CN101863934B - Salicylic acid glucosides methyl compound, and synthesis method and purposes thereof - Google Patents
Salicylic acid glucosides methyl compound, and synthesis method and purposes thereof Download PDFInfo
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Abstract
The invention discloses a salicylic acid glucosides methyl compound, and a synthesis method and purposes thereof, in particular to a novel type of salicylic acid glucosides methyl compound; and the synthesis method of the type of compound comprises the medicine compounds and the purposes thereof, particularly as inflammation, heat clearing and analgesia medicine. The specific names of the two novel compounds are methyl salicylate lactose nucleoside and methyl salicylate maltoside. The synthesis method is simple and the synthesis cost is low. The result of activity evaluation shows that the compounds have similar pharmacological action with salicylic acid and greatly reduced side effect.
Description
Technical field
The present invention relates to the salicylic acid glucosides methyl compound that a class is new, its synthetic method, the pharmaceutical composition that contains them, and as medicine, especially as the purposes of antipyretic, analgesia, anti-inflammation drugs.
Background technology
The effect that wintergreen oil glycosides compound has is antipyretic, analgesia, anti-inflammatory etc. and Whitfield's ointment are similar, in order to find the non-steroid antiinflammatory drug that toxic side effect is little, we have carried out structural modification to Whitfield's ointment, synthesized two kinds of new salicylic acid derivatives, and carried out activity rating, result shows that they are except having obvious pharmacological action, side effect reduces greatly, and synthetic method is simple, synthetic cost is low, is expected to be developed to competitive antipyretic, analgesia, anti-inflammatory type new drug.
Summary of the invention
The technical problem to be solved in the present invention is to provide the salicylic acid glucosides methyl compound that a class is new.
Another technical problem that the present invention will solve is to provide the preparation method of this class salicylic acid glucosides methyl compound;
Another technical problem that the present invention will solve is to provide the pharmaceutical composition of this class salicylic acid glucosides methyl compound.
Another technical problem that the present invention will solve is to provide the application of this class salicylic acid glucosides methyl compound in antipyretic, the anti-inflammation and analgesic drugs of preparation.
For solving technical problem of the present invention, the present invention adopts following technical scheme:
Salicylic acid glucosides methyl compound of the present invention is as shown in general formula (I)
Compound 1R=lactose (lactose)
Compound 2R=maltose (maltose)
The present invention also provides the method for preparing the compounds of this invention, comprises the steps:
(1), lactose or maltose and the synthetic full acetyl disaccharides of acetic anhydride reaction;
(2), full acetyl disaccharides is prepared into carbohydrate ligands;
(3), full acetyl disaccharides is prepared into carbohydrate ligands and the full acetylated glucosides of wintergreen oil salicylate methyl esters;
(4), the full acetylated glucosides deacetylation of wintergreen oil.
Step (one), lactose or maltose and the synthetic full acetyl disaccharides of acetic anhydride reaction;
Under the condition that the reaction of lactose or maltose and acetic anhydride preferably exists at catalyzer, carry out, preferred catalyzer is selected from pyridine, sodium acetate or perchloric acid.
I.e. synthetic for full acetyl disaccharides, the invention provides three kinds of technical schemes, and concrete technical scheme is as follows:
(one, 1) lactose or maltose react in the mixing solutions of pyridine and acetic anhydride, after reaction terminating, and organic solvent extraction, the washing of washing extraction liquid is to neutral, and dry, evaporated under reduced pressure, obtains full acetylated disaccharides.
The temperature of preferred reaction is 20-30 DEG C, is more preferably at ambient temperature and carries out.
Reaction time preferably, more than 5 hours.
The method of termination reaction is to add frozen water.
Preferred extraction organic solvent is selected from chloroform or ethyl acetate.
Extraction liquid washing preferably makes water or dilute hydrochloric acid.
In drying step, preferred siccative is anhydrous sodium sulphate.
(one, 2), by diacetyl oxide and anhydrous sodium acetate Hybrid Heating, adds lactose or maltose, and stirring reaction by reaction solution impouring trash ice, stirs after reacting completely, and has dope to separate out, and leaches solid; Water regulates pH value to pH6-7, then uses organic solvent extraction, washing extraction liquid, and dry, evaporate to dryness, merges the above-mentioned solid that leaches.
When diacetyl oxide and anhydrous sodium acetate Hybrid Heating, be preferably heated to 100 DEG C.
The time of reaction is more than 1.5 hours.
The method of termination reaction is to add frozen water.
While adjusting pH value, preferably use saturated sodium bicarbonate aqueous solution,
When extraction, preferred organic solvent is ethyl acetate.
Extraction liquid washing preferably makes water.
In drying step, preferred siccative is anhydrous sodium sulphate.
(one, 3) diacetyl oxide and perchloric acid mix, then add lactose or maltose reaction.Without separation and purification, directly carry out next step reaction.
The temperature of reaction, preferably at room temperature reaction, temperature is no more than 40 DEG C.
The time of reaction is 15 minutes to 3 hours, is preferably 0.5 hour-2 hours, more preferably 1 hour.
Step (two), full acetyl disaccharides is prepared into carbohydrate ligands.
The invention provides three kinds of technical schemes, comprise full acetylated disaccharides and bromide reagent reaction; 1 first deacetylate of full acetylated disaccharides, then react the full acetylated carbohydrate ligands of Trichloroacetonitrile with Trichloroacetonitrile; Or after lactose or maltose and diacetyl oxide and perchloric acid reaction not separation and purification is directly and use phosphorus tribromide bromination.
Concrete technical scheme is as follows:
(two, 1),, the full acetyl sugar of bromo synthetic:
By full acetylated disaccharides and bromide reagent reaction, after reaction terminating, organic solvent extracting extracts reaction solution, washing extraction liquid, and dry, evaporate to dryness organic solvent obtains the full acetyl sugar of bromo.
The temperature of reaction, preferably room temperature.
The method of termination reaction is to add frozen water.
Preferred organic solvent is chloroform or ethyl acetate.
Extraction liquid washing preferably makes water.
In drying step, preferred siccative is anhydrous sodium sulphate.
Synthesizing of (two, 2), the full acetyl sugar of Trichloroacetonitrile:
(1), 1 deacetylate:
Full acetylated sugar is in anhydrous tetrahydro furan and benzylamine reaction, and after reaction terminating, organic solvent extraction, washs extraction liquid, dry, evaporated under reduced pressure.
The temperature of reaction, preferably room temperature.
The process of reaction is by monitoring raw material point, and raw material point disappearance explanation reacts completely.
The method of termination reaction is to add frozen water.
Preferred organic solvent is chloroform or ethyl acetate.
Extraction liquid washing is preferably used uses dilute hydrochloric acid, saturated sodium bicarbonate solution, saturated sodium-chloride, the each washing of water once successively again.
In drying step, preferred siccative is anhydrous magnesium sulfate.
Evaporate to dryness organic solvent preferably carries out under reduced pressure.
(2), 1 activation:
Upper step product is dissolved in Trichloroacetonitrile, dichloromethane solution, then adds Anhydrous potassium carbonate, after reacting completely, filter, filtrate evaporate to dryness organic solvent obtains the full acetylated carbohydrate ligands of Trichloroacetonitrile;
The detection method reacting completely is that raw material point disappears.
Filter and preferably use diatomite filtration.
(two, 3), phosphorus tribromide bromination.In the reaction flask of step (, 3), drip phosphorus tribromide, control temperature, add water, continue reaction to reacting completely.
After reaction finishes, will in reaction solution impouring frozen water, stir, adularescent solid is separated out, and washing filters, and evaporate to dryness obtains white solid.
The temperature of reaction, preferably temperature control is below 40 DEG C.
The time response of reaction 2 hours.
The method of termination reaction is to add frozen water.
Step (three), full acetyl disaccharides are prepared into carbohydrate ligands and the full acetylated glucosides of wintergreen oil salicylate methyl esters;
Under the condition that wintergreen oil exists at organic solvent; be uniformly mixed with molecular sieve, heavy metal catalyst; add again carbohydrate ligands; after reaction finishes; elimination heavy metal catalyst, organic solvent extraction, washing extraction liquid; dry, evaporate to dryness organic solvent obtains the full acetylated glucosides of reaction product bigcatkin willow acid methyl esters.
The time of reaction is preferably more than 48 hours
Preferred organic solvent is dry quinoline,
Preferred heavy metal catalyst is various silver salt and mercury salt, and preferred heavy metal catalyst is silver suboxide.
Reaction is preferably carried out under the condition of lucifuge nitrogen protection.
When extraction, preferred organic solvent is selected from ether, chloroform or ethyl acetate.
The washing of extraction liquid is preferably used dilute hydrochloric acid or water,
In drying step, preferred siccative is anhydrous sodium sulphate.
The purifying of product can use the method such as normal-phase chromatography or recrystallization.
The separation and purification of product is preferably used normal phase silica gel column chromatography separation and purification.
Eluent is chloroform: acetone volume ratio 3.5: 1; Or sherwood oil: acetone volume ratio 4: 1.
The unfolding condition that thin layer plate detects is sherwood oil: acetone volume ratio 2: 1.
Step (four), the full acetylated glucosides deacetylation of wintergreen oil;
The full acetylated glucosides of wintergreen oil is dissolved in protic solvent, then adds highly basic reaction, then uses acid-conditioning solution PH to 6-7, evaporated under reduced pressure, and dissolve with methanol, by solution evaporate to dryness, obtains the crude product of salicylic acid glucosides methyl.
Macroporous resin depigmentation, positive or reversed phase chromatography separation purifying obtain final purpose product.
Preferred protic solvent is selected from anhydrous methanol, dehydrated alcohol;
Preferred highly basic, preferred highly basic is sodium methylate, potassium methylate, without water sodium hydroxide, anhydrous potassium hydroxide;
The time of reaction is more than 3 hours;
Preferred acid, preferred acid is strong acid, more preferably inorganic acid, preferred inorganic acid is hydrochloric acid.
While using purification on normal-phase silica gel to separate, sample: the part by weight of mixing sample silica gel is preferably 1: 1.5, sample: the part by weight of post silica gel is 1: 15-60, eluting solvent is chloroform: the volume ratio of methyl alcohol is 4: 1.Thin layer testing conditions chloroform: methyl alcohol: water volume ratio is 8: 2: 0.2.
According to the present invention, preferred preparation method comprises the steps:
Step (one), lactose or maltose and the synthetic full acetyl disaccharides of acetic anhydride reaction;
(one, 1), lactose or maltose are added in pyridine and acetic anhydride mixing solutions, stir, normal-temperature reaction, adds frozen water termination reaction, the extraction of chloroform or ethyl acetate, water or dilute hydrochloric acid washing extraction liquid, anhydrous sodium sulfate drying, evaporated under reduced pressure.
(one, 2) diacetyl oxide, anhydrous sodium acetate, being heated to 100 DEG C has part insoluble, adds lactose or maltose, continues stirring reaction 1.5 hours, by reaction solution impouring trash ice, stirs, and has dope to separate out, and leaches solid; Water is adjusted to pH6-7 with saturated sodium bicarbonate aqueous solution, is extracted with ethyl acetate three times, and combined ethyl acetate part, washing, anhydrous sodium sulfate drying, evaporate to dryness, merges the above-mentioned solid that leaches.
(one, 3) diacetyl oxide, perchloric acid is made catalyzer, and stirring at room temperature adds alpha-lactose, controls temperature and is no more than 40 DEG C, adds rear continuation and stirs one hour, directly carries out next step reaction.
Step (two), full acetyl disaccharides is prepared into carbohydrate ligands;
(two, 1), red phosphorus and Glacial acetic acid mixing ice bath are stirred, slowly drip bromine, control temperature be no more than 20 DEG C, after dripping off by mixed solution leave standstill 30 minutes, elimination red phosphorus, obtains yellow bromide reagent.Full acetylated disaccharides and bromide reagent are mixed, after room temperature reaction, add frozen water termination reaction, chloroform or ethyl acetate extractive reaction liquid, washing extract layer, anhydrous sodium sulfate drying, evaporate to dryness organic phase.
(two, 2), full acetylated sugar is dissolved in anhydrous tetrahydro furan, benzylamine, stirring at normal temperature is reacted to raw material point and is disappeared.Pour frozen water into, organic solvent extraction, extraction liquid respectively washs once with dilute hydrochloric acid, saturated sodium bicarbonate solution, saturated sodium-chloride, water successively again, anhydrous magnesium sulfate drying, evaporated under reduced pressure.Gains are dissolved in Trichloroacetonitrile, dichloromethane solution, then add Carbon Dioxide nak response to disappear to raw material point, diatomite filtration, merging filtrate evaporated under reduced pressure.
(two, 3) drip phosphorus tribromide in the reaction flask of step (one, 3), and temperature control is below 40 DEG C, add water, continue reaction 2 hours, will in reaction solution impouring frozen water, stir several minutes, adularescent solid is separated out, washing filters, and evaporate to dryness obtains white solid and obtains.
Step (three), full acetyl disaccharides are prepared into carbohydrate ligands and the full acetylated glucosides of wintergreen oil salicylate methyl esters:
Wintergreen oil, dry quinoline, molecular sieve, heavy metal catalyst are uniformly mixed, and lucifuge nitrogen protection, adds carbohydrate ligands again after being uniformly mixed, and continues reaction more than 48 hours.After reaction finishes, elimination heavy metal catalyst, organic solvent extraction, dilute hydrochloric acid or water washing organic phase, anhydrous sodium sulfate drying, evaporate to dryness.With the separation and purification of the method such as normal-phase chromatography or recrystallization, can obtain the full acetylated glucosides of pure wintergreen oil.
Step (four), the full acetylated glucosides deacetylation of wintergreen oil.
Full acetylated wintergreen oil glucosides is dissolved in to protic solvent anhydrous methanol or dehydrated alcohol, adds sodium methylate or anhydrous K OH confined reaction more than 3 hours, then use hydrochloric acid conditioning solution PH to 6-7 neutrality; evaporated under reduced pressure; dissolve with methanol, by solution evaporate to dryness, obtains the crude product of salicylic acid glucosides methyl.Macroporous resin depigmentation, positive or reversed phase chromatography separation purifying obtain final purpose product.
The method of separation and purification of the present invention comprises that the several different methods such as normal-phase chromatography, reverse-phase chromatography, macroporous resin, recrystallization, charcoal absorption and preparative chromatography are applied alone or in combination and their applicable elements.
Concrete preparation feedback route is including but not limited to following reaction scheme
Preparation feedback route 1:
Preparation feedback route 2:
Preparation feedback route 3
Preparation feedback route 4
Preparation feedback route 5
Preparation feedback route 6
Wintergreen oil maltoside (compound 2)
Preparation feedback route 7:
Further aspect of the present invention also relates to the pharmaceutical composition using the compounds of this invention as active ingredient.This pharmaceutical composition can be according to method preparation well known in the art.Can be suitable for any formulation of human or animal's use by pharmaceutically acceptable to the compounds of this invention and one or more solid or liquid excipient and/or assistant agent being combined, making.The content of the compounds of this invention in its pharmaceutical composition is generally 0.1-95 % by weight.
The compounds of this invention or the pharmaceutical composition that contains it can unit dosage form administrations, route of administration can be enteron aisle or non-enteron aisle, as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.
Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
The compounds of this invention can be made ordinary preparation, also make is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For the compounds of this invention is made to tablet, can be widely used various vehicle well known in the art, comprise thinner, tamanori, wetting agent, disintegrating agent, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, calcium carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate, sodium bicarbonate and Citric Acid, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate etc.; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.
Tablet further can also be made to coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
For capsule is made in administration unit, effective constituent the compounds of this invention can be mixed with thinner, glidant, mixture is directly placed in to hard capsule or soft capsule.Also can by effective constituent the compounds of this invention first with thinner, tamanori, disintegrating agent granulation or micropill, then be placed in hard capsule or soft capsule.Also can be used for preparing the capsule of the compounds of this invention for the preparation of each thinner, tamanori, wetting agent, disintegrating agent, the glidant kind of the compounds of this invention tablet.
For the compounds of this invention is made to injection, can water, ethanol, Virahol, propylene glycol or their mixture as solvent and add the conventional solubilizing agent in appropriate this area, solubility promoter, pH to adjust agent, osmotic pressure regulator.Solubilizing agent or solubility promoter can be poloxamer, Yelkin TTS, hydroxypropyl-beta-cyclodextrin etc.; PH adjustment agent can be phosphoric acid salt, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can be sodium-chlor, N.F,USP MANNITOL, glucose, phosphoric acid salt, acetate etc.As prepare lyophilized injectable powder, also can add N.F,USP MANNITOL, glucose etc. as propping agent.
In addition,, as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives or other additive.
For reaching medication object, strengthen result for the treatment of, medicine of the present invention or pharmaceutical composition can be with any known medication administrations.
The compounds of this invention by pharmacological evaluation prove its can for the preparation of antipyretic, anti-inflammatory and or analgesic medicine.
The dosage of the compounds of this invention pharmaceutical composition is according to character and the severity that will prevent or treat disease, the individual instances of patient or animal, and route of administration and formulation etc. can have large-scale variation.In general, the suitable dose scope of the every day of the compounds of this invention is 0.001-150mg/Kg body weight, is preferably 0.1-100mg/Kg body weight, and more preferably 1-60mg/Kg body weight, most preferably is 2-30mg/Kg body weight.Above-mentioned dosage can a dose unit or is divided into several dose unit administrations, and this depends on doctor's clinical experience and comprises the dosage regimen of using other treatment means.
Compound of the present invention or composition can be taken separately, or merge and use with other treatment medicine or symptomatic drugs.In the time of compound of the present invention and other medicine existence synergy, should adjust according to practical situation its dosage.
Major advantage of the present invention has:
1, directly taking wintergreen oil cheap on market and disaccharides as raw material, two new compounds have been synthesized first through 5 steps reactions: wintergreen oil lactoside and wintergreen oil maltoside.Raw materials usedly in whole reaction process be cheaply easy to get, experimental installation is simple, and synthetic cost is low, and whole experiment toxicity is little, reproducible, and easily operation, is applicable to industrial mass production.
2, two new wintergreen oil glycosides compounds have significantly antipyretic, anti-inflammatory, analgesic effect, and side effect is less than Whitfield's ointment, is expected to be developed to the potential antipyretic-antalgic kind new medicine of tool.
Embodiment
To contribute to understand the present invention by following specific implementation method, but not limit content of the present invention.
Synthesizing of step 1, full acetylated sugar
Synthesizing of the full acetylated lactose of step 1.1
Embodiment 1
5g lactose is added in 80ml pyridine and 80ml acetic anhydride mixing solutions; stir; normal-temperature reaction 5 hours, adds frozen water termination reaction, chloroform extraction; extract 2 times; 50ml/ time, extremely neutral with rare 1mol/L salt acid elution extraction liquid, anhydrous sodium sulfate drying; evaporated under reduced pressure organic phase, obtains full acetylated lactose solid 8.1g.
Embodiment 2
5g lactose is added in 80ml pyridine and 80ml acetic anhydride mixing solutions; stir; normal-temperature reaction 6 hours, adds frozen water termination reaction, ethyl acetate extraction; extract 3 times; 50ml/ time, extremely neutral with rare 1mol/L salt acid elution extraction liquid, anhydrous sodium sulfate drying; evaporated under reduced pressure organic phase, obtains full acetylated lactose solid 8.1g.
Embodiment 3
Theoretical feed ratio alpha-lactose: diacetyl oxide: sodium acetate (1: 10: 1)
In the there-necked flask of 25ml, add 17ml (0.178mol) diacetyl oxide, 1.671g (0.02mol) anhydrous sodium acetate, being heated to 100 DEG C has part insoluble, add 6g (0.167mol) alpha-lactose to add for approximately 1 hour in batches, continue stirring reaction 1.5 hours, by reaction solution impouring 100g trash ice, stir, there is dope to separate out, leach solid; Water is adjusted to pH6-7 with saturated sodium bicarbonate aqueous solution, is extracted with ethyl acetate 3 times, and combined ethyl acetate part, washing, anhydrous sodium sulfate drying, evaporate to dryness, merges the above-mentioned solid that leaches, and obtains full acetylated lactose 11.271g, calculates productive rate approximately 92%.
Synthesizing of the full acetylated maltose of step 1.2
Embodiment 4
5g maltose is added in 80ml pyridine and 80ml acetic anhydride mixing solutions; stir; normal-temperature reaction 5 hours, adds frozen water termination reaction, chloroform extraction; extract 2 times; 50ml/ time, extremely neutral with rare 1mol/L salt acid elution extraction liquid, anhydrous sodium sulfate drying; evaporated under reduced pressure organic phase, obtains full acetylated maltose solid 8.1g.
Embodiment 5
5g maltose is added in 80ml pyridine and 80ml acetic anhydride mixing solutions; stir; normal-temperature reaction 6 hours, adds frozen water termination reaction, ethyl acetate extraction; extract 3 times; 50ml/ time, extremely neutral with rare 1mol/L salt acid elution extraction liquid, anhydrous sodium sulfate drying; evaporated under reduced pressure organic phase, obtains full acetylated maltose solid 8.1g.
Synthesizing of step 2, carbohydrate ligands:
Preparation example: bromide reagent synthetic:
Red phosphorus and Glacial acetic acid mixing ice bath are stirred 10 minutes, slowly drip bromine, control temperature and be no more than 20 DEG C, after dripping off, mixed solution is left standstill to 30 minutes, elimination red phosphorus, obtains yellow bromide reagent.
Synthesizing of the full acetyl carbohydrate ligands of step 2.1 bromo:
Synthesizing of the full acetyl lactose of embodiment 6 bromo:
Full acetylated 8.0g lactose and 24ml bromide reagent are mixed, and stirring at room temperature reaction 24 hours, adds 150ml frozen water termination reaction, with 150ml ethyl acetate extractive reaction liquid, 3 times, merges reaction solution evaporate to dryness.100ml chloroform dissolves it, then uses 100ml water washing chloroform layer, 2 times.Anhydrous sodium sulfate drying, boils off organic phase, obtains the about 7.5g of the full acetyl lactose of bromo.
Synthesizing of the full acetyl maltose of embodiment 7 bromo:
Full acetylated 8.0g maltose and 24ml bromide reagent are mixed, and stirring at room temperature reaction 24 hours, adds 150ml frozen water termination reaction, with 150ml chloroform extraction reaction solution, 3 times, merges reaction solution evaporate to dryness.100ml chloroform dissolves it, then uses 100ml water washing chloroform layer, 2 times.Anhydrous sodium sulfate drying, boils off organic phase, obtains the about 7.5g of the full acetyl maltose of bromo.
Synthesizing of the full acetyl sugar of step 2.2 Trichloroacetonitrile:
Synthesizing of the full acetyl lactose of embodiment 8 Trichloroacetonitrile:
(1), 1 deacetylate:
Full acetylated 5g lactose is dissolved in to 25ml anhydrous tetrahydro furan, 2.8ml benzylamine stirring at normal temperature and reacts to raw material point and disappear (thin layer detects, developping agent sherwood oil: acetone=3: 1 volume ratio), be more than approximately 7 hours.Pour frozen water termination reaction into, organic solvent dichloromethane extraction 2 times, 30ml/ time, extraction liquid respectively washs once with 1% dilute hydrochloric acid, saturated sodium bicarbonate solution, saturated sodium-chloride, water successively again, anhydrous magnesium sulfate drying, evaporated under reduced pressure is for subsequent use.
(2), 1 activation:
The about 4g of upper step product is dissolved in 8ml Trichloroacetonitrile and 140ml anhydrous methylene chloride solution; add again 11g Carbon Dioxide nak response to raw material point to disappear, react after 18 hours filter paper or diatomite filtration; merging filtrate evaporated under reduced pressure, obtains the full acetylated lactose part of Trichloroacetonitrile.
Synthesizing of the full acetyl maltose of embodiment 9 Trichloroacetonitrile:
(1), 1 deacetylate:
Full acetylated 5g maltose is dissolved in to 25ml anhydrous tetrahydro furan, 2.8ml benzylamine stirring at normal temperature and reacts to raw material point and disappear (thin layer detects, developping agent sherwood oil: acetone=3: 1 volume ratio), be more than approximately 7 hours.Pour frozen water termination reaction into, organic solvents, chloroform extraction 2 times, 30ml/ time, extraction liquid respectively washs once with 1% dilute hydrochloric acid, saturated sodium bicarbonate solution, saturated sodium-chloride, water successively again, anhydrous magnesium sulfate drying, evaporated under reduced pressure is for subsequent use.
(2), 1 activation:
The about 4g of upper step product is dissolved in 8ml Trichloroacetonitrile and 140ml anhydrous methylene chloride solution; add again 11g Carbon Dioxide nak response to raw material point to disappear, react after 18 hours filter paper or diatomite filtration; merging filtrate evaporated under reduced pressure, obtains the full acetylated maltose part of Trichloroacetonitrile.
The full acetyl carbohydrate ligands of step 2.3 direct synthesis bromo
Synthesizing of the full acetyl lactose of embodiment 10 bromo
Theoretical feed ratio alpha-lactose: diacetyl oxide: perchloric acid: phosphorus tribromide (2: 15: 0.1: 1)
In the there-necked flask of 50ml, add the diacetyl oxide of 15ml, 90ul perchloric acid is made catalyzer, stirring at room temperature, add alpha-lactose 7.193g in batches, control temperature and be no more than 40 DEG C, add rear continuation and stir 1 hour, in above-mentioned reaction flask, drip phosphorus tribromide 1.05ml, temperature control, below 40 DEG C, adds 0.2ml water, continue reaction 2 hours, will in reaction solution impouring frozen water, stir several minutes, adularescent solid is separated out, washing filters, evaporate to dryness, obtains the about 11g of white solid, calculates productive rate and is about 78%.
Synthesizing of the full acetyl maltose of embodiment 11 bromo
Theoretical feed ratio maltose: diacetyl oxide: perchloric acid: phosphorus tribromide (2: 15: 0.1: 1)
In the there-necked flask of 50ml, add the diacetyl oxide of 15ml, 90ul perchloric acid is made catalyzer, stirring at room temperature, add maltose 7.193g in batches, control temperature and be no more than 40 DEG C, add rear continuation and stir 1 hour, in above-mentioned reaction flask, drip phosphorus tribromide 1.05ml, temperature control, below 40 DEG C, adds 0.2ml water, continue reaction 2 hours, will in reaction solution impouring frozen water, stir several minutes, adularescent solid is separated out, washing filters, evaporate to dryness, obtains the about 11g of white solid, calculates productive rate and is about 78%.
Synthesizing of step 3, the full acetylated glucosides of wintergreen oil:
Synthesizing of the full acetylated lactoside of embodiment 12 wintergreen oil
By dry wintergreen oil 35ml and dry quinoline 160ml be uniformly mixed, nitrogen protection; add again that the about 20g of molecular sieve mixes, heavy metal catalyst silver suboxide 7.5g lucifuge stirs; mix after 45 minutes and add again 7.5g lactose part, continue reaction more than 48 hours.After reaction finishes, elimination heavy metal catalyst, organic solvent extracted with diethyl ether, then uses 5% dilute hydrochloric acid, water washing organic phase successively, anhydrous sodium sulfate drying, evaporate to dryness, obtains reaction product.
The purifying of the full acetylated glucosides of wintergreen oil
On upper step gained reactant crude product, normal phase silica gel column chromatography separates, eluent is chloroform: acetone=3.5: 1 (volume ratio), every 250ml is collected as a flow point, sample is 1: 20 with the amount ratio of silica gel, sample is soluble in the organic solvent that chloroform isopolarity is less, wet method loading, eluent is chloroform: acetone volume ratio 3.5: 1, eluting solvent is about 2000ml.Thin layer plate detects (unfolding condition: sherwood oil: acetone=2: 1 volume ratio), collects evaporate to dryness, and sample is brown powder shape solid, can obtain the about 3.5g of the full acetylated glucosides of pure wintergreen oil.(having pigment impurity).
Synthesizing of the full acetylated maltoside of embodiment 13 wintergreen oil
By dry wintergreen oil 35ml and dry quinoline 160ml be uniformly mixed, nitrogen protection; add again that the about 20g of molecular sieve mixes, heavy metal catalyst silver suboxide 7.5g lucifuge stirs; mix after 45 minutes and add again 7.5g maltose part, continue reaction more than 48 hours.After reaction finishes, elimination heavy metal catalyst, organic solvents, chloroform extraction, then uses 5% dilute hydrochloric acid, water washing organic phase successively, anhydrous sodium sulfate drying, evaporate to dryness, obtains reaction product.
The purifying of the full acetylated glucosides of wintergreen oil
On upper step gained reactant crude product, normal phase silica gel column chromatography separates, eluent is sherwood oil: acetone=4: 1 (volume ratio), every 250ml is collected as a flow point, sample is 1: 20 with the amount ratio of silica gel, sample is soluble in the organic solvent that chloroform isopolarity is less, wet method loading, eluent is sherwood oil: acetone volume ratio 4: 1, eluting solvent is about 2000ml.Thin layer plate detects (unfolding condition: sherwood oil: acetone=2: 1 volume ratio), collects evaporate to dryness, and sample is brown powder shape solid (having pigment impurity).
Step 4, deacetylation:
Embodiment 14
The about 3.5g of the full acetylated lactoside of wintergreen oil is dissolved in anhydrous methanol 250ml, adds the about 2.0g confined reaction of anhydrous methanol sodium more than 3 hours, then uses hydrochloric acid conditioning solution PH to 6-7; evaporated under reduced pressure, methyl alcohol fully dissolves, and filters; by filtrate evaporate to dryness, obtain the crude product of wintergreen oil lactoside.
Macroporous resin D101 purifying
Sample dry method is mixed sample upper prop, and sample is 1g: 2ml with the ratio of mixing sample resin, and the ratio of sample and upper prop resin is 1g: 20ml, first washes a column volume with water, discards.Use again 3 of 30% ethanolic soln wash-outs more than column volume to collect 30% ethanol eluate, concentrated evaporate to dryness.The method can effectively be removed pigment and water-soluble impurity, and eluate, obtains sterling through crystallization process.
Normal phase column chromatographic separation and purification salicylic acid glucosides methyl crude product:
Sample dry method is mixed sample upper prop, and sample is 1: 1.5 with the part by weight of mixing sample silica gel, sample: the part by weight of post silica gel is 1: 30, and eluting solvent is chloroform; Methyl alcohol, volume ratio is 4: 1, collects cut, thin layer testing conditions is chloroform: methyl alcohol: water volume ratio is 8: 2: 0.2, and purity reaches 98%.
Embodiment 15
The about 3.5g of the full acetylated maltoside of wintergreen oil is dissolved in anhydrous methanol 250ml; add the about 2.0g confined reaction of anhydrous methanol sodium more than 3 hours; then use hydrochloric acid conditioning solution PH to 6-7; evaporated under reduced pressure; methyl alcohol fully dissolves; filter, by filtrate evaporate to dryness, obtain the crude product of wintergreen oil maltoside.
Macroporous resin D101 purifying
Sample dry method is mixed sample upper prop, and sample is 1g: 2ml with the ratio of mixing sample resin, and the ratio of sample and upper prop resin is 1g: 20ml, first washes a column volume with water, discards.Use again 3 of 30% ethanolic soln wash-outs more than column volume to collect 30% ethanol eluate, concentrated evaporate to dryness.The method can effectively be removed pigment and water-soluble impurity, and eluate, obtains sterling through crystallization process.
Normal phase column chromatographic separation and purification salicylic acid glucosides methyl crude product:
Sample dry method is mixed sample upper prop, and sample is 1: 1.5 with the part by weight of mixing sample silica gel, sample: the part by weight of post silica gel is 1: 40, and eluting solvent is chloroform; Methyl alcohol, volume ratio is 4: 1, collects cut, thin layer testing conditions is chloroform: methyl alcohol: water volume ratio is 8: 2: 0.2, and purity reaches 98%.
The nuclear magnetic data of compound 1 and compound 2:
Compound 1 wintergreen oil lactoside; C
20h
28o
13; FW 476
1h-NMR (500MHz, DMSO) δ: 7.62 (1H, dd, J=8.0,2.0Hz, H-6), 7.52 (1H, dt, J=7.5,2.0Hz, H-4), 7.26 (1H, d, J=8.0Hz, H-3), 7.09 (1H, t, J=8.0Hz, H-5), 5.25 (1H, d, J=4.5Hz, H-1, gal), 4.99 (1H, d, J=8.0Hz, H-1, glu), 3.79 (3H, s, OCH
3), seven alcoholic extract hydroxyl group hydrogen signals are respectively: 5.08 (1H, d, J=4.5Hz), 4.77 (2H, s), 4.66 (1H, d, J=5.0Hz), 4.60 (1H, d, J=6.0Hz), 4.51 (1H, d, J=4.5Hz), 4.24 (1H, d, J=7.0Hz).On sugar, hydrogen signal appears at 3.77-3.39ppm (10H).
13c-NMR (125MHz, DMSO) δ: 166.3 (CO), 51.9 (OCH
3), phenyl ring carbon is attributed to by number successively: 155.9,133.2,121.7,121.3,130.3,116.3.The signal of glu is followed successively by 100.4,73.2, and 75.5,80.0,73.0,60.3.The signal of gal is attributed to 103.7,74.7, and 74.9,68.1,70.5,60.1.
Compound 2 wintergreen oil maltosides; C
20h
28o
13; FW 476
1h-NMR (500MHz, DMSO) δ: 7.62 (1H, d, J=8.0Hz, H-6), 7.51 (1H, dd, J=8.5,7.0Hz, H-4), 7.26 (1H, d, J=8.5Hz, H-3), 7.08 (1H, dd, J=8.5,7.0Hz, H-5), 5.59 (1H, d, J=3.0Hz, H-1, glu-1), 5.05 (1H, d, J=3.5Hz), 5.00 (1H, d, J=8Hz, H-1glu-1), 3.79 (3H, s, OCH
3), seven alcoholic extract hydroxyl group hydrogen signals are respectively: 5.43 (1H, d, J=5.5Hz), 5.19 (1H, d, J=5.0Hz), 4.97 (1H, d, J=8.0Hz), 4.90 (1H, d, J=5.0Hz), 4.88 (1H, d, J=5.0Hz), 4.54 (1H, d, J=5.0Hz), 4.50 (1H, d, J=6.0Hz).On sugar, hydrogen signal appears at 3.04-3.73ppm (10H).
13c-NMR (125MHz, DMSO) δ: 166.4 (CO), 51.9 (OCH
3), phenyl ring carbon is attributed to by number successively: 155.9,133.2,121.6,121.3,130.3,116.2.The signal of glu-1 is followed successively by 100.5,72.9, and 76.1,79.0,72.4,60.7.The signal of glu-2 is attributed to 100.7,73.5, and 75.3,69.9,73.3,60.2.
Pharmacological evaluation
The anti-inflammatory action of experimental example 1. compounds 1 in the mice ear model of Oleum Tiglii induction
Utilize the mice ear model of Oleum Tiglii induction to detect the anti-inflammatory action of sr-2.Get 30 of mouse, be divided at random 3 groups, be control group, acetylsalicylic acid (200mg/kg) group and compound 1 (400mg/kg) group, 1 group of difference gavage of acetylsalicylic acid group and compound is to 10mg/ml aspirin solution 20ml/kg and 20mg/ml compound 1 solution 20ml/kg, control group is to equivalent solvent, administration every day 1 time, administration 3 days.10min after last administration, by mouse etherization, the acetone soln that 50 μ l are contained to 1mg Oleum Tiglii is applied to mouse right ear inner side.After 3h, by sacrifice of animal, cut respectively the disk of diameter 8mm from the same position of mouse left and right ear, weigh, reflect its swelling with its weight differential.
Compound 1 (400mg/kg) can obviously suppress the mice ear that Oleum Tiglii causes, with 200mg/kg
Acetylsalicylic acid effect is (be shown in table 1) quite.
Table 1. compound 1 brings out the action effect of mice ear to Oleum Tiglii
| Group | Swelling degree (mg) | Inhibiting rate (%) |
| Contrast (n=10) | 19.3±1.3 | |
| Acetylsalicylic acid (200mg/kg, n=10) | 11.6±1.6* | 45 |
| Compound 1 (400mg/kg, n=10) | 12.8±1.8* | 39 |
Note: with control group comparison, compound 1 and acetylsalicylic acid all significantly suppress ear thickness (* P < 0.01).
The analgesic activity of experimental example 2. compounds 1 in the mouse writhing model of acetic-acid induced
Get 50 of mouse, be divided at random 5 groups, be i.e. control group, acetylsalicylic acid (200mg/kg) group, compound 1 (200,400 and 800mg/kg) group.Gavage is to 10mg/ml aspirin solution, 10mg/ml, 20mg/ml, 40mg/ml compound 1 solution 20ml/kg respectively for the each dosage group of acetylsalicylic acid group and compound 1, and control group is to equivalent solvent.Administration 3h pneumoretroperitoneum is injected 0.6% acetum 0.1ml/10g, observes immediately 5～15min writhing number of times after abdominal injection acetic acid, and with belly indent, trunk and back leg are upheld, and hips up is as the standard that produces writhing response.Compound 1200,400 and 800mg/kg group mouse writhing reaction times are significantly lower than blank group, inhibiting rate is respectively 45.84% (P < 0.05), 49.36% (P < 0.01) and 69.62% (P < 0.001), illustrate that compound 1 has obvious analgesic activity (in table 2).
The analgesic activity of table 2. compound 1 in the mouse writhing model of acetic-acid induced
| Group | Dosage (mg/kg) | N | Writhing number of times | Inhibiting rate (%) |
| Contrast | 0 | 10 | 29.04±3.05 | 0 |
| Compound 1 | 200 | 10 | 16.72±4.45 | 45.84* |
| Compound 1 | 400 | 10 | 15.73±3.56 | 49.36** |
| Compound 1 | 800 | 10 | 9.83±2.60 | 69.62*** |
| Acetylsalicylic acid | 200 | 10 | 7.67±2.12 | 77.07*** |
Note: writhing number of times represents with mean number ± S.E.M., * P < 0.05, material P < 0.01, * * * P < 0.001 represents the result with control group comparison.
Claims (16)
1. the wintergreen oil lactoside shown in formula (I):
2. the method for preparing compound described in claim 1, is characterized in that, comprises the steps:
(1), lactose and the synthetic full acetyl disaccharides of acetic anhydride reaction;
(2), full acetyl disaccharides is prepared into carbohydrate ligands;
(3), full acetyl disaccharides is prepared into carbohydrate ligands and the full acetylated glucosides of wintergreen oil salicylate methyl esters:
(4), the full acetylated glucosides deacetylation of wintergreen oil.
3. according to the preparation method of claim 2, it is characterized in that, under the condition that the reaction of step (one) lactose and acetic anhydride exists at catalyzer, carry out.
4. according to the preparation method of claim 3, it is characterized in that, described catalyzer is selected from pyridine, sodium acetate or perchloric acid.
5. according to the preparation method of any one in claim 2-4, it is characterized in that, the preparation method of step () is selected from either method in following 3:
(one, 1) lactose reacts in the mixing solutions of pyridine and acetic anhydride, after reaction terminating, and organic solvent extraction, the washing of washing extraction liquid is to neutral, and dry, evaporated under reduced pressure, obtains full acetylated disaccharides;
Or
(one, 2), by diacetyl oxide and anhydrous sodium acetate Hybrid Heating, adds lactose, and stirring reaction by reaction solution impouring trash ice, stirs after reacting completely, and has dope to separate out, and leaches solid; Water regulates pH value to pH6-7, then uses organic solvent extraction, washing extraction liquid, and dry, evaporate to dryness, merges the above-mentioned solid that leaches;
Or
(one, 3) diacetyl oxide and perchloric acid mix, then add lactose reaction, without separation and purification, directly carry out next step reaction.
6. according to the preparation method of claim 2, it is characterized in that, the method that in step (two), full acetyl disaccharides is prepared into carbohydrate ligands is selected from: full acetylated disaccharides and bromide reagent reaction; 1 first deacetylate of full acetylated disaccharides, then react the full acetylated carbohydrate ligands of Trichloroacetonitrile with Trichloroacetonitrile; Or after lactose and diacetyl oxide and perchloric acid reaction not separation and purification is directly and use phosphorus tribromide bromination.
7. according to the preparation method of claim 6, it is characterized in that, the method for step (two) is selected from either method in following 3:
Synthesizing of (two, 1), the full acetyl sugar of bromo:
By full acetylated disaccharides and bromide reagent reaction, after reaction terminating, organic solvent extracting extracts reaction solution, washing extraction liquid, and dry, evaporate to dryness organic solvent obtains the full acetyl sugar of bromo;
Or
Synthesizing of (two, 2), the full acetyl sugar of Trichloroacetonitrile:
(1), 1 deacetylate:
Full acetylated sugar is in anhydrous tetrahydro furan and benzylamine reaction, and after reaction terminating, organic solvent extraction, washs extraction liquid, dry, evaporated under reduced pressure;
(2), 1 activation:
Upper step product is dissolved in Trichloroacetonitrile, dichloromethane solution, then adds Anhydrous potassium carbonate, after reacting completely, filter, filtrate evaporate to dryness organic solvent obtains the full acetylated carbohydrate ligands of Trichloroacetonitrile;
Or
(two, 3), the direct bromination of phosphorus tribromide:
In the reaction flask of step (, 3), drip phosphorus tribromide, control temperature, add water, continue reaction to reacting completely.
8. according to the preparation method of claim 2, it is characterized in that, the method for step (three) is
Under the condition that wintergreen oil exists at organic solvent; be uniformly mixed with molecular sieve, heavy metal catalyst; add again carbohydrate ligands; after reaction finishes; elimination heavy metal catalyst, organic solvent extraction, washing extraction liquid; dry, evaporate to dryness organic solvent obtains the full acetylated glucosides of reaction product bigcatkin willow acid methyl esters.
9. preparation method according to Claim 8, is characterized in that, described heavy metal catalyst is selected from silver suboxide.
10. according to the preparation method of claim 2, it is characterized in that, the method for step (four) is
The full acetylated glucosides of wintergreen oil is dissolved in protic solvent, then adds sodium methylate reaction, then uses acid-conditioning solution PH to 6-7, evaporated under reduced pressure, and dissolve with methanol, by solution evaporate to dryness, obtains salicylic acid glucosides methyl.
11. 1 kinds of pharmaceutical compositions, is characterized in that, the claimed in claim 1 arbitrary compound that contains effective dose and pharmaceutically acceptable carrier.
12. according to the pharmaceutical composition of claim 11, it is characterized in that, described pharmaceutical composition is selected from tablet, capsule, pill, injection.
13. according to the pharmaceutical composition of claim 11, it is characterized in that, described pharmaceutical composition is selected from sustained release preparation, controlled release preparation or various particulate delivery system.
The compound of 14. claims 1 is in the application of preparing in antipyretic analgesics.
The compound of 15. claims 1 is in the application of preparing in anti-inflammation drugs.
The compound of 16. claims 1 is in the application of preparing in analgesic.
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| CN102526080B (en) * | 2011-12-12 | 2014-07-30 | 中国医学科学院药物研究所 | Medicinal composition and tablet containing salicylic acid methyl ester lactoside and preparation methods thereof |
| CN103181928B (en) * | 2011-12-28 | 2016-08-31 | 中国医学科学院药物研究所 | Salicylic acid glucosides methyl is in prevention and/or the application for the treatment of Alzheimer |
| WO2013152470A1 (en) * | 2012-04-09 | 2013-10-17 | 中国医学科学院药物研究所 | Ethyl salicylate glycosides compound, synthetic method and application thereof |
| CN106924272B (en) * | 2015-12-31 | 2021-04-13 | 中国医学科学院药物研究所 | Application of methyl salicylate glucoside in preparation of medicines for preventing and/or treating systemic lupus erythematosus and complications thereof |
| CN105622681B (en) * | 2016-02-29 | 2019-02-26 | 湘潭大学 | A method of preparing alkyl-β-D-Maltose glycosides |
| CN108239126B (en) * | 2016-12-26 | 2021-07-06 | 中国医学科学院药物研究所 | Salicylic acid methyl ester lactoside crystal III type solid matter, preparation method, composition and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1593428A (en) * | 2004-06-23 | 2005-03-16 | 合肥工业大学 | Dextran-aspirin combined medicine and its preparation method |
| WO2005075492A1 (en) * | 2004-02-03 | 2005-08-18 | Nippon Shinyaku Co., Ltd. | Prodrug comprising 5-aminosalicylate glycoside |
| CN1727354A (en) * | 2004-07-30 | 2006-02-01 | 丁怡 | Compound in category of trioside methyl salicylate, oside ester saccharide |
-
2009
- 2009-04-20 CN CN200910082224.0A patent/CN101863934B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005075492A1 (en) * | 2004-02-03 | 2005-08-18 | Nippon Shinyaku Co., Ltd. | Prodrug comprising 5-aminosalicylate glycoside |
| CN1593428A (en) * | 2004-06-23 | 2005-03-16 | 合肥工业大学 | Dextran-aspirin combined medicine and its preparation method |
| CN1727354A (en) * | 2004-07-30 | 2006-02-01 | 丁怡 | Compound in category of trioside methyl salicylate, oside ester saccharide |
Non-Patent Citations (1)
| Title |
|---|
| 蔡孟深，等.糖化学—基础、反应、合成、分离及结构.《糖化学—基础、反应、合成、分离及结构》.化学工业出版社,2007,(第1版),第38、73-77、114-121页. * |
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