CN101270052A - Eugenol aspirin ester pharmaceutical compound, preparation and preparing method - Google Patents
Eugenol aspirin ester pharmaceutical compound, preparation and preparing method Download PDFInfo
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- CN101270052A CN101270052A CNA200810017950XA CN200810017950A CN101270052A CN 101270052 A CN101270052 A CN 101270052A CN A200810017950X A CNA200810017950X A CN A200810017950XA CN 200810017950 A CN200810017950 A CN 200810017950A CN 101270052 A CN101270052 A CN 101270052A
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Abstract
The present invention discloses a compound for eugenol aspirin ester medicine, which has a structure as shown in formula (I). The compound has the characteristics of more obvious pharmacological effects and more stable structure. Aspirin is used as raw material, chloridized by acyle and has the esterification reaction in a menstruum; the compound can be prepared after re-crystallization. The compound for eugenol aspirin ester medicine is an effective medical component and can be used for treating various clinical high fever diseases by doctors for human beings and animals, in particular the high fever diseases caused by viral infection. And the compound can be used for solid preparation, liquid preparation, injection, ophthalmic preparation, ointment, suppository, pellicle, aerosol, or external preparation, so as to prevent thrombosis and fungal infection of the skin.
Description
Technical field
The present invention relates to medical technical field, exactly it is a kind of eugenol aspirin ester pharmaceutical compound and preparation and preparation method with analgesic, anti-inflammatory, analgesia, antithrombotic, antimycotic and antivirus action, and is the pharmaceutical preparation of formulations such as the made solid preparation of effective medicinal ingredients, liquid preparation, injection, ophthalmic preparation, ointment, suppository, film, aerosol or external preparation with this compound.
Background technology
Eugenol is the main component in the volatile oil that extracts in the dry flower of Chinese medicine Myrtaceae eugenia plant of clove (Eugenia caryophyllata Thumb).Pharmacological experiments shows, pharmacologically actives such as that Eugenol has is antiviral, antibiotic, analgesic, analgesia, anti-inflammatory, anti-oxidant, antiulcer agent, inhibition bowel movement, diarrhea, anti-hypoxia, inhibition arachidonic acid metabolism, platelet aggregation-against, anti-freezing, antithrombotic formation can be used for comprising treatment of diseases such as toothache, hepatopathy, gi tract; Also be useful on mould inhibitor production.But, owing to contain phenolic hydroxyl group in the Eugenol, itself have volatility and pungency, its application that room temperature has been placed also factor affecting such as instability.Therefore, be lead compound with the Eugenol, carry out structure of modification, it is particularly necessary that the development novel cpd seems.At present, be that the preparation and the preparation method of the eugenol ibuprofen ester of feedstock production declared patent with the Eugenol.And be that other Esters with dual function of feedstock production are not seen any report as yet with the Eugenol.
Summary of the invention
For develop with the Eugenol be feedstock production other have the value of the Ester of dual function, the present invention will provide a kind of eugenol aspirin ester pharmaceutical compound.
Another object of the present invention provides a kind of eugenol aspirin ester pharmaceutical compound and preparation and preparation method.
The object of the present invention is achieved like this:
A kind of eugenol aspirin ester pharmaceutical compound, it is to be raw material with Asprin, through chloride, carries out esterification in solvent, the compound that makes through recrystallization.The structure of this compound is shown in (I) formula:
Above-claimed cpd of the present invention, can synthesize in two steps:
1. in 250 milliliters there-necked flask of magnetic stirrer, thermometer is housed, add Asprin and DMF, sulfur oxychloride,, remove unreacted sulfur oxychloride under reduced pressure, be dissolved in benzene or the trichloromethane acyl chlorides stand-by in 60-75 ℃ of stirring reaction 2-3 hour;
2. in reaction flask, add Eugenol and water, under 5-10 ℃ of condition, add 5%NaOH solution and PEG-1000, stir, after 0.5 hour, in reaction flask, add above-mentioned stand-by acyl chlorides liquid, continue reaction 2-5 hour, standing demix, the organic phase concentrating under reduced pressure gets solids, recrystallizing methanol, get the white crystals product, yield 65%, fusing point are 71-72 ℃.
The structural confirmation analysis of eugenol aspirin ester
Ultimate analysis (%): C 69.94, and H 5.52, and O 24.54;
Ultra-violet absorption spectrum: in the interscan of 200-500 wavelength region, λ max is respectively 210,230,279nm with the methanol solution of compound;
Infrared absorption spectrum: charateristic avsorption band (cm
-1) 1762.9,1729.3cm
-1(C=O), 1606.05cm
-1(C=C);
Nucleus magnetic resonance: ((CD
3)
2SO, TMS, 400MHZ)
1HNMRδppm：8.126，7.750，7.471，7.306，7.071，6.992，6.813(6H，Ar-H)；5.979(1H，-CH＝)；5.090(2H，＝CH
2)；3.736(3H，OCH
3)；3.387(2H，-CH
2-)；2.215(3H，CH
3)
13CNMR δ ppm:169.116,162.142,150.620,150.505,139.220,134.993,122.159 (quaternary carbon); 137.435,135.001,131.727,126.516,124.341,122.536,120.396 (1C, CH); 116.070 (1C, CH
2); 113.010 (1C, CH); 55.714 (1C, CH
3); 39.347 (1C, CH
2); 20.668 (1C, CH
3)
Mass spectrum: M
+=326, in conjunction with results of elemental analyses, determine that molecular formula is C
19H
18O
5
Can prove that by above-mentioned test the molecular composition of the compound eugenol aspirin ester that the present invention is above-mentioned is C
19H
18O
5By mass spectrum as can be known, its molecular ion peak 326 is its molecular weight; By
1The HNMR spectrogram, and, can prove that its structure is as shown in (I) in conjunction with the integration analysis of ultraviolet and infared spectrum.
Relevant toxicology, pharmacodynamics test that the present invention carries out with the eugenol aspirin ester sample, test-results is as follows:
Acute toxicity effect experimental animal is a mouse, and karber's method carries out, and carboxymethylcellulose sodium solution is made suspension with eugenol aspirin ester and carried out, the result, and 20 mouse all do not cause death by 10000 milligrams of medicines of per kilogram of body weight, i.e. LD
50＞10000mg/kg, therefore, former medicine is actual nontoxic.
The analgesic activity experimental animal is a mouse, and hot plate method carries out, every group of 10 female mices, gastric infusion, Eugenol and Asprin contrast the results are shown in Table 1, and the effect that eugenol aspirin ester produces under same dose will be compared according to medicine Eugenol and Asprin strong.
Table 1 eugenol aspirin ester analgesic test result
| Compound | Dosage (mg/kg) | Turn round body number of times (X ± SD) |
| Eugenol aspirin ester | 0.5 | 2.2±1.2 |
| Eugenol | 0.5 | 6.6±5.2 |
| Acetylsalicylic acid | 0.5 | 7.2±4.6 |
| The blank group | - | 18.1±7.1 |
Anti-inflammatory action carries out with mice caused by dimethylbenzene xylene ear swelling model, 40 of the mouse (male and female half and half) that test restrains with body weight 18-22, every group 10, gastric infusion, Eugenol and Asprin are contrast, the results are shown in Table 2, the effect that eugenol aspirin ester produces under same dose will be compared according to medicine Eugenol and Asprin strong.
Table 2 eugenol aspirin ester anti-inflammatory action result
| Compound | Dosage (mg/kg) | The ear weight (X ± SD) |
| Eugenol aspirin ester | 0.5 | 6.9±2.2 |
| Eugenol | 0.5 | 10.3±3.3 |
| Acetylsalicylic acid | 0.5 | 7.6±2.6 |
| The blank group | - | 13.4±2.1 |
40 of the healthy male rats of refrigeration function, body weight 180～220g, animal rearing environment are routine cycle day and night, room temperature, and single cage is raised, ad lib food, water.Test and placed experimental situation to simulate experimental implementation (comprise and arrest, fix, lay thermometer) rat so that it adapts to experiment condition in preceding 3 days, every day 7～8h, the formal experiment of beginning in the 4th day divides 4 groups at random with 40 rats, every group 10, be respectively: control group subcutaneous injection physiological saline; Yeast group subcutaneous injection 10% yeast suspension; Eugenol aspirin ester group subcutaneous injection physiological saline, subcutaneous injection behind the 6h (10 μ g/kg) eugenol aspirin ester preparation; Analgesic group of subcutaneous injection 10% yeast suspension, subcutaneous injection behind the 6h (10 μ g/kg) eugenol aspirin ester injection liquid.Then rat is placed special Setup Box, the digital thermometer probe inserts rat rectum 6cm, and is fixed in root of the tail portion.3 mean values every 15 minutes note temperature are once got as basal body temperature in the stable back of rat.As a result, eugenol aspirin ester can make the body temperature of normal rat reduce about 1 ℃, but the body temperature of heating rat is reduced 2-3 ℃.
Bacteriostatic action is carried out the bacteriostatic activity test with the steel pipe method, the result shows, eugenol aspirin ester all has restraining effect in various degree to ox source golden staphylococci, pig gastro-enteritis bacterium, streptococcus dysgalactiae, streptococcus agalactiae, Pseudomonas aeruginosa, Salmonella gallinarum, Radix Polygalae Crotalarioidis bacterium, chicken colibacillus, and is especially stronger to pig gastro-enteritis bacterium, Pseudomonas aeruginosa, Salmonella gallinarum restraining effect.
The anti-platelet aggregation active function
Experimental animal: rabbit
The medicine collocation method:
Getting 65ml0.09% physiological saline, 35ml DMSO mixes and is made into standardized solution
Accurately take by weighing eugenol aspirin ester sample (being accurate to 0.001g), with the standardized solution dissolving, being made into concentration respectively is the solution for standby of 30 μ g/ml, 10 μ g/ml, 3 μ g/ml, 1 μ g/ml.
The positive control acetylsalicylic acid also is made into as above concentration respectively with standardized solution.
Experimental technique
In the 10ml plastic test tube, add 0.2ml 3.8% sodium citrate aqueous solution, carefully clean the rabbit ear with alcohol, clean the rabbit ear with dimethylbenzene again, treat to smear Vaseline at ear edge place after blood vessel expands, sever blood vessel, collect 10ml blood with the preparation test tube, blood is mixed,, isolate supernatant blood plasma PRP (being rich in thrombocyte blood plasma) with the centrifugal 2-3 of 900r/min rotating speed minute, then with the centrifugal 8-10 of rotating speed 3500r/min minute, isolate supernatant blood plasma PPP (the poor thrombocyte blood plasma that contains).
The accurate 300 μ l PRP of absorption add and assemble in the pipe, in assembling pipe, add 35% dimethyl sulphoxide aqueous solution, the 30 μ l that contain medicine, to be marked with the gathering pipe of the PRP of 300 μ l and PPP blood plasma respectively 37 ± 0.01 ℃ of preheatings, return to zero with PPP 300 μ l, adding 40 μ l arachidonic acid (ADP) induced platelets again in cuvette assembles, under 37 ℃ of agitation conditions, curve plotting, measure the thrombocyte MA, and compare with blank solvent, utilize following formula can calculate the IC of anticoagulant rate and sample platelet aggregation inhibitory activity
50Value.
The results are shown in Table 3, show that eugenol aspirin ester has significant inhibitory effect to the rabbit platelet aggregation of arachidonic acid-induction.Eugenol aspirin ester (IC
50=0.206 μ mol/ml) the rabbit anticoagulant effect to arachidonic acid-induction is better than acetylsalicylic acid (IC
50=0.451 μ mol/ml).
Table 3 compound is to the platelet aggregation inhibitory activity of arachidonic acid-induction
| Medicine | Maximal percentage inhibition (%) | IC 50(μmol/ml) |
| Eugenol aspirin ester | 52.6 | 0.206 |
| Asprin | 35.6 | 0.451 |
Therefore eugenol aspirin ester toxicity is little, has the characteristics of relieving inflammation and relaxing pain preferably, analgesic, anti-platelet aggregation, antibacterial antifungal effect, is expected to be developed to the multiple use newtype drug.
Advantage of the present invention is:
1, shows by above-mentioned relevant toxicology, pharmacodynamics test, eugenol aspirin ester pharmaceutical compound, have analgesic, analgesia, anti-inflammatory, antithrombotic agent, antimycotic and antivirus action, nontoxic, stability of drug is good, and some aspect of pharmacologically active effect can be better than present Eugenol and Asprin.Therefore, with this compound is effective constituent, pharmaceutical methods and processing requirement by present various routines, after and/or added ingredients auxiliary with acceptable in the pharmacy mixes, promptly can make can be used for treating on people doctor and the veterinary clinic due to various hyperpyrexia disease disease, the especially viral infections, the pharmaceutical preparation of various ways such as dermatophytid infection, the thrombotic corresponding oral solid formulation of prevention, liquid preparation, injection, ophthalmic preparation, ointment, suppository, film, aerosol or external preparation.
2, utilize the present invention can prepare the medicine of multiple formulation, can be doctor/animal doctor and patient on the kind of medication or being suitable for of patient bigger more valuable range of choice is provided.Particularly can prepare injection, the patient that adversary's postoperative can not be taken food provides convenience, improves the single situation of clinical application, rises to patient's service quality;
3, according to pharmacodynamics test report, some aspect of pharmacologically active effect of the present invention can be better than present Eugenol and Asprin, for the commercial operations of preparation provides test basis.
Embodiment
Below, by embodiment the present invention is described in further detail again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Eugenol aspirin ester pharmaceutical compound is to be raw material with Asprin, with the sulfur oxychloride reaction, generates needed compound through esterification again under the situation of organic solvent and catalyzer existence.
The concrete preparation route of eugenol aspirin ester is as follows:
In 250 milliliters there-necked flask of magnetic stirrer, thermometer is housed, add 3.6g Asprin and 1ml DMF, 2.8g sulfur oxychloride, in 60-75 ℃ of stirring reaction 2-3 hour, remove unreacted sulfur oxychloride under reduced pressure, be dissolved in 8ml benzene or the 8ml trichloromethane acyl chlorides of gained stand-by.In reaction flask, add 3.3g Eugenol and 5ml water, under 5-10 ℃ of condition, add 16ml 5%NaOH solution and PEG-1000, stir, add above-mentioned stand-by acyl chlorides liquid after 0.5 hour, continue reaction 2-5 hour.Standing demix, the organic phase concentrating under reduced pressure gets solids, and recrystallizing methanol gets the white crystals product, and yield 65%, fusing point are 71-72 ℃.
The present invention is effective medicinal ingredients with the eugenol aspirin ester pharmaceutical compound of above-mentioned preparation, and the solid preparation of making after and/or added ingredients auxiliary with acceptable in the pharmacy mixes comprises tablet, capsule, pill, granule; Described external preparation comprises common mucocutaneous medication and eye drops; Described injection comprises the medicine at different application targets such as injection liquid and freeze-dried powder formulation, position.
Embodiment 1
Prescription: Eugenol acetylsalicylic acid ester 25mg
Medium chain triglycerides 34-50mg
Soybean phospholipid 20-30mg
Polyoxyethylene glycol-12-hydroxy stearic acid ester 20-30mg
Dehydrated alcohol 30-40mg
PEG-400 10-20mg
Water 180-300ml
Method for making: Eugenol acetylsalicylic acid ester is dissolved in the medium chain triglycerides that contains dehydrated alcohol, PEG-400, soybean phospholipid, polyoxyethylene glycol-12-hydroxy stearic acid ester, and 37 ℃ of following stirrings are spent the night to balance; Water titration oil phase just can form the Eugenol acetylsalicylic acid ester microemulsion of stable homogeneous.
Embodiment 2
Prescription: Eugenol acetylsalicylic acid ester 25mg
Phosphatidase 14 0-60mg
Cholesterol 10-40mg
Chloroform 20-30mg
Water 2-3ml
Method for making: Eugenol acetylsalicylic acid ester is dissolved in the chloroformic solution that contains phosphatide, cholesterol, and rotary evaporation is gone out chloroform and is formed the phosphide film; Water dissolved phosphorus adipose membrane is through the liposome of the ultrasonic formation homogeneous of cell pulverization.
Embodiment 3
Prescription: Eugenol acetylsalicylic acid ester 25mg
Phosphatidase 14 0-60mg
Poloxamer 188 10-40mg
Mono-glycerides 10-40mg
Water 2-3ml
Method for making: Eugenol acetylsalicylic acid ester is dissolved in the hot solution that contains phosphatide, mono-glycerides, stirs, the aqueous solution that will contain poloxamer 188 is added dropwise to oil phase, and thorough mixing becomes colostrum, again through the ultrasonic formation solid lipid nanoparticle of cell pulverization.
Embodiment 4
Prescription: Eugenol acetylsalicylic acid ester 100g
Ethanol (75%) adds to 1000ml
Method for making: get eugenol aspirin ester and be dissolved in the ethanol, filter, add 75% ethanol again, make 1000ml, stir evenly, promptly get the liquid preparation paint.
Embodiment 5
Prescription: Eugenol acetylsalicylic acid ester 25mg
PEG-6000 120-140mg
Amylum pregelatinisatum 200mg
CMS-Na 40mg
Magnesium Stearate 30mg
Method for making: with the PEG-6000 100mL beaker of packing into, place to heat to make in the water-bath and be melted into settled solution, to take by weighing 25mg Eugenol acetylsalicylic acid ester fine powder adds wherein, stirring makes dispersing and dissolving, the refrigerator of putting into-20 ℃ rapidly solidifies, pulverized 60 mesh sieves, got Eugenol acetylsalicylic acid ester PEG-6000 solid dispersion, preserved standby in the moisture eliminator.Cross the 80-100 mesh sieve with amylum pregelatinisatum then and mix, add CMS-Na and Magnesium Stearate again and mix the back direct compression promptly.
Embodiment 6
Prescription: Eugenol acetylsalicylic acid ester 25mg
Beta-cyclodextrin 120-140mg
Amylum pregelatinisatum 200mg
CMS-Na 40mg
Magnesium Stearate 30mg
Method for making: accurately take by weighing 130mg β-CD in the 100mL Erlenmeyer flask, add 8mL distilled water, heating for dissolving.Taking by weighing 25mg Eugenol acetylsalicylic acid ester is dissolved in the 3mL dehydrated alcohol it, slowly drip in β-CD, and on magnetic stirring apparatus stir about 6h, after placing 10h in the refrigerator, suction filtration, dry 8h under 80 ℃ makes Eugenol acetylsalicylic acid ester beta cyclodextrin clathrate, cross the 80-100 mesh sieve with amylum pregelatinisatum behind the porphyrize and mix, add evenly back direct compression of CMS-Na and Magnesium Stearate remix.
Embodiment 7
Prescription: Eugenol acetylsalicylic acid ester 1g
Icing Sugar 9g
Dextrin 10
50% ethanol (volume fraction) 20ml
Method for making: eugenol aspirin ester, dextrin, Icing Sugar are crossed 100 mesh sieves respectively, progressively increase method with eugenol aspirin ester and auxiliary material-dextrin, Icing Sugar mixing by equivalent, add 50% ethanol (volume fraction) again in said mixture, mixing, the system softwood is crossed 16 order nylon mesh and granulated, and is dry below 60 ℃, plastic bag packaging is used in whole grain back, promptly gets granule.
Embodiment 8
Prescription: Eugenol acetylsalicylic acid ester 1g
PEG6000 2g
Method for making: get PEG6000 in furnace pot, heat fused in water-bath, add the eugenol aspirin ester stirring again and make it dissolving, insulation, utilize the dripping pill device that above-mentioned eutectic mixture is dripped in cold water refrigerative whiteruss, collect dripping pill, drop is clean and put dry liquids paraffin on the skin, place seasoning, promptly get dripping pill.
Embodiment 9
Prescription: Eugenol acetylsalicylic acid ester 10g
Lime carbonate 210g
Starch 21g
Ethanol 40ml
Method for making: with lime carbonate and starch mixing, cross the 80-100 mesh sieve, again with the eugenol aspirin ester mixing of using the 40ml dissolve with ethanol, cross sieve No. seven, in 50-60 ℃ of oven dry, encapsulated, make 1000 altogether, every contains Eugenol acetylsalicylic acid ester 10mg, promptly gets capsule.
Embodiment 10
Prescription: Eugenol acetylsalicylic acid ester 1g
Semi-synthetic fatty acid ester is an amount of
Make 10 pieces altogether
Method for making: get Eugenol acetylsalicylic acid ester and cross the 80-100 mesh sieve; The semi-synthetic fatty acid ester that takes by weighing melts in water-bath, and the Eugenol acetylsalicylic acid ester fine powder of screening is added in the fused fatty acid ester matrix, stir, make into uniform suspension, inject the bolt film, scrape off unnecessary base-material after cooling, the demoulding promptly gets suppository.
Embodiment 11
Prescription: Eugenol acetylsalicylic acid ester 20g
Single stearic acid glycerine lipoprotein 70g
Stearic acid 110g
Glycerine 85g
White vaseline 85g
Sodium lauryl sulphate 10g
Ethyl p-hydroxybenzoate 1g
Adding distil water is to 1000g
Method for making: get it filled thing single stearic acid glycerine lipoprotein, white vaseline, stearic acid, place the vessel in heating fusing, keep 80 ℃, get sodium lauryl sulphate, glycerine, distilled water in addition and place another container, be heated to 80 ℃, add ethyl p-hydroxybenzoate, slowly add in the above-mentioned oil phase after the dissolving, be stirred to the fine and smooth paste that is white in color by same direction, condensation promptly gets ointment.
Embodiment 12
Prescription: Eugenol acetylsalicylic acid ester 20g
Vaseline 980g
Make 1000g
Method for making: get Vaseline, heating makes its 1/2～3/5 fusing, stirs, and when treating that temperature is reduced to below 50 ℃, adds the eugenol aspirin ester fine powder, with adding with stirring, continues stirring until condensation, promptly gets ointment.
Embodiment 13
Prescription: Eugenol acetylsalicylic acid ester 1.2g
Xylo-Mucine 3g
Polyvinyl alcohol (17-88) 1g
Gelatin 1g
Laurocapram 1ml
Propylene glycol 2ml
Tween-80 2ml
Adding distil water is to 100ml
Method for making: get Xylo-Mucine, polyvinyl alcohol, gelatin adding 70ml distilled water, stir, soak 24h, make its abundant swelling, be heated to dissolving in 90 ℃ of water-baths, it is standby to get rubber cement; Get eugenol aspirin ester, laurocapram, propylene glycol and Tween-80, place mortar successively, fully be ground to uniform and smooth.Under agitation it slowly is added in the above-mentioned rubber cement, adds 30ml distilled water, stir evenly, promptly get the film rubber cement to capacity.Place, remove bubble, treat that bubble eliminates after, the impouring of film rubber cement was coated with in advance on the aseptic sheet glass of Oils,glyceridic,cod-liver, make film by hand.Seasoning or put 50 ℃ of left and right sides loft drier inner drying rear demouldings.Calculate dosage, cut into 1.5cm
2Fritter, in the aseptic technique cupboard, with ultra violet lamp medicine film 15min, sterilization is packaged in the aseptic glassine paper, promptly gets film.
Embodiment 14
Prescription: Eugenol acetylsalicylic acid ester 10g
Viscotrol C adds to 1000ml
Method for making: get eugenol aspirin ester with aseptic method and place drying receptacle, add aseptic Viscotrol C, stir, be sub-packed in the 10ml eye drop bottle, promptly get eye drops to 1000ml.
Embodiment 15
Prescription: Eugenol acetylsalicylic acid ester 20g
Glycerine 50g
Laurocapram 5g
60% ethanol adds to 1000ml
Method for making: get eugenol aspirin ester and add 60% ethanol 800ml and stir and to make dissolving, add laurocapram, glycerine more successively, the dissolving after-filtration, filtered liquid adds 60% ethanol to full dose, is sub-packed in the dynalysor after stirring evenly, and promptly gets sprays.
Claims (19)
1. eugenol aspirin ester pharmaceutical compound, it can be described as the 2-acetoxy-benzoic acid, 2 '-methoxyl group-4 '-(2 '-allyl group) phenyl ester, it is characterized in that: the structural formula of compound is shown in (I):
2. method for preparing the described eugenol aspirin ester pharmaceutical compound of claim 1, its preparation route is as follows,
In 250 milliliters there-necked flask of magnetic stirrer, thermometer is housed, add Asprin and DMF, sulfur oxychloride, in 60-75 ℃ of stirring reaction 2-3 hour, remove unreacted sulfur oxychloride under reduced pressure, be dissolved in benzene or the trichloromethane acyl chlorides stand-by; In reaction flask, add Eugenol and water, under 5-10 ℃ of condition, add 5%NaOH solution and PEG-1000, stir, after 0.5 hour, in reaction flask, add above-mentioned stand-by acyl chlorides liquid, continue reaction 2-5 hour, standing demix, the organic phase concentrating under reduced pressure gets solids, recrystallizing methanol, get the white crystals product, yield 65%, fusing point are 71-72 ℃.
3. the preparation of an eugenol aspirin ester pharmaceutical compound as claimed in claim 1, it is characterized in that: with eugenol aspirin ester pharmaceutical compound is effective medicinal ingredients, injection, solid preparation, liquid preparation, ophthalmic preparation, ointment, suppository, film, aerosol or the external preparation made after and/or added ingredients auxiliary with acceptable in the pharmacy mixes.
4, the method for preparing the eugenol aspirin ester pharmaceutical compound preparation as claimed in claim 3 is characterized in that: solid preparation is tablet or capsule or pill or granule.
5. the method for preparing the eugenol aspirin ester pharmaceutical compound preparation as claimed in claim 3, it is characterized in that: eugenol aspirin ester is dissolved in the medium chain triglycerides that contains dehydrated alcohol, PEG-400, soybean phospholipid, polyoxyethylene glycol-12-hydroxy stearic acid ester, 37 ℃ of following stirrings are spent the night to balance; Water titration water can form the Eugenol acetylsalicylic acid ester microemulsion of stable homogeneous.
6. the method for preparing the eugenol aspirin ester pharmaceutical compound preparation as claimed in claim 3 is characterized in that: eugenol aspirin ester is dissolved in contains in phosphatide, cholesterol and the chloroformic solution, rotary evaporation is removed chloroform and is formed immobilized artificial membrane; Water dissolved phosphorus adipose membrane is through the liposome of the ultrasonic formation homogeneous of cell pulverization.
7. the method for preparing the eugenol aspirin ester pharmaceutical compound preparation as claimed in claim 3, it is characterized in that: eugenol aspirin ester is dissolved in the hot solution that contains phosphatide, mono-glycerides, stir, the aqueous solution that will contain poloxamer 188 is added dropwise to oil phase and thorough mixing becomes colostrum, again through the ultrasonic formation solid lipid nanoparticle of cell pulverization.
8. the method for preparing the eugenol aspirin ester pharmaceutical compound preparation as claimed in claim 3 is characterized in that: get eugenol aspirin ester and be dissolved in the ethanol, filter, add 75% ethanol again, constant volume stirs evenly, and promptly gets the liquid preparation paint.
9. as claim 3 or the 4 described methods that prepare the eugenol aspirin ester pharmaceutical compound preparation, it is characterized in that: eugenol aspirin ester solid dispersion and amylum pregelatinisatum sieve and mix, add again after CMS-Na and Magnesium Stearate mix, directly be pressed into tablet.
10. as claim 3 or the 4 described methods that prepare the eugenol aspirin ester pharmaceutical compound preparation, it is characterized in that: eugenol aspirin ester beta cyclodextrin clathrate and amylum pregelatinisatum are sieved to mix, add after CMS-Na and Magnesium Stearate mix the direct compression agent again.
11. as claim 3 or the 4 described methods that prepare the eugenol aspirin ester pharmaceutical compound preparation, it is characterized in that: get PEG6000 in furnace pot, heat fused in water-bath, add the eugenol aspirin ester stirring again and make dissolving, insulation utilizes the dripping pill device that above-mentioned eutectic mixture is dripped in cold water refrigerative whiteruss, collects dripping pill, drop is clean and put dry liquids paraffin on the skin, places seasoning and promptly gets dripping pill.
12. as claim 3 or the 4 described methods that prepare the eugenol aspirin ester pharmaceutical compound preparation, it is characterized in that: eugenol aspirin ester, dextrin, Icing Sugar are crossed 100 mesh sieves respectively, progressively increase method with eugenol aspirin ester and dextrin, Icing Sugar mixing by equivalent, add 50% ethanol again in said mixture, mixing, system softwood, crossing 16 order nylon mesh granulates, dry below 60 ℃, whole grain back plastic bag packaging gets granule.
13. as claim 3 or the 4 described methods that prepare the eugenol aspirin ester pharmaceutical compound preparation, it is characterized in that: with lime carbonate and starch mixing, sieve, again with the eugenol aspirin ester mixing of using dissolve with ethanol, cross sieve No. seven, in 50-60 ℃ of oven dry, incapsulate, be capsule.
14. the method for preparing the eugenol aspirin ester pharmaceutical compound preparation as claimed in claim 3, it is characterized in that: get eugenol aspirin ester and cross the 80-100 mesh sieve, semi-synthetic fatty acid ester with taking by weighing melts in water-bath, and the Eugenol acetylsalicylic acid ester fine powder that sieves is added in the fused fatty acid ester matrix, stir, make into uniform suspension, behind the injection bolt film, scrape off unnecessary base-material after the cooling, the demoulding promptly gets suppository.
15. the method for preparing the eugenol aspirin ester pharmaceutical compound preparation as claimed in claim 3, it is characterized in that: get it filled thing glyceryl monostearate, white vaseline, stearic acid, place vessel in heating fusing, keep 80 ℃, get sodium lauryl sulphate, glycerine, distilled water in addition and place another container, be heated to 80 ℃, add ethyl p-hydroxybenzoate, slowly add after the dissolving in the above-mentioned oil phase, be stirred to the fine and smooth paste that is white in color by same direction, condensation promptly gets ointment.
16. the method for preparing the eugenol aspirin ester pharmaceutical compound preparation as claimed in claim 3, it is characterized in that: get Vaseline, heating makes 1/2～3/5 fusing, stir, when treating that temperature is reduced to below 50 ℃, add the eugenol aspirin ester fine powder, with adding with stirring, continue stirring until condensation, promptly get ointment.
17. the method for preparing the eugenol aspirin ester pharmaceutical compound preparation as claimed in claim 3, it is characterized in that: get Xylo-Mucine, polyvinyl alcohol, gelatin and add an amount of distilled water, stir, soak 24h, make its abundant swelling, be heated to dissolving in 90 ℃ of water-baths, it is standby to get rubber cement; Get eugenol aspirin ester, laurocapram, propylene glycol and Tween-80, place mortar successively, fully be ground to uniform and smooth; Under agitation it slowly is added in the above-mentioned rubber cement, adding distil water stirs evenly to capacity, promptly gets the film rubber cement; Place, remove bubble, treat that bubble eliminates after, the impouring of film rubber cement was coated with in advance on the aseptic sheet glass of Oils,glyceridic,cod-liver, make film by hand; Seasoning or put 50 ℃ of left and right sides loft drier inner drying rear demouldings; Calculate dosage, cut into 1.5cm
2Fritter, in the aseptic technique cupboard, with ultra violet lamp medicine film 15min, sterilization is packaged in the aseptic glassine paper, promptly gets film.
18. the method for preparing the eugenol aspirin ester pharmaceutical compound preparation as claimed in claim 3, it is characterized in that: get eugenol aspirin ester with aseptic method and place drying receptacle, add aseptic Viscotrol C constant volume, stir, be sub-packed in the eye drop bottle, promptly get eye drop.
19. the method for preparing the eugenol aspirin ester pharmaceutical compound preparation as claimed in claim 3, it is characterized in that: get eugenol aspirin ester and add 60% ethanol and stir and to make dissolving, add laurocapram, glycerine more successively, the dissolving after-filtration, filtered liquid adds 60% ethanol to full dose, be sub-packed in after stirring evenly in the dynalysor, promptly get sprays.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104151167A (en) * | 2013-05-14 | 2014-11-19 | 中国农业科学院兰州畜牧与兽药研究所 | Preparation method for medicinal compound aspirin eugenol ester |
| CN105796575A (en) * | 2016-04-12 | 2016-07-27 | 中国农业科学院兰州畜牧与兽药研究所 | Application of Aspirin eugenol ester in preparation of drug for preventing or treating atherosclerosis |
| CN106349076A (en) * | 2016-08-26 | 2017-01-25 | 中国农业科学院兰州畜牧与兽药研究所 | Crystal form B of aspirin eugenol ester and preparation method thereof |
| CN108635358A (en) * | 2018-06-15 | 2018-10-12 | 中国农业科学院兰州畜牧与兽药研究所 | Aspirin eugenol ester is preparing the application in preventing or treating Alzheimer disease drugs |
| CN109172582A (en) * | 2018-10-13 | 2019-01-11 | 李瑞清 | Salicylic acid eugenol ester synthetic method and its application in field of medicaments |
| CN113387809A (en) * | 2020-03-11 | 2021-09-14 | 中国农业科学院兰州畜牧与兽药研究所 | Aspirin eugenol ester process impurity and preparation method thereof |
-
2008
- 2008-04-08 CN CN200810017950XA patent/CN101270052B/en active Active
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104151167A (en) * | 2013-05-14 | 2014-11-19 | 中国农业科学院兰州畜牧与兽药研究所 | Preparation method for medicinal compound aspirin eugenol ester |
| CN104151167B (en) * | 2013-05-14 | 2016-04-20 | 中国农业科学院兰州畜牧与兽药研究所 | A kind of preparation method of medicinal compound acetylsalicylic acid eugenol ester |
| CN105796575A (en) * | 2016-04-12 | 2016-07-27 | 中国农业科学院兰州畜牧与兽药研究所 | Application of Aspirin eugenol ester in preparation of drug for preventing or treating atherosclerosis |
| CN106349076A (en) * | 2016-08-26 | 2017-01-25 | 中国农业科学院兰州畜牧与兽药研究所 | Crystal form B of aspirin eugenol ester and preparation method thereof |
| CN108635358A (en) * | 2018-06-15 | 2018-10-12 | 中国农业科学院兰州畜牧与兽药研究所 | Aspirin eugenol ester is preparing the application in preventing or treating Alzheimer disease drugs |
| CN108635358B (en) * | 2018-06-15 | 2021-07-02 | 中国农业科学院兰州畜牧与兽药研究所 | Application of aspirin eugenol ester in preparation of medicine for preventing or treating Alzheimer disease |
| CN109172582A (en) * | 2018-10-13 | 2019-01-11 | 李瑞清 | Salicylic acid eugenol ester synthetic method and its application in field of medicaments |
| CN113387809A (en) * | 2020-03-11 | 2021-09-14 | 中国农业科学院兰州畜牧与兽药研究所 | Aspirin eugenol ester process impurity and preparation method thereof |
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|---|---|
| CN101270052B (en) | 2010-06-09 |
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