CN102180809A - Salicylamide ether compounds of pleuromutilin and preparation method thereof - Google Patents
Salicylamide ether compounds of pleuromutilin and preparation method thereof Download PDFInfo
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- CN102180809A CN102180809A CN2011100550296A CN201110055029A CN102180809A CN 102180809 A CN102180809 A CN 102180809A CN 2011100550296 A CN2011100550296 A CN 2011100550296A CN 201110055029 A CN201110055029 A CN 201110055029A CN 102180809 A CN102180809 A CN 102180809A
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Abstract
The invention relates to pleuromutilin derivatives, particularly salicylamide ether compounds of pleuromutilin and a preparation method thereof. The structural formula of the salicylamide ether compounds of pleuromutilin is disclosed as a general formula I, wherein R is NHCmH2mCH3, and m is a whole number which is greater than or equal to 0. In the invention, the pleuromutilin, which is used as the raw material, is esterified, subjected to amine-ester exchange and etherified to obtain the pleuromutilin derivatives. The related pharmaceutic adjuvant groups are changed to enhance the pharmaceutic activity, thereby achieving the corresponding pharmacodynamic goal. In normal cases, most receptors are proteins or derivatives thereof; the amido group contained in the pharmaceutic molecule can promote the pharmaceutic molecule to be combined with the corresponding receptor in an easier way, thereby enhancing the pharmaceutic effect. All the pharmaceutic materials in the synthetic process are common, cheap and accessible, thereby lowering the production cost.
Description
Technical field
The present invention relates to the chemical synthetic drug field, salicylic amide ether compound of particularly a kind of pleuromutilin of pleuromutilin analog derivative and preparation method thereof.
Background technology
Pleuromutilin is to be separated and carried out preliminary evaluation in nineteen fifty-one by Kavanagh etc. at first, it is by higher fungi the pick up the ears diterpene carbapenem antibiotic of the class wide spectrum that bacterium produces of bacterium and Pa Shi of picking up the ears, can effectively suppress gram-positive microorganism, especially the most obvious with staphylococcus, suis, simultaneously therapeutic action is also arranged for mycoplasma infection, the bacteriostatic activity and the scope of its many derivatives are stronger than pleuromutilin, and antimicrobial spectrum is more extensive simultaneously.In recent years, along with G+ bacterium resistance, comprise the serious day by day of methicillin-resistant staphylococcus aureus, penicillin resistant parapneumonia coccus, vancomycin-resistant enterococcus, though commonly used antibacterials linezolid, Quinupristin/dalfopristin and impersonating draws that fixed etc. microbial infection has certain curative effect to resistance in the institute, because serious adverse effects and lower bioavailability have limited its widespread use.Therefore, exploitation has novel antibacterial mechanism, bioavailability and the be difficult for compound that produces crossing drug resistant with traditional microbiotic becomes the primary approach of containing resistant organism preferably.Pleuromutilin is as a kind of tricyclic diterpene class microbiotic, it mainly acts on the 50S ribosomal subunit, activity by the inhibiting peptide based transferase makes the protein of bacteria biosynthesis block, has unique anti-microbial activity, be difficult for producing characteristics such as crossing drug resistant, so this analog derivative becomes the antibiotic main starting point of research novel human gradually with clinical used traditional microbiotic.And on behalf of medicine Tiamulin and valnemulin, such microbiotic mainly be widely used as microbiotic for animals, particularly in April, 2007 first pleuromutilin analog derivative human microbiotic Rui Tamolin (Retapamulin) is ratified successfully listing by U.S. food drug surveilance office (FDA), realized the antibiotic leap of this compounds, started the tide of novel human pleuromutilin analog derivative research and development from microbiotic for animals to human.Therefore select pleuromutilin derivative to carry out study on the synthesis no matter be all to have bright development prospect at veterinary drug or in people's medication.
Summary of the invention
Technical problem to be solved by this invention is that a kind of salicylic amide ether compound that can be used as the pleuromutilin of microbiotic use is provided at above-mentioned prior art.
Another object of the present invention provides the preparation method of the salicylic amide ether compound of pleuromutilin.
The present invention for the solution that problem adopts of the above-mentioned proposition of solution is: the salicylic amide ether compound of pleuromutilin has the represented structural formula of general formula I:
In the formula:
R is NHC
mH
2mCH
3, m 〉=0 and be integer wherein.-C
mH
2m-structure comprises the alkyl all straight chains and that have side chain that satisfies this expression formula.
The preferred m=2 of m or 3.
The preparation method of the salicylic amide ether compound of pleuromutilin includes following steps:
1) pleuromutilin and triethylamine 1: 1 in molar ratio～10 are mixed stirring at normal temperature in solvent and obtained reaction mixture in 50～70 minutes, be cryosel bathe under to be added drop-wise in reaction mixture at 1～5: 1 more in molar ratio with methane sulfonyl chloride or Tosyl chloride and triethylamine, under cryosel is bathed, continue stirring reaction 0.5～6 hour, obtain pleuromutilin methane sulfonate or pleuromutilin p-toluenesulfonic esters;
2) be 1: 1～20 to add down catalyzer at 25～90 ℃ and in solvent, mixed stirring reaction 4～24 hours in molar ratio with Whitfield's ointment and methyl alcohol, obtain wintergreen oil;
3) in solvent with step 2) wintergreen oil of gained and amine is 1: 1～5 at 25～125 ℃ of following stirring reaction 2-24 hours in molar ratio, obtains salicylic amide;
4) in solvent with the salicylic amide 1: 1 in molar ratio～2 of the pleuromutilin methane sulfonate of gained in the step 1) or pleuromutilin P-TOLUENE SULFO ACID 99 ester and step 3) gained 25～80 ℃ of following stirring reactions 1～10 hour, obtain the salicylyl amidogen ether of pleuromutilin.
Press such scheme, the described solvent of step 1) is methylene dichloride or methyl alcohol.Will cut off water as much as possible in this process, water is bigger to the influence of reaction.
Press such scheme, step 2) described solvent is methyl alcohol, benzene or toluene.This reaction adds an amount of vitriol oil or Phenylsulfonic acid can be to reacting favourable.
Press such scheme, the described solvent of step 3) is the aqueous solution of water, amine or hexanaphthene.
Press such scheme, the described solvent of step 4) is the mixed solvent of the methylene dichloride and the NaOH aqueous solution.The molten intermediate compound IV of solvent NaOH, methylene dichloride are used for molten intermediate II, so solvent is a mixed solvent, this step is phase transfer reaction, and two-phase solvent must be mixed solvent.
Press such scheme, the general structure of the described amine of step 3) is CH
3C
mH
2mNH
2, m 〉=0 and be integer wherein.The definition of m is identical with the definition of general formula I.
Reaction process of the present invention is as follows:
Beneficial effect of the present invention is:
The effect of medicine is mainly brought into play corresponding drug effect by effective group of medicine receptors bind corresponding with it, if effectively group is bad with corresponding receptors bind effect, the activity of this medicine then can be very low even have drug effect, so thereby the present invention increases the purpose that its pharmaceutical activity reaches corresponding drug effect by changing relevant medicine prothetic group group.Usually most receptors is the protein or derivatives thereof, thereby and the amide group that contains in this drug molecule can impel easier combination of itself and corresponding acceptor to improve its drug effect.And the medicine material of this building-up process all is common and cheap, is easy to get, thereby can reduces production cost.
Description of drawings
Fig. 1 is the inhibition zone test-results figure of embodiment 1 and 2 target compounds;
Fig. 2 is the inhibition zone test-results figure of embodiment 3 target compounds;
The figure as a result that Fig. 3 tests with colony counting method;
Fig. 4 is with Fig. 3 related data, the graphic representation of the sterilizing rate of different concns sample.
Embodiment
In order to understand the present invention better, further illustrate content of the present invention below in conjunction with embodiment, but content of the present invention not only is confined to following enforcement.
Reaction process of the present invention is as follows:
Embodiment 1 when m=2 (among the target compound I):
Synthesizing of intermediate pleuromutilin methane sulfonate (II)
Step 1: the pleuromutilin of in the there-necked flask of 250ml, packing into (37.85 grams, 0.1 mole), add the 120ml methylene dichloride and make solvent, add triethylamine (12.144 grams earlier, 0.12 mole) normal temperature stirred 1 hour down, (14.31 restrain with methane sulfonyl chloride under cryosel is bathed again, 0.125 mole) slowly be added drop-wise in the reaction mixture, drip the back and continue under cryosel is bathed behind the stirring reaction 30min, under being lower than 12 ℃ condition water with reaction solution in excessive triethylamine and methane sulfonyl chloride flush away can obtain intermediate II;
Synthesizing of intermediate wintergreen oil (III)
Step 2: in the there-necked flask of 100ml, add Whitfield's ointment (20.7 grams, 0.15 mole) and methyl alcohol (24 grams, 0.75 mole) add the reaction of proper catalyst vitriol oil stirring and refluxing down after 24 hours at 60～65 ℃, wherein solvent is a methyl alcohol, and water can obtain intermediate III with unnecessary methyl alcohol in the reaction mixture and catalyzer flush away;
Synthesizing of intermediate salicylyl Tri N-Propyl Amine (IV)
Step 3: in the there-necked flask of 100ml, add intermediate III (17.02 grams, 0.112 mole) and Tri N-Propyl Amine (13.24 grams, 0.224 mole) be blended in 35～45 ℃ of following lasting stirring reactions 24 hours, wherein solvent is a Tri N-Propyl Amine, remove excessive Tri N-Propyl Amine with an amount of dilute hydrochloric acid neutralization after reaction is finished, water flush away salt wherein can obtain intermediate compound IV again.
Step 4: NaOH solution dissolved intermediate compound IV (17.02 grams that in the there-necked flask of 250ml, use 2mol/L, 0.095 (43.37 restrain mole) and with the solvent intermediate II of methylene dichloride, 0.095 mole) mix, add the proper catalyst tetra-n-butyl ammonium bromide 12～15 ℃ of 4 hours (centre intermittently add an amount of NaOH and keeps its pH value about 13) of lasting stirring reaction down, under cold condition, reaction mixture is neutralized to neutrality with appropriate hydrochloric acid solution after reaction is finished and promptly obtains the order Compound I.
Embodiment 2 (m=2 in the order Compound I):
Synthesizing of the methane sulfonate of intermediate pleuromutilin (II)
Step 1: the pleuromutilin of in the there-necked flask of 100ml, packing into (5.67 grams, 0.015 mole), add the 30ml methylene dichloride and make solvent, add triethylamine (7.59 grams earlier, 0.075 mole) normal temperature stirred 1 hour down, under cryosel is bathed methane sulfonyl chloride (8.59 grams, 0.075 mole) was added drop-wise in the reaction mixture again, drip after the back continues stirring reaction 30min, under being lower than 12 ℃ condition water with reaction solution in excessive triethylamine and methane sulfonyl chloride flush away can obtain intermediate II.
Synthesizing of intermediate wintergreen oil (III)
Step 2: in the there-necked flask of 100ml, add Whitfield's ointment (2.07 grams, 0.015 mole) and methyl alcohol (7.2 grams, 0.225 mole) add the reaction of proper catalyst vitriol oil stirring and refluxing down after 8 hours at 60～65 ℃, wherein solvent is a methyl alcohol, and water can obtain intermediate III with unnecessary methyl alcohol in the reaction mixture and catalyzer flush away;
Synthesizing of intermediate salicylyl propylamine (IV)
Step 3: in the there-necked flask of 100ml, add intermediate III (1.85 grams, 0.012 mole) and Tri N-Propyl Amine (3.54 grams, 0.06 mole) descended lasting stirring reactions 8 hours at 35～45 ℃, wherein solvent is a Tri N-Propyl Amine, remove excessive Tri N-Propyl Amine with an amount of dilute hydrochloric acid neutralization after reaction is finished, water flush away salt wherein can obtain intermediate compound IV again;
Step 4: NaOH solution dissolved intermediate compound IV (1.83 grams that in the there-necked flask of 250ml, use 2mol/L, 0.01 (4.57 restrain mole) and with the solvent intermediate II of methylene dichloride, 0.01 mole) mix, add the proper catalyst tetra-n-butyl ammonium bromide 12～15 ℃ of 4 hours (centre intermittently add an amount of NaOH and keeps its pH value about 13) of lasting stirring reaction down, under cold condition, reaction mixture is neutralized to neutrality with appropriate hydrochloric acid solution after reaction is finished and promptly obtains the order Compound I.
Embodiment 3 (m=3 in the order Compound I):
Synthesizing of the methane sulfonate of intermediate pleuromutilin (II)
Step 1: the pleuromutilin of in the there-necked flask of 250ml, packing into (37.85 grams, 0.1 mole), add the 120ml methylene dichloride and make solvent, add triethylamine (12.144 grams earlier, 0.12 mole) normal temperature stirred 1 hour down, (14.31 restrain with methane sulfonyl chloride under cryosel is bathed again, 0.125 mole) slowly be added drop-wise in the reaction mixture, drip after the back continues stirring reaction 30min, under being lower than 12 ℃ condition water with reaction solution in excessive triethylamine and methane sulfonyl chloride flush away can obtain intermediate II;
Synthesizing of intermediate wintergreen oil (III)
Step 2: in the there-necked flask of 100ml, add Whitfield's ointment (20.7 grams, 0.15 mole) and methyl alcohol (24 grams, 0.75 mole) add the reaction of proper catalyst vitriol oil stirring and refluxing down after 24 hours at 60～65 ℃, wherein solvent is a methyl alcohol, and water can obtain intermediate III with unnecessary methyl alcohol in the reaction mixture and catalyzer flush away.
Synthesizing of intermediate salicylyl n-Butyl Amine 99 (IV)
Step 3: in the there-necked flask of 100ml, add intermediate III (16.42 grams, 0.108 mole) and n-Butyl Amine 99 (15.8 grams, 0.216 mole) be blended in 50～60 ℃ of following lasting stirring reactions 24 hours, wherein solvent is a n-Butyl Amine 99, remove excessive n-Butyl Amine 99 with an amount of dilute hydrochloric acid neutralization after reaction is finished, water flush away salt wherein can obtain intermediate compound IV again.
Step 4: the lysed intermediate compound IV of NaOH (10.3 grams that in the there-necked flask of 250ml, use 2mol/L, 0.053 (24.20 restrain mole) and with the solvent intermediate II of methylene dichloride, 0.053 mole) mix, add the proper catalyst tetra-n-butyl ammonium bromide 12～15 ℃ of 4 hours (centre intermittently add an amount of NaOH and keeps its pH value about 13) of lasting stirring reaction down, under cold condition, reaction mixture is neutralized to neutrality with appropriate hydrochloric acid solution after reaction is finished and promptly obtains the order Compound I.
Embodiment 4
Order Compound I among the synthetic embodiment 2 is dissolved in 5% the DMSO aqueous solution, be mixed with the solution of 2mg/mL, is diameter the filter paper of 6mm behind high pressure steam sterilization, drops into respectively in the solution and 5% the DMSO aqueous solution of above-mentioned order Compound I, soaks behind the 2min standby.Compound concentration is 10
5The streptococcus aureus of cfu/mL (Staphylococcus aureus ATCC9118) bacterium liquid is an amount of, getting this bacterium liquid of 20 μ L spreads upon in the Luria-Bertani substratum equably, then above-mentioned processing filter paper place this substratum respectively, in 37 ℃ electro-heating standing-temperature cultivator, cultivate after 24 hours, the filter disc that soaks the order Compound I has produced obvious inhibition zone on every side, its diameter is 34.2mm, and its result is illustrated in fig. 1 shown below, unit: millimeter.Can find out clearly that from this figure this chemical combination has good bacteriostatic action.The white circle that two diameters are 6mm among the figure is a blank sample, uses in contrast.
Embodiment 5
Order Compound I among the synthetic embodiment 3 is dissolved in 5% the DMSO aqueous solution, be mixed with the solution of 2mg/mL, is diameter the filter paper of 6mm behind high pressure steam sterilization, drops into respectively in the solution and 5% the DMSO aqueous solution of above-mentioned order Compound I, soaks standby after 2 minutes.Compound concentration is 10
5The streptococcus aureus bacterium liquid of cfu/mL is an amount of, getting this bacterium liquid of 20 μ L spreads upon in the Luria-Bertani substratum equably, then above-mentioned processing filter paper place this substratum respectively, in 37 ℃ electro-heating standing-temperature cultivator, cultivate after 24 hours, the filter disc that soaks the order Compound I has produced obvious inhibition zone on every side, its diameter is 35.7mm, and its result is illustrated in fig. 2 shown below, unit: millimeter.Can find out clearly that from this figure this chemical combination has good bacteriostatic action.The white circle that two diameters are 6mm among the figure is a blank sample, uses in contrast.
Embodiment 6
Order Compound I among the synthetic embodiment 3 (following abbreviation product fourth) is tested with colony counting method.
Take out single bacterium colony with transfering loop and be dissolved in the Luria-Bertani liquid nutrient medium from culture dish, mixing under spectrophotometer, is measured its OD=0.075, and then with 1000 times of this bacterium liquid dilutions.Preparing product fourth sample concentration and be 4mg/mL. gets 13 test tubes and is put on the test-tube stand, the Luria-Bertani liquid nutrient medium that adds 2mL in each test tube, then original concentration is added 2mL in first test tube and mixing for the 4mg/mL sample, get first test tube mixing solutions 2mL in second test tube, doubling dilution to the twelve earthly branches test tube successively, 13 test tubes all add 2mL bacterium liquid (OD=0.075, and then dilute 1000 times) then.The test tube that mark is good is respectively placed on the shaking table, and 150rpm cultivated 6 hours under 37 ℃ of conditions, thereafter, got each test tube mixed bacteria liquid 0.1mL respectively and was coated with plate, and mark is placed on 37 ℃ of incubators and cultivated 24 hours, the counting bacterium colony, and its result is illustrated in fig. 3 shown below.1,2,3,4,5 these five all bacteriums of pilot region all are killed, and illustrate that it not only has anti-microbial activity as can be seen from this figure, but reach an also kill bacteria regularly when concentration.
Annotate: the concentration of product fourth: 1-12 is followed successively by 1,0.75,0.5,0.375,0.25,0.125,0.1,0.075,0.05,0.025,0.0125,0.00625mg/mL; 1-is respectively the blank that does not add sample to 4.
According to Fig. 3 related data, the sterilizing rate of different concns sample, curve plotting, as shown in Figure 4: the 0.05mg/mL sample, its sterilizing rate reaches 54%, and when sample concentration reached 0.25mg/mL, its sterilizing rate reached 100%.
By this target compound of systematic research streptococcus aureus is acted on, and can find out significantly that from the foregoing description 4～6 this target compound has good antibacterial effect, active testing to other bacterial classification is proceeded, comprising a series of pathogenic bacterium of extensive harm humans health, as Streptococcus sanguis (Streptococcus Sanguis ATCC 10556), Streptococcus mutans (Streptococcus mutans ATCC 35668), porphyromonas gingivalis (Porphyromonas gingivalis ATCC 33277), mouse typhus few door Salmonella (Salmonella typhi CCTCC AB 94010) and Klebsiella pneumonia bacterial classifications such as (Klcbsiella preumoniae ATCC 10082).Estimate that this target compound also can have obvious restraining effect to above bacterium.
Claims (8)
1. the salicylic amide ether compound of pleuromutilin has the represented structural formula of general formula I:
In the formula:
R is NHC
mH
2mCH
3, m 〉=0 and be integer wherein.
2. by the salicylic amide ether compound of the described pleuromutilin of claim 1, it is characterized in that described m=2 or m=3.
3. the preparation method of the salicylic amide ether compound of the described pleuromutilin of claim 1 is characterized in that including following steps:
1) pleuromutilin and triethylamine 1: 1 in molar ratio～10 are mixed stirring at normal temperature in solvent and obtained reaction mixture in 50～70 minutes, be cryosel bathe under to be added drop-wise in reaction mixture at 1～5: 1 more in molar ratio with methane sulfonyl chloride or Tosyl chloride and triethylamine, under cryosel is bathed, continue stirring reaction 0.5～6 hour, obtain pleuromutilin methane sulfonate or pleuromutilin p-toluenesulfonic esters;
2) be 1: 1～20 to add down catalyzer at 25～90 ℃ and in solvent, mixed stirring reaction 4～24 hours in molar ratio with Whitfield's ointment and methyl alcohol, obtain wintergreen oil;
3) in solvent with step 2) wintergreen oil of gained and amine is 1: 1～5 at 25～125 ℃ of following stirring reaction 2-24 hours in molar ratio, obtains salicylic amide;
4) in solvent with the salicylic amide 1: 1 in molar ratio～2 of the pleuromutilin methane sulfonate of gained in the step 1) or pleuromutilin P-TOLUENE SULFO ACID 99 ester and step 3) gained 25～80 ℃ of following stirring reactions 1～10 hour, obtain the salicylyl amidogen ether of pleuromutilin.
4. press the preparation method of the salicylic amide ether compound of the described pleuromutilin of claim 3, it is characterized in that the described solvent of step 1) is methylene dichloride or methyl alcohol.
5. by the preparation method of the salicylic amide ether compound of the described pleuromutilin of claim 3, it is characterized in that step 2) described solvent is methyl alcohol, benzene or toluene.
6. press the preparation method of the salicylic amide ether compound of the described pleuromutilin of claim 3, it is characterized in that the described solvent of step 3) is the aqueous solution of water, amine or hexanaphthene.
7. press the preparation method of the salicylic amide ether compound of the described pleuromutilin of claim 3, it is characterized in that the described solvent of step 4) is the mixed solvent of the methylene dichloride and the NaOH aqueous solution.
8. press the preparation method of the salicylic amide ether compound of claim 3 or 6 described pleuromutilins, the general structure that it is characterized in that the described amine of step 3) is CH
3C
mH
2mNH
2, m 〉=0 and be integer wherein.
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Cited By (2)
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|---|---|---|---|---|
| CN103351309A (en) * | 2013-07-24 | 2013-10-16 | 中国船舶重工集团公司第七二五研究所 | Salicylic amide antifoulant and preparation method thereof |
| US11401233B1 (en) * | 2021-02-12 | 2022-08-02 | Shaanxi University Of Science And Technology | Pleuromutilin salicylic acid ester with antibacterial activity and a method of preparing the same |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2014645A1 (en) * | 2007-07-13 | 2009-01-14 | Nabriva Therapeutics AG | Pleuromutilin derivatives and their use as antimicrobials |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2014645A1 (en) * | 2007-07-13 | 2009-01-14 | Nabriva Therapeutics AG | Pleuromutilin derivatives and their use as antimicrobials |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103351309A (en) * | 2013-07-24 | 2013-10-16 | 中国船舶重工集团公司第七二五研究所 | Salicylic amide antifoulant and preparation method thereof |
| CN103351309B (en) * | 2013-07-24 | 2015-04-22 | 中国船舶重工集团公司第七二五研究所 | Salicylic amide antifoulant and preparation method thereof |
| US11401233B1 (en) * | 2021-02-12 | 2022-08-02 | Shaanxi University Of Science And Technology | Pleuromutilin salicylic acid ester with antibacterial activity and a method of preparing the same |
| US20220259138A1 (en) * | 2021-02-12 | 2022-08-18 | Shaanxi University Of Science And Technology | Pleuromutilin salicylic acid ester with antibacterial activity and a method of preparing the same |
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Granted publication date: 20131211 Termination date: 20160308 |