CN105949131B - Pleuromutilin-metronidazole heterozygosis medicine and preparation method thereof - Google Patents
Pleuromutilin-metronidazole heterozygosis medicine and preparation method thereof Download PDFInfo
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- CN105949131B CN105949131B CN201610296429.9A CN201610296429A CN105949131B CN 105949131 B CN105949131 B CN 105949131B CN 201610296429 A CN201610296429 A CN 201610296429A CN 105949131 B CN105949131 B CN 105949131B
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- pleuromutilin
- metronidazole
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/91—Nitro radicals
- C07D233/92—Nitro radicals attached in position 4 or 5
- C07D233/94—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
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Abstract
The present invention relates to a kind of pleuromutilin metronidazole heterozygosis medicine and preparation method thereof, and this method is first using pleuromutilin and succinic anhydride as raw material, with 1:0.26 0.46 weight ratio has only synthesized pleuromutilin derivative intermediate under the conditions of existing for ethanol and triethylamine by a step esterification, and the derivatives intermediates are with metronidazole with 1:0.38 0.42 weight ratio carries out a step esterification and obtains crude product, and crude product can obtain pleuromutilin metronidazole heterozygosis antituberculotic through column chromatography for separation.The present invention is easy to operate, pollution is small, cost is low, raw material are easy to acquirements, high income, suitable enterprise produce.
Description
Technical field
The invention belongs to synthesize pharmaceutical technology field, and in particular to a kind of pleuromutilin-metronidazole heterozygosis medicine and its
Preparation method.
Background technology
Pleuromutilin is the diterpene antibiotic of a kind of wide spectrum produced by Pleurotus sp2, is that pleuromulins are hemizygous
Into the precursor of derivative.Although pleuromutilin has certain antibacterial activity, due to its slightly soluble and body absorption rate in water
It is relatively low, it is difficult to develop as effective antibacterials.Therefore, since pleuromutilin is found, researcher always carries out it
Structure activity study and structural modification, it is high, water-soluble preferably and raw to find antibacterial activity to attempt the various polar groups of introducing
The higher pleuromutilin analog derivative of thing availability.Early in the seventies in last century, Franz and Michel etc. are respectively by cutting
The fermentation condition of short pleurin producing strains Clitoilus passeckerianus and Clitopilus pseudo pinsitus
Research is found：Under the conditions of different fermentations, in culture in addition to pleuromutilin, the long-chain that side chain contains double bond is also isolated
The derivative of alkyl (compound 9-12) and glycosidic structure (compound 13), and find the bioactivity of these derivatives than cutting
Short pleurin is high.This discovery was inspiring people by being chemically modified the active higher of searching to the R on side chain at that time
Derivative.
Metronidazole is mainly used for treating or preventing system or local infection caused by above-mentioned anaerobic bacteria, as abdominal cavity, alimentary canal,
The anaerobic infection at the position such as female reproductive system, lower respiratory tract, skin and soft tissue, bone and joint, to septicemia, the internal membrane of heart
Colitis caused by scorching, infection of meninges and use antibiotic is also effective.Lockjaw is treated often with tetanus antitoxin (TAT) to join
With, it may also be used for oral cavity anaerobium infects.Metronidazole structural formula is as follows：
The single target drug of several differences is combined according to " cocktail therapy " or selection use acts on multiple molecular targets
Preferable curative effect is then had during target " Mutiple Targets " drug therapy complex disease.By the method for chemical synthesis by different ligands molecule
Pharmacophore connect to form Mutiple Targets medicine, be current Mutiple Targets drug design main method, due to two drug effects
Group's molecule lacks general character, so can each retain all or part of architectural feature of original molecule in vivo；And for linker
Group can then select the group for occurring in vivo or not cracking according to the needs of design.Most of linking group of cleavable contains
Thus ester group, can be fragmented into two independent medicines, then be distinguished by blood plasma esterase hydrolyzed, two pharmacophore molecules in blood
Act on respective target spot and play a role.According to this discovery, a kind of target compound (metronidazole) has been filtered out on side chain
R modification after obtain two kinds of hybrid antibiotics.
The content of the invention
It is an object of the invention to overcome the deficiencies of the prior art and provide a kind of pleuromutilin-metronidazole heterozygosis medicine
And preparation method thereof, which adds without any catalyst, product yield is high, raw material are easy to obtain, and suitable enterprise pushes away
Wide production.
Technical scheme is as follows：
Pleuromutilin-metronidazole heterozygosis medicine, molecular formula C32H45N3O10, its molecular structure is as follows：
The preparation method of above-mentioned pleuromutilin-metronidazole heterozygosis medicine, comprises the following steps：
A) it is 1 that weight ratio is added into reactor:The pleuromutilin and succinic anhydride of 0.26-0.46, adds certain
Ethanol and triethylamine are measured, is uniformly mixed to obtain solution, is transferred in separatory funnel, adds after solution is heated to 40-70 DEG C of reaction 2-10h
Enter buck to be extracted, lower floor's extract is washed, obtains pleuromutilin derivative intermediate after drying；
B) it is 1 that weight ratio is added into reactor:Pleuromutilin derivative intermediate, the metronidazole of 0.38-0.42, then
Add a certain amount of tetrahydrofuran to be uniformly mixed, mixed solution is filtered under diminished pressure after stirring reaction 2-4h at 24-30 DEG C, and filtrate is subtracted
Pressure is evaporated to obtain pleuromutilin-metronidazole crude product；
C) pleuromutilin-metronidazole crude product is subjected to column chromatography for separation and obtains pleuromutilin-metronidazole sterling.
The ethanol of 1.5-2L and the triethylamine of 0.15-0.2L, lower floor's extract are added in step a) per mol pleuromutilins
Successively with evaporated under reduced pressure after ether, saturated common salt water washing.
The tetrahydrofuran of 2-3L is added in step b) per mol pleuromutilin derivatives intermediate.
The chromatography column condition of column chromatography for separation operation is in step c)：Adsorbent is silica gel, and solvent is molar ratio 40：1
Dichloromethane and methanol solvate.
Beneficial effects of the present invention are：(1) using pleuromutilin and succinic anhydride as raw material, a step esterification is only passed through
Pleuromutilin derivative intermediate is synthesized, is added without any catalyst；(2) pleuromutilin derivative intermediate and metronidazole
Hybrid antibiotic molecule is synthesized by a step esterification；(3) the method for the present invention is simple, pollution is small, raw material are easily obtained, into
This low, high income.(4) present invention uses Computeraided drug design, by scoring functions, filters out new heterozygosis and resists
Raw element compound, obtains the preferable, safe and reliable pleuromutilin-metronidazole hybrid antibiotic molecule of drug effect.
Brief description of the drawings
Fig. 1 is the infrared spectrogram of pleuromutilin-metronidazole prepared by the embodiment of the present invention 1；
Fig. 2 is pleuromutilin-metronidazole prepared by the embodiment of the present invention 11H nmr spectrums.
Embodiment
To make those of ordinary skill in the art fully understand technical scheme and beneficial effect, below in conjunction with the accompanying drawings
And specific embodiment is further described.
The reaction principle that the present invention prepares pleuromutilin-metronidazole heterozygosis medicine is as follows：
Embodiment 1
Thermometer, reflux condensing tube are installed successively on 100ml three-necked flasks, pleuromutilin is added into three-necked flask
3.78g (0.01mol), succinic anhydride 1g (0.01mol), toluene 15mL and triethylamine 1.5mL, add magnetic stir bar glass beyond the Great Wall
Heating water bath is placed on heat collecting type constant-temperature heating magnetic stirring apparatus after glass plug to 40 DEG C, 2 it is small when after stop reaction.Will reaction
Solution afterwards is transferred in separatory funnel, is added 50mL soda lye washes and is carried out extracting and demixing, lower floor's solution is first washed with 50mL ether, connect
And washed with saturated common salt, lower floor's solution after washing is finally placed in evaporated under reduced pressure ether on decompression rotary evaporator, 60
DEG C drying obtains pleuromutilin derivative intermediate 5.2g.
4.8g pleuromutilin derivative intermediates are taken, by itself and 1.8g (0.01mol) metronidazoles and 20mL tetrahydrofurans
It is uniformly mixed, is filtered under diminished pressure at 24 DEG C after stirring reaction 2h, filtrate is placed in evaporated under reduced pressure tetrahydrochysene furan on decompression rotary evaporator
Mutter to obtain pleuromutilin-metronidazole crude product 4.7g.By pleuromutilin-metronidazole crude product carry out post separation obtain pleuromutilin-
Metronidazole sterling 3.8g.Column chromatography for separation operation chromatography column condition be：Adsorbent is silica gel, solvent 40：1 (molar ratio)
Dichloromethane and methanol solvate.
Embodiment 2
Thermometer, reflux condensing tube are installed successively on 100ml three-necked flasks, pleuromutilin is added into three-necked flask
3.78g (0.01mol), succinic anhydride 1.7g, toluene 20mL and triethylamine 2.0mL, addition magnetic stir bar is beyond the Great Wall after glass stopper
Heating water bath is placed on heat collecting type constant-temperature heating magnetic stirring apparatus to 70 DEG C, 10 it is small when after stop reaction.After reaction
Solution is transferred in separatory funnel, is added soda lye wash and is carried out extracting and demixing, lower floor's solution is first washed with ether, then uses saturated common salt
Washing, is finally placed in evaporated under reduced pressure ether on decompression rotary evaporator by lower floor's solution after washing, is cut in 60 DEG C of drying
Short pleurin derivatives intermediates 5.26g.
4.8g pleuromutilin derivative intermediates are taken, it is uniformly mixed with 2.0g metronidazoles and 30mL tetrahydrofurans,
It is filtered under diminished pressure at 30 DEG C after stirring reaction 4h, filtrate is placed in evaporated under reduced pressure tetrahydrofuran on decompression rotary evaporator must truncate side
Ear element-metronidazole crude product 4.82g.Pleuromutilin-metronidazole crude product is subjected to post separation and obtains pleuromutilin-metronidazole sterling
4.0g.Column chromatography for separation operation chromatography column condition be：Adsorbent is silica gel, and solvent is (molar ratio) 40：1 dichloromethane
And methanol solvate.
Embodiment 3
Thermometer, reflux condensing tube are installed successively on 100ml three-necked flasks, pleuromutilin is added into three-necked flask
3.78g (0.01mol), succinic anhydride 1.36g, toluene 17.5mL and triethylamine 1.75mL, add magnetic stir bar glass beyond the Great Wall
Heating water bath is placed on heat collecting type constant-temperature heating magnetic stirring apparatus after plug to 45 DEG C, 6 it is small when after stop reaction.After reacting
Solution be transferred in separatory funnel, add soda lye wash and carry out extracting and demixing, lower floor's solution first washed with ether, then eaten with saturation
Salt is washed, and lower floor's solution after washing finally is placed in evaporated under reduced pressure ether on decompression rotary evaporator, is obtained in 60 DEG C of drying
Pleuromutilin derivative intermediate 5.4g.
4.8g pleuromutilin derivative intermediates are taken, it is uniformly mixed with 1.9g metronidazoles and 25mL tetrahydrofurans,
It is filtered under diminished pressure at 27 DEG C after stirring reaction 3h, filtrate is placed in evaporated under reduced pressure tetrahydrofuran on decompression rotary evaporator must truncate side
Ear element-metronidazole crude product 5.1g.Pleuromutilin-metronidazole crude product is subjected to post separation and obtains pleuromutilin-metronidazole sterling
4.19g.Column chromatography for separation operation chromatography column condition be：Adsorbent is silica gel, and solvent is (molar ratio) 40：1 dichloromethane
Alkane and methanol solvate.
High performance liquid chromatography, infrared spectrum have been carried out respectively to pleuromutilin made from embodiment 1-metronidazole sterling
IR、1H nuclear magnetic resonance spectroscopies, as a result such as Fig. 1-2.High-efficient liquid phase chromatogram condition is：C18Chromatographic column (4.6nm × 250nm, filler
SinoChrom, 5 μm of granularity), with acetonitrile：Methanol aqueous solution (10mmol/L) 60:40 mobile phase is 254nm in absorbing wavelength
Under carry out analysis measure.It is 90% to measure pleuromutilin-metronidazole purity, and the conversion ratio being calculated is 52.4%.Truncate
Pleurin-metronidazole results of IR is as shown in Figure 1, key data is as follows：
Claims (5)
1. a kind of pleuromutilin-metronidazole heterozygosis medicine, molecular formula C32H45N3O10, it is characterised in that its molecular structure is：
2. the preparation method of pleuromutilin-metronidazole heterozygosis medicine described in claim 1, it is characterised in that including following step
Suddenly：
A) it is 1 that weight ratio is added into reactor:The pleuromutilin and succinic anhydride of 0.26-0.46, adds a certain amount of second
Alcohol and triethylamine, are uniformly mixed to obtain solution, are transferred to after solution is heated to 40-70 DEG C of reaction 2-10h in separatory funnel, add alkali
Water is extracted, and lower floor's extract is washed, obtains pleuromutilin derivative intermediate after drying；
B) it is 1 that weight ratio is added into reactor:Pleuromutilin derivative intermediate, the metronidazole of 0.38-0.42, adds
A certain amount of tetrahydrofuran is uniformly mixed, and mixed solution is filtered under diminished pressure after reaction 2-4h is stirred at 24-30 DEG C, and filtrate decompression is steamed
Do to obtain pleuromutilin-metronidazole crude product；
C) pleuromutilin-metronidazole crude product is subjected to column chromatography for separation and obtains pleuromutilin-metronidazole sterling.
3. the preparation method of pleuromutilin as claimed in claim 2-metronidazole heterozygosis medicine, it is characterised in that：Step a)
In add the ethanol of 1.5-2L and the triethylamine of 0.15-0.2L per mol pleuromutilins, lower floor's extract is successively with ether, full
With evaporated under reduced pressure after brine It.
4. the preparation method of pleuromutilin as claimed in claim 2-metronidazole heterozygosis medicine, it is characterised in that：Step b)
In the tetrahydrofuran of 2-3L is added per mol pleuromutilin derivatives intermediates.
5. the preparation method of pleuromutilin as claimed in claim 2-metronidazole heterozygosis medicine, it is characterised in that：Step c)
The chromatography column condition of middle column chromatography for separation operation is：Adsorbent is silica gel, and solvent is molar ratio 40：1 dichloromethane and first
Alcoholic solvent.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102229580A (en) * | 2011-05-12 | 2011-11-02 | 南通大学 | Novel pleuromutilin derivate, preparation method and medical use thereof |
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| AU3036200A (en) * | 1998-12-18 | 2000-07-12 | Smithkline Beecham Plc | Mutilin 14-ester derivatives having antibacterial activity |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102229580A (en) * | 2011-05-12 | 2011-11-02 | 南通大学 | Novel pleuromutilin derivate, preparation method and medical use thereof |
Non-Patent Citations (2)
| Title |
|---|
| New Pleuromutilin Derivatives with Enhanced Antimicrobial Activity II Structure-Activity Correlations;Helmut E.et al.;《The Journal of Antibiotics》;19760612;第XXIX卷(第9期);第923-927页 * |
| 截短侧耳素及其衍生物的研究进展;邹懿 等;《中国抗生素杂志》;20090228;第34卷(第2期);第65-68、73页 * |
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