CN109053798A - A kind of rheum officinale acid ester derivant and the preparation method and application thereof - Google Patents
A kind of rheum officinale acid ester derivant and the preparation method and application thereof Download PDFInfo
- Publication number
- CN109053798A CN109053798A CN201810814627.9A CN201810814627A CN109053798A CN 109053798 A CN109053798 A CN 109053798A CN 201810814627 A CN201810814627 A CN 201810814627A CN 109053798 A CN109053798 A CN 109053798A
- Authority
- CN
- China
- Prior art keywords
- acid ester
- rheum officinale
- ester derivant
- necked bottle
- staphylococcus
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4056—Esters of arylalkanephosphonic acids
- C07F9/4059—Compounds containing the structure (RY)2P(=X)-(CH2)n-C(=O)-(CH2)m-Ar, (X, Y = O, S, Se; n>=1, m>=0)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
This programme discloses a kind of rheum officinale acid ester derivant in anti-microbial type compound field, and general formula of the chemical structure is following (II):
Description
Technical field
The invention belongs to anti-microbial type compound fields, and in particular to a kind of rheum officinale acid ester derivant and preparation method thereof with answer
With.
Background technique
The discovery of antibiotic brings unprecedented Gospel to the treatment of infectious diseases.However, as antibiotic exists
Clinical is excessive using even abusing, and antibiotic resistant bacteria also occurs in succession, increasing.Wherein, the resistance to first of discovery in 1961
Oxygen XiLin staphylococcus aureus (MRSA) has the characteristics that high pathogenicity rate and the death rate, and clinical treatment is very intractable.Currently,
Clinically, the last line of defense for the treatment of MRSA infection is the glycopeptide class antibacterials using vancomycin as representative, however, with
The discovery and detection of vancomycin resistance staphylococcus aureus (VRSA), from now on, MRSA may face no medicine treatablely
Step.Therefore new anti-MRSA drug is studied to be of great significance.
Natural products is found to have from natural products and is faced in recent years due to the diversity of structure type and bioactivity
The anti-MRSA activity candidate compound of bed application prospect has become a hot topic of research.
Rhein, from Schossberger in 1844 etc. for the first time from natural plants rheum officinale extract, purify, identification and structure
It is a series of research shows that Rhein has extensive pharmacological activity, such as antitumor, anti-inflammatory, antibacterial, antiviral, anti-after confirmation
The effects of oxidation, hypoglycemic, liver protection anti-fibrosis.
But since Rhein has Anthraquinones tricyclic aromatic structure, its dissolubility is not special ideal, insoluble
Yu Shui, ethyl alcohol and most of organic solvents, vivo biodistribution availability is lower, this significantly limits Rhein in clinicing aspect
Using.Therefore, structure of modification is carried out to Rhein, improves its physicochemical property, and further study its bioactivity, extremely having must
It wants.
For these reasons, according to modern medicines design theory and organic synthetic experiment technology, present invention design is synthesized
A series of rheum officinale acid ester derivant of brand news carries out antibacterial activity research.To obtain anti-methicillin-resistant staphylococcus staphylococcus
(MRSA) candidate compound is further furtherd investigate.
Summary of the invention
In order to achieve the above objectives, the present invention is on antibacterials Research foundation early period, in conjunction with modern medicines design theory and
Organic synthetic experiment technology, design have synthesized Novel series rheum officinale acid ester derivant.
One of this programme rheum officinale acid ester derivant, general formula of the chemical structure are following (II):
Wherein, R is the chain substituent group of 1~5 carbon atom or the naphthenic base or aryl radical of 3~6 carbon atoms.
The preparation method of rheum officinale acid ester derivant, operating process are as follows: by Rhein, intermediate (I), [Bmim] BF4Or
[Pmim][HSO4] ionic liquid feeds intake according to 1:1.1:0.5 molar ratio and be added in three-necked bottle, it is added at 0~5 DEG C mole
Than DCC, DMAP for 1:0.8 in the three-necked bottle, the anhydrous dichloro of 20~50mL finally is added by the dosage of 1mmol Rhein
The three-necked bottle is put into ultrasonic synthesizer by methane in the three-necked bottle, in 80~100W of power, is warming up to 20~25
DEG C, it is filtered after reacting 15~30min, is concentrated under reduced pressure, obtains crude product, then with column chromatography separating purification, finally obtain target product
(Ⅱ)；
Reaction equation are as follows:
Reaction condition a is ionic liquid [Bmim] BF4Or [Pmim] [HSO4], b is ultrasonic reaction condition, ultrasonic power 80
~100W.
[Bmim] BF above4For 1- butyl -3- methyl imidazolium tetrafluoroborate；[Pmim][HSO4] it is 1- propyl -3- methyl
Imidazole bisulfate.
Synthesis has efficient collaboration facilitation to the reaction under this method intermediate ion liquid and ultrasound condition.Base
In the high income for the target product (II) that this method obtains, 81%~88% can reach.
Further, the rheum officinale acid ester derivant of this kind of structure novel has methicillin-resistant staphylococcus staphylococcus (MRSA) anti-
Bacterium activity.Some objects have significant antibacterial action to methicillin-resistant staphylococcus staphylococcus (MRSA), are better than comparison medicine benzene azoles
XiLin can be used as anti-methicillin-resistant staphylococcus staphylococcus (MRSA) candidate compound research close to comparison medicine vancomycin.
Specific embodiment
It is further described the present invention below with reference to embodiment, but the present invention is not limited only to following embodiments, it is anticipated that this
For field technical staff in the case where combining the prior art, there may be many variations for performance.
The general structure of the novel rheum officinale acid ester derivant of object isR be 1~
The chain substituent group of 5 carbon atoms or the naphthenic base or aryl radical of 3~6 carbon atoms.Its synthetic reaction formula are as follows:
Reaction condition a is ionic liquid [Bmim] BF4Or [Pmim] [HSO4], b is ultrasonic reaction condition, ultrasonic power 80
~100W.
[Bmim] BF above4For 1- butyl -3- methyl imidazolium tetrafluoroborate；[Pmim][HSO4] it is 1- propyl -3- methyl
Imidazole bisulfate.
Its specific steps prepared are as follows: by Rhein, intermediate (I), [Bmim] BF4Or [Pmim] [HSO4] ionic liquid
Feed intake and be added in three-necked bottle according to 1:1.1:0.5 molar ratio, at 0-5 DEG C be added molar ratio be 1:0.8 DCC, DMAP in
In three-necked bottle, 20~50mL anhydrous methylene chloride finally is added in reaction flask by the dosage of 1mmol Rhein, is put into ultrasonic conjunction
Cheng Yizhong warms naturally to 20-25 DEG C in power 80-100W, reacts 15-30min, finishes, and filters, and is concentrated under reduced pressure, and obtains thick
Product, then with column chromatography separating purification, target product (II) is finally obtained, yield is in 81%-88%.Ionic liquid and ultrasound condition
Lower synthesis has efficient collaboration facilitation to the reaction.Specific embodiment:
Embodiment 1
The preparation of O ', O- dimethyl-α-rheum officinale acyl-alpha-phenyl-methyl-phosphonate (II a)
By 2.0mmol Rhein, the intermediate I (Alpha-hydroxy benzyl dimethyl phosphonate) and 1.0mmol of 2.2mmol
[Bmim]BF4Ionic liquid is added in three-necked bottle, and 2.0mmolDCC, 1.6mmolDMAP are added at 0-5 DEG C to three-necked bottle
In, 40mL anhydrous methylene chloride is eventually adding in reaction flask, is put into ultrasonic synthesizer, in power 100W, is warmed naturally to
It 20 DEG C, maintains the temperature to be stirred to react 20min, finishes, filter, be concentrated under reduced pressure, obtain crude product, then with column chromatography separating purification,
Target product is finally obtained, is light yellow solid (II a), yield 84.3%.Compound1H NMR and13C NMR:1H-NMR
(400MHz,CDCl3)δ:12.08(s,1H,OH),11.99(s,1H,OH),7.80-7.85(m,2H,ArH),7.63(s,1H,
ArH),7.22-7.40(m,7H,ArH),6.55(s,1H,PCH),3.32-3.40(m,6H,2OCH3).13C-NMR(100MHz,
CDCl3)δ:53.3,52.4,73.6,117.5,118.8,118.9,121.6,123.4,124.0,128.7,133.3,134.8,
137.9,162.6,167.6,182.9.
Embodiment 2
The preparation of O ', O- diethyl-α-rheum officinale acyl-alpha-o-fluorophenyl-methyl-phosphonate (II b)
By 2.0mmol Rhein, the intermediate I (Alpha-hydroxy neighbour's benzyl diethyl phosphonate) of 2.2mmol and
1.0mmol[Bmim]BF4Ionic liquid is added in three-necked bottle, and 2.0mmolDCC, 1.6mmolDMAP is added extremely at 0-5 DEG C
In three-necked bottle, 60mL anhydrous methylene chloride is eventually adding in reaction flask, is put into ultrasonic synthesizer, it is natural in power 100W
25 DEG C are warming up to, maintains the temperature to be stirred to react 15min, finishes, is filtered, is concentrated under reduced pressure, obtains crude product, then use pillar layer separation
Purifying, finally obtains target product, is light yellow solid (II a), yield 82.6%.Compound1H NMR and13C NMR:1H-
NMR(400MHz,CDCl3)δ:12.08(s,1H,OH),11.98(s,1H,OH),7.84-7.90(m,2H,ArH),7.69-
7.73(s,1H,ArH),7.24-7.40(m,6H,ArH),6.58(s,1H,PCH),3.93-4.02(m,4H,2OCH2),1.03-
1.15(m,6H,2CH3).13C-NMR(100MHz,CDCl3)δ:13.4,13.5,62.3,62.4,73.2,115.6,119.0,
119.1,122.6,123.3,124.7,129.8,133.6,134.7,137.5,159.0,162.2,167.3,183.1.
Embodiment 3
The preparation of O ', O- diethyl-α-rheum officinale acyl-alpha-(2- furyl)-methyl-phosphonate (II c)
By 2.0mmol Rhein, the intermediate I [Alpha-hydroxy-(2- furfuryl) diethyl phosphonate] of 2.2mmol and
1.0mmol[Pmim][HSO4] ionic liquid be added three-necked bottle in, at 0-5 DEG C be added 2.0mmolDCC, 1.6mmolDMAP
Into three-necked bottle, 100mL anhydrous methylene chloride is eventually adding in reaction flask, is put into ultrasonic synthesizer, in power 80W, certainly
20 DEG C so are warming up to, maintains the temperature to be stirred to react 30min, finishes, is filtered, is concentrated under reduced pressure, obtains crude product, then divided with column chromatography
From purifying, target product is finally obtained, is light yellow solid (II a), yield 85.0%.Compound1H NMR and13C NMR:1H-NMR(400MHz,CDCl3)δ:12.08(s,1H,OH),11.97(s,1H,OH),7.88-8.01(m,2H,ArH),7.12-
7.35(m,4H,ArH),6.72-6.87(m,2H,ArH),6.44(s,1H,PCH),3.96-4.05(m,4H,2OCH2),1.09-
1.16 (m, 6H, 2CH3).13C-NMR(100MHz,CDCl3)δ:13.4,13.5,62.3,62.4,73.6,109.1,110.7,
119.0,119.2,122.3,122.5,126.7,133.6,135.0,136.9,142.2,155.6,161.3,166.9,
182.5.
The antibacterial activity of target compound is tested:
Using vancomycin and oxacillin as control drug, using the MIC of micro-dilution method measurement object, target is measured
Antibacterial activity of the compound to staphylococcus aureus (S.aureus), methicillin-resistant staphylococcus aureus (MRSA).Table 1
List the anti-MRSA activity of part of compounds.
MIC and MBC (μ g/ml) of 1 part of compounds of table to MRSA
As shown in Table 1, compound has different degrees of inhibitory activity, part of compounds table to the drug-fast bacteria tested in table
Reveal preferably antimicrobial agent activity, if compound 3, compound 4 are better than comparison medicine oxacillin to MIC, MBC of MRSA, slightly
Lower than comparison medicine vancomycin, show that such compound has antimicrobial agent activity.
Claims (3)
1. a kind of rheum officinale acid ester derivant, which is characterized in that general formula of the chemical structure is following (II):
Wherein, R is the chain substituent group of 1~5 carbon atom or the naphthenic base or aryl radical of 3~6 carbon atoms.
2. the preparation method of rheum officinale acid ester derivant according to claim 1, it is characterised in that: by Rhein, intermediate
(Ⅰ)、[Bmim]BF4Or [Pmim] [HSO4] ionic liquid feeds intake according to 1:1.1:0.5 molar ratio and be added in three-necked bottle, then at 0~
It is DCC, DMAP of 1:0.8 in the three-necked bottle that molar ratio is added at 5 DEG C, is finally added 20 by the dosage of 1mmol Rhein
The three-necked bottle is put into ultrasonic synthesizer by~50mL anhydrous methylene chloride in the three-necked bottle, in 80~100W of power,
It is warming up to 20~25 DEG C, is filtered after reacting 15~30min, is concentrated under reduced pressure, obtain crude product, then with column chromatography separating purification, finally
Obtain target product (II)；
Reaction equation is as follows:
Reaction condition a is ionic liquid [Bmim] BF4Or [Pmim] [HSO4], b be ultrasonic reaction condition, ultrasonic power 80~
100W。
3. rheum officinale acid ester derivant according to claim 1 is used to prepare anti-methicillin-resistant staphylococcus staphylococcus drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810814627.9A CN109053798B (en) | 2018-07-23 | 2018-07-23 | Rhein ester derivative and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810814627.9A CN109053798B (en) | 2018-07-23 | 2018-07-23 | Rhein ester derivative and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109053798A true CN109053798A (en) | 2018-12-21 |
| CN109053798B CN109053798B (en) | 2020-11-17 |
Family
ID=64836141
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810814627.9A Active CN109053798B (en) | 2018-07-23 | 2018-07-23 | Rhein ester derivative and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109053798B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111732565A (en) * | 2020-07-28 | 2020-10-02 | 遵义医科大学 | Osthole ester compound and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5330981A (en) * | 1991-05-03 | 1994-07-19 | Istituto Gentili S.P.A. | Arylalkyl esters of 4,5-dihydroxy-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid having therapeutical activity |
| US5362750A (en) * | 1990-12-11 | 1994-11-08 | Istituto Gentili S.P.A. | 4,5-dihydroxy- and 4,5,8-trihydroxy- 9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid dicarbonates and urethans having therapeutical activities |
| CN101475484A (en) * | 2009-01-05 | 2009-07-08 | 东南大学 | Synthesizing method and use of bone-targeted antiphlogistic medicament |
| CN102775291A (en) * | 2012-08-02 | 2012-11-14 | 四川大学 | Emodin derivative and application thereof in preparing antibacterial agents |
| CN108285469A (en) * | 2018-03-15 | 2018-07-17 | 遵义医学院 | A kind of anti-microbial type Carbostyril derivative and its preparation method and application |
-
2018
- 2018-07-23 CN CN201810814627.9A patent/CN109053798B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5362750A (en) * | 1990-12-11 | 1994-11-08 | Istituto Gentili S.P.A. | 4,5-dihydroxy- and 4,5,8-trihydroxy- 9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid dicarbonates and urethans having therapeutical activities |
| US5330981A (en) * | 1991-05-03 | 1994-07-19 | Istituto Gentili S.P.A. | Arylalkyl esters of 4,5-dihydroxy-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid having therapeutical activity |
| CN101475484A (en) * | 2009-01-05 | 2009-07-08 | 东南大学 | Synthesizing method and use of bone-targeted antiphlogistic medicament |
| CN102775291A (en) * | 2012-08-02 | 2012-11-14 | 四川大学 | Emodin derivative and application thereof in preparing antibacterial agents |
| CN108285469A (en) * | 2018-03-15 | 2018-07-17 | 遵义医学院 | A kind of anti-microbial type Carbostyril derivative and its preparation method and application |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111732565A (en) * | 2020-07-28 | 2020-10-02 | 遵义医科大学 | Osthole ester compound and application thereof |
| CN111732565B (en) * | 2020-07-28 | 2022-09-13 | 遵义医科大学 | Osthole ester compound and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109053798B (en) | 2020-11-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1072112A (en) | Benzylidene derivatives | |
| CN113336705B (en) | Cannabidiol-2-imidazole-1-formate and application thereof | |
| WO2017175064A1 (en) | Bioenzymatic synthesis of tetrahydrocannabivarin (thc-v), cannabinol (cbn), and cannabivarin (cbv) and their use as therapeutic agents | |
| WO2015180485A1 (en) | Amantadine nitrate compound having a neuroprotective effect and preparation and medical use thereof | |
| Maitra et al. | First asymmetric synthesis of the Troger's base unit on a chiral template | |
| CN103601768B (en) | A kind of preparation method of amikacin | |
| CN113735709B (en) | Cannabidiol-2-butyrate and application thereof | |
| EP3611170B1 (en) | Deuterated compounds and medical use thereof as antianxiety agents | |
| CN114292249B (en) | Cannabidiol-2-piperazinoate and application thereof | |
| Yin et al. | Violaceimides A–E, sulfur-containing metabolites from a sponge-associated fungus Aspergillus violaceus | |
| WO2014012495A1 (en) | Chiral α-methylene-β-lactam compound and preparation method and application thereof | |
| CN109053798A (en) | A kind of rheum officinale acid ester derivant and the preparation method and application thereof | |
| CN114315823A (en) | Intermediate of berberine hydrochloride and analogue thereof and preparation method thereof | |
| WO2023116193A1 (en) | Method for preparing antibacterial antioxidant and use thereof | |
| CN101591316B (en) | Homoisoflavone, dihydrohomoisoflavone and homoisoflavane derivatives and application thereof | |
| CN111808062B (en) | Osthole sulfonate compound and application thereof | |
| CN114292241A (en) | Cannabidiol-2-dioxopiperazinoate and application thereof | |
| US6545149B2 (en) | Synthesis and crystallization of piperazine ring-containing compounds | |
| CN101759716A (en) | Preparation method for water-soluble pleuromutilin compound and intermediate thereof | |
| CN112174870B (en) | Preparation method and medicinal application of (R) -1-alkanoyl-2-substituted pyrrolidine-2-carboxamide | |
| CN114907228B (en) | Colchicine and magnolol compound, synthesis method thereof and application thereof in resisting new coronaviruses | |
| JP2021535927A (en) | GABAA receptor allosteric enhancing compound and its preparation and application | |
| CN108285469A (en) | A kind of anti-microbial type Carbostyril derivative and its preparation method and application | |
| CN113214199B (en) | Synthetic method of benzofuran-3-oxocarboxylate compound | |
| CN113248465B (en) | Synthetic method of biochanin A |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: 563000 Dalian Road, Guizhou, China, No. 201, No. Applicant after: ZUNYI MEDICAL University Address before: 563000 No. 201 Dalian Road, Huichuan District, Zunyi City, Guizhou Province Applicant before: ZUNYI MEDICAL University |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |