CN106565564A - Pleuromutilin derivative with 2-amino phenyl mercaptan side chain and preparing method and application of pleuromutilin derivative - Google Patents
Pleuromutilin derivative with 2-amino phenyl mercaptan side chain and preparing method and application of pleuromutilin derivative Download PDFInfo
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- CN106565564A CN106565564A CN201610876597.5A CN201610876597A CN106565564A CN 106565564 A CN106565564 A CN 106565564A CN 201610876597 A CN201610876597 A CN 201610876597A CN 106565564 A CN106565564 A CN 106565564A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
Abstract
The invention belongs to the field of medicinal chemistry and discloses a pleuromutilin derivative with a 2-amino phenyl mercaptan side chain and a preparing method and application of the pleuromutilin derivative. The compound has the structures shown in formula 2 and formula 3, wherein R1, R2 and R3 are respectively and independently selected from the hydrogen atom, the hydroxyl, the amino, the sulfydryl, the hydroxymethyl, the amine methyl, the nitro, the halogen, the trihalogenated methyl, the methyl, the natural amino acid acylamino and the C1-6 alkoxy. The pleuromutilin derivative with the 2-amino phenyl mercaptan side chain has good activity for inhibiting the drug resistant staphylococcus aureus and the mycoplasma and is particularly suitable for serving as a novel antibacterial medicine for preventing infectious diseases caused by the human or animal mycoplasma or drug resistant staphylococcus aureus or multidrug resistant bacteria.
Description
Technical field
The invention belongs to medicinal chemistry art, more particularly to a kind of pleuromutilin with 2- aminobenzene mercapto alcohol side chains spreads out
Biology and its production and use.
Background technology
Methicillin-resistant staphylococcus aureus (MRSA) are that a kind of Epidemic Scope is wide, pathogenicity strong, sickness rate and death
The high pathogen of rate.Human body can cause heating once infecting, spirit poor, local infection symptom, most commonly pulmonary infection,
Such as skin, urinary tract, puerpera's reproductive tract infection, severe one is septicemia for other, extends length of patient stay, such as treatment not in time,
The life of patient can be jeopardized.The investigation of Dutch one in 2003 shows in slaughter pigs that about 39% contains ST398 types MRSA, 27%
Keeper carries pig source MRSA.Animal sources MRSA ST398 can cause the human infection with animal contact.MRSA is to all β
Lactam antibioticses drug resistance, and to the antibacterials such as Macrolide, aminoglycoside, fluoroquinolones majority drug resistance, lead
Caused by causing the bacterium, treatment of infection is difficult, and case fatality rate is high.
Pleuromutilin (formula 1) is by higher funguses Pleurotusmutiliz (Fr.) Sacc. and Pleurotus
Passeckeranius Pilat are produced, and close a kind of tricyclic diterpene compound of (5-6-8) three ring with a pair of horses going side by side.Such compound with
Ribosome 50S subunits interact and suppress bacterioprotein synthesis.To drug resistance gram positive bacteria, drug resistance mycoplasma and part
Gram negative bacteria has very strong antibacterial activity.Pleuromulins compound is with different from clinical common antimicrobial drug parent nucleus knot
Cross resistance is not likely to produce between structure, with other structures class antimicrobial drug.By the transformation to pleuromutilin C14 side chains, mesh
Front existing taimulin (Tiamulin) and two pleuromulins of valnemulin (Valnemulin) antimicrobial drug for animals are entered
Market.
His wonderful woods (retapamulin) auspicious passed through U.S. in 2007 with pleuromulins antibacterials as first man
State FDA examination ＆ approval listings.It is mainly used in the treatment of the dermatitis impetiginosa that staphylococcus aureuses and streptococcus pyogeness infection cause.It is auspicious
He is respectively provided with well in interior multiple drug-resistant bacteria to clinical common antimicrobial drug such as oxazacillin, erythromycin, Mupirocin etc. wonderful woods
Antibacterial activity, they also have found that his wonderful woods auspicious, compared with traditional antimicrobial drug, is less susceptible to cause the drug resistance of staphylococcus aureuses
Property.
As the mechanism of action of pleuromulins compound is different from the antibiotic of current wide clinical application, therefore it is directed to
The fastbacteria of pleuromulins antimicrobial drug is still rare.With with penicillin, cephalosporin, xacin-series antimicrobial drug, based on same
The medicine that parent nucleus is succeeded in developing is compared for tens of kinds easily, only successfully develops three kinds of antimicrobial drugs based on pleuromutilin, and the present invention will
There is provided class formation novelty, antibacterial activity strong new pleuromulins compound.
The content of the invention
In order to solve above-mentioned the shortcomings of the prior art, the primary and foremost purpose of the present invention is to provide one kind to have
The pleuromutilin derivative of 2- aminobenzene mercapto alcohol side chains.
Another object of the present invention is to provide the above-mentioned pleuromutilin derivative with 2- aminobenzene mercapto alcohol side chains
Preparation method.
It is yet a further object of the present invention to provide a kind of pharmaceutical composition, which includes above-mentioned 2- aminobenzenes mercapto alcohol side chain
Pleuromutilin derivative is used as active component；
A further object of the present invention is the pleuromutilin derivative for providing above-mentioned 2- aminobenzenes mercapto alcohol side chain in system
Standby treatment infectious disease is particularly the infection that Jing mycoplasmas or resistant Staphylococcus aureus or Multidrug resistant bacteria sense cause
Purposes in the medicine of property disease.
The purpose of the present invention is realized by following technical proposals：
A kind of pleuromutilin derivative with 2- aminobenzene mercapto alcohol side chains, the pleuromutilin derivative are that have such as
The compound and its officinal salt of formula 2 and structure shown in formula 3：
Wherein, R1For hydrogen atom, hydroxyl, amino, sulfydryl, methylol, amine methyl, nitro, halogen, trihalomethyl group, first
One kind in base, natural amino acid acylamino- and alkoxyl that carbon number is 1～6；
R2For hydrogen atom, hydroxyl, amino, sulfydryl, methylol, amine methyl, nitro, halogen, trihalomethyl group, methyl, day
Right one kind in aminoacid acylamino- and alkoxyl that carbon number is 1～6；
R3For hydrogen atom, hydroxyl, amino, sulfydryl, methylol, amine methyl, nitro, halogen, trihalomethyl group, methyl, day
Right one kind in aminoacid acylamino- and alkoxyl that carbon number is 1～6.
Preferably, R1For hydrogen, hydroxyl, amino, methylol, amine methyl, fluorine, trifluoromethyl, nitro, trifluoromethyl, methoxy
One kind in base, ethyoxyl, prolinamidyl and valyl amino；
R2For hydrogen, hydroxyl, amino, methylol, amine methyl, fluorine, trifluoromethyl, nitro, trifluoromethyl, methoxyl group, ethoxy
One kind in base, prolinamidyl and valyl amino；
R3For hydrogen, hydroxyl, amino, methylol, amine methyl, fluorine, trifluoromethyl, nitro, trifluoromethyl, methoxyl group, ethoxy
One kind in base, prolinamidyl and valyl amino.
Term " halogen " represents fluorine, chlorine, bromine, iodine.
More preferred, the R1For methyl, R2For hydrogen atom, R3For hydrogen atom；
Or R1For hydrogen atom, R2For methyl, R3For hydrogen atom；
Or R1For hydrogen atom, R2For hydrogen atom, R3For methyl；
Or R1For fluorine atom, R2For hydrogen atom, R3For hydrogen atom；
Or R1For hydrogen atom, R2For fluorine atom, R3For hydrogen atom；
Or R1For hydrogen atom, R2For hydrogen atom, R3For fluorine atom；
Or R1For chlorine atom, R2For hydrogen atom, R3For hydrogen atom；
Or R1For hydrogen atom, R2For chlorine atom, R3For hydrogen atom；
Or R1For hydrogen atom, R2For hydrogen atom, R3For chlorine atom；
Or R1For methoxyl group, R2For hydrogen atom, R3For hydrogen atom；
Or R1For hydrogen atom, R2For first hydrogen-based, R3For hydrogen atom；
Or R1For hydrogen atom, R2For hydrogen atom, R3For methoxyl group.
Above-mentioned optimal way can also be as shown in table 1：
1 representative compound 1-12 structural formula of the present invention of table
The officinal salt is with such as formula 2 and the compound of structure shown in formula 3, with hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid,
Phosphoric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, malic acid, methanesulfonic acid, ethyl sulfonic acid, benzene sulphur
The salt that acid, toluenesulfonic acid, glutamic acid or aspartic acid are formed.
Preferably, in formula 2 of the invention and the compound shown in formula 3 compound of part of representative it is pharmaceutically acceptable
Salt structural formula is as shown in table 2：
The officinal salt of 2 part of compounds of table
The preparation method of the above-mentioned pleuromutilin derivative with 2- aminobenzene mercapto alcohol side chains, including following operation step
Suddenly：
(1) pleuromutilin is reacted with paratoluensulfonyl chloride, obtains the intermediate I of structure as shown in Equation 4；
(2) using intermediate I as raw material, by further activating with sodium iodide reaction, then with 2- amino benzenethiols in alkali
Property under the conditions of react, obtain the intermediate II of structure as shown in Equation 3；
(3) using intermediate II as raw material, and each substituted benzoyl acid reaction, obtain structure as shown in Equation 2 with 2- ammonia
The pleuromulins compound of base benzene mercapto alcohol side chain.
Step (1) reaction is, as solvent, to react 3 hours under the conditions of 0 DEG C using pyridine；The tolysulfonyl
Chlorine is 1.1 with pleuromutilin mol ratio：1.
Step (2) reaction is, as solvent, intermediate I to be dissolved in non-protonic solvent first using non-protonic solvent
In, solvent load is 30 times of intermediate I quality, adds anhydrous sodium iodide, is heated to reflux 1 hour, wherein intermediate I and nothing
Water sodium iodide mol ratio is 1：1.1；Before the reaction, first will be 2- amino benzenethiol and alkali soluble in water, then with activation gained
Product is heated to reflux 2 hours together, and wherein intermediate I and 2- amino benzenethiols mol ratio are 1：1.1,2- amino benzenethiols and alkali
Mol ratio is 1：2；The alkali is sodium hydroxide, potassium hydroxide, Cesium hydrate., sodium carbonate, potassium carbonate or cesium carbonate；The non-matter
Sub- property solvent is N,N-dimethylformamide.
Step (3) reaction adds substituted benzoic acid using aprotic solvent as solvent, in urging for condensing agent and alkali
Under change, condensation reaction 1-36 hours are carried out at 0-70 DEG C with intermediate II, heated and stirred reaction obtains final product target product, recrystallization
Or column chromatography purification；Wherein, the aprotic solvent be dichloromethane, ethyl acetate, DMF, N, N- diformazans
Yl acetamide, pyridine；The condensing agent be methylchloroformate, ethyl chloroformate, isobutylchloroformate, carbonyl dimidazoles (CDI),
Sulfonic acid chloride, Boc anhydride, N, N- dicyclohexylcarbodiimides (DCC), 6- Chloro-Benzotriazole -1,1,3,3- tetramethylurea hexafluoro
Phosphate ester (HCTU), O- BTA-N, (7- aoxidizes three nitrogen of benzo for N, N', N'- tetramethylurea Tetrafluoroboric acid (TBTU), 2-
Azoles)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU), 1- (3- dimethylaminopropyls) -3- ethyl carbodiimides
(EDC), 1- hydroxyls-BTA (HOBt) or 1H- benzotriazole -1- base oxygen tripyrrole alkyl hexafluorophosphates
(PyBOP), oxalyl chloride or thionyl chloride；The alkali is pyridine, triethylamine, morpholine, N-methylmorpholine or N, N- diisopropyl second
Amine (DIEA).
Synthetic route is shown below：
A kind of pharmaceutical composition, pharmaceutical composition contain the above-mentioned pleuromutilin with 2- aminobenzene mercapto alcohol side chains and spread out
Biology is used as active component.
The above-mentioned pleuromutilin derivative with 2- aminobenzene mercapto alcohol side chains is in treatment infectious disease medicament is prepared
Purposes, it is characterised in that：The infectious disease is human or animal Jing mycoplasmas or resistant Staphylococcus aureus or many
The infectious disease that medicine drug-fast bacteria infection causes.
Hinge structure of the present invention, has the following advantages and beneficial effect：The pleuromulins that the present invention is provided
Compound is the new type compound of reported first.The present inventor has synthesized a large amount of compounds through extensively in-depth study
And extensive bioactivity screening has been carried out, and find that formula 2 and 3 compound of formula have good antibacterial activity in vitro first, it is special
It is not suitable as novel antibacterial medicine and infects for animal or people's whole body system.
Specific embodiment
With reference to embodiment, the present invention is described in further detail, but embodiments of the present invention not limited to this.
With reference to embodiment, the present invention is described in further detail, but embodiments of the present invention not limited to this.
Obtained by following embodiments 1-12, the numbering of compound is as shown in claims.
Intermediate I prepares embodiment：
Pleuromutilin 5.4g (14.27mmol) is dissolved in 30ml pyridines, and ice bath adds paratoluensulfonyl chloride to 0 DEG C or so
8.6g(45.11mmol).Add 50ml frozen water that reaction is quenched after ice bath stirring reaction 3h.Pour reactant liquor into separatory funnel, first
Plus the layering of 50ml chloroforms, water phase of going out, after organic faciess 2 times are washed with the sulfuric acid solution 100ml that concentration is 2mol/L, then use saturation
Sodium bicarbonate solution 50ml washings organic faciess 2 times, last deionized water 100ml washing organic faciess 2 times simultaneously use anhydrous sodium sulfate
It is dried.Rotary evaporation does organic faciess, and 10ml isopropanols heating for dissolving are added toward residual solid, and a large amount of whites are separated out after cooling
Powder, reduce pressure sucking filtration, and much filtrate is washed with isopropanol, and product as white powder remaining liq evaporates into drying naturally, obtains white powder
End is intermediate I, yield 88.84%.
(13) 3 compound of formula, compound prepare embodiment to intermediate II：
Intermediate I 1g (1.88mmol) is dissolved in 35ml ethyl acetate, adds anhydrous sodium iodide 0.31g (2.07mmol), and 70
DEG C or so heated and stirred reaction 1h.Take 2- amino benzenethiol 0.25g (2.04mmol) to be placed in 10ml water, add toward aqueous solution
Sodium hydroxide 0.08g (2.04mmol), above-mentioned aqueous solution is added in reaction system, and 70 DEG C or so heated and stirred react 2h.Will
Reactant liquor is poured in separatory funnel, plus 30ml chloroform extractions, takes organic faciess.Gained organic faciess rotation is evaporated to obtain mixture Jing dichloros
Methane redissolves, and adds 100-200 mesh silica gel 1g to be sufficiently mixed, after solvent is evaporated completely, by above-mentioned crude product-silica gel powder mixture
With column chromatography cross post purification (200～300 mesh silica whites be fixing phase, petroleum ether：Ethyl acetate=1：2 is mobile phase), obtain
The sterling of the product Intermediate II of structure as shown in Equation 3.Yield 81.22%.
Embodiment 1：22-O- [2- (2- toluyl amidos) phenyl] the wonderful woods of sulfur acetyl group (compound 1) synthesizes
Intermediate II 0.82g (1.88mmol) is dissolved in 35ml ethyl acetate, adds 2- ar-Toluic acids (2.07mmol), grass
Acyl chlorides 2.07mmol, 70 DEG C or so heated and stirred react 1h, obtain final product target product.Gained mixed solution rotation is evaporated to obtain mixture
Jing dichloromethane redissolves, and adds 100-200 mesh silica gel 1g to be sufficiently mixed, after solvent is evaporated completely, by above-mentioned crude product-silica white
Mixture column chromatography cross post purification (200～300 mesh silica whites be fixing phase, petroleum ether：Ethyl acetate=1：1 is flowing
Phase), obtain the sterling of product 22-O- [2- (2- toluyl amidos) phenyl] the wonderful woods of sulfur acetyl group (compound 1).Yield
86.55%.HR-MS(ESI):Cal:604.3091；Found:604.3117.
Embodiment 2：22-O- [2- (3- toluyl amidos) phenyl] the wonderful woods of sulfur acetyl group (compound 2) synthesizes
Intermediate II 0.82g (1.88mmol) is dissolved in 35ml dichloromethane, adds 3- ar-Toluic acids (2.07mmol), chlorine
T-butyl formate 2.07mmol, 70 DEG C or so heated and stirred react 1h, obtain final product target product.Gained mixed solution rotation is evaporated
Mixture Jing dichloromethane redissolve, add 100-200 mesh silica gel 1g be sufficiently mixed, after solvent is evaporated completely, by above-mentioned crude product-
Silica gel powder mixture column chromatography cross post purification (200～300 mesh silica whites be fixing phase, petroleum ether：Ethyl acetate=1：1 is
Mobile phase), obtain the sterling of product 22-O- [2- (3- toluyl amidos) phenyl] the wonderful woods of sulfur acetyl group (compound 2).Produce
Rate 85.75%.HR-MS(ESI):Cal:604.3091；Found:604.3110.
Embodiment 3：22-O- [2- (4- toluyl amidos) phenyl] the wonderful woods of sulfur acetyl group (compound 3) synthesizes
Intermediate II 0.82g (1.88mmol) is dissolved in 35ml dichloromethane, adds 4- ar-Toluic acids (2.07mmol), and two
Chlorine sulfoxide 2.07mmol, 70 DEG C or so heated and stirred react 1h, obtain final product target product.Gained mixed solution rotation is evaporated and must mix
Thing Jing dichloromethane redissolves, and adds 100-200 mesh silica gel 1g to be sufficiently mixed, after solvent is evaporated completely, by above-mentioned crude product-silica gel
Powder mixture column chromatography cross post purification (200～300 mesh silica whites be fixing phase, petroleum ether：Ethyl acetate=1：1 is flowing
Phase), obtain the sterling of product 22-O- [2- (4- toluyl amidos) ethyl] the wonderful woods of sulfur acetyl group (compound 3).Yield
83.09%.HR-MS(ESI):Cal:604.3091；Found:604.3110.
Embodiment 4：22-O- [2- (2- fluorobenzoyl amidos) phenyl] the wonderful woods of sulfur acetyl group (compound 4) synthesizes
Intermediate II 0.82g (1.88mmol) is dissolved in 35ml DMFs, adds 2- fluobenzoic acids
2.06mmol, 1H- benzotriazole -1- base oxygen tripyrrole alkyl hexafluorophosphate 2.06mmol, DIPEA
6mmol, 70 DEG C or so heated and stirred react 1h, obtain final product target product.Gained mixed solution rotation is evaporated to obtain mixture Jing dichloros
Methane redissolves, and adds 100-200 mesh silica gel 1g to be sufficiently mixed, after solvent is evaporated completely, by above-mentioned crude product-silica gel powder mixture
With column chromatography cross post purification (200～300 mesh silica whites be fixing phase, petroleum ether：Ethyl acetate=1：1 is mobile phase), obtain
The sterling of product 22-O- [2- (2- fluorobenzoyl amidos) phenyl] the wonderful woods of sulfur acetyl group (compound 4).Yield 91.47%.HR-
MS(ESI):Cal:608.2840；Found:608.2867.
Embodiment 5：22-O- [2- (3- fluorobenzoyl amidos) phenyl] the wonderful woods of sulfur acetyl group (compound 5) synthesizes
Intermediate II 0.82g (1.88mmol) is dissolved in 35ml ethyl acetate, adds 3- fluobenzoic acids (2.06mmol), 6- chlorine
BTA -1,1,3,3- tetramethylurea hexafluorophosphoric acid ester 2.06mmol, triethylamine 6mmol, 70 DEG C or so heated and stirred are anti-
1h is answered, target product is obtained final product.Gained mixed solution rotation is evaporated to obtain the redissolution of mixture Jing dichloromethane, adds 100-200 mesh silicon
Glue 1g is sufficiently mixed, after solvent is evaporated completely, by above-mentioned crude product-silica gel powder mixture column chromatography cross post purification (200～
300 mesh silica whites be fixing phase, petroleum ether：Ethyl acetate=1：1 is mobile phase), obtain product 22-O- [2- (3- fluorobenzoyls
Amido) phenyl] the wonderful woods of sulfur acetyl group (compound 5) sterling.Yield 87.39%.HR-MS(ESI):Cal:608.2840；
Found:608.2856。
Embodiment 6：22-O- [2- (4- fluorobenzoyl amidos) phenyl] the wonderful woods of sulfur acetyl group (compound 6) synthesizes
Intermediate II 0.82g (1.88mmol) is dissolved in 35ml dichloromethane, adds 4- fluobenzoic acids (2.06mmol), carbonyl
Diimidazole 2.06mmol, is stirred at room temperature reaction 1h, obtains final product target product.Gained mixed solution rotation is evaporated to obtain mixture Jing dichloros
Methane redissolves, and adds 100-200 mesh silica gel 1g to be sufficiently mixed, after solvent is evaporated completely, by above-mentioned crude product-silica gel powder mixture
With column chromatography cross post purification (200～300 mesh silica whites be fixing phase, petroleum ether：Ethyl acetate=1：1 is mobile phase), obtain
The sterling of product 22-O- [2- (4- fluorobenzoyl amidos) phenyl] the wonderful woods of sulfur acetyl group (compound 6).Yield 84.91%.HR-
MS(ESI):Cal:608.2840；Found:608.2836.
Embodiment 7：22-O- [2- (2- chloro-benzoyl aminos) phenyl] the wonderful woods of sulfur acetyl group (compound 7) synthesizes
Intermediate II 0.82g (1.88mmol) is dissolved in 35ml ethyl acetate, adds 2- chlorobenzoic acid 2.06mmol, 1- (3-
Dimethylaminopropyl) -3- ethyl carbodiimides 2.06mmol, 50 DEG C of heated and stirred react 1h, obtain final product target product.Gained is mixed
Close solution rotating and be evaporated to obtain the redissolution of mixture Jing dichloromethane, add 100-200 mesh silica gel 1g to be sufficiently mixed, treat that solvent is evaporated completely
Afterwards, by above-mentioned crude product-silica gel powder mixture column chromatography cross post purification (200～300 mesh silica whites be fixing phase, petroleum ether：
Ethyl acetate=1：1 is mobile phase), obtain product 22-O- [2- (2- chloro-benzoyl aminos) phenyl] wonderful woods (chemical combination of sulfur acetyl group
Thing sterling 7).Yield 87.86%.HR-MS(ESI):Cal:624.2545；Found:624.2575.
Embodiment 8：22-O- [2- (3- chloro-benzoyl aminos) phenyl] the wonderful woods of sulfur acetyl group (compound 8) synthesizes
Intermediate II 0.82g (1.88mmol) is dissolved in 35ml DMFs, adds 3- chlorobenzoic acids
2.06mmol, N, N- dicyclohexylcarbodiimide 2.06mmol, 25 DEG C of heated and stirred react 1h, obtain final product target product.Gained is mixed
Close solution rotating and be evaporated to obtain the redissolution of mixture Jing dichloromethane, add 100-200 mesh silica gel 1g to be sufficiently mixed, treat that solvent is evaporated completely
Afterwards, by above-mentioned crude product-silica gel powder mixture column chromatography cross post purification (200～300 mesh silica whites be fixing phase, petroleum ether：
Ethyl acetate=1：1 is mobile phase), obtain product 22-O- [2- (3- chloro-benzoyl aminos) phenyl] wonderful woods (chemical combination of sulfur acetyl group
Thing sterling 8).Yield 85.04%.HR-MS(ESI):Cal:624.2545；Found:624.2562.
Embodiment 9：22-O- [2- (4- chloro-benzoyl aminos) phenyl] the wonderful woods of sulfur acetyl group (compound 9) synthesizes
Intermediate II 0.82g (1.88mmol) is dissolved in 35ml N,N-dimethylacetamide, adds 4- chlorobenzoic acids
2.06mmol, carbonyl dimidazoles 2.06mmol, 30 DEG C or so heated and stirred react 1h, obtain final product target product.Gained mixed solution
Rotation is evaporated to obtain the redissolution of mixture Jing dichloromethane, adds 100-200 mesh silica gel 1g to be sufficiently mixed, after solvent is evaporated completely, will
Above-mentioned crude product-silica gel powder mixture column chromatography cross post purification (200～300 mesh silica whites be fixing phase, petroleum ether：Acetic acid
Ethyl ester=1：1 is mobile phase), obtain product 22-O- [2- (4- chloro-benzoyl aminos) phenyl] the wonderful woods of sulfur acetyl group (compound 9)
Sterling.Yield 89.66%.HR-MS(ESI):Cal:624.2545；Found:624.2540.
Embodiment 10：22-O- [2- (2- methoxy benzamide bases) phenyl] the wonderful woods of sulfur acetyl group (compound 10) synthesizes
Intermediate II 0.82g (1.88mmol) is dissolved in 35ml ethyl acetate, adds 2-methoxybenzoic acid 2.05mmol, chlorine
Methyl formate 2.05mmol, morpholine 2.5mmol, 25 DEG C of stirring reactions 1h, obtain final product target product.Gained mixed solution rotation is evaporated
Obtain mixture Jing dichloromethane to redissolve, add 100-200 mesh silica gel 1g to be sufficiently mixed, after solvent is evaporated completely, by above-mentioned thick product
Thing-silica gel powder mixture column chromatography cross post purification (200～300 mesh silica whites be fixing phase, petroleum ether：Ethyl acetate=1：1
For mobile phase), obtain the pure of product 22-O- [2- (2- methoxy benzamide bases) phenyl] the wonderful woods of sulfur acetyl group (compound 10)
Product.Yield 92.24%.HR-MS(ESI):Cal:620.3040；Found:620.3037.
Embodiment 11：22-O- [2- (3- methoxy benzamide bases) phenyl] the wonderful woods of sulfur acetyl group (compound 11) synthesizes
Intermediate II 0.82g (1.88mmol) is dissolved in 35ml DMFs, adds 3- methoxybenzoic acids
2.05mmol, O- BTA-N, N, N', N'- tetramethylurea Tetrafluoroboric acid 2.05mmol, N-methylmorpholine 6mmol, 0 DEG C
Stirring reaction 3h, obtains final product target product.Gained mixed solution rotation is evaporated to obtain the redissolution of mixture Jing dichloromethane, adds 100-
200 mesh silica gel 1g are sufficiently mixed, and after solvent is evaporated completely, above-mentioned crude product-silica gel powder mixture column chromatography are crossed post purification
(200～300 mesh silica whites be fixing phase, petroleum ether：Ethyl acetate=1：1 is mobile phase), obtain product 22-O- [2- (3- first
Oxybenzamide base) phenyl] the wonderful woods of sulfur acetyl group (compound 11) sterling.Yield 94.82%.HR-MS(ESI):Cal:
620.3040；Found:620.3062.
Embodiment 12：22-O- [2- (4- methoxy benzamide bases) phenyl] the wonderful woods of sulfur acetyl group (compound 12) synthesizes
Intermediate II 0.82g (1.88mmol) is dissolved in 35ml ethyl acetate, adds 4- methoxybenzoic acid 2.05mmol, chlorine
Ethyl formate 2.05mmol, 70 DEG C of heated and stirred react 36h, obtain final product target product.Gained mixed solution rotation is evaporated and must mix
Thing Jing dichloromethane redissolves, and adds 100-200 mesh silica gel 1g to be sufficiently mixed, after solvent is evaporated completely, by above-mentioned crude product-silica gel
Powder mixture column chromatography cross post purification (200～300 mesh silica whites be fixing phase, petroleum ether：Ethyl acetate=1：1 is flowing
Phase), obtain the sterling of product 22-O- [2- (4- methoxy benzamide bases) phenyl] the wonderful woods of sulfur acetyl group (compound 12).Produce
Rate 87.07%.HR-MS(ESI):Cal:620.3040；Found:620.3067.
EXPERIMENTAL EXAMPLE：Antibacterial experiment in vitro
Experimental technique
The minimal inhibitory concentration (MIC) of the series compound of present invention gained, experiment are determined using Double broth dilution method
Control drug selects valnemulin, and valnemulin is pleuromulins antibiotic, is to be widely used in such antibiotic at present
Veterinary antibiotic.Bacterium solution is seeded in the culture dish containing variable concentrations medicine using multi-point inoculator, quantity of microorganism inoculated is
106CFU/ml.37 DEG C incubation 24 hours after observe result, using the compound concentration in the culture dish of not long bacterium as the compound
Minimal inhibitory concentration (MIC).
In experiment, bacterial strain used is escherichia coli ATCC25922, staphylococcus aureuses ATCC29213, resistance to methoxy west
Woods staphylococcus aureuses ATCC43300, chicken virus mycoplasma S6.
Precision weighs the target compound synthesized by 25.6mg, is placed in the volumetric flask of 10mL, first uses a small amount of N, N- diformazans
After base formyl amine solvent, then 10mL is settled to DMF, be made into the storing solution of 2560 μ g/mL.Another essence respectively
It is close to weigh 25.6mg pleuromutilins, taimulin, valnemulin, his wonderful woods auspicious, it is placed in 10ml volumetric flasks, N, N- dimethyl
Methanamide dilutes and is settled to 10mL, is made into the control storing solution of 2560 μ g/mL.
Storing solution is diluted in culture dish with coubling dilution, each culture dish 1ml containing medicinal liquid, with the MH agar for melting
20ml is diluted to, makes the final concentration of test-compound in serial culture ware be respectively 64,32,16,8,4,2,1,0.5,0.25,
0.125,0.0625 μ g/ml.
Table 3 below is MIC results.
3 In Vitro Bacteriostasis data of table
Target complete compound shows preferable antibacterial activity to staphylococcus aureuses, and most compounds are to golden yellow
Staphylococcuses and methicillin-resistant staphylococcus aureus antibacterial activity are close to or better than clinically widely used taimulin
(tiamulin), compound 13 is substantially better than to staphylococcus aureuses and methicillin-resistant staphylococcus aureus antibacterial activity
At present clinically widely used valnemulin (valnemulin) and his wonderful woods (retapamulin) auspicious.
Above-described embodiment is the present invention preferably embodiment, but embodiments of the present invention not by above-described embodiment
Limit, other any spirit without departing from the present invention and the change, modification, replacement made under principle, combine, simplification,
Equivalent substitute mode is should be, is included within protection scope of the present invention.
Claims (10)
1. a kind of pleuromutilin derivative with 2- aminobenzene mercapto alcohol side chains, it is characterised in that：The pleuromutilin derives
Thing is with such as formula 2 and the compound and its officinal salt of structure shown in formula 3：
Wherein, R1For hydrogen atom, hydroxyl, amino, sulfydryl, methylol, amine methyl, nitro, halogen, trihalomethyl group, methyl, day
Right one kind in aminoacid acylamino- and alkoxyl that carbon number is 1～6；
R2For hydrogen atom, hydroxyl, amino, sulfydryl, methylol, amine methyl, nitro, halogen, trihalomethyl group, methyl, native amino
Sour acylamino- and carbon number are the one kind in 1～6 alkoxyl；
R3For hydrogen atom, hydroxyl, amino, sulfydryl, methylol, amine methyl, nitro, halogen, trihalomethyl group, methyl, native amino
Sour acylamino- and carbon number are the one kind in 1～6 alkoxyl.
2. a kind of pleuromutilin derivative with 2- aminobenzene mercapto alcohol side chains according to claim 1, its feature exist
In：R1For hydrogen, hydroxyl, amino, methylol, amine methyl, fluorine, trifluoromethyl, nitro, trifluoromethyl, methoxyl group, ethyoxyl, dried meat
One kind in aminoacyl amino and valyl amino；
R2For hydrogen, hydroxyl, amino, methylol, amine methyl, fluorine, trifluoromethyl, nitro, trifluoromethyl, methoxyl group, ethyoxyl, dried meat
One kind in aminoacyl amino and valyl amino；
R3For hydrogen, hydroxyl, amino, methylol, amine methyl, fluorine, trifluoromethyl, nitro, trifluoromethyl, methoxyl group, ethyoxyl, dried meat
One kind in aminoacyl amino and valyl amino.
3. a kind of pleuromutilin derivative with 2- aminobenzene mercapto alcohol side chains according to claim 1, its feature exist
In：
The R1For methyl, R2For hydrogen atom, R3For hydrogen atom；
Or R1For hydrogen atom, R2For methyl, R3For hydrogen atom；
Or R1For hydrogen atom, R2For hydrogen atom, R3For methyl；
Or R1For fluorine atom, R2For hydrogen atom, R3For hydrogen atom；
Or R1For hydrogen atom, R2For fluorine atom, R3For hydrogen atom；
Or R1For hydrogen atom, R2For hydrogen atom, R3For fluorine atom；
Or R1For chlorine atom, R2For hydrogen atom, R3For hydrogen atom；
Or R1For hydrogen atom, R2For chlorine atom, R3For hydrogen atom；
Or R1For hydrogen atom, R2For hydrogen atom, R3For chlorine atom；
Or R1For methoxyl group, R2For hydrogen atom, R3For hydrogen atom；
Or R1For hydrogen atom, R2For first hydrogen-based, R3For hydrogen atom；
Or R1For hydrogen atom, R2For hydrogen atom, R3For methoxyl group.
4. a kind of pleuromutilin derivative with 2- aminobenzene mercapto alcohol side chains according to claim 1, its feature exist
In：The officinal salt is with such as formula 2 and the compound of structure shown in formula 3, with hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid,
Acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, malic acid, methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, toluene
The salt that sulfonic acid, glutamic acid or aspartic acid are formed.
5. a kind of pleuromutilin derivative with 2- aminobenzene mercapto alcohol side chains according to any one of claim 1-4
Preparation method, it is characterised in that including following operating procedure：
(1) pleuromutilin is reacted with paratoluensulfonyl chloride, obtains the intermediate I of structure as shown in Equation 4；
(2) using intermediate I as raw material, by further activating with sodium iodide reaction, then with 2- amino benzenethiol in alkaline bar
React under part, obtain the intermediate II of structure as shown in Equation 3；
(3) using intermediate II as raw material, and each substituted benzoyl acid reaction, obtain structure as shown in Equation 2 with 2- aminobenzenes
The pleuromulins compound of mercapto alcohol side chain.
6. preparation method according to claim 5, it is characterised in that：Step (1) reaction is as molten using pyridine
Agent, reacts 3 hours under the conditions of 0 DEG C；The paratoluensulfonyl chloride is 1.1 with pleuromutilin mol ratio：1.
7. preparation method according to claim 5, it is characterised in that：Step (2) reaction is molten using aprotic
Agent is first dissolved in intermediate I in non-protonic solvent as solvent, and solvent load is 30 times of intermediate I quality, adds nothing
Water sodium iodide, is heated to reflux 1 hour, and wherein intermediate I and anhydrous sodium iodide mol ratio are 1：1.1；Before the reaction, first will
2- amino benzenethiol and alkali are soluble in water, then together with activation products therefrom are heated to reflux 2 hours, wherein intermediate I and 2- ammonia
Base benzenethiol mol ratio is 1：1.1,2- amino benzenethiols are 1 with alkali mol ratio：2；The alkali be sodium hydroxide, potassium hydroxide,
Cesium hydrate., sodium carbonate, potassium carbonate or cesium carbonate；The non-protonic solvent is N,N-dimethylformamide.
8. preparation method according to claim 5, it is characterised in that：Step (3) reaction is made using aprotic solvent
For solvent, substituted benzoic acid is added, under the catalysis of condensing agent and alkali, condensation reaction 1-36 is carried out at 0-70 DEG C with intermediate II
Hour, heated and stirred reaction obtains final product target product, recrystallization or column chromatography purification；Wherein, the aprotic solvent is dichloromethane
Alkane, ethyl acetate, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, pyridine；The condensing agent is methylchloroformate, chlorine
Ethyl formate, isobutylchloroformate, carbonyl dimidazoles, sulfonic acid chloride, Boc anhydride, N, N- dicyclohexylcarbodiimides, 6- chlorobenzenes are simultaneously
Triazole -1,1,3,3- tetramethylurea hexafluorophosphoric acid esters, O- BTA-N, N, N', N'- tetramethylurea Tetrafluoroboric acid, 2-
(7- aoxidizes BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, 1- (3- dimethylaminopropyls) -3- ethyl carbon
Diimine, 1- hydroxyls-BTA or 1H- benzotriazole -1- base oxygen tripyrrole alkyl hexafluorophosphates, oxalyl chloride or two
Chlorine sulfoxide；The alkali is pyridine, triethylamine, morpholine, N-methylmorpholine or N, N- diisopropylethylamine.
9. a kind of pharmaceutical composition, it is characterised in that：The pharmaceutical composition contains having described in any one of claim 1-4
The pleuromutilin derivative of 2- aminobenzene mercapto alcohol side chains is used as active component.
10. a kind of pleuromutilin derivative with 2- aminobenzene mercapto alcohol side chains according to any one of claim 1-4
Purposes in treatment infectious disease medicament is prepared, it is characterised in that：The infectious disease is human or animal's Jing mycoplasmas
Or the infectious disease that resistant Staphylococcus aureus or Multidrug resistant bacteria infection cause.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107417586A (en) * | 2017-06-21 | 2017-12-01 | 华南农业大学 | A kind of pleuromulins antibiotic and its preparation method and application |
| CN108929253A (en) * | 2018-07-03 | 2018-12-04 | 华南农业大学 | A kind of pleuromulins compound and its preparation method and application |
| CN109666009A (en) * | 2018-11-02 | 2019-04-23 | 华南农业大学 | One kind is using 2- aminobenzene mercapto alcohol as linking group pleuromutilin derivative preparation method and purposes |
| CN110372615A (en) * | 2019-07-08 | 2019-10-25 | 华南农业大学 | A kind of pleuromutilin derivative and preparation and application with 2- amino benzenethiol and 1,2,3- triazole side chain |
| CN113121355A (en) * | 2021-04-13 | 2021-07-16 | 陕西科技大学 | Pleuromutilin rhein ester and preparation method and application thereof |
| CN114436870A (en) * | 2021-12-21 | 2022-05-06 | 华南农业大学 | Pleuromutilin derivative with amino side chain as well as preparation method and application thereof |
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| CN107417586A (en) * | 2017-06-21 | 2017-12-01 | 华南农业大学 | A kind of pleuromulins antibiotic and its preparation method and application |
| CN108929253A (en) * | 2018-07-03 | 2018-12-04 | 华南农业大学 | A kind of pleuromulins compound and its preparation method and application |
| CN109666009A (en) * | 2018-11-02 | 2019-04-23 | 华南农业大学 | One kind is using 2- aminobenzene mercapto alcohol as linking group pleuromutilin derivative preparation method and purposes |
| CN109666009B (en) * | 2018-11-02 | 2023-02-03 | 华南农业大学 | Preparation method and application of pleuromutilin derivative by taking 2-aminobenzenethiol as connecting group |
| CN110372615A (en) * | 2019-07-08 | 2019-10-25 | 华南农业大学 | A kind of pleuromutilin derivative and preparation and application with 2- amino benzenethiol and 1,2,3- triazole side chain |
| CN110372615B (en) * | 2019-07-08 | 2023-02-03 | 华南农业大学 | Pleuromutilin derivative with 2-aminobenzenethiol and 1,2, 3-triazole side chain as well as preparation and application thereof |
| CN113121355A (en) * | 2021-04-13 | 2021-07-16 | 陕西科技大学 | Pleuromutilin rhein ester and preparation method and application thereof |
| CN114436870A (en) * | 2021-12-21 | 2022-05-06 | 华南农业大学 | Pleuromutilin derivative with amino side chain as well as preparation method and application thereof |
| WO2023115691A1 (en) * | 2021-12-21 | 2023-06-29 | 华南农业大学 | Pleuromutilin derivative with amino side chain, and preparation method therefor and use thereof |
| CN114940671A (en) * | 2022-05-10 | 2022-08-26 | 华南农业大学 | Pleuromutilin derivative with 4-aminobenzenethiol side chain as well as preparation method and application thereof |
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