CN113929570B - Myrtle derivative and preparation method and application thereof - Google Patents

Myrtle derivative and preparation method and application thereof Download PDF

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CN113929570B
CN113929570B CN202111286397.1A CN202111286397A CN113929570B CN 113929570 B CN113929570 B CN 113929570B CN 202111286397 A CN202111286397 A CN 202111286397A CN 113929570 B CN113929570 B CN 113929570B
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王毅清
谭桂山
谭海波
康峰华
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Hunan Zhongjia Biomedical Co ltd
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Abstract

A myrtle ketone derivative is a compound shown in formula (I), optical isomer, enantiomer, diastereomer, racemate and pharmaceutically acceptable salt thereof,wherein: r is R 1 、R 2 Independently selected from H, halogen, nitro, hydroxyl, amino, C1-C12 straight chain, C1-C12 branched chain, C3-C12 cycloalkyl, C3-C12 alkenyl, C3-C12 alkynyl, heterocyclic, aromatic ring, substituted aromatic ring, C2-C12 alkoxy or C2-C12 halogenated alkyl. The compound provided by the invention has better in-vitro activity of different types of pathogenic bacteria, and pharmacological experiments prove that most of the compounds provided by the invention have better inhibitory activity on various pathogenic bacteria than vancomycin, especially compound I 7 Can effectively induce the reduction of colony count, has good selectivity to bacterial cell membranes, and has about 50 times of the activity of vancomycin on resisting MRSA.

Description

Myrtle derivative and preparation method and application thereof
Technical Field
The invention belongs to the fields of pharmaceutical chemistry and pharmacotherapeutics, and in particular relates to a myrtle ketone derivative, a preparation method and medical application.
Background
Methicillin-resistant staphylococcus aureus (MRSA) is a common multi-drug resistant pathogen in clinic, and the infection rate and death rate of the methicillin-resistant staphylococcus aureus are gradually increased in recent years, so that the human health is seriously threatened. At present, MRSA infection is parallel to hepatitis B and AIDS and is three most difficult infectious diseases in the world. Vancomycin (vancomycin) is the first medicament for treating MRSA infection currently, but the antibiotic has great toxic and side effects, serious damage to kidneys after long-term large-dose use, extremely easy deafness and limited further application. In addition, few drugs such as linezolid, daptomycin, and tigecycline have been approved by the FDA in the united states and, although they can also be used in the clinical treatment of MRSA infections, MRSA has developed resistance to these drugs in recent years. Therefore, the search for and discovery of novel anti-MRSA drugs or drug lead compounds is both an urgent need for clinical treatment and a primary problem in developing anti-MRSA drugs.
Myrtaceae (myrtaceae) plants are abundant in resources in China, are mostly medicinal plants, and are conventionally used for treating bacterial infection-related diseases such as nasosinusitis, bronchitis, bronchiectasis, chronic obstructive pulmonary diseases, pulmonary fungus infection, pulmonary tuberculosis, silicosis and the like. The phloroglucinol compound is used as main characteristic chemical components and functional active substances, has novel and changeable structural characteristics and remarkable biological activity, and has unique advantages in the field of medicine research and development. In recent years, it has been found that most of phloroglucinol active ingredients derived from plants of the Myrtaceae family have an anti-MRSA activity. In particular to phloroglucinol compounds such as rhodozyrtone, rhodozyrsone B, tomotosenol A, tomotosone C and the like, and the anti-MRSA activity of the phloroglucinol compounds is close to or even better than that of vancomycin.
The prior art CN 105859537B discloses ring-opening myrtle ketone analogues, a preparation method thereof and application thereof in antibacterial medicines. The ring-opening myrtle ketone analogue has a structure shown in a formula (1):
wherein R is a H, C-C15 linear, branched or cyclic alkyl, or aromatic group. The ring-opened myrtle ketone analogues have significant activity against MRSA, staphylococcus aureus, bacillus cereus, B.subtis, B.thuringiensis or Escherichia coli. Wherein the compound 11i-11n has remarkable antibacterial activity, and the MIC value is as low as 0.25-0.50 mug/mL, which is 2-4 times that of vancomycin (1.0 mug/mL) which is the last barrier of the antibacterial agent.
Therefore, in view of the traditional efficacy and modern pharmacological activity of myrtaceae plants, structural modification and optimization of the characteristic MRSA-resistant active ingredients thereof are expected to become an effective way for discovering novel structural lead compounds/drugs with more remarkable MRSA-resistant curative effects.
Disclosure of Invention
The invention aims to provide a ring-opening myrtle ketone derivative with activity superior to that of the existing myrtle ketone derivative, and optical isomer, enantiomer, diastereomer, racemate and pharmaceutically acceptable salt thereof, and also provides a preparation method and application thereof in medicine.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
a myrtle ketone derivative is a compound shown in formula (I), optical isomer, enantiomer, diastereomer, racemate and pharmaceutically acceptable salt thereof,
wherein:
R 1 、R 2 independently selected from H, halogen, nitro, hydroxyl, amino, C1-C12 straight chain, C1-C12 branched chain, C3-C12 cycloalkyl, C3-C12 alkenyl, C3-C12 alkynyl, heterocyclic, aromatic ring, substituted aromatic ring, C2-C12 alkoxy or C2-C12 halogenated alkyl.
Preferably, R 1 、R 2 Independently selected from C5-C10 straight chain, C5-C10 branched chain, C3-C6 cycloalkyl, aromatic ring, substituted aromatic ring and C5-C10 halogenated alkyl.
Preferably, the aromatic ring is a benzene ring.
Preferably, the substituted aromatic ring is a substituted benzene ring.
Preferably, the substituent of the substituted aromatic ring is selected from C1-C12 straight chain, C1-C12 branched chain, aromatic ring, halogen, nitro, hydroxyl and amino.
Preferably, said R 1 And R is 2 The same applies.
Preferably, said R 1 And R is 2 And simultaneously is C5-C10 straight chain, C5-C10 branched chain, C3-C6 cycloalkyl, C5-C10 halogenated alkyl, benzene ring or substituted benzene ring, wherein the substituent of the substituted benzene ring is selected from C1-C12 straight chain, C1-C12 branched chain, aromatic ring, halogen, nitro, hydroxyl and amino.
Preferably, said R 1 And R is 2 And is C5-C10 straight chain, C5-C10 branched or C5-C10 haloalkyl.
Preferably, the myrtle ketone derivative is selected from the following compounds:
preferably, the myrtle ketone derivative is selected from the following compounds:
the invention also provides a preparation method of the compound shown in the formula (I), and the synthetic route is as follows:
wherein:
R 1 、R 2 independently selected from H, halogen, nitro, hydroxyl, amino, C1-C12 straight chain, C1-C12 branched chain, C3-C12 cycloalkyl, C3-C12 alkenyl, C3-C12 alkynyl, heterocyclic, aromatic ring, substituted aromatic ring, C2-C12 alkoxy or C2-C12 halogenated alkyl.
The invention also provides a preparation method of the compound shown in the formula (I), which comprises the following steps:
(1) The compound II and methyl iodide are subjected to hydroxyl oxidation and selective carbon methylation reaction in an alkaline environment to obtain a compound III;
(2) The compound III is subjected to thermal inversion Friedel Crafts acylation reaction to obtain a compound IV;
(3) The compound IV is reacted with isovaleraldehyde under the catalysis of proline to obtain a compound V through Knoevenagel;
(4) The compound VI and substituted acyl chloride are subjected to Friedel Crafts acylation reaction under an acidic condition to obtain a compound VII;
(5) The compound V and the compound VII undergo Michael addition reaction under the catalysis of sodium hydride, and finally the compound with the structural formula (I) is obtained;
wherein R in the compound of formula (I) 1 、R 2 Independently selected from H, halogen, nitro, hydroxyl, amino, C1-C12 straight chain, C1-C12 branched chain, C3-C12 cycloalkyl, C3-C12 alkenyl, C3-C12 alkynyl, heterocyclic, aromatic ring, substituted aromatic ring, C2-C12 alkoxy or C2-C12 halogenated alkyl.
Preferably, in the reaction for preparing the compound III from the compound II, the solvent is selected from one or more of anhydrous dichloromethane, chloroform, ethyl acetate, ethanol, methanol, tetrahydrofuran, acetone, dimethyl sulfoxide, N, N-dimethylformamide or dioxane; the base is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, and lithium amide.
Preferably, in the reaction for preparing compound IV from compound III, the solvent is selected from aqueous hydrochloric acid solutions of different equivalents; the reaction temperature is-10 ℃ to heating reflux.
Preferably, in the reaction for preparing compound V from compound IV, the solvent is selected from one or more of anhydrous dichloromethane, chloroform, ethyl acetate, ethanol, methanol, tetrahydrofuran, acetone, dimethyl sulfoxide, N-dimethylformamide or dioxane.
Preferably, in the reaction for preparing compound VII from compound VI, the reaction temperature is from-10 ℃ to reflux by heating.
Preferably, in the reaction for preparing compound VII from compound V, the solvent is selected from one or more of anhydrous dichloromethane, chloroform, ethyl acetate, ethanol, methanol, tetrahydrofuran, acetone, dimethyl sulfoxide, N-dimethylformamide or dioxane.
These intermediates or target compounds can each be purified according to conventional isolation techniques, if desired separated into monomers according to conventional isolation techniques, and further converted, if desired, into addition salts of pharmaceutically acceptable bases.
The invention also provides the use of a compound of formula (I) for the manufacture of a medicament or pharmaceutical composition for the treatment or prophylaxis of infectious diseases, including in particular but not limited to MRSA, gram-positive coccoid infections, gram-positive bacillary infections.
An antibacterial agent comprising any one of the compounds of the above-mentioned ring-opened myrtle ketone analogues as an active ingredient, and a pharmaceutically acceptable carrier.
The antibacterial agent is preferably an anti-metacilin-resistant Staphylococcus aureus (MRSA), staphylococcus aureus, bacillus cereus, P.acnes, E.faecalis, S.epiduralis, E.coli, S.tyrphinium or S.dyssenteriae bacteria agent.
The term "drug" as used herein refers to a compound of the present invention, one or more, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, in admixture with another chemical component, such as a pharmaceutically acceptable carrier. But also pharmaceutical compositions intended to facilitate the administration process to animals.
"pharmaceutical carrier" in the present invention refers to inactive ingredients in pharmaceutical compositions that do not cause significant irritation to the organism and do not interfere with the biological activity and properties of the compound being administered, such as, but not limited to: starch, water, polyethylene glycol, castor oil, cyclodextrin, sesame oil, peanut oil, various sugars (such as mannitol, glucose, etc.), acrylic polymers, and the like.
In the present invention, the compound I and pharmaceutically acceptable salts thereof, and solvates of these compounds, may be administered to a mammal either alone or in combination with a pharmaceutically acceptable carrier or diluent, preferably in accordance with standard pharmaceutical practice. The mode of administration may be via a variety of routes including oral, parenteral or topical. Parenteral administration as referred to herein includes, but is not limited to, intravenous, intramuscular, intraperitoneal, subcutaneous, and transdermal administration.
The compound provided by the invention has better inhibitory activity on different types of pathogenic bacteria in vitro, and pharmacological experiments prove that most of the compounds provided by the invention have better inhibitory activity on various pathogenic bacteria than vancomycin, especially compound I 7 Can effectively induce the reduction of colony count, has good selectivity to bacterial cell membranes, and has about 50 times of the activity of vancomycin on resisting MRSA. I 7 By breaking bacterial cell membrane junctionsThe modified disubstituted acyl compound can enhance the capability of penetrating MRSA cell wall and destroying cell membrane compared with the prior art.
Detailed description of the preferred embodiments
To make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions in the present invention will be clearly and completely described below, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art without the inventive effort, are within the scope of the present invention based on the embodiments of the present invention.
Example 1:
a compound:
4- (1- (3, 5-Diacetyl-2,4, 6-trihydroxyphenyl) -3-methyl-5-hydroxy-2, 6-tetramethylycyclohex-4-ene-1, 3-dione, I 1 Is prepared from the following steps:
compound II (100 mmol) was dissolved in 300mL of anhydrous methanol under ice-bath conditions, followed by slow addition of sodium hydroxide (600 mmol). After stirring uniformly in an ice bath for 10 minutes, methyl iodide (600 mmol) was slowly added dropwise to the reaction system. After stirring under ice bath conditions for 30 minutes, the reaction mixture was immediately stirred at room temperature for 12 hours. After completion of the reaction, 300mL of a 2N aqueous hydrochloric acid solution was added to terminate the reaction, the mixture was extracted 4 times with ethyl acetate (500 mL), and the organic phases were combined. The obtained organic phase was washed with 500mL of saturated brine for 2 times, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound III in 90% yield.
Compound III (100 mmol) was placed in a 500mL round bottom flask, and then 300mL of 6N aqueous hydrochloric acid was added thereto. The reaction was then placed in an oil bath at 120℃with vigorous stirring and heated to reflux for 12 hours. After the reaction system gradually cooled to room temperature, filtering, washing a filter cake 3 times by 50mL of tap water, and drying to obtain a pale black powdery solid compound IV, wherein the yield is 80%.
To a 100mL round bottom flask containing compound IV (30 mmol) and isovaleraldehyde (90 mmol) was added anhydrous dichloromethane (50 mL) and after stirring uniformly for 5 min, proline (3 mmol) was added thereto in one portion at room temperature. After the reaction system was stirred for half an hour, 200mL of n-hexane was added at a time, and then washed twice with saturated brine, and dried and concentrated to give compound V in 90% yield.
Compound VI (100 mmol) and methanesulfonic acid (300 mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, acetyl chloride (300 mmol) was slowly added dropwise to the reaction system. After the completion of the dropping, the reaction system was stirred for 10 minutes while continuing to be maintained at the temperature, cooled to room temperature after the completion of the reaction, and the reaction mixture was poured into 150mL of ice water, extracted 3 times with n-hexane (150 mL), and the organic phases were combined and washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then washed once with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried under reduced pressure to give compound VII 1 ，R 1 ＝CH 3 ，R 2 ＝CH 3 The yield was 85%.
Sodium hydride (30 mmo) was slowly added to dissolve VII 1 To a tetrahydrofuran solution (250 mL) of (20 mmol) was added a tetrahydrofuran solution (50 mL) containing intermediate V (20 mmol), and the mixture was stirred at room temperature for half an hour. The TCL assay was reacted with 150mL of 1N aqueous hydrochloric acid. The organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate (150 mL), washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure yellowish powder (I) 1 )，R 1 ＝CH 3 ，R 2 ＝CH 3 The yield was 80%.
1 H NMR(500MHz,CD 3 OD):δ0.91-0.84(m,6H),1.45-1.31(m,10H),1.52(s,3H),2.15-1.76(m,2H),2.78(s,6H),4.35-4.40(t,J＝7.6Hz,2H),further peaks show a pair of atropisomers in a ratio of 1:2；major:δ＝10.27(s,0.67H),12.96(s,0.66H)；minor:δ＝11.13(s,1H),12.07(s,1H)； 13 C NMR(100MHz,CD 3 OD):major:δ211.7,205.4,205.1,203.9,177.3,170.9,167.8,167.5,114.5,107.3,105.7,103.7,55.0,48.7,38.2,33.5,32.3,27.6,27.1,26.9,26.2,24.2,22.5,22.3,22.3；minor:δ212.2,205.5,205.4,204.2,178.1,170.9,168.8,166.9,114.5,107.4,105.5,104.1,54.1,49.1,39.0,33.4,29.4,27.1,25.8,25.8,24.7,24.2,22.5,22.4,22.3。
Example 2:
a compound:
4- (1- (3, 5-Dibutylyl-2, 4, 6-trihydroxyphenyl) -3-methylibutylyl) -5-hydroxy-2, 6-tetramethylycyclohex-4-ene-1, 3-dione, I 2 Is prepared from the following steps:
the synthesis of compounds I-VI in the subsequent examples is the same as in example 1.
Compound VI (100 mmol) and methanesulfonic acid (300 mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, butyryl chloride (300 mmol) was slowly added dropwise to the reaction system. After the completion of the addition, the reaction system was stirred at the temperature for 15 minutes, cooled to room temperature after the completion of the reaction, and the reaction mixture was poured into 150mL of ice water, extracted 3 times with n-hexane (150 mL), and the organic phases were combined and washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then once with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried under reduced pressure to give compound VII 2 ，R 1 ＝n-C 3 H 7 ，R 2 ＝n-C 3 H 7 The yield was 80%.
Sodium hydride (30 mmol) was slowly added with dissolved VII 2 To a tetrahydrofuran solution (250 mL) of (20 mmol) was added a tetrahydrofuran solution (50 mL) containing intermediate V (20 mmol), and the mixture was stirred at room temperature for half an hour. The TCL assay was reacted with 150mL of 1N aqueous hydrochloric acid. The organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate (150 mL), washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure yellowish powder (I) 2 )，R 1 ＝n-C 3 H 7 ，R 2 ＝n-C 3 H 7 A pale yellow powder was obtained in 87% yield.
1 H NMR(500MHz,CDCl 3 )δ12.89(s,0.67H,major),12.01(s,0.33H,minor),11.24(s,0.33H,minor),10.39(s,0.67H,major),4.39(t,J＝7.7Hz,0.67H,major),4.36(t,7.7Hz,0.33H,minor),3.29-3.11(m,4H),2.1-1.97(m,1H),1.83-1.69(m,4H),1.52(s,3H),1.47-1.32(m,10H),1.03(t,J＝6.7Hz,6H),0.95-0.79(m,6H)； 13 C NMR(125MHz,CDCl 3 ):major:δ211.8,208.1,207.9,203.8,177.4,170.8,167.8,167.1,114.6,107.3,105.4,103.5,55.0,48.7,46.5,45.6,38.2,27.8,27.0,26.9,26.2,24.2,22.6,22.5,22.3,18.1,18.0,14.0,13.9；minor:δ212.3,208.3,208.0,204.2,178.2,170.8,168.8,166.5,114.6,107.5,105.3,103.8,54.1,54.1,49.1,46.5,45.6,39.0,29.5,27.1,25.7,25.7,24.5,22.5,22.4,18.1,18.0,14.0,13.9。
Example 3:
a compound:
5-Hydroxy-2, 6-tetramethyl-4- (3-methyl-1- (2, 4,6-trihydroxy-3, 5-diiso-crylphenyl) butyl) cyclo-hex-4-ene-1, 3-dione, i.e.I 3 Is prepared from the following steps:
compound VI (100 mmol) and methanesulfonic acid (300 mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, isobutyryl chloride (300 mmol) was slowly added dropwise to the reaction system. After the completion of the addition, the reaction system was stirred at the temperature for 15 minutes, cooled to room temperature after the completion of the reaction, and the reaction mixture was poured into 150mL of ice water, extracted 3 times with n-hexane (150 mL), and the organic phases were combined and washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then once with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried under reduced pressure to give compound VII 3 ，R 1 ＝i-C 3 H 7 ，R 2 ＝i-C 3 H 7 The yield was 82%.
Sodium hydride (30 mmol) was slowly added with dissolved VII 3 To a tetrahydrofuran solution (250 mL) of (20 mmol) was added a tetrahydrofuran solution (50 mL) containing intermediate V (20 mmol), and the mixture was stirred at room temperature for half an hour. The TCL assay was reacted with 150mL of 1N aqueous hydrochloric acid. The organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate (150 mL), washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure yellowish powder (I) 3 )，R 1 ＝i-C 3 H 7 ，R 2 ＝i-C 3 H 7 Pale yellow powder was obtained in 77% yield.
1 H NMR(500MHz,CDCl 3 )δ12.90(s,0.67H,major),12.02(s,0.33H,minor),11.21(s,0.33H,minor),10.35(s,1H,major),4.38(m,1H),3.35-3.14(m,2H),2.17-1.93(m,1H),2.12-1.74(m,1H),1.54-1.47(m,3H),1.45-1.30(m,10H),1.20(m,12H),0.89(m,6H).； 13 C NMR(100MHz,CDCl 3 ):major:δ211.8,208.7,208.5,203.9,177.3,170.7,167.4,167.1,114.6,107.3,105.3,103.4,55.0,48.7,38.2,38.0,37.2,27.7,27.1,26.9,26.2,24.2,22.6,22.4,22.3,8.7,8.5.minor:δ212.3,208.9,208.6,204.1,178.1,170.6,168.4,166.5,114.6,107.4,105.2,103.8,54.1,49.1,39.0,38.0,37.2,29.4,27.1,25.8,25.7,24.7,24.3,22.5,22.3,8.7,8.4。
Example 4:
5-Hydroxy-2, 6-tetramethyl-4- (3-methyl-1- (2, 4, 6-trihydroxy-3-pentanylphenyl) butyl) cyclohex-4-ene-1,3-dione, I 4 Is prepared from the following steps:
compound VI (100 mmol) and methanesulfonic acid (300 mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, pentanoyl chloride (300 mmol) was slowly added dropwise to the reaction system. The reaction system was stirred for 10 minutes while continuing to keep the temperature after the dropping, cooled to room temperature after the reaction was sufficiently performed, and the reaction mixture was poured into 150mL of ice water, extracted 3 times with n-hexane (150 mL), and the organic phases were combined,and washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then once with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried under reduced pressure to give compound VII 4 ，R 1 ＝n-C 4 H 9 ，R 2 ＝n-C 4 H 9 The yield was 80%.
Sodium hydride (30 mmol) was slowly added with dissolved VII 4 To a tetrahydrofuran solution (250 mL) of (20 mmol) was added a tetrahydrofuran solution (50 mL) containing intermediate V (20 mmol), and the mixture was stirred at room temperature for half an hour. The TCL assay was reacted with 150mL of 1N aqueous hydrochloric acid. The organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate (150 mL), washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure yellowish powder (I) 4 )，R 1 ＝n-C 4 H 9 ，R 2 ＝n-C 4 H 9 A pale yellow powder was obtained in 89% yield.
1 H NMR(400MHz,CDCl 3 ):δ12.89(s,1H,major),12.01(s,1H,minor),11.25(s,1H,minor),10.39(s,1H,major),4.38(m,1H),3.29-3.11(m,4H),2.16-1.95(m,1H),1.82-1.63(m,5H),1.55-1.48(m,3H),1.45-1.30(m,22H),0.99-0.91(m,6H),0.91-0.84(m,6H)； 13 C NMR(125MHz,CDCl 3 )δ211.8,208.3,208.1,203.8,177.4,170.8,167.8,167.1,114.6,107.3,105.4,103.5,54.9,48.7,44.6,43.7,38.2,31.6,27.8,27.0,26.9,26.2,24.6,24.3,24.2,22.6,22.6,22.5,22.5,22.3,14.0,14.0；minor:δ212.3,208.5,208.3,204.1,178.2,170.8,168.8,166.5,114.6,107.5,105.2,103.8,54.1,49.1,44.6,43.7,39.0,31.6,31.6,29.5,27.1,25.7,25.6,24.8,24.5,24.4,24.3,22.6,22.5,22.4,14.0,14.0。
Example 5:
4-Hydroxy-2, 6-tetramethyl-4- (3-methyl-1- (2, 4, 6-trihydroxy-3-propynylphenyl) butyl) cyclohex-4-ene-1,3-dione, i.e.I 5 Is prepared from the following steps:
compound VI (100 mmol) and methanesulfonic acid (300 mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, isovaleryl chloride (300 mmol) was slowly added dropwise to the reaction system. After the completion of the addition, the reaction system was stirred at the temperature for 10 minutes, cooled to room temperature after the completion of the reaction, and the reaction mixture was poured into 150mL of ice water, extracted 3 times with n-hexane (150 mL), and the organic phases were combined and washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then once with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried under reduced pressure to give compound VII 5 ，R 1 ＝i-C 4 H 9 ，R 2 ＝i-C 4 H 9 The yield was 70%.
Sodium hydride (30 mmol) was slowly added with dissolved VII 5 To a tetrahydrofuran solution (250 mL) of (20 mmol) was added a tetrahydrofuran solution (50 mL) containing intermediate V (20 mmol), and the mixture was stirred at room temperature for half an hour. The TCL assay was reacted with 150mL of 1N aqueous hydrochloric acid. The organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate (150 mL), washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure yellowish powder (I) 5 )，R 1 ＝i-C 4 H 9 ，R 2 ＝i-C 4 H 9 A pale yellow powder was obtained in 88% yield.
1 H NMR(400MHz,CDCl 3 ):δ12.90(s,0.67H,major),12.01(s,0.33H,minor),11.25(s,0.33H,minor),10.40(s,1H,major),4.39(m,1H),3.23-3.14(m,4H),2.10(m,1H),1.78-1.66(m,5H),1.53-1.48(m,3H),1.47-1.31(m,14H),0.97(m,6H),0.93-0.83(m,6H).； 13 C NMR(100MHz,CDCl 3 ):major:δ211.8,208.3,208.1,203.8,177.4,170.8,167.8,167.1,114.6,107.3,105.4,103.5,55.0,48.7,44.4,43.4,38.2,27.8,27.0,27.0,26.9,26.7,26.2,24.2,22.6,22.6,22.5,22.4,22.3,14.1,14.0.minor:δ212.4,208.5,208.3,204.1,178.2,170.8,168.8,166.5,114.6,107.5,105.2,103.9,54.1,49.1,44.4,43.5,38.7,30.4,29.5,28.9,27.1,26.7,25.7,25.7,24.8,24.4,23.8,23.0,22.4,14.1,14.1。
Example 6:
5-Hydroxy-2, 6-tetramethyl-4- (3-methyl-1- (2, 4,6-trihydroxy-3- (3-methylglutanyl) phenyl) butyl) cyclohexyl-4-ene-1, 3-dione, i.e. I 6 Is prepared from the following steps:
compound VI (100 mmol) and methanesulfonic acid (300 mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, hexanoyl chloride (300 mmol) was slowly added dropwise to the reaction system. After the completion of the addition, the reaction system was stirred at the temperature for 10 minutes, cooled to room temperature after the completion of the reaction, and the reaction mixture was poured into 150mL of ice water, extracted 3 times with n-hexane (150 mL), and the organic phases were combined and washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then once with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried under reduced pressure to give compound VII 6 ，R 1 ＝n-C 5 H 11 ，R 2 ＝n-C 5 H 11 Yield 78%.
Sodium hydride (30 mmol) was slowly added with dissolved VII 6 To a tetrahydrofuran solution (250 mL) of (20 mmol) was added a tetrahydrofuran solution (50 mL) containing intermediate V (20 mmol), and the mixture was stirred at room temperature for half an hour. The TCL assay was reacted with 150mL of 1N aqueous hydrochloric acid. The organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate (150 mL), washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure yellowish powder (I) 6 )，R 1 ＝n-C 5 H 11 ，R 2 ＝n-C 5 H 11 Pale yellow powder was obtained in 81% yield.
1 H NMR(500MHz,CDCl 3 )δ12.90(s,0.67H,major),12.03(s,0.33H,minor),11.28(s,0.67H,major),10.42(s,1H,minor),4.38(m,1H),3.20-2.92(m,4H),2.35-2.19(m,2H),2.13-1.75(m,2H),1.52(m,3H),1.46-1.31(m,10H),1.08-0.97(m,12H),0.93-0.83(m,6H)； 13 C NMR(126MHz,CDCl 3 )δ211.8,207.8,207.5,203.8,177.4,170.9,168.0,167.1,114.5,107.4,105.6,103.7,54.9,53.2,52.3,48.7,38.2,27.8,27.0,26.9,26.2,25.4,25.1,24.3,22.9,22.8,22.8,22.8,22.5,22.4. 13 C NMR(126MHz,CDCl 3 )δ212.3,208.0,207.7,204.1,178.2,170.9,169.1,166.5,114.5,107.6,105.4,104.1,54.1,53.2,52.4,49.1,39.0,29.7,29.5,27.1,25.7,25.7,25.2,24.8,24.4,22.9,22.8,22.8,22.8,22.5,22.4。
Example 7:
4- (1- (3, 5-Dihexanoyl-2,4, 6-trihydroxyphenyl) -3-methyl-5-hydroxy-2, 6-tetramethycyclohex-4-ene-1, 3-dione, i.e. I 7 Is prepared from the following steps:
compound VI (100 mmol) and methanesulfonic acid (300 mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, heptanoyl chloride (300 mmol) was slowly added dropwise to the reaction system. After the completion of the addition, the reaction system was stirred at the temperature for 10 minutes, cooled to room temperature after the completion of the reaction, and the reaction mixture was poured into 150mL of ice water, extracted 3 times with n-hexane (150 mL), and the organic phases were combined and washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then once with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried under reduced pressure to give compound VII 7 ，R 1 ＝n-C 6 H 13 ，R 2 ＝n-C 6 H 13 The yield was 80%.
Sodium hydride (30 mmol) was slowly added with dissolved VII 7 To a tetrahydrofuran solution (250 mL) of (20 mmol) was added a tetrahydrofuran solution (50 mL) containing intermediate V (20 mmol), and the mixture was stirred at room temperature for half an hour. The TCL assay was reacted with 150mL of 1N aqueous hydrochloric acid. The organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate (150 mL), washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure yellowish powderPowder (I) 7 )，R 1 ＝n-C 5 H 11 ，R 2 ＝n-C 5 H 11 A pale yellow powder was obtained in 60% yield.
1 H NMR(400MHz,CDCl 3 ):δ12.89(s,1H,major),12.01(s,1H,minor),11.25(s,1H,minor),10.39(s,1H,major),4.38(m,1H),3.29-3.11(m,4H),2.16-1.95(m,1H),1.82-1.63(m,5H),1.55-1.48(m,3H),1.45-1.30(m,22H),0.99-0.91(m,6H),0.91-0.84(m,6H)； 13 C NMR(125MHz,CDCl 3 )δ211.8,208.3,208.1,203.8,177.4,170.8,167.8,167.1,114.6,107.3,105.4,103.5,54.9,48.7,44.6,43.7,38.2,31.6,27.8,27.0,26.9,26.2,24.6,24.3,24.2,22.6,22.6,22.5,22.5,22.3,14.0,14.0；minor:δ212.3,208.5,208.3,204.1,178.2,170.8,168.8,166.5,114.6,107.5,105.2,103.8,54.1,49.1,44.6,43.7,39.0,31.6,31.6,29.5,27.1,25.7,25.6,24.8,24.5,24.4,24.3,22.6,22.5,22.4,14.0,14.0。
Example 8:
4- (1- (3, 5-Diheptanyl-2, 4, 6-trihydroxyphenyl) -3-methyl-5-hydroxy-2, 6-tetramethycyclohex-4-ene-1, 3-dione, i.e. I 8 Is prepared from the following steps:
compound VI (100 mmol) and methanesulfonic acid (300 mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, octanoyl chloride (300 mmol) was slowly added dropwise to the reaction system. After the completion of the addition, the reaction system was stirred at the temperature for 10 minutes, cooled to room temperature after the completion of the reaction, and the reaction mixture was poured into 150mL of ice water, extracted 3 times with n-hexane (150 mL), and the organic phases were combined and washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then once with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried under reduced pressure to give compound VII 8 ，R 1 ＝n-C 7 H 15 ，R 2 ＝n-C 7 H 15 The yield was 81%.
Sodium hydride(30 mmol) the solution VII was slowly added 8 To a tetrahydrofuran solution (250 mL) of (20 mmol) was added a tetrahydrofuran solution (50 mL) containing intermediate V (20 mmol), and the mixture was stirred at room temperature for half an hour. The TCL assay was reacted with 150mL of 1N aqueous hydrochloric acid. The organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate (150 mL), washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure yellowish powder (I) 8 )，R 1 ＝n-C 7 H 15 ，R 2 ＝n-C 7 H 15 Pale yellow powder was obtained in 81% yield.
1 H NMR(500MHz,CDCl 3 )δ12.90(s,0.67H,major),12.01(s,0.33H,minor),11.25(s,0.33H,major),10.40(s,0.67H,major),4.38(m,1H),3.30-3.11(m,4H),2.16-1.25(m,54H),0.89(m,12H). 13 C NMR(125MHz,CDCl 3 ):major:δ211.8,208.3,208.1,203.8,177.3,170.8,167.8,167.1,114.6,107.3,105.4,103.5,54.9,48.7,44.7,43.7,38.2,31.7,29.4,29.4,29.3,29.2,27.8,27.0,26.9,26.2,24.9,24.6,24.2,22.7,22.6,22.6,22.5,22.3；minor:δ212.3,208.5,208.3,204.1,178.1,170.8,168.8,166.5,114.6,107.5,105.2,103.8,54.1,49.1,44.6,43.7,39.1,31.8,29.5,29.4,29.3,29.2,27.1,25.7,25.7,24.8,24.8,24.6,24.4,22.7,22.6,22.5,22.4,14.1。
Example 9:
5-Hydroxy-2, 6-tetramethyl-4- (3-methyl-1- (2, 4,6-trihydroxy-3, 5-dinonylphenyl) butyl) cyclo-ohex-4-ene-1, 3-dione, i.e.I 9 Is prepared from the following steps:
compound VI (100 mmol) and methanesulfonic acid (300 mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, nonanoyl chloride (300 mmol) was slowly added dropwise to the reaction system. The reaction was stirred for 10 minutes while keeping the temperature, cooled to room temperature after the reaction was sufficiently carried out, and the reaction mixture was poured into 150mL of ice water, extracted 3 times with n-hexane (150 mL), and the organics were combinedThe phases were washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then washed once with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried under reduced pressure to give compound VII 9 ，R 1 ＝n-C 8 H 17 ，R 2 ＝n-C 8 H 17 The yield was 86%.
Sodium hydride (30 mmol) was slowly added with dissolved VII 9 To a tetrahydrofuran solution (250 mL) of (20 mmol) was added a tetrahydrofuran solution (50 mL) containing intermediate V (20 mmol), and the mixture was stirred at room temperature for half an hour. The TCL assay was reacted with 150mL of 1N aqueous hydrochloric acid. The organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate (150 mL), washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure yellowish powder (I) 9 )，R 1 ＝n-C 8 H 17 ，R 2 ＝n-C 8 H 17 Pale yellow powder was obtained in 90% yield.
1 H NMR(400MHz,CDCl 3 ):δ12.89(s,0.67H,major),12.01(s,0.33H,minor),11.25(s,0.33H,minor),10.40(s,0.67H,major),4.38(m,1H),3.29-3.11(m,4H),2.15-1.25(m,39H),0.89(m,12H)； 13 C NMR(100MHz,CDCl 3 ):major:δ211.8,208.4,208.1,203.8,177.4,170.8,167.8,167.1,114.6,107.3,105.4,103.5,55.0,48.7,44.7,43.7,38.2,31.9,31.9,29.6,29.5,29.2,27.8,27.0,26.9,26.2,24.9,24.6,24.2,22.7,22.6,22.5,22.3,14.1,14.1.minor:δ212.3,208.5,208.3,204.1,178.2,170.7,168.8,166.5,114.6,107.5,105.2,103.9,54.1,49.1,44.6,43.8,39.0,31.9,31.9,29.6,29.5,29.4,27.1,25.7,25.7,24.8,24.7,24.6,24.4,22.7,22.5,22.4,14.1,14.1。
Example 10:
4- (1- (3-Heptanoyl-2, 4, 6-trihydroxyphenyl) -3-methyl-5-hydroxy-2, 6-tetramethyltubing-4-ene-1, 3-dione, I 10 Is prepared from the following steps:
compound VI (100 mmol) and methanesulfonic acid (300 mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, decanoyl chloride (300 mmol) was slowly added dropwise to the reaction system. After the completion of the addition, the reaction system was stirred at the temperature for 10 minutes, cooled to room temperature after the completion of the reaction, and the reaction mixture was poured into 150mL of ice water, extracted 3 times with n-hexane (150 mL), and the organic phases were combined and washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then once with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried under reduced pressure to give compound VII 10 ，R 1 ＝n-C 9 H 19 ，R 2 ＝n-C 9 H 19 The yield was 81%.
Sodium hydride (30 mmol) was slowly added with dissolved VII 9 To a tetrahydrofuran solution (250 mL) of (20 mmol) was added a tetrahydrofuran solution (50 mL) containing intermediate V (20 mmol), and the mixture was stirred at room temperature for half an hour. The TCL assay was reacted with 150mL of 1N aqueous hydrochloric acid. The organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate (150 mL), washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure yellowish powder (I) 10 )，R 1 ＝n-C 9 H 19 ，R 2 ＝n-C 9 H 19 A pale yellow powder was obtained in 76% yield.
1 H NMR(500MHz,CDCl 3 )δ12.90(s,0.67H,major),12.01(s,0.33H,minor),11.25(s,0.33H,minor),10.40(s,0.67H,major),4.38(m,1H),3.31-3.10(m,4H),2.16-1.21(m,43H),0.96-0.81(m,12H). 13 C NMR(125MHz,CDCl 3 ):major:δ211.8,208.4,208.1,203.8,177.4,170.8,167.8,167.1,114.6,107.3,105.4,103.5,55.0,48.7,44.7,43.7,38.2,31.8,29.4,29.4,29.3,29.2,27.8,27.0,26.9,26.2,24.9,24.6,24.2,22.7,22.7,22.7,22.7,22.6,22.5,22.3,14.1,14.1.minor:δ212.3,208.5,208.3,204.2,178.2,170.8,168.7,166.5,114.6,107.5,105.3,103.8,54.1,49.1,44.6,43.8,39.0,31.8,29.5,29.4,29.3,29.3,29.2,27.1,25.7,25.7,24.8,24.8,24.6,24.4,22.7,22.6,22.5,22.4,14.1,14.1.
Example 11:
4- (1- (3, 5-Didodecanoyl-2,4, 6-trihydroxyphenyl) -3-methyl-5-hydroxy-2, 6-tetramethycyclohex-4-ene-1, 3-dione, i.e.I 11 Is prepared from the following steps:
compound VI (100 mmol) and methanesulfonic acid (300 mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, lauroyl chloride (300 mmol) was slowly added dropwise to the reaction system. After the completion of the addition, the reaction system was stirred at the temperature for 10 minutes, cooled to room temperature after the completion of the reaction, and the reaction mixture was poured into 150mL of ice water, extracted 3 times with n-hexane (150 mL), and the organic phases were combined and washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then once with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried under reduced pressure to give compound VII 11 ，R 1 ＝n-C 11 H 23 ，R 2 ＝n-C 11 H 23 The yield was 83%.
Sodium hydride (30 mmol) was slowly added with dissolved VII 11 To a tetrahydrofuran solution (250 mL) of (20 mmol) was added a tetrahydrofuran solution (50 mL) containing intermediate V (20 mmol), and the mixture was stirred at room temperature for half an hour. The TCL assay was reacted with 150mL of 1N aqueous hydrochloric acid. The organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate (150 mL), washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure yellowish powder (I) 11 )，R 1 ＝n-C 11 H 23 ，R 2 ＝n-C 11 H 23 A pale yellow powder was obtained in 87% yield.
1 H NMR(500MHz,CDCl 3 )δ12.90(s,0.67H,major),12.01(s,0.33H,minor),11.25(s,0.33H,minor),10.40(s,0.67H,major),4.38(m,1H),3.29-3.10(m,4H),2.15-1.20(m,51H),0.93-0.83(m,12H)； 13 C NMR(125MHz,CDCl 3 ):major:δ211.8,208.3,208.1,203.8,177.3,170.8,167.8,167.1,114.6,107.3,105.4,103.5,54.9,48.7,44.7,43.7,38.2,31.9,31.9,29.6,29.6,29.6,29.4,27.8,27.0,26.9,26.2,24.9,24.6,24.2,22.7,22.6,22.5,22.3；minor:δ212.3,208.5,208.3,204.1,178.1,170.8,168.8,166.5,125.5,107.5,105.2,103.8,54.1,49.1,44.7,43.8,39.0,31.9,31.9,30.3,29.5,29.5,29.4,29.4,27.1,25.7,25.7,24.8,24.7,24.6,24.4,22.7,22.5,22.4。
Example 12:
4- (1- (3-Hexanoyl-2, 4, 6-trihydroxyphenyl) -3-methyl-5-hydroxy-2, 6-tetramethyltubing-4-ene-1, 3-dione, I 12 Is prepared from the following steps:
compound VI (100 mmol) and methanesulfonic acid (300 mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, cyclobutylformyl chloride (300 mmol) was slowly added dropwise to the reaction system. After the completion of the addition, the reaction system was stirred at the temperature for 10 minutes, cooled to room temperature after the completion of the reaction, and the reaction mixture was poured into 150mL of ice water, extracted 3 times with n-hexane (150 mL), and the organic phases were combined and washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then once with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried under reduced pressure to give compound VII 12 ，R 1 ＝c-C 4 H 7 ，R 2 ＝c-C 4 H 7 Yield 78%.
Sodium hydride (30 mmol) was slowly added with dissolved VII 12 To a tetrahydrofuran solution (250 mL) of (20 mmol) was added a tetrahydrofuran solution (50 mL) containing intermediate V (20 mmol), and the mixture was stirred at room temperature for half an hour. The TCL assay was reacted with 150mL of 1N aqueous hydrochloric acid. The organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate (150 mL), washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure yellowish powder (I) 12 )，R 1 ＝c-C 4 H 7 ，R 2 ＝c-C 4 H 7 Pale yellow powder was obtained in 77% yield.
1 H NMR(500MHz,CDCl 3 )δ12.77(s,0.67H,major),11.86(s,0.33H,minor),11.27(s,0.33H,minor),10.42(s,0.67H,major),4.44-4.30(m,3H),2.45-1.80(m,14H),1.52(m,3H),1.45-1.26(m,10H),0.94-0.81(m,6H). 13 C NMR(126MHz,CDCl 3 )major:δ211.9,208.2,207.7,203.8,177.3,170.6,168.0,166.9,114.7,107.2,104.2,102.4,54.9,48.7,46.9,46.0,38.1,27.8,26.9,26.9,26.2,25.5,24.7,24.7,24.3,22.7,22.6,22.2,17.6,17.6；minor:δ212.3,208.2,208.2,204.1,178.2,170.5,169.0,166.2,114.7,107.4,104.1,102.8,54.0,49.1,46.8,46.0,38.9,29.3,27.1,25.6,25.4,24.8,24.8,24.5,22.6,22.6,22.2,17.6,17.6。
Example 13:
4- (1- (3, 5-Di (cyclohexanecarbonyl) -2,4, 6-trihydroxyphenyl) -3-methyl) -5-hydroxy-2, 6-tetramethycyclohex-4-ene-1, 3-dione, I 13 Is prepared from the following steps:
compound VI (100 mmol) and methanesulfonic acid (300 mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, cyclohexylformyl chloride (300 mmol) was slowly added dropwise to the reaction system. After the completion of the addition, the reaction system was stirred at the temperature for 10 minutes, cooled to room temperature after the completion of the reaction, and the reaction mixture was poured into 150mL of ice water, extracted 3 times with n-hexane (150 mL), and the organic phases were combined and washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then once with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried under reduced pressure to give compound VII 13 ，R 1 ＝c-C 6 H 11 ，R 2 ＝c-C 6 H 11 The yield was 74%.
Sodium hydride (30 mmol) was slowly added with dissolved VII 13 (20 mmol) tetrahydrofuran solublesTo the solution (250 mL) was added a tetrahydrofuran solution (50 mL) containing intermediate V (20 mmol), and the mixture was stirred at room temperature for half an hour. The TCL assay was reacted with 150mL of 1N aqueous hydrochloric acid. The organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate (150 mL), washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure yellowish powder (I) 13 )，R 1 ＝c-C 6 H 11 ，R 2 ＝c-C 6 H 11 Pale yellow powder was obtained in 79% yield.
1 H NMR(500MHz,CDCl 3 ):δ12.89(s,0.66H,major),12.01(s,0.33H,minor),11.35(s,0.33H,minor),10.51(s,1H,major),4.39(m,1H),3.87-3.71(m,2H),2.16-1.21(m,31H),0.96-0.81(m,10H)； 13 C NMR(126MHz,CDCl 3 )major:δ211.9,211.6,211.3,203.8,177.5,171.0,168.4,166.8,125.5,114.6,107.5,104.8,103.0,54.9,49.9,49.3,48.8,38.2,30.3,29.7,29.4,29.4,29.2,27.9,26.9,26.9,26.3,26.2,26.1,26.1,26.0,26.0,25.8,24.30 22.6,22.3；minor: 13 C NMR(125MHz,CDCl 3 ):δ212.4,211.7,211.5,204.1,178.3,171.0,169.4,166.2,128.3,114.6,107.8,104.6,103.4,54.1,49.9,49.3,49.2,39.0,30.1,29.5,29.3,27.1,26.2,26.1,25.9,25.7,25.6,24.8,24.6,22.7,22.5。
Example 14:
5-Hydroxy-2, 6-tetramethyl-4- (3-methyl-1- (2, 4,6-trihydroxy-3,5-bis (2-phenylacrylyl) phenyl) butyl) cyclohex-4-ene-1,3-dione, i.e.I 14 Is prepared from the following steps:
compound VI (100 mmol) and methanesulfonic acid (300 mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, cyclophenylacetyl chloride (300 mmol) was slowly added dropwise to the reaction system. The reaction was stirred for 10 minutes while keeping the temperature, cooled to room temperature after the reaction was sufficiently carried out, and the reaction mixture was poured into 150mL of ice water, extracted 3 times with n-hexane (150 mL), and the organic phases were combinedAnd washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then once with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried under reduced pressure to give compound VII 14 ，R 1 ＝CH 2 Ph，R 2 ＝CH 2 Ph, yield 76%.
Sodium hydride (30 mmol) was slowly added with dissolved VII 14 To a tetrahydrofuran solution (250 mL) of (20 mmol) was added a tetrahydrofuran solution (50 mL) containing intermediate V (20 mmol), and the mixture was stirred at room temperature for half an hour. The TCL assay was reacted with 150mL of 1N aqueous hydrochloric acid. The organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate (150 mL), washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure yellowish powder (I) 14 )，R 1 ＝CH 2 Ph，R 2 ＝CH 2 Ph, a pale yellow powder was obtained in 71% yield.
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1 H NMR(500MHz,CDCl 3 ):δ13.23(s,0.67H,major),12.35(s,0.33H,minor),10.99(s,0.33H,minor),10.16(s,0.67H,major),7.38-7.26(m,10H),4.65-4.43(m,4H),4.37(t,J＝6.8Hz,1H),2.14-1.28(m,15H),0.87(dd,J＝8.2,6.7Hz,6H)； 13 C NMR(125MHz,CDCl 3 ):major:δ211.7,205.3,204.8,204.0,177.5,170.9,167.9,167.3,135.1,134.5,130.0,129.9,128.4,128.3,127.0,126.8,114.4,107.6,105.3,103.4,55.0,50.6,49.5,48.7,38.2,27.7,27.0,26.9,26.2,24.2,22.6,22.5,22.3；minor: 13 C NMR(125MHz,CDCl 3 )δ212.12,205.27,205.22,204.25,178.30,170.79,168.91,166.70,134.98,134.36,129.96,129.90,128.43,128.37,127.00,126.83,114.46,107.79,105.16,103.79,54.10,50.58,49.54,49.12,38.95,29.45,27.09,25.69,25.66,24.76,24.44,22.54,22.30。
Example 15:
5-Hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-trihydroxy-3,5-bis(3-phenylpropanoyl)phenyl)butyl) Cyclohex-4-ene-1,3-dione, i.e. I 15 Is prepared from the following steps:
compound VI (100 mmol) and methanesulfonic acid (300 mmol) were placed in a 100mL dry round bottom flask and heated to 60 ℃. After stirring for 10 minutes, cyclobenzoyl chloride (300 mmol) was slowly added dropwise to the reaction system. After the completion of the addition, the reaction system was stirred at the temperature for 10 minutes, cooled to room temperature after the completion of the reaction, and the reaction mixture was poured into 150mL of ice water, extracted 3 times with n-hexane (150 mL), and the organic phases were combined and washed twice with 150mL of water and 150mL of 80% methanol water, respectively, and then once with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried under reduced pressure to give compound VII 15 ，R 1 ＝C 2 H 4 Ph，R 2 ＝C 2 H 4 Ph, 75% yield.
Sodium hydride (30 mmol) was slowly added with dissolved VII 15 To a tetrahydrofuran solution (250 mL) of (20 mmol) was added a tetrahydrofuran solution (50 mL) containing intermediate V (20 mmol), and the mixture was stirred at room temperature for half an hour. The TCL assay was reacted with 150mL of 1N aqueous hydrochloric acid. The organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate (150 mL), washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure yellowish powder (I) 15 )，R 1 ＝C 2 H 4 Ph，R 2 ＝C 2 H 4 Ph, a pale yellow powder was obtained in 68% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝ 1 HNMR(500MHz,CDCl 3 )δ13.04(s,0.67H,major),12.16(s,0.33H,minor),11.11(s,0.33H,minor),10.27(s,0.67H,major),7.35-7.20(m,10H),4.39(t,J＝14.5Hz,1H),3.55(m,4H),3.05(d,J＝7.4Hz,4H),2.09-1.71(m,2H),1.55-1.25(m,13H),0.93-0.75(m,6H)； 13 C NMR(125MHz,CDCl 3 ):major:δ211.7,206.8,206.5,203.9,177.4,170.7,167.6,167.2,141.5,141.2,128.7,128.5,128.5,128.4,126.1,126.0,114.5,107.5,105.5,103.5,55.0,48.7,46.3,45.4,38.2,30.7,30.5,27.72,27.02,26.93,26.24,25.75,24.21,22.56,22.42,22.34；minor: 13 C NMR(125MHz,CDCl 3 )δ212.2,207.0,206.7,204.2,178.1,170.6,168.6,166.6,141.4,141.1,128.6,128.5,128.4,128.4,126.1,126.0,114.5,107.6,105.3,103.9,54.1,49.1,46.2,45.4,39.0,30.6,30.5,29.7,29.5,27.1,26.2,25.8,24.7,24.3,22.5,22.4,22.3。
Example 16:
4- (1- (3-Acetyl-5-butyl-2, 4, 6-trihydroxyphenyl) -3-methyl-5-hydroxy-2, 6-tetramethylethylene-4-ene-1, 3-dione, I 16 Is prepared from the following steps:
according to the process disclosed in prior art CN 105622379A, compound VII is obtained 16 ，R 1 ＝CH 3 ，R 2 ＝n-C 3 H 7 The yield was 60%.
Sodium hydride (30 mmol) was slowly added with dissolved VII 16 To a tetrahydrofuran solution (250 mL) of (20 mmol) was added a tetrahydrofuran solution (50 mL) containing intermediate V (20 mmol), and the mixture was stirred at room temperature for half an hour. The TCL assay was reacted with 150mL of 1N aqueous hydrochloric acid. The organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate (150 mL), washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure yellowish powder (I) 16 )，R 1 ＝CH 3 ，R 2 ＝n-C 3 H 7 Pale yellow powder was obtained in 79% yield.
1 H NMR(500MHz,CDCl 3 )δ12.92(d,0.67H,major),12.04(d,0.33H,minor),11.18(d,0.33H,minor),10.33(d,0.67H,major),4.37(m,1H),3.28-3.06(m,2H),2.76(s,3H),2.20-1.30(m,17H),1.09-0.96(t,J＝7.4Hz,3H),0.94-0.82(m,6H)； 13 C NMR(100MHz,CDCl 3 ):the pairs of major regio-isomers:δ211.8,211.7,208.1,207.9,205.4,205.1,203.9,203.8,177.3,171.0,170.8,168.1,167.4,167.4,167.2,114.5,114.5,107.4,107.2,105.7,105.5,103.8,103.4,55.0,48.7,46.5,45.6,38.2,38.2,33.5,32.4,27.7,27.1,27.0,26.9,26.2,25.7,24.7,24.2,24.2,22.6,22.5,22.4,22.4,22.4,22.3,18.1,18.0,14.0,13.9；the pairs of minor regio-isomers: 13 C NMR(126MHz,CDCl 3 )δ212.2,212.2,208.3,208.0,205.5,205.4,204.2,204.2,178.1,178.1,170.9,170.7,169.1,168.5,167.4,166.8,166.7,114.5,114.5,107.7,107.4,105.4,105.3,104.2,103.7,54.1,49.1,46.5,45.6,39.0,39.0,33.4,32.4,29.5,29.4,27.7,27.1,27.1,26.9,26.2,25.8,24.7,24.3,24.3,22.5,22.5,22.4,22.4,22.3,22.3,18.0,17.9,14.0,13.9.Note:This compound existed as a pair of atropisomers and regio-isomers。
Example 17:
4- (1- (3-Acetyl-5-hexanoyl-2, 4, 6-trihydroxyphenyl) -3-methyl-5-hydroxy-2, 6-tetramethycyclohex-4-ene-1, 3-dione, i.e. I 17 Is prepared from the following steps:
according to the process disclosed in prior art CN 105622379A, compound VII is obtained 17 ，R 1 ＝CH 3 ，R 2 ＝n-C 5 H 11 The yield was 65%.
Sodium hydride (30 mmol) was slowly added with dissolved VII 17 To a tetrahydrofuran solution (250 mL) of (20 mmol) was added a tetrahydrofuran solution (50 mL) containing intermediate V (20 mmol), and the mixture was stirred at room temperature for half an hour. The TCL assay was reacted with 150mL of 1N aqueous hydrochloric acid. The organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate (150 mL), washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure yellowish powder (I) 17 )，R 1 ＝CH 3 ，R 2 ＝n-C 5 H 11 A pale yellow powder was obtained in 71% yield.
1 H NMR(400MHz,CDCl 3 ): 1 H NMR(500MHz,CDCl 3 )δ12.92(d,0.67H,major),12.04(d,0.33H,minor),11.18(d,0.33H,minor),10.33(d,0.66H,major),4.37(m,1H),3.28-3.06(m,2H),2.76(m,3H),2.22-1.30(m,21H),1.09-0.96(m,3H),0.94-0.82(m,6H)； 13 C NMR(125MHz,CDCl 3 ):the pairs of major regio-isomers:δ211.8,211.7,208.3,208.1,205.4,205.1,204.2,203.9,203.8,177.3,177.2,171.0,170.8,168.1,167.5,167.3,167.2,114.6,114.5,107.4,107.2,105.7,105.4,103.8,103.4,54.9,48.7,44.7,43.7,38.2,38.1,33.5,32.4,31.6,27.7,27.1,27.0,26.9,26.2,25.7,24.7,24.5,24.3,24.2,22.6,22.6,22.5,22.4,22.4,22.3,22.3,14.0,13.9；the pairs of minor regio-isomers: 13 C NMR(125MHz,CDCl 3 ):δ212.3,212.2,208.5,208.2,205.5,205.4,204.2,204.1,178.1,178.0,170.9,170.7,169.2,168.5,166.74,166.65,114.55,114.50,107.52,107.38,105.44,105.26,103.80,103.72,54.12,49.14,44.59,43.68,39.07,38.99,33.44,32.38,31.58,29.49,29.45,27.10,27.08,26.22,25.82,24.44,24.34,24.26,24.20,22.62,22.54,22.48,22.32,14.01,13.99.Note:This compound existed as a pair of atropisomers and regio-isomers。
Example 18:
4- (1- (3-Dodecanoyl-2, 4, 6-trihydroxyphenyl) -3-methyl-5-hydroxy-2, 6-tetramethycyclohex-4-ene-1, 3-dione, I 18 Is prepared from the following steps:
according to the process disclosed in prior art CN 105622379A, compound VII is obtained 18 ，R 1 ＝CH 3 ，R 2 ＝n-C 7 H 15 The yield was 62%.
Sodium hydride (30 mmol) was slowly added with dissolved VII 18 To a tetrahydrofuran solution (250 mL) of (20 mmol) was added a tetrahydrofuran solution (50 mL) containing intermediate V (20 mmol), and the mixture was stirred at room temperature for half an hour. The TCL assay was reacted with 150mL of 1N aqueous hydrochloric acid. The organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate (150 mL), washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. Recrystallizing the crude product with methanol to obtain pure yellowish powder (I) 18 )，R 1 ＝CH 3 ，R 2 ＝n-C 7 H 15 Pale yellow powder was obtained in 66% yield.
1 H NMR(500MHz,CDCl 3 ):δ12.93(d,0.67H,major),12.04(d,0.33H,minor),11.19(d,0.33H,minor),10.33(d,0.66H,major),4.44-4.33(m,1H),3.28-3.12(m,2H),2.78(s,3H),2.18-1.19(m,25H),0.95-0.84(m,9H)； 13 C NMR(125MHz,CDCl 3 ):δ211.8,211.7,208.3,208.1,205.4,205.1,204.2,203.8,177.3,177.3,171.0,170.8,168.1,167.4,167.3,167.2,166.7,165.3,114.6,114.5,107.4,107.3,105.7,105.5,103.4,100.0,55.0,48.7,44.7,43.7,38.2,33.5,32.4,31.7,29.4,29.3,29.2,27.7,27.1,26.9,26.2,25.7,24.9,24.6,24.2,22.7,22.6,22.5,22.4.Note:This compound existed as a pair of atropisomers and regio-isomers。
Example 19: in vitro anti-MRSA Activity assay of the Compounds of the invention
This example will determine the Minimum Inhibitory Concentration (MIC) of the anti-MRSA activity of a sample using the resazurin chromogenic method. The 96-well plate dilution titer technique will be used in the assay, with the Minimum Inhibitory Concentration (MIC) of the various substances being determined. First, 7.5mL of an indicator solution (100. Mu.g/mL of an aqueous solution of Resazurin) and 5mL of a solution of a test bacterium (10 8 CFU/mL), and 100 μl of the mixed bacterial liquid was added to each of all test wells of columns 1 to 8. Then 100. Mu.L of the sample I to be tested 1 -I 18 Sequentially added to each well of the first column (2. Mu.g/mL), mixed well, 100. Mu.L of the solution was removed and transferred to the corresponding well of the second column, and multiplied by dilution to column 8 in the same manner. Finally, the well plate with the added sample is put into a constant temperature incubator for 10-12h at 37 ℃. The bacteria liquid turns red to have no antibacterial activity, and blue has antibacterial activity, and the minimum dilution concentration of the bacteria liquid for maintaining the blue is regarded as the minimum antibacterial concentration of the compound to be detected.
The results are shown in Table 1, which shows that: in the case of the compound I to be tested 1 -I 18 In the middle, the activity of most of the differentiation products is obviously superior to that of the clinical antibacterial drug 'last barrier' vancomycin. In particularIs a compound I 6 -I 9 They all have remarkable anti-MRSA activity, the MIC value of the anti-MRSA bacteria is as low as 0.02-0.08 mug/mL, which is 12.5-50 times stronger than the final barrier vancomycin (1.00 mug/mL) of the clinical antibacterial drug, and the anti-MRSA primer is one of the novel structure anti-MRSA primer molecules with the strongest reported activity at home and abroad.
TABLE 1 Compounds I 1 -I 18 anti-MRSA Activity at the cellular level
Example 20: evaluation of anti-SA Activity of the Compounds of the invention
This example will determine the Minimum Inhibitory Concentration (MIC) of anti-SA activity of a sample using the resazurin chromogenic method. The 96-well plate dilution titer technique will be used in the assay, with the Minimum Inhibitory Concentration (MIC) of the various substances being determined. First, 7.5mL of an indicator solution (100. Mu.g/mL of an aqueous solution of Resazurin) and 5mL of a solution of a test bacterium (10 8 CFU/mL), and 100 μl of the mixed bacterial liquid was added to each of all test wells of columns 1 to 8. Then 100. Mu.L of the sample I to be tested 6 -I 9 Sequentially added to each well of the first column (0.2. Mu.g/mL), mixed well, 100. Mu.L of the solution was removed and transferred to the corresponding well of the second column, and multiplied by dilution to column 8 in the same manner. Finally, the well plate with the added sample is put into a constant temperature incubator for 10-12h at 37 ℃. The bacteria liquid turns red to have no antibacterial activity, and blue has antibacterial activity, and the minimum dilution concentration of the bacteria liquid for maintaining the blue is regarded as the minimum antibacterial concentration of the compound to be detected.
The results show that: compound I 6 -I 9 All have very obvious SA-resistant activity, and the MIC values of the strains tested are obviously lower than those of vancomycin. In particular Compound I 7 MIC values for most strains were as low as 0.01-0.04. Mu.g/mL, 30-100 times better than the antibacterial "last barrier" vancomycin (1.25. Mu.g/mL).
TABLE 2 Compounds I 7 Inhibitory Activity against different types of pathogenic bacteria
Example 21: evaluation of the Activity of the Compounds of the invention against Bacillus cereus
This example will employ the resazurin chromogenic method to determine the Minimum Inhibitory Concentration (MIC) of a sample against Bacillus cereus activity. The 96-well plate dilution titer technique will be used in the assay, with the Minimum Inhibitory Concentration (MIC) of the various substances being determined. First, 7.5mL of an indicator solution (100. Mu.g/mL of an aqueous solution of Resazurin) and 5mL of a solution of a test bacterium (10 8 CFU/mL), and 100 μl of the mixed bacterial liquid was added to each of all test wells of columns 1 to 8. Then 100. Mu.L of the sample I to be tested 6 -I 9 Sequentially added to each well of the first column (0.2. Mu.g/mL), mixed well, 100. Mu.L of the solution was removed and transferred to the corresponding well of the second column, and multiplied by dilution to column 8 in the same manner. Finally, the well plate with the added sample is put into a constant temperature incubator for 10-12h at 37 ℃. The bacteria liquid turns red to have no antibacterial activity, and blue has antibacterial activity, and the minimum dilution concentration of the bacteria liquid for maintaining the blue is regarded as the minimum antibacterial concentration of the compound to be detected.
The results show that: compound I 6 -I 9 Has very remarkable anti-Bacillus cereus activity, and has MIC values for the tested strain which are obviously lower than those of vancomycin. In particular I 7 MIC value of (2) is 0.01-0.04 mug/mL, which is 15-60 times stronger than final barrier vancomycin (0.62 mug/mL) of clinical antibacterial drug.
Example 22: evaluation of the Activity of the Compounds against B.subtilis, B.thuringiensis or Escherichia coli
The evaluation of the anti-B.subtilis, B.thuringiensis or Escherichia coli activity of the compounds was carried out in a similar manner to the procedure described above for the anti-Bacillus cereus activity. The results are shown in Table II above, compound I 6 -I 9 Has very remarkable anti-Bacillus cereus activity, has the MIC value for the tested strain obviously lower than that of vancomycin, and has the I 7 Exhibit an optimal broad spectrumAntibacterial activity.
While the fundamental and principal features of the invention and advantages of the invention have been shown and described, it will be apparent to those skilled in the art that the invention is not limited to the details of the foregoing exemplary embodiments, but may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.

Claims (5)

1. A myrtle ketone derivative, which is characterized in that the myrtle ketone derivative is a compound shown in a formula (I):
the specific compounds are as follows:
2. the method for preparing the myrtle derivative according to claim 1, characterized in that the synthetic route is as follows:
3. use of a myrtle ketone derivative according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of an infectious disease, which is MRSA, a gram-positive coccoid infection or a gram-positive bacilli infection.
4. An antibacterial agent comprising any one of the myrtle derivatives according to claim 1 as an active ingredient, and a pharmaceutically acceptable carrier.
5. The antibacterial agent according to claim 4, wherein the antibacterial agent is an anti-metacin-resistant Staphylococcus aureus (MRSA), staphylococcus aureus, bacillus cereus, P.acnes, E.faecalis or S.epididymis bacterium.
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