitory activity according to claim 2 wherein during the reaction in steps (1) to (4), thin layer chromatography is performed to monitor the progress of the reaction, and if the reaction is not complete, the reaction is continued until the reaction is complete.
4. The method for preparing a compound having an inhibitory activity against HIV-1 integrase according to claim 2, wherein the post-experimental treatment comprises adjusting the pH of the reaction solution, extracting with ethyl acetate, concentrating, and separating.
5. The method for preparing a compound having HIV-1 integrase inhibitory activity according to claim 4, wherein the steps of adjusting pH of the reaction solution, extracting with EA, concentrating, separating, specifically adjusting pH to weak alkaline, extracting with EA, concentrating the extract, packing with a column, and separating and purifying the target product by silica gel column chromatography.
6. The process for preparing a compound having HIV-1 integrase inhibitory activity according to claim 5, wherein the adjustment of the pH to a slightly alkaline pH is carried out using anhydrous sodium carbonate.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1294580A (en) * | 1998-03-26 | 2001-05-09 | 盐野义制药株式会社 | Indole derivatives with antiviral activity |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1294580A (en) * | 1998-03-26 | 2001-05-09 | 盐野义制药株式会社 | Indole derivatives with antiviral activity |
Non-Patent Citations (1)
| Title |
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| Findlay, Stephen P. ; Dougherty, Gregg.《The synthesis of certain substituted indoleacetic acids》.《Journal of Organic Chemistry》.1948, * |
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