CN112300240A - Hederagenin anhydride derivative and preparation method and application thereof - Google Patents
Hederagenin anhydride derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN112300240A CN112300240A CN202011205123.0A CN202011205123A CN112300240A CN 112300240 A CN112300240 A CN 112300240A CN 202011205123 A CN202011205123 A CN 202011205123A CN 112300240 A CN112300240 A CN 112300240A
- Authority
- CN
- China
- Prior art keywords
- hederagenin
- ethyl acetate
- water
- ethyl ester
- recovering
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- NTWLPZMPTFQYQI-UHFFFAOYSA-N (3alpha)-olean-12-ene-3,23-diol Natural products C1CC(O)C(C)(CO)C2CCC3(C)C4(C)CCC5(C)CCC(C)(C)CC5C4=CCC3C21C NTWLPZMPTFQYQI-UHFFFAOYSA-N 0.000 title claims abstract description 150
- GCGBHJLBFAPRDB-UHFFFAOYSA-N Hederagenin Natural products CC1(C)CCC2(CCC3(C)C4CCC5C(C)(CO)C(O)CCC5(C)C4CC=C3C2C1)C(=O)O GCGBHJLBFAPRDB-UHFFFAOYSA-N 0.000 title claims abstract description 150
- GCGBHJLBFAPRDB-KCVAUKQGSA-N Scutellaric acid Natural products CC1(C)CC[C@@]2(CC[C@@]3(C)[C@@H]4CC[C@H]5[C@@](C)(CO)[C@H](O)CC[C@]5(C)[C@H]4CC=C3[C@@H]2C1)C(=O)O GCGBHJLBFAPRDB-KCVAUKQGSA-N 0.000 title claims abstract description 150
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- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
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- A—HUMAN NECESSITIES
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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Abstract
The invention relates to a preparation method and application of hederagenin anhydride derivatives, wherein the hederagenin anhydride derivatives comprise any isomer, racemate and mixture of C6 internal anhydride derivatives, or pharmaceutically acceptable salt or hydrate, have the activity of anti-HIV protease and anti-hepatitis C virus protease, have no inhibition effect on normal aspartic protease of a human body and the like, and can be applied to the preparation of anti-HIV and anti-hepatitis C virus medicines.
Description
Technical Field
The invention relates to the technical field of medicaments, in particular to a preparation method of an hederagenin C6 internal anhydride derivative and application thereof in preparing medicaments for treating virus infection, in particular to an anti-AIDS and anti-hepatitis C virus protease inhibitor.
Technical Field
After Human Immunodeficiency Virus (HIV) invades human body, the immune function of the human body is destroyed, so that the human body can generate various incurable infections and tumors. Currently, the total number of HIV infectors is 4200 ten thousand worldwide, the total number of deaths is 2000 to more than ten thousand, and about 2.3 ten new HIV infectors are added globally every day. HIV infection has become one of the most fatal infectious diseases in the world, seriously harming human health. The HIV virus consists of a core and an envelope, the core comprising two single strands of RNA, the core structural proteins and the enzymes necessary for viral replication (reverse transcriptase, integrase and protease). During virus maturation and infection, HIV protease (HIV-1PR), cleaves gag and gag-pol gene products into structural proteins (organic matter, shell, putamen) and enzymes (protease, integrase, reverse transcriptase) required for virus maturation. Therefore, HIV-1PR (human immunodeficiency Virus) protease has been considered as an important target for screening AIDS drugs. Since the first HIV PR inhibitor Saquinavir is approved by the FDA in the united states, 10 protease peptide inhibitors are applied to the clinic in sequence, but because of drug resistance and the fact that the drugs contain multiple chiral centers, the drug synthesis process is difficult, the yield is low, the production process is complex, and the international patent protection problems exist in the aspects of compounds, preparation processes and the like, the anti-HIV treatment cost is high, so that a large number of patients cannot be effectively treated, serious complications or death occur, and therefore, unique protease inhibitors need to be continuously developed to solve the problems.
Hepatitis c, which is caused by infection of the human body with hepatitis c virus, has become the most troublesome health problem worldwide, and currently 1.7 million people are infected worldwide. Without drug treatment, chronic hepatitis c virus infection will develop into chronic hepatitis, hepatic necrosis, liver cancer, etc. The most effective treatment method at present is combination of polyethylene glycol interferon and ribavirin, the effective rate of the method for treating the type I hepatitis C commonly existing in vast developing countries is lower than 50%, and a plurality of side effects exist after long-term use of the interferon, such as: reduction of leukocytes, platelets, neutrophils, depression, and the like; if the ribavirin is used for a long time, side effects such as hemolytic anemia and the like can be generated, so that patients cannot be treated continuously, and the development of unique, effective and safer hepatitis C treatment medicines is particularly urgent. The hepatitis C virus protease NS3/4A plays an important role in the virus maturation process and is proved to be one of effective targets for finding a medicament for treating hepatitis C. At present, three hepatitis C NS3/4A protease inhibitors, BILN 2061, VX-950 and SCH 503034, have been clinically proven to have obvious curative effect, but are mostly peptide inhibitors, are difficult to synthesize and have certain toxic and side effects.
Hederagenin [ (3 beta, 4 alpha) -3, 23-dyhydroxyl olean-12-alkene-28-acid ] is an oleanane type pentacyclic triterpene compound, has biological activities of resisting HIV protease, resisting malignant cell proliferation, resisting cancer, relieving spasm, protecting liver, resisting bacteria and the like, and has no obvious cytotoxicity to normal human renal tubular epithelial cells (HK2) and human gastric cancer cells (MKN 45). In the structure, the ring A has 3, 23-dihydroxy, and has effective functional groups for preparing 3-hydroxy half-ester and 3, 23-dihydroxy half-ester derivatives.
In order to solve the problems, the invention researches the hederagenin anhydride derivative, and tests prove that the hederagenin anhydride derivative has the activity of resisting HIV protease and hepatitis C virus protease, has no inhibition effect on normal human aspartic protease and the like, and can be applied to the preparation of medicines for treating AIDS and hepatitis C virus.
Disclosure of Invention
The invention aims to provide an hederagenin C6 internal anhydride derivative.
The invention also aims to provide a preparation method of the hederagenin anhydride derivative.
The invention also aims to provide the application of the hederagenin C6 anhydride derivative in preparing the medicaments for treating the virus infection; or adding medicinal adjuvants or carriers to make into various pharmaceutically acceptable preparations for preparing medicines for treating viral infection.
The invention also aims to provide the application of the hederagenin C6 internal anhydride derivative in preparing the drugs for treating AIDS or hepatitis C virus protease; or adding medicinal adjuvants or carriers to make into pharmaceutically acceptable preparations for preparing HIV protease inhibitor for treating AIDS or hepatitis C virus.
The hederagenin anhydride derivative comprises any isomer, racemate and mixture of C6 internal anhydride derivatives, or pharmaceutically acceptable salt or hydrate, the structure of the derivative is shown in a general formula I,
wherein R is hydrogen or ethyl, R1、R2Is hydroxy, tert-butyldimethylsilyloxy (TBS), 3' -Dimethylsuccinoyl (DMS), Glutaroyl (GA),
the derivatives comprise (3 beta, 23) -di-O- [ (3',3' -dimethylsuccinyl) ] hederagenin (1a), (3 beta, 23) -di-O-glutaryl hederagenin (1b), 3 beta-O- [ (3',3' -dimethylsuccinyl) ] -23-hydroxy hederagenin (1c), (3 beta, 23) -di-O- [ (3',3' -dimethylsuccinyl) ] hederagenin ethyl ester (2a), 3 beta-hydroxy-23-tert-butyldimethylsilyloxy hederagenin ethyl ester (3a), 3-O- [ (3',3' -dimethylsuccinyl) ] -23-tert-butyldimethylsilyloxy hederagenin ethyl ester (3b), 3-O- [ (3',3' -dimethylsuccinoyl) ] -23-hydroxyhederagenin ethyl ester (4a) and hederagenin ethyl ester (HES) any stereoisomer.
The preparation method of hederagenin ethyl ester (HES) comprises the following steps: dissolving hederagenin (0.5-1.5 g, 1.5-2.5 mmoL), ethyl iodide (0.4-0.8 mL, 7-9 mmoL) and potassium carbonate (1200-1600 mg, 8-12 mmoL) in 15mL of DMF, stirring at room temperature for reaction and staying overnight, monitoring the reaction by TLC, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, and performing gradient elution on an ethyl acetate extract by using a silica gel column and petroleum ether-ethyl acetate (20:0-1:1) to obtain amorphous powder HES;
synthetic route I:
the preparation method of the 3 beta-hydroxy-23-tert-butyldimethylsilyloxy hederagenin ethyl ester (3a) comprises the following steps: placing hederagenin ethyl ester (800-1200 mg, 1.5-2.5 mmoL) in a round bottom flask, adding TBSCl (1200-1700 mg, 8-12 mmoL) and DMAP (600-800 mg, 4-8 mmoL), dissolving with 20-30 mL of dichloromethane and 5-9 mL of pyridine, heating and stirring in an oil bath at 30-40 ℃ for 2-8 h, monitoring by TLC for complete reaction, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, and performing gradient elution on an ethyl acetate extract by using a silica gel column according to the ratio of petroleum ether-ethyl acetate (100:0-1:1) to obtain 3 a;
synthetic route II:
the preparation method of (3 beta, 23) -di-O- [ (3',3' -dimethylsuccinyl) ] hederagenin (1a), (3 beta, 23) -di-O-glutaryl hederagenin (1b) and 3 beta-O- [ (3',3' -dimethylsuccinyl) ] -23-hydroxyhederagenin (1c) comprises the following steps: adding 2, 2-dimethylsuccinic anhydride (260-360 mg, 2-3 mmoL), glutaric anhydride (260-300 mg, 2-3 mmoL) and DMAP (90-105 mg, 0.6-1.0 mmoL) into hederagenin (80-120 mg, 0.18-0.23 mmoL), dissolving with 1.8-2.0mL pyridine, refluxing at 100-130 deg.C for 16-30h, monitoring by TLC, adding 1moL/L hydrochloric acid to adjust pH to neutral, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, subjecting ethyl acetate extract to primary purification by open reversed phase chromatography (ODS) column, eluting with methanol-water as eluent and gradient of 5:5-100:0, recovering sample, performing gradient elution by semi-preparative high performance liquid chromatography (methanol-0.1% TFA/water (9:1-100:0)) with flow rate of 1mL/min and purification wavelength of 190-220 nmnm, amorphous powders 1a,1b and 1c are obtained respectively;
synthetic route III
The preparation method of the (3 beta, 23) -di-O- [ (3',3' -dimethylsuccinyl) ] hederagenin saponin ethyl ester (2a) comprises the following steps: adding 2, 2-dimethylsuccinic anhydride (120-180 mg, 1-1.5 mmoL) and DMAP (45-52 mg, 0.2-0.6 mmoL) into the mmoL of hederagenin ethyl ester (40-60 mg, 0.05-0.15), dissolving by using 4mL of pyridine, carrying out reflux reaction at 110-130 ℃ for 8-10 h, monitoring the reaction by TLC (thin layer chromatography), adding 1moL/L of hydrochloric acid to adjust the pH to be neutral, extracting by using water and ethyl acetate, recovering the ethyl acetate under reduced pressure, carrying out primary purification on an ethyl acetate extract by using an ODS open reverse phase chromatographic column, using methanol water as an eluent, and carrying out elution gradient of 5:5-100:0, and recovering a sample. Performing secondary separation and purification by using a semi-preparative high performance liquid chromatograph, performing gradient elution by using methanol-0.1% TFA/water at a ratio of 9:1-100:0, wherein the flow rate is 1mL/min, and the wavelength is 208nm to obtain amorphous powder 2 a;
the synthesis route is as follows:
the preparation method of the compound 3-O- [ (3',3' -dimethylsuccinoyl) ] -23-tert-butyldimethylsilyloxy hederagenin ethyl ester (3b) comprises the following steps: adding 2, 2-dimethylsuccinic anhydride (100-150 mg, 0.8-1.2 mmoL) and DMAP (30-50 mg, 0.2-0.4 mmoL) into a compound 3a (50-150 mg, 0.12-0.20 mmoL), dissolving with 3mL pyridine, carrying out reflux reaction at 100-140 ℃ for 16-30h, monitoring the reaction by TLC (thin layer chromatography), adding 1moL/L hydrochloric acid to adjust the pH to be neutral, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, purifying the ethyl acetate extract by a silica gel column, and carrying out gradient elution by petroleum ether-acetone (60:1-1:1) to obtain amorphous powder 3 b;
synthetic route IV
The preparation method of the 3-O- [ (3',3' -dimethylsuccinyl) ] -23-hydroxy hederagenin ethyl ester (4a) comprises the following steps: taking 3b (80-100 mg, 0.1-0.15) mmoL, adding TBAF (450-550 mg, 1.2-1.7 mmoL), dissolving with 2mL tetrahydrofuran, carrying out reflux reaction for 8-14 h at 50-80 ℃, monitoring the reaction completion by TLC, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, carrying out primary purification on an ethyl acetate extract by using an ODS (ozone depleting substance) open reverse phase chromatographic column, using methanol water as an eluent, carrying out elution gradient of 5:5-100:0, recovering a sample, and carrying out gradient elution by using a semi-preparative high performance liquid chromatograph (methanol-0.1% TFA/water (9:1-100:0)) at the flow rate of 1mL/min and the wavelength of 190-220 nm to obtain amorphous powder 4 a.
Synthetic route V
Preferably, the preparation method of the hederagenin C6 internal anhydride derivative provided by the invention comprises the following steps:
the preparation method of the hederagenin ethyl ester (HES) comprises the following steps: dissolving hederagenin (1.0g,2.12mmoL), ethyl iodide (0.68mL,8.40mmoL) and potassium carbonate (1451.1mg,10.50mmoL) in 15mL DMF, stirring at room temperature overnight, monitoring reaction completion by TLC, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, eluting ethyl acetate extract with silica gel column, and gradient eluting with petroleum ether-ethyl acetate (20:0-1:1) to obtain amorphous powder HES.
Synthetic route I:
the preparation method of the 3 beta-hydroxy-23-tert-butyldimethylsilyloxy hederagenin ethyl ester (3a) comprises the following steps: placing hederagenin ethyl ester (1000.0mg,2.0mmoL) in a round bottom flask, adding TBSCl (1507.0mg,10.00mmoL) and DMAP (733.0mg,6.00mmoL), dissolving with 25mL dichloromethane and 7mL pyridine, heating and stirring for 5h in 35 ℃ oil bath, monitoring reaction completion by TLC, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, and eluting ethyl acetate extract with silica gel column and petroleum ether-ethyl acetate (100:0-1:1) gradient to obtain 3 a.
Synthetic route II:
the preparation method of the (3 beta, 23) -di-O- [ (3',3' -dimethylsuccinyl) ] hederagenin (1a), (3 beta, 23) -di-O-glutaryl hederagenin (1b) and (3 beta-O- [ (3',3' -dimethylsuccinyl) ] -23-hydroxyhederagenin (1c) comprises the following steps: adding 2, 2-dimethylsuccinic anhydride (320mg,2.5mmoL), glutaric anhydride (283.0mg,2.48mmoL) and DMAP (97.8mg,0.80mmoL) into hederagenin (100.0mg,0.21mmoL), dissolving with 1.8-2.0mL pyridine, refluxing at 120 deg.C for 24h, monitoring reaction by TLC, adding 1moL/L hydrochloric acid to adjust pH to neutrality, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, subjecting ethyl acetate extract to primary purification by ODS open reverse phase chromatographic column of 1.5 × 40cm, eluting with methanol water as eluent and gradient of 5:5-100:0, and recovering sample. Purification by semi-preparative HPLC (methanol-0.1% TFA/water (9:1-100:0)) gradient elution at a flow rate of 1mL/min at a wavelength of 208nm gave amorphous powders 1a (30.6mg, 21% yield), 1b (13.7mg, 11.5% yield) and 1c (45mg, 30% yield), respectively.
Synthetic route III
The preparation method of the (3 beta, 23) -di-O- [ (3',3' -dimethylsuccinyl) ] hederagenin ethyl ester (2a) comprises the following steps: adding 2, 2-dimethylsuccinic anhydride (153.7mg,1.20mmoL) and DMAP (48.9mg,0.40mmoL) into hederagenin ethyl ester (50mg,0.10mmoL), dissolving with 4mL pyridine, refluxing at 120 deg.C for 10h, monitoring reaction completion by TLC, adding 1moL/L hydrochloric acid to adjust pH to neutrality, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, subjecting ethyl acetate extract to primary purification by ODS open reverse phase chromatography column (1.5 × 40cm), eluting with methanol water as eluent with gradient of 5:5-100:0, and recovering sample. The two-step separation and purification was performed by semi-preparative HPLC using methanol-0.1% TFA/water (9:1-100:0) gradient elution at a flow rate of 1mL/min and a wavelength of 208nm to give amorphous powder 2a (15mg, 20% yield).
The preparation method of the 3-O- [ (3',3' -dimethylsuccinoyl) ] -23-tert-butyldimethylsilyloxy hederagenin ethyl ester (3b) comprises the following steps: adding 2, 2-dimethylsuccinic anhydride (128.1mg,1.00mmoL) and DMAP (40.0mg,0.32mmoL) to compound 3a (100.0mg,0.16mmoL), dissolving with 3mL of pyridine, refluxing at 120 ℃ for 24 hours, monitoring by TLC for completion of the reaction, adjusting pH to neutral by adding 1moL/L hydrochloric acid, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, purifying the ethyl acetate extract with a silica gel column (1.5X 30cm), and eluting with petroleum ether-acetone (60:1-1:1) gradient to obtain amorphous powder 3b (70mg, 56% yield)
Synthetic route IV
The preparation method of the 3-O- [ (3',3' -dimethylsuccinoyl) ] -23-hydroxy hederagenin ethyl ester (4a) comprises the following steps: 3b (90.0mg,0.12mmoL), TBAF (500.0mg,1.58mmoL) was added, dissolved in 2mL of tetrahydrofuran, reacted at 75 ℃ under reflux for 12 hours, TLC monitored the completion of the reaction, extracted with water and ethyl acetate, and ethyl acetate was recovered under reduced pressure, and the ethyl acetate extract was preliminarily purified by an ODS open reverse phase chromatography column (1.5X 40cm), eluting with methanol-water as an eluent, at an elution gradient of 5:5 to 100:0, and the sample was recovered, and eluted by a semi-preparative high performance liquid chromatograph (methanol-0.1% TFA/water (9:1 to 100:0)) at a gradient of 1mL/min and 208nm to give amorphous powder 4a (15mg, 17% yield).
Synthetic route V
The application of the hederagenin anhydride derivative in preparing a medicament for treating virus infection; or adding medicinal adjuvants or carriers to make into pharmaceutically acceptable dosage forms, and can be used as medicine for treating viral infection.
The application of the hederagenin anhydride derivative in preparing a medicine for treating AIDS or hepatitis C virus protease; or adding medicinal adjuvants or vehicle to make into pharmaceutically acceptable dosage form to make into anti-AIDS or hepatitis C virus protease inhibitor.
The preparation is prepared into a pharmaceutically acceptable preparation by adding pharmaceutically acceptable auxiliary materials according to a conventional process, the pharmaceutically acceptable preparation is a solid preparation or a liquid preparation, and the solid preparation is granules, capsules, tablets, pills, powder or freeze-dried powder injection; the liquid preparation is injection preparation and oral liquid.
The acceptable auxiliary materials are not limited, and the requirements of the pharmaceutical field are met.
Has the advantages that:
1. the invention researches a series of novel hederagenin anhydride derivatives and a preparation method thereof, and tests prove that the derivatives have the effect of resisting the protease activity of AIDS and hepatitis C viruses.
2. The invention researches the capability of high-activity antiviral protease compounds (1a-1c,2a,3b and 4a) in inhibiting human normal proteases of Renin and trypsin, wherein the Renin and HIV-1 protease are both aspartyl protease, and the trypsin and HCV protease are both serine protease, and when the concentration is 1mg/mL, all the compounds have no inhibition effect on the Renin and the trypsin, and discloses that the hederagenin derivatives highly selectively inhibit the HIV-1 or HCV protease.
Description of the drawings:
FIG. 1 (3. beta., 23) -bis-O- [ 3',3' -dimethylsuccinoyl)]Hederagenin (1a)1H-NMR spectrum.
FIG. 2 Compound (3. beta., 23) -bis-O- [ (3',3' -dimethylsuccinoyl)]Hederagenin (1a)13C-NMR spectrum.
FIG. 3 (3. beta., 23) -di-O-glutaryl hederagenin (1b)1H-NMR spectrum.
FIG. 4 (3. beta., 23) -di-O-glutaryl hederagenin (1b)13C-NMR spectrum.
FIG. 53 beta-O- [ (3',3' -dimethylsuccinyl)]-23-hydroxy hederagenin (1c)1H-NMR spectrum.
FIG. 63 β -O- [ (3',3' -dimethylsuccinoyl)]-23-hydroxy hederagenin (1c)13C-NMR spectrum.
FIG. 7 Compound (3. beta., 23) -bis-O- [ (3',3' -dimethylsuccinoyl)]Hederagenin ethyl ester (2a)1H-NMR spectrum.
FIG. 8 Compound (3. beta., 23) -bis-O- [ (3',3' -dimethylsuccinoyl)]Hederagenin ethyl ester (2a)13C-NMR spectrum.
FIG. 9 Compound 3 β -hydroxy-23-tert-butyldimethylsilyloxy hederagenin Ethyl ester (3a)1H-NMR spectrum.
FIG. 10 Compound 3 β -hydroxy-23-tert-butyldimethylsilyloxy hederagenin ethyl ester (3a)13C-NMR spectrum.
FIG. 11 Compound 3-O- [ (3',3' -dimethylsuccinoyl)]-23-tert-Butyldimethylsilanylhederagenin ethyl ester (3b)1H-NMR spectrum.
FIG. 12 Compound 3-O- [ (3',3' -dimethylsuccinoyl)]-23-tert-Butyldimethylsilanylhederagenin ethyl ester (3b)13C-NMR spectrum.
FIG. 13 Compound 3-O- [ (3',3' -dimethylsuccinoyl)]-23-Hydroxyhederagenin ethyl ester (4a))1H-NMR spectrum.
FIG. 14 Compound 3-O- [ (3',3' -dimethylsuccinoyl)]-23-Hydroxyhederagenin ethyl ester (4a)13C-NMR spectrum.
The specific implementation mode is as follows:
the technical solution of the present invention will be further specifically described below by way of specific examples.
Determination of compounds by 600 million NMR1H-NMR、13C-NMR, Hewlett packard HP-5973 to determine its molecular weight; the reagents used were chemically pure and analytically pure.
Example 1: process for the preparation of compounds
Hederagenin (1.0g,2.12mmoL), iodoethane (0.68mL,8.40mmoL) and potassium carbonate (1451.1mg,10.50mmoL) were dissolved in 15mL DMF, the reaction was stirred at room temperature and left overnight. TLC monitored completion of the reaction, extraction with water and ethyl acetate, recovery of ethyl acetate under reduced pressure, and gradient elution of the ethyl acetate extract on a silica gel column (2.5X 60cm) with petroleum ether-ethyl acetate (20:0-1:1) to give HES as an amorphous powder (800mg, 76% yield).
Synthetic route I:
the preparation method of the 3 beta-hydroxy-23-tert-butyldimethylsilyloxy hederagenin ethyl ester (3a) comprises the following steps:
placing hederagenin ethyl ester (1000.0mg,2.0mmoL) in 100mL round bottom flask, adding TBSCl (1507.0mg,10.00mmoL) and DMAP (733.0mg,6.00mmoL), dissolving with 25mL dichloromethane and 7mL pyridine, heating in 35 deg.C oil bath and stirring for 5h, monitoring reaction completion by TLC, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, eluting ethyl acetate extract with silica gel column (2.5X 60cm), petroleum ether-ethyl acetate (100:0-1:1) gradient to obtain 3a (800mg, 65% yield).
Synthetic route II:
(3 beta, 23) -di-O- [ (3',3' -dimethyl succinyl) ] hederagenin (1a), (3)
The preparation method of the beta, 23) -di-O-glutaryl hederagenin (1b) and the 3 beta-O- [ (3',3' -dimethylsuccinoyl) ] -23-hydroxy hederagenin (1c) comprises the following steps: adding 2, 2-dimethylsuccinic anhydride (320mg,2.5mmoL), glutaric anhydride (283.0mg,2.48mmoL) and DMAP (97.8mg,0.80mmoL) into hederagenin (100.0mg,0.21mmoL), dissolving with 1.8-2.0mL pyridine, refluxing at 120 deg.C for 24h, monitoring reaction completion by TLC, adding 1moL/L hydrochloric acid to adjust pH to neutrality, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, subjecting ethyl acetate extract to primary purification by ODS open reverse phase chromatography column (1.5 × 40cm), eluting with methanol water as eluent and gradient of 5:5-100:0, and recovering sample. Purification by semi-preparative HPLC (methanol-0.1% TFA/water (9:1-100:0)) gradient elution at a flow rate of 1mL/min at a wavelength of 208nm gave amorphous powders 1a (30.6mg, 21% yield), 1b (13.7mg, 11.5% yield) and 1c (45mg, 30% yield), respectively.
Synthetic route III
The preparation method of the (3 beta, 23) -di-O- [ (3',3' -dimethylsuccinyl) ] hederagenin ethyl ester (2a) comprises the following steps: adding 2, 2-dimethylsuccinic anhydride (153.7mg,1.20mmoL) and DMAP (48.9mg,0.40mmoL) into hederagenin ethyl ester (50mg,0.10mmoL), dissolving with 4mL pyridine, refluxing at 120 deg.C for 10h, monitoring reaction completion by TLC, adding 1moL/L hydrochloric acid to adjust pH to neutrality, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, subjecting ethyl acetate extract to primary purification by ODS open reverse phase chromatography column (1.5 × 40cm), eluting with methanol water as eluent with gradient of 5:5-100:0, and recovering sample. The two-step separation and purification was performed by semi-preparative HPLC using methanol-0.1% TFA/water (9:1-100:0) gradient elution at a flow rate of 1mL/min and a wavelength of 208nm to give amorphous powder 2a (15mg, 20% yield).
The preparation method of the 3-O- [ (3',3' -dimethylsuccinoyl) ] -23-tert-butyldimethylsilyloxy hederagenin ethyl ester (3b) comprises the following steps: adding 2, 2-dimethylsuccinic anhydride (128.1mg,1.00mmoL) and DMAP (40.0mg,0.32mmoL) to compound 3a (100.0mg,0.16mmoL), dissolving with 3mL of pyridine, refluxing at 120 ℃ for 24 hours, monitoring by TLC for completion of the reaction, adjusting pH to neutral by adding 1moL/L hydrochloric acid, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, purifying the ethyl acetate extract with a silica gel column (1.5X 30cm), and eluting with petroleum ether-acetone (60:1-1:1) gradient to obtain amorphous powder 3b (70mg, 56% yield)
Synthetic route IV
The preparation method of the 3-O- [ (3',3' -dimethylsuccinoyl) ] -23-hydroxy hederagenin ethyl ester (4a) comprises the following steps: 3b (90.0mg,0.12mmoL), TBAF (500.0mg,1.58mmoL) was added, dissolved in 2mL of tetrahydrofuran, reacted at 75 ℃ under reflux for 12 hours, TLC monitored the completion of the reaction, extracted with water and ethyl acetate, and ethyl acetate was recovered under reduced pressure, and the ethyl acetate extract was preliminarily purified by an ODS open reverse phase chromatography column (1.5X 40cm), eluting with methanol-water as an eluent, at an elution gradient of 5:5 to 100:0, and the sample was recovered, and eluted by a semi-preparative high performance liquid chromatograph (methanol-0.1% TFA/water (9:1 to 100:0)) at a gradient of 1mL/min and 208nm to give amorphous powder 4a (15mg, 17% yield).
Synthetic route V
The application is as follows: it can be used for viral infection, especially for resisting AIDS virus and hepatitis C virus.
Example 2 preparation of Compounds
The preparation method of hederagenin ethyl ester HES comprises the following steps: dissolving hederagenin 0.5g,1.5mmoL, iodoethane 0.4mL,7mmoL and potassium carbonate 1200mg,8mmoL in DMF 15mL, stirring at room temperature for reaction and standing overnight, monitoring by TLC for reaction completion, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, and eluting ethyl acetate extract with silica gel column and petroleum ether-ethyl acetate gradient of 20:0-1:1 to obtain amorphous powder HES.
Synthetic route I:
the preparation method of the 3 beta-hydroxy-23-tert-butyldimethylsilyloxy hederagenin ethyl ester (3a) comprises the following steps:
placing hederagenin ethyl ester 800mg and 1.5mmoL in a round bottom flask, adding TBSCl 1200mg,8mmoL and DMAP 600mg and 4mmoL, dissolving with 20mL dichloromethane and 5mL pyridine, heating and stirring in an oil bath at 30 ℃ for 2h, monitoring the reaction by TLC, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, and performing gradient elution on an ethyl acetate extract by using a silica gel column according to the ratio of 100:0-1:1 petroleum ether-ethyl acetate to obtain 3 a.
Synthetic route II:
the preparation method of (3 beta, 23) -di-O- [ (3',3' -dimethyl succinyl) ] hederagenin (1a), (3 beta, 23) -di-O-glutaryl hederagenin (1b) and 3 beta-O- [ (3',3' -dimethyl succinyl) ] -23-hydroxy hederagenin (1c) comprises the following steps: 80mg of hederagenin and 0.18mmoL of hederagenin are respectively added with 260mg of 2, 2-dimethylsuccinic anhydride, 2mmoL of glutaric anhydride, 260mg of glutaric anhydride, 2mmoL of DMAP90mg and 0.6mmoL of pyridine, dissolved by 1.8mL of pyridine, refluxed for 16h at 100 ℃, monitored by TLC to be completely reacted, 1moL/L of hydrochloric acid is added to adjust the pH to be neutral, water and ethyl acetate are used for extraction, ethyl acetate is recovered under reduced pressure, an ethyl acetate extract is subjected to primary purification by an ODS open reverse phase chromatographic column (1.5 multiplied by 40cm), methanol water is used as an eluent, the elution gradient is 5:5-100:0, a sample is recovered, and the sample is eluted by a semi-preparative high performance liquid chromatograph at the ratio of 9:1-100:0 methanol-0.1% TFA/water gradient, the flow rate is 1mL/min, and the wavelength is 190nm to respectively obtain amorphous powders 1a,1b and 1 c.
Synthetic route III
The preparation method of (3 beta, 23) -di-O- [ (3',3' -dimethyl succinyl) ] hederagenin ethyl ester (2a) comprises the following steps: adding the 2, 2-dimethyl succinic anhydride 120mg,1mmoL and DMAP 45mg to the hederagenin ethyl ester of 0.05mmoL, dissolving the mixture with 4mL of pyridine, carrying out reflux reaction for 8h at 110 ℃, monitoring the reaction completion by TLC, adding 1moL/L hydrochloric acid to adjust the pH to be neutral, extracting with water and ethyl acetate, recovering the ethyl acetate under reduced pressure, carrying out primary purification on an ethyl acetate extract by using an ODS open reverse phase chromatographic column, taking methanol water as an eluent, and recovering a sample, wherein the molar ratio of the eluent to the ethyl acetate extract is 5:5-100: 0. Performing secondary separation and purification by semi-preparative high performance liquid chromatograph, and performing gradient elution with methanol-0.1% TFA/water at a ratio of 9:1-100:0 at a flow rate of 1mL/min and a wavelength of 208nm to obtain amorphous powder 2 a.
The preparation method of the 3-O- [ (3',3' -dimethylsuccinoyl) ] -23-tert-butyldimethylsilyloxy hederagenin ethyl ester (3b) comprises the following steps: adding 100mg of 2, 2-dimethylsuccinic anhydride, 0.8mmoL and 30mg of DMAP (dimethyl acetamide) into 0.12mmoL of the compound 3a, dissolving 0.2mmoL by using 3mL of pyridine, carrying out reflux reaction at 100 ℃ for 16h, monitoring the reaction completion by TLC (thin layer chromatography), adding 1moL/L hydrochloric acid to adjust the pH to be neutral, extracting by using water and ethyl acetate, recovering ethyl acetate under reduced pressure, purifying the ethyl acetate extract by using a silica gel column, and carrying out gradient elution by using petroleum ether-acetone according to the ratio of 60:1-1:1 to obtain amorphous powder 3 b;
synthetic route IV
The preparation method of the 3-O- [ (3',3' -dimethylsuccinoyl) ] -23-hydroxy hederagenin ethyl ester (4a) comprises the following steps: 3b 80mg,0.1mmoL, adding TBAF450 mg,1.2mmoL, dissolving with 2mL tetrahydrofuran, refluxing at 50 ℃ for 8h, monitoring the reaction by TLC, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, performing primary purification on an ethyl acetate extract by using an ODS open reverse phase chromatographic column, eluting with methanol water as an eluent at an elution gradient of 5:5-100:0, recovering a sample, and eluting with a semi-preparative high performance liquid chromatograph at a flow rate of 1mL/min and a wavelength of 190nm by using a 9:1-100:0 methanol-0.1% TFA/water gradient to obtain amorphous powder 4 a.
Synthetic route V
Example 3 preparation of Compounds
The preparation method of hederagenin ethyl ester HES comprises the following steps: 1.5g of hederagenin, 2.5mmoL of hederagenin, 0.8mL of iodoethane, 9mmoL of potassium carbonate and 1600mg of potassium carbonate, 12mmoL of hederagenin are dissolved in 15mL of DMF, the mixture is stirred at room temperature and reacted overnight, TLC monitors that the reaction is complete, water and ethyl acetate are used for extraction, ethyl acetate is recovered under reduced pressure, and an ethyl acetate extract is subjected to silica gel column and gradient elution of petroleum ether-ethyl acetate at a ratio of 20:0-1:1 to obtain amorphous powder HES.
Synthetic route I:
the preparation method of the 3 beta-hydroxy-23-tert-butyldimethylsilyloxy hederagenin ethyl ester (3a) comprises the following steps:
placing hederagenin ethyl ester 1200mg,2.5mmoL into round bottom flask, adding TBSCl 1700mg,12mmoL and DMAP 800mg,8mmoL, dissolving with 30mL dichloromethane and 9mL pyridine, heating in 40 deg.C oil bath and stirring for 8h, TLC monitoring reaction completion, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, and gradient eluting ethyl acetate-petroleum ether at ratio of 100:0-1:1 with silica gel column to obtain 3 a.
Synthetic route II:
the preparation method of (3 beta, 23) -di-O- [ (3',3' -dimethyl succinyl) ] hederagenin (1a), (3 beta, 23) -di-O-glutaryl hederagenin (1b) and 3 beta-O- [ (3',3' -dimethyl succinyl) ] -23-hydroxy hederagenin (1c) comprises the following steps: 120mg of hederagenin and 0.23mmoL of the hederagenin are respectively added with 360mg of 2, 2-dimethylsuccinic anhydride, 3mmoL of the hederagenin and 300mg of glutaric anhydride, 3mmoL of the glutaric anhydride and DMAP105mg,1.0mmoL of the hederagenin are dissolved by 2.0mL of pyridine, reflux reaction is carried out for 30 hours at 130 ℃, TLC is used for monitoring the reaction to be complete, 1moL/L of hydrochloric acid is added for adjusting the pH to be neutral, water and ethyl acetate are used for extraction, ethyl acetate is recovered under reduced pressure, an ethyl acetate extract is primarily purified by an ODS open reverse phase chromatographic column (1.5 multiplied by 40cm), methanol water is used as an eluent, the elution gradient is 5:5-100:0, a sample is recovered, and the sample is purified by a semi-preparative high performance liquid chromatograph at the ratio of 9:1-100:0 methanol-0.1% TFA/water gradient and the flow rate of 1mL/min and the wavelength of 220nm to respectively obtain amorphous powder 1 a.
Synthetic route III
The preparation method of (3 beta, 23) -di-O- [ (3',3' -dimethyl succinyl) ] hederagenin ethyl ester (2a) comprises the following steps: 60mg of hederagenin ethyl ester and 0.15mmoL, adding 180mg of 2, 2-dimethylsuccinic anhydride, 1.5mmoL of 2, 2-dimethylsuccinic anhydride and 52mg of DMAP and 0.6mmoL of pyridine, dissolving the mixture by using 4mL of pyridine, carrying out reflux reaction for 10 hours at 130 ℃, monitoring the reaction completion by TLC, adding 1moL/L of hydrochloric acid to adjust the pH to be neutral, extracting the mixture by using water and ethyl acetate, recovering the ethyl acetate under reduced pressure, carrying out primary purification on an ethyl acetate extract by using an ODS open reverse phase chromatographic column, taking methanol water as an eluent, and recovering a sample, wherein the elution gradient is 5:5-100: 0. Performing secondary separation and purification by semi-preparative high performance liquid chromatograph, and performing gradient elution with methanol-0.1% TFA/water at a ratio of 9:1-100:0 at a flow rate of 1mL/min and a wavelength of 208nm to obtain amorphous powder 2 a.
The preparation method of the 3-O- [ (3',3' -dimethylsuccinoyl) ] -23-tert-butyldimethylsilyloxy hederagenin ethyl ester (3b) comprises the following steps: 150mg of compound 3a, 0.20mmoL, adding 150mg of 2, 2-dimethylsuccinic anhydride, 1.2mmoL and 50mg of DMAP, 0.4mmoL, dissolving with 3mL of pyridine, carrying out reflux reaction at 140 ℃ for 30h, monitoring the reaction completion by TLC, adding 1moL/L hydrochloric acid to adjust the pH to be neutral, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, purifying the ethyl acetate extract by a silica gel column, and carrying out gradient elution by petroleum ether-acetone according to the ratio of 60:1-1:1 to obtain amorphous powder 3 b;
synthetic route IV
The preparation method of the 3-O- [ (3',3' -dimethylsuccinoyl) ] -23-hydroxy hederagenin ethyl ester (4a) comprises the following steps: 3b 100mg,0.15mmoL), adding TBAF 550mg,1.7mmoL, dissolving with 2mL tetrahydrofuran, refluxing at 80 ℃ for 14h, monitoring the reaction by TLC, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, preliminarily purifying the ethyl acetate extract by using an ODS open reverse phase chromatographic column, eluting with methanol water as an eluent at an elution gradient of 5:5-100:0, recovering the sample, eluting with a semi-preparative high performance liquid chromatograph at a flow rate of 1mL/min and a wavelength of 220nm by using a 9:1-100:0 methanol-0.1% TFA/water gradient, and obtaining amorphous powder 4 a.
Synthetic route V
The application is as follows: it can be used for viral infection, especially for resisting AIDS virus and hepatitis C virus.
Example 4: spectral data for each compound:
(3. beta., 23) -bis-O- [ (3',3' -dimethylsuccinoyl)]Hederagenin (1 a; number: HS-8): [ alpha ]]D 20.0＝-3.2°(C＝0.1,CH3OH)；IRνKBr max cm-1:2926,1729,1720,1710,1465；1H-NMR(MeOD，600MHz)δ:0.80(3H,s),0.84(3H,s),0.90(3H,s),0.93(3H,s),1.00(3H,s),1.18(3H,s),1.26(9H,s),1.29(3H,s)(10×CH3),2.83(1H,d,J＝18.0Hz,H-18),3.67(1H,d,J＝12.0Hz),3.94(1H,d,J＝12.0Hz),4.75(1H,t,J＝8.0Hz),5.25(1H,t-like,H-12)；13The C-NM (MeOD,125MHz) delta is 12.3,15.0,16.4,17.6,22.5,22.7,22.9,23.1,23.9,24.2,24.5,24.5,25.1,25.2,27.3,29.4,30.3,32.1,32.3,33.5,36.6,39.1,39.9,40.4,40.5,42.1,43.8,44.4,45.6,46.2,47.2,47.4,48.2,64.8,74.7,122.2,143.4,171.2,171.3,179.1,179.2,180.4. the spectrogram is shown in figure 1 and figure 2.
3 beta-O- [ (3',3' -dimethylsuccinoyl)]-23-hydroxyhederagenin (1 c; No. HS-7) spectral data: [ alpha ]]D 20.5＝-4.6°(C＝0.1,CH3OH)；IRνKBr max cm-1:1739,1720，1710,1387；1H-NMR(MeOD，600MHz)δ:0.82(3H,s),0.85(3H,s),0.91(3H,s),0.94(3H,s),1.01(3H,s),1.23(3H,s),1.27(6H,s)(8×CH3),2.85(1H,d,J＝18.0Hz,H-18),3.69(1H,d,J＝12.0Hz),3.95(1H,d,J＝12.0Hz),4.80(1H,d,J＝12.0Hz),5.25(1H,t-like,H-12)；13C-NMR (MeOD,125MHz) delta 12.2,14.8,16.3,17.5,19.5,22.6,23.1,24.3,24.5,25.1,27.4,29.1,30.2,32.0,32.1,32.5,33.4,36.6,37.2,37.4,39.1,40.4,41.3,41.5,43.1,43.8,44.2,45.8,46.3,65.1,74.7,122.1,143.3,172.7,178.0,180.3. the spectra are shown in FIG. 5 and FIG. 6.
(3 beta, 23) -di-O-glutaryl hederagenin (1b, No: HY-25) [ alpha-]D 21.5＝-2.7°(0.1,CH3OH)；IRνKBr max cm-1:2945,1720,1708；1H-NMR(CDCl3，600MHz)δ:0.76(3H,s),0.86(3H,s),0.93(3H,s),0.95(3H,s),1.00(3H,s),1.14(3H,s)(6×CH3),2.41-2.45(12H,m),2.89(1H,d,J＝18.0Hz,H-18),3.78(1H,d,J＝12.0Hz),3.86(1H,d,J＝12.0Hz),4.78(1H,d,J＝6.0,12.0Hz),5.30(1H,t-like,H-12)；13C-NMR(CDCl3125MHz) delta of 13.2,15.9,16.9,18.0,20.0,20.0,22.8,23.0,23.4,23.6,25.8,27.2,27.6,29.3,29.7,30.7,32.3,33.0,33.1,33.4,33.6,33.8,36.9,37.5,39.2,40.9,41.5,45.8,46.5,47.6,48.3,65.6,74.6,122.3,143.6,172.5,172.8,178.0,178.0,184.3, see fig. 3, fig. 4.
(3. beta., 23) -bis-O- [ (3',3' -dimethylsuccinoyl)]Hederagenin ethyl ester (2a, number: HL-4): [ alpha ]]D 21.1＝-1.2°(C＝0.1,CH3OH)；IRνKBr max cm-1:2947,1731,1474；1H-NMR(CDCl3，600MHz)δ:0.75(3H,s),0.82(3H,s),0.91(3H,s),0.94(3H,s),0.97(3H,s),1.15(3H,s),1.24(3H,s),1.28(3H,s),1.30(3H,s),1.31(3H,s),1.33(3H,s)(11×CH3),2.56-2.68(4H,m,H-2a′,H-2b′,H-2a″,H-2b″),2.89(1H,d,J＝18.0Hz,H-18),3.62(1H,d,J＝12.0Hz),4.01(1H,d,J＝12.0Hz),4.09(2H,m),5.30(1H,t-like,H-12)；13C-NMR(CDCl3125MHz) delta of 13.0,13.1,14.3,15.8,17.0,17.9,22.8,23.0,23.4,23.6,23.6,25.2,25.4,25.6,25.6,25.7,27.6,30.7,32.2,32.4,33.1,33.9,36.8,37.5,39.3,40.6,41.3,41.7,44.7,44.8,45.9,46.5,47.5,47.7,60.1,65.6,75.4,122.2,143.7171.0,171.3,173.3,177.8,182.6. the spectra are shown in fig. 7 and fig. 8.
3 beta-hydroxy-23-tert-butyldimethylsilyloxy hederagenin ethyl ester (3a, numbering: HY-7): [ alpha ]]D 21.5＝-4.4°(C＝0.1,CH3OH)；IRνKBr max cm-1:2950,2368,1725,1463；1H-NMR(CDCl3,600MHz)δ:0.09(3H,s),0.10(3H,s),0.76(3H,s),0.89(3H,s),0.91(3H,s),0.92(3H,s),0.94(3H,s),0.96(3H,s),1.15(3H,s),1.23(3H,s),1.25(3H,s),1.26(3H,s)(12×CH3),2.89(1H,d,J＝6.0Hz),3.38(1H,d,J＝12.0Hz),3.62(1H,m),3.69(1H,d,J＝6.0),4.10(2H,m),5.31(1H,t-like,H-12)；13C-NMR(CDCl3125MHz) delta: -5.7, -5.6,11.7,14.3,15.5,17.0,18.1,23.0,23.4,23.6,25.8,25.9,25.9,25.9,25.9,25.9,26.0,27.7,30.7,32.4,32.5,33.1,33.9,36.9,38.1,39.3,41.3,41.6,45.9,46.5,47.7,50.0,60.1,73.4,73.4,122.4,143.7,177.8. The spectrogram is shown in FIGS. 9 and 10.
3 beta-O- [ (3',3' -dimethylsuccinoyl) ] -23-tert-butyldimethylsilyloxy hederagenin ethyl ester (3b, numbering: HY-9):
[ɑ]D 20.0＝-1.8°(C＝0.1,CH3OH)；IRνKBr max cm-1:1732,1472,1389,1364；ESI-QTOFMS:m/z 742.5162,(calcd for C44H74O7Si,742.5204).1H-NMR(CDCl3,600MHz)δ:0.01(6H,s),0.68(3H,s),0.76(3H,s),0.90(6H,s),0.91(3H,s),0.92(3H,s),0.94(3H,s),0.95(3H,s),1.14(3H,s),1.24(3H,s),1.29(3H,s),1.30(3H,s),(14×CH3),2.54(1H,d,J＝18.0Hz),2.68(1H,d,J＝18.0Hz),2.88(1H,d,J＝18.0Hz),3.10(1H,d,J＝6.0Hz),3.24(1H,d,J＝12.0Hz),4.10(2H,m),4.91(1H,d,J＝12.0Hz),5.31(1H,t-like,H-12)；13C-NMR(CDCl3125MHz) delta: -5.7, -5.9,13.1,14.2,15.7,17.0,17.7,18.0,22.8,23.0,23.4,23.6,24.8,25.6,25.6,25.8,25.8,27.6,30.8,32.2,32.3,32.9,33.2,33.9,36.4,38.0,39.3,40.4,41.4,41.5,41.8,44.6,45.9,46.2,46.7,47.6,60.1,63.7,75.6,122.3,143.7,170.3,178.1,182.9 the spectra are shown in fig. 11 and fig. 12.
3 beta-O- [ (3',3' -dimethylsuccinoyl)]-23-hydroxy hederagenin ethyl ester (4a, number: HY-29-N): [ alpha ]]D 21.5＝-4.4°(C＝0.1,CH3OH)；IRνKBr max cm-1:3432,2946,1726；1H-NMR(CDCl3,600MHz)δ:0.76(3H,s),0.78(3H,s),0.91(9H,s),0.95(3H,s),0.96(3H,s),1.15(3H,s),1.25(3H,s),1.34(3H,s),1.36(3H,s)(9×CH3),2.66(1H,s),2.88(1H,d,J＝6.0Hz),3.48(2H,d,J＝6.0Hz),3.91(1H,d,J＝12.0Hz),4.10(2H,m),5.30(1H,t-like,H-12)；13C-NMR(CDCl3,125MHz)δ:12.0,14.3,14.3,15.8,17.0,18.1,23.0,23.4,23.6,25.6,25.7,25.8,26.1,27.6,30.6,32.3,32.4,33.1,33.9,36.9,38.1,39.3,41.3,41.7,41.9,44.7,45.9,46.5,47.7,47.9,60.0,67.4 and 72.4,122.3,143.7,171.6,177.8,181.9, the spectrogram is shown in fig. 13 and fig. 14.
Hederagenin ethyl ester (HES) is white and invisible powder; HREIMS M/z 523.3757[ M + Na ]]+,(calcd.For C32H52O4,500.38656)；[ɑ]D 25.9＝+60°(C＝0.05,CHCl3)；IRνKBr max cm-1:3367,2946,1725,1463；1H-NMR(CDCl3，600MHz)δ:0.74(3H,s),0.89(3H,s),0.92(3H,s),1.13(3H,s),1.26(3H,s),1.26(3H,s),1.23(3H,s),3.42(1H,d,J＝8Hz),3.63(1H,dd,J＝8.0,16.0Hz),3.72(1H,d,J＝8.0Hz),4.08(2H,t,J＝8.0,16.0Hz),5.28(1H,t-like,H-12)；13C-NMR(CDCl3,125MHz)δ:11.0,14.2,15.8,16.9,18.3,23.5,25.8,25.8,26.6,27.6,29.6,29.6,30.6,32.4,32.4,33.1,36.9,38.1,39.3,41.2,41.7,41.7,46.1,46.4,47.7,49.7,60.2,72.1,76.8,122.5,143.5,177.5。
Example 5
Taking any one of the hederagenin derivatives of the invention as a raw material medicine, adding 1/20 dextrin, and granulating to obtain granules.
Example 6
Taking any one of the hederagenin derivatives of the invention as a raw material medicine, adding 1/18 dextrin, mixing uniformly, and encapsulating to obtain a capsule.
Example 7
Taking any one of the hederagenin derivatives of the invention as a raw material medicine, adding 1/17 dextrin, mixing uniformly, drying, and preparing into pills.
Example 8
Taking any one of the hederagenin derivatives of the invention as a raw material medicine, adding 1/18 starch, granulating, tabletting and preparing into tablets.
Example 9
Taking any one of the hederagenin derivatives of the invention as a raw material medicine, adding 23 times of injection water, standing for 30-40 minutes, filtering, and sterilizing to obtain the injection.
Example 10
Taking any one of the hederagenin derivatives of the invention as a raw material medicine, adding 15 times of water for injection, filtering, and freeze-drying to obtain freeze-dried powder.
Example 11
Taking any one of the hederagenin derivatives of the invention as a raw material medicine, adding 21 times of purified water, mixing uniformly, filtering, and sterilizing to obtain the oral liquid.
To further verify the feasibility of the invention, the invention team performed a series of experiments, as follows:
test example 1: anti-HIV protease and hepatitis C virus protease activity of derivatives
HIV-1 protease and HCV NS3/4A protease are adopted to test the in vitro anti-AIDS and hepatitis C virus activity of the derivatives; the test derivatives of Renin protease and Trypsin protease have normal protease activity in human body.
1. The test principle is as follows:
HIV-1 protease and HCV NS3/4A protease are respectively used as virus target proteins to determine the ability of the sample to inhibit HIV and hepatitis C virus.
2. Test materials and methods:
the kit comprises: SensoLyte 520HIV-1 protease kit (batch: AS-71147, Anaspec san Jose USA), SensoLyte 520MS4002TS kit (batch: AK71145-1011, Anaspec san Jose USA)
A detection instrument: microplate reader (Synergy II, usa), one hundred thousandth electronic analytical balance (METTLER MS4002TS switzerland).
Positive control: pepstatin a (HIV-1PR inhibitor) and messenger quinone (HCV NS3/4A PR inhibitor) data processing and analysis: the data are expressed by mean standard deviation (X +/-S), statistical processing is completed through Microsoft Windows 2003Excel software, and the inhibition rate of the measured data is calculated by using STDEV-t test.
Inhibition rate calculation formula:
inhibition rate × (Fvehicle-Fsample)/Fvehicle; f in the formula is the fluorescence value of the control group and the sample group.
3. Experimental methods and results:
preparation of test solution (according to the kit instruction manual):
buffer solution: 2 × assay buffer (Component D), 1M DDT (Component F) and deionized water were mixed at 1: 0.06: 1, and mixing and carrying out ice bath for standby.
HCV NS3/4A protease substrate lysis: adding 0.12ml of DMSO (component C) to the HCV NS3/4A protease substrate [ Ac-Asp-Glu-Dap (QXLTM520) -Glu-Glu-Abu-COO-Ala-Ser-Cys (5-FAMsp) -NH2](Component A) was stored frozen at-20 ℃ as a stock solution. Stock solutions were taken before each experiment and buffered at 1: diluted by 100 proportion and then prepared for use.
HCV NS3/4A protease solution: the protease solution is diluted 20 or 60 times with a buffer solution.
Measurement method (operation according to kit manual): in 384-well black plates (Cornin, USA), substrate blank solution, solvent blank solution, positive control, inhibitor control, test compound control, and HCV NS3/4A protease and substrate are added. Each concentration is 3 complex holes, after shaking and mixing uniformly, warm incubation is carried out for 30 minutes at room temperature, and fluorescence intensity is tested by an enzyme-labeling instrument under the excitation wavelength of 485nm and the emission wavelength of 535 nm. The results are shown in Table 1.
TABLE 1 hederagenin derivatives anti-HIV protease and hepatitis C virus protease activity (N ═ 3)
Data mean ± RSD, three independent experiments.aPC a, Pepstatin a, HIV protease positive control;bPC B Emberlin, HCV protease positive control; and nt is not measured.
The results of the evaluation of the activity of the derivatives against various target proteases by means of quantitative fluorometric analysis of the cleaved synthetic substrates are given in Table 1, and the two known protease inhibitors pepstatin A and embelin, used as positive controls in HIV-1 and HCV protease experiments, respectively, have their IC' s50The values were 0.02 and 8.5. mu.M, respectively.
Hederagenin derivative (3 beta, 23) -di-O- [ (3',3' -dimethylsuccinate)Percarboxylic acid acyl group)]Hederagenin (1 a; number: HS-8) and (3 beta, 23) -di-O-glutaryl hederagenin (1b, number: HY-25) strongly inhibit HIV protease (IC)504.3-9.3 μ M), inactive against HCV protease. 3 beta-O- [ (3',3' -dimethylsuccinoyl)]-23-hydroxy hederagenin (1c, number: HS-7), (3 beta, 23) -di-O- [ (3',3' -dimethylsuccinoyl)]Hederagenin ethyl ester (2a, number: HL-4) and 3 beta-O- [ (3',3' -dimethylsuccinyl)]-23-hydroxyhederagenin ethyl ester (4a, No.: HY-29-N) inhibits not only HIV protease but also HCV protease; while 3 beta-hydroxy-23-tert-butyldimethylsilyloxy hederagenin ethyl ester (3a, No. HY-7) is inactive to both viral proteases.
Six high-activity antiviral protease compounds (1a-1c,2a,3b and 4a) are studied by the invention to examine the capability of the compounds in inhibiting the normal proteases of human body, namely, Renin and HIV-1 protease are aspartyl protease, and trypsin and HCV protease are serine protease, and all the compounds have no inhibition effect on the Renin and the trypsin at the concentration of 1mg/mL, thereby revealing that the hederagenin derivatives can highly selectively inhibit the HIV-1 or HCV protease.
While the invention has been described in detail in the foregoing by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that certain changes and modifications may be made therein based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. A hederagenin anhydride derivative is characterized in that the hederagenin anhydride derivative comprises any isomer, racemate and mixture of C6 internal anhydride derivatives, or pharmaceutically acceptable salt or hydrate, the structure of the derivative is shown in a general formula I,
wherein R is hydrogen or ethyl, R1、R2Is hydroxy, tert-butyldimethylsilyloxy (TBS), 3' -Dimethylsuccinoyl (DMS), Glutaroyl (GA);
2. the hederagenin anhydride derivative according to claim 1, wherein the derivative comprises (3 β,23) -di-O- [ (3',3' -dimethylsuccinyl) ] hederagenin (1a), (3 β,23) -di-O-glutaryl hederagenin (1b), 3 β -O- [ (3',3' -dimethylsuccinyl) ] -23-hydroxyhederagenin (1c), (3 β,23) -di-O- [ (3',3' -dimethylsuccinyl) ] hederagenin ethyl ester (2a), 3 β -hydroxy-23-tert-butyldimethylsilyloxy hederagenin ethyl ester (3a), 3-O- [ (3',3' -Dimethylsuccinato) ] -23-tert-butyldimethylsilyloxy hederagenin ethyl ester (3b), 3-O- [ (3',3' -dimethylsuccinato) ] -23-hydroxyhederagenin ethyl ester (4a) and hederagenin ethyl ester (HES) any stereoisomer.
3. The hederagenin anhydride derivative according to claim 2, wherein the preparation method of the hederagenin ethyl ester (HES) is as follows: dissolving 0.5-1.5 g of hederagenin, 1.5-2.5 mmoL, 0.4-0.8 mL of iodoethane, 7-9 mmoL and 1200-1600 mg of potassium carbonate in 15mL of DMF (dimethyl formamide), stirring at room temperature for reaction and staying overnight, monitoring the reaction by TLC (thin layer chromatography), extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, and performing gradient elution on an ethyl acetate extract by using a silica gel column and 20:0-1:1 petroleum ether-ethyl acetate to obtain amorphous powder HES;
synthetic route I:
the preparation method of the 3 beta-hydroxy-23-tert-butyldimethylsilyloxy hederagenin ethyl ester (3a) comprises the following steps:
placing 800-1200 mg of hederagenin ethyl ester and 1.5-2.5 mmoL in a round bottom flask, adding 1200-1700 mg of TBSCl, 8-12 mmoL and 600-800 mg of DMAP and 4-8 mmoL, dissolving with 20-30 mL of dichloromethane and 5-9 mL of pyridine, heating and stirring in an oil bath at 30-40 ℃ for 2-8 h, monitoring the reaction by TLC (thin layer chromatography), extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, and performing gradient elution on an ethyl acetate extract by using a silica gel column according to the ratio of 100:0-1:1 petroleum ether-ethyl acetate to obtain 3 a;
synthetic route II:
the preparation method of the (3 beta, 23) -di-O- [ (3',3' -dimethylsuccinyl) ] hederagenin (1a), (3 beta, 23) -di-O-glutaryl hederagenin (1b) and (3 beta-O- [ (3',3' -dimethylsuccinyl) ] -23-hydroxyhederagenin (1c) comprises the following steps: 80-120 mg of hederagenin, 0.18-0.23 mmoL, 260-360 mg of 2, 2-dimethylsuccinic anhydride, 2-3 mmoL, 260-300 mg of glutaric anhydride, 2-3 mmoL and 90-105 mg of DMAP, 0.6-1.0 mmoL are respectively added, 1.8-2.0mL of pyridine is used for dissolving, reflux reaction is carried out for 16-30h at 100-130 ℃, TLC is used for monitoring the reaction is complete, 1moL/L of hydrochloric acid is added for adjusting the pH to be neutral, water and ethyl acetate are used for extraction, ethyl acetate is recovered under reduced pressure, an ethyl acetate extract is primarily purified by an ODS open reversed phase chromatographic column, methanol water is used as an eluent, the elution gradient is 5:5-100:0, a sample is recovered, a semi-preparative high performance liquid chromatography is used for elution with the ratio of 9:1-100:0 methanol-0.1% TFA/water gradient, the flow rate is 1mL/min, the wave length is 190-220 nm, amorphous powder 1a is respectively obtained, 1b and 1 c;
synthetic route III
The preparation method of the (3 beta, 23) -di-O- [ (3',3' -dimethylsuccinyl) ] hederagenin ethyl ester (2a) comprises the following steps: 40-60 mg of hederagenin ethyl ester, 0.05-0.15 mmoL, adding 120-180 mg of 2, 2-dimethylsuccinic anhydride, 1-1.5 mmoL and 45-52 mg of DMAP (dimethyl acetamide P), 0.2-0.6 mmoL, dissolving with 4mL of pyridine, carrying out reflux reaction at 110-130 ℃ for 8-10 h, monitoring the reaction completion by TLC (thin layer chromatography), adding 1moL/L hydrochloric acid to adjust the pH to be neutral, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, carrying out primary purification on an ethyl acetate extract by using an ODS (ozone depleting substance) open reverse phase chromatographic column, using methanol water as an eluent, and carrying out elution gradient of 5:5-100:0, and recovering a sample. Performing secondary separation and purification by using a semi-preparative high performance liquid chromatograph, performing gradient elution by using methanol-0.1% TFA/water at a ratio of 9:1-100:0, wherein the flow rate is 1mL/min, and the wavelength is 208nm to obtain amorphous powder 2 a; the synthesis route is as follows:
the preparation method of the compound 3-O- [ (3',3' -dimethylsuccinoyl) ] -23-tert-butyldimethylsilyloxy hederagenin ethyl ester (3b) comprises the following steps: adding 100-150 mg of 2, 2-dimethylsuccinic anhydride, 0.8-1.2 mmoL and 30-50 mg of DMAP (dimethyl acetamide) and 0.2-0.4 mmoL into 0.12-0.20 mmoL of the compound 3a, dissolving by using 3mL of pyridine, carrying out reflux reaction at 100-140 ℃ for 16-30h, monitoring the reaction completion by TLC (thin layer chromatography), adding 1moL/L of hydrochloric acid to adjust the pH to be neutral, extracting by using water and ethyl acetate, recovering ethyl acetate under reduced pressure, purifying an ethyl acetate silica gel column extract by using a petroleum ether-acetone gradient elution with the ratio of 60:1-1:1 to obtain amorphous powder 3 b;
synthetic route IV
The preparation method of the 3-O- [ (3',3' -dimethylsuccinoyl) ] -23-hydroxy hederagenin ethyl ester (4a) comprises the following steps: taking 3b 80-100 mg and 0.1-0.15 mmoL, adding TBAF 450-550 mg and 1.2-1.7 mmoL, dissolving with 2mL tetrahydrofuran, carrying out reflux reaction at 50-80 ℃ for 8-14 h, monitoring complete reaction by TLC, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, carrying out preliminary purification on an ethyl acetate extract by using an ODS open reverse phase chromatographic column, taking methanol water as an eluent, carrying out elution gradient of 5:5-100:0, recovering a sample, carrying out elution by using a semi-preparative high performance liquid chromatograph with a methanol-0.1% TFA/water gradient of 9:1-100:0, carrying out elution at the flow rate of 1mL/min and the wavelength of 190-220 nm to obtain amorphous powder 4 a;
synthetic route V
4. The hederagenin anhydride derivative according to claim 3, wherein the preparation method of the hederagenin ethyl ester (HES) is as follows: dissolving hederagenin 1.0g,2.12mmoL, iodoethane 0.68mL,8.40mmoL and potassium carbonate 1451.1mg in DMF 10.50mmoL, stirring at room temperature for reaction overnight, monitoring by TLC for complete reaction, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, and eluting ethyl acetate extract with silica gel column and petroleum ether-ethyl acetate gradient of 20:0-1:1 to obtain amorphous powder HES;
synthetic route I:
5. the hederagenin anhydride derivative according to claim 3, wherein the preparation method of the 3 beta-hydroxy-23-tert-butyldimethylsilyloxy hederagenin ethyl ester (3a) is as follows:
placing hederagenin ethyl ester 1000.0mg and 2.0mmoL into a round bottom flask, adding TBSCl 1507.0mg,10.00mmoL and DMAP 733.0mg,6.00mmoL, dissolving with 25mL dichloromethane and 7mL pyridine, heating and stirring in an oil bath at 35 ℃ for 5h, monitoring the reaction by TLC, extracting with water and ethyl acetate, recovering ethyl acetate under reduced pressure, and performing gradient elution on the ethyl acetate extract by using a silica gel column by using petroleum ether-ethyl acetate according to the ratio of 100:0-1:1 to obtain 3 a;
synthetic route II:
6. the hederagenin anhydride derivative according to claim 3, wherein the preparation method of (3 β,23) -di-O- [ (3',3' -dimethylsuccinoyl) ] hederagenin (1a), (3 β,23) -di-O-glutaroyl hederagenin (1b), and (3 β -O- [ (3',3' -dimethylsuccinoyl) ] -23-hydroxyhederagenin (1c) is as follows: adding 100.0mg of hederagenin and 0.21mmoL of 2, 2-dimethylsuccinic anhydride 320mg,2.5mmoL of 2, glutaric anhydride 283.0mg,2.48mmoL of 2, DMAP97.8 mg and 0.80mmoL respectively, dissolving with 1.8-2.0mL of pyridine, refluxing and reacting at 120 ℃ for 24h, monitoring the reaction by TLC, adding 1moL/L of hydrochloric acid to adjust the pH to be neutral, extracting with water and ethyl acetate, recovering the ethyl acetate under reduced pressure, primarily purifying the ethyl acetate extract by using an ODS open reversed phase chromatographic column of 1.5 multiplied by 40cm, using methanol water as an eluent and having an elution gradient of 5:5-100:0, and recovering a sample. Performing gradient elution with methanol-0.1% TFA/water at a ratio of 9:1-100:0 by using a semi-preparative high performance liquid chromatograph at a flow rate of 1mL/min and a wavelength of 208nm to obtain amorphous powders 1a,1b and 1c respectively;
synthetic route III
The preparation method of the (3 beta, 23) -di-O- [ (3',3' -dimethylsuccinyl) ] hederagenin ethyl ester (2a) comprises the following steps: 50mg of hederagenin ethyl ester and 0.10mmoL, adding 153.7mg of 2, 2-dimethylsuccinic anhydride, 1.20mmoL of hederagenin ethyl ester and 48.9mg of DMAP and 0.40mmoL of 0.10mmoL of pyridine, dissolving the mixture by using 4mL of pyridine, carrying out reflux reaction for 10 hours at 120 ℃, monitoring the reaction completion by TLC, adding 1moL/L of hydrochloric acid to adjust the pH to be neutral, extracting the mixture by using water and ethyl acetate, recovering the ethyl acetate under reduced pressure, carrying out primary purification on an ethyl acetate extract by using an ODS open reversed phase chromatographic column, using methanol water as an eluent, and recovering a sample, wherein the elution gradient is 5:5-100: 0. Performing secondary separation and purification by using a semi-preparative high performance liquid chromatograph, performing gradient elution by using methanol-0.1% TFA/water at a ratio of 9:1-100:0, wherein the flow rate is 1mL/min, and the wavelength is 208nm to obtain amorphous powder 2 a;
the synthesis route is as follows:
7. hederagenin anhydride derivative according to claim 3, wherein the compound 3-O- [ (3',3' -dimethylsuccinoyl) ] -23-tert-butyldimethylsilyloxy hederagenin ethyl ester (3b) is prepared by: adding 100.0mg of compound 3a and 0.16mmoL of 2, 2-dimethylsuccinic anhydride 128.1mg,1.00mmoL and DMAP40.0mg and 0.32mmoL into 0.16mmoL, dissolving by using 3mL of pyridine, carrying out reflux reaction at 120 ℃ for 24 hours, monitoring the reaction by TLC to be complete, adding 1moL/L of hydrochloric acid to adjust the pH to be neutral, extracting by using water and ethyl acetate, recovering ethyl acetate under reduced pressure, purifying the ethyl acetate extract by using a silica gel column by using 1.5 multiplied by 30cm, and carrying out gradient elution by using petroleum ether-acetone according to the ratio of 60:1-1:1 to obtain amorphous powder 3 b;
synthetic route IV
8. The hederagenin anhydride derivative according to claim 3, wherein the preparation method of the 3-O- [ (3',3' -dimethylsuccinoyl) ] -23-hydroxyhederagenin ethyl ester (4a) is as follows: 3b, adding 500.0mg of TBAF and 1.58mmoL into 0.12mmoL, dissolving the mixture by using 2mL of tetrahydrofuran, carrying out reflux reaction for 12h at 75 ℃, monitoring the reaction by TLC to be complete, extracting the mixture by using water and ethyl acetate, recovering the ethyl acetate under reduced pressure, carrying out primary purification on an ethyl acetate extract by using an ODS open reverse phase chromatographic column of 1.5 multiplied by 40cm, taking methanol water as an eluent and carrying out elution gradient of 5:5-100:0, recovering a sample, carrying out elution by using a semi-preparative high performance liquid chromatograph according to a ratio of roasted 9:1-100:0 methanol-0.1% TFA/water gradient, carrying out elution at a flow rate of 1mL/min and a wavelength of 208nm to obtain amorphous powder 4 a;
synthetic route V
9. The hederagenin anhydride derivative according to any one of claims 1 to 8, wherein the use of the hederagenin anhydride derivative for the manufacture of a medicament for the treatment of a viral infection; or adding medicinal adjuvants or carriers to make into various pharmaceutically acceptable preparations for preparing medicines for treating viral infection.
10. The hederagenin anhydride derivative according to claim 9, wherein the application of the hederagenin anhydride derivative in preparing a medicament for treating AIDS or hepatitis C virus protease; or adding medicinal adjuvants or carriers to make into pharmaceutically acceptable preparations for preparing medicines for treating AIDS or inhibiting hepatitis C virus protease.
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