CN102772402A - Application of ascorbyl ibuprofenate in preparing brain-targeted preparation and preparation method thereof - Google Patents
Application of ascorbyl ibuprofenate in preparing brain-targeted preparation and preparation method thereof Download PDFInfo
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Abstract
The invention discloses application of ascorbyl ibuprofenate in preparing a brain-targeted preparation and a preparation method thereof. The preparation method comprises the following steps: reaction of vitamin C and benzyl bromide to generate vitamin C2, 3- site hydroxy protective reaction, 6- site esterification reaction, and debenzylation reaction. The invention has the advantages of simple method, high yield, cheap and accessible reactants, low production cost and the like. The experiment proves that the ascorbyl ibuprofenate (IAA) is stable in plasma and can be quickly hydrolyzed into ibuprofen in brains. The mouse in-vivo distribution result indicates that after injecting the ascorbyl ibuprofenate via the caudal vein, the ibuprofen concentration in brains is obviously higher than the ibuprofen unit (IBU), and the AUC0-8h is twice as the IBU, which indicates strong brain targeting action.
Description
Technical field
The present invention relates to preparation and application, especially vitamin C-ibuprofen ester application in preparation brain targeting preparation of prodrugs of ibuprofen and preparation method thereof.
Background technology
Non-steroidal anti-inflammatory drug (NSAID) are a class of drugs widely used in recent years, there is much evidence that non-steroidal anti-inflammatory drugs can serve as a neuroprotective agent, Summerside for Alzheimer disease (AD) and neuropathic prevention and treatment of disease.Therapeutics research shows that life-time service NSAID can reduce the risk of suffering from AD.Experiment in vitro shows that NSAID can suppress amyloid-beta (A β) propagation, reduces the generation of A β, and the activity of restriction microgliacyte and astrocyte.Many NSAID have curative effect preferably to AD, and like ibuprofen, BTS-18322 and indomethacin etc., but their distributions in brain are few.Mainly be to hinder because of the picked-up and the utilization existence of brain to acid NSAID.Its brain drug delivery is the same with most drug, all receives the restriction of blood brain barrier (BBB).Most NSAID has lipotropy, might go into brain through passive transport, but under the physiological pH condition, the hydroxy-acid group of NSAID all exists with ionic species, appreciable impact passive diffusion transhipment; BBB also expresses a large amount of transporters, between brain and blood plasma, forms significant Concentraton gradient, wherein has many transporters to confirm all can combine with NSAID.In addition, NSAID and serum albumin all have stronger adhesion, make the Cf of blood plasma Chinese medicine be lower than 5%, and this also produces certain influence to its distribution in brain.
Ibuprofen because in the similar medicine of NSAID, have the curative effect height, toxicity is low, has clinical value.However, due to traditional formulations of ibuprofen is difficult through the blood-brain barrier in the brain distribution of rare, largely limits the ibuprofen as a neuroprotective agent, Summerside for Alzheimer disease (AD) and neurological lesions of the extensive application.Therefore, design that a kind of safe and effective to improve ibuprofen brain targeting preparation of distributed density in brain be the key that addresses the above problem.
Summary of the invention
For solving the problems of the technologies described above; The invention provides the brain targeting preparation of a kind of prodrugs of ibuprofen as ibuprofen; It is vitamin C-ibuprofen ester; This prodrug is linked to each other synthetic with ester bond by vitamin C and ibuprofen, be easy to see through blood brain barrier, and in brain, be hydrolyzed to ibuprofen and vitamin C performance synergistic therapeutic action.
Experiment showed, that the saturation solubility of prodrug vitamin C-ibuprofen ester in water compare with ibuprofen, improved nearly 10 times.Compare with ibuprofen, vitamin C-ibuprofen ester lipid drops to 7.3 from 13.Vitamin C-ibuprofen ester stability in different pH buffer is different, and is more stable in acid and neutral environment, and degraded rapidly under alkali condition.Hatch the result in 37 ℃ of blood plasma and show, vitamin C-ibuprofen ester is in the slow hydrolysis of blood plasma, and 1 hour degradation amount is about 10%, guarantees that it is not hydrolyzed before arriving BBB.Hydrolysis rate is very fast in brains, hydrolysis 50% approximately in 1 hour, and product is an ibuprofen, and basic hydrolysis is complete after 8 hours, prompting vitamin C-ibuprofen ester can transform ibuprofen performance drug effect rapidly in brain.
Behind intravenous injection vitamin C-ibuprofen ester, its hydrolyzate ibuprofen mouse core, liver, lung, etc. organ-tissue distribute and descend, in brain, obviously raise.The AUC of vitamin C-ibuprofen ester group
0 → 8hBe 2 times of the ibuprofen group, targeting index Tl is 199.82 %, and total targeting efficient RTE is 78%.The holdup time of vitamin C-ibuprofen ester in blood plasma and brain improved 1.5 times and 1.4 times respectively, pointed out the brain targeting of vitamin C-ibuprofen ester.
Ascorbic acid (AscorbicAcid), i.e. vitamin C as the necessary nutrient substance of human body, plays an important role to the normal operation of brain.Being proved the intrasystem ascorbic acid concentrations of human central nervous is 200 times in the blood.Because vitamin C is physiological endogenous material, " nutrient substance (or derivant)-medicine " type prodrug also is that safe----prodrug regenerates nutrient substance usually after hydrolysis, can supply the body utilization.On several animal models, ascorbic brain protection's effect all is proved.Therefore, can predict that vitamin C-ibuprofen ester is a safety to human body.
For making things convenient for the preparation of this prodrug, the present invention further discloses the method for preparing of vitamin C-ibuprofen ester.With the ibuprofen is initiation material, adopts three-step reaction, and esterification, the deprotection reaction of promptly ascorbic prosposition hydroxyl protection reaction, 6 hydroxyls and ibuprofen obtain target compound vitamin C-ibuprofen ester.This method may further comprise the steps:
1) vitamin C prosposition hydroxyl protection reaction: vitamin C, potassium carbonate are dissolved in the dimethyl sulfoxide, stir under the room temperature after 2 hours, add bromobenzyl reaction 3-6 hour.Vitamin C, potassium carbonate and bromobenzyl mol ratio are 1 ~ 3:2 ~ 5:1 ~ 4.
2) 6 bit esterified reactions: the vitamin C and the ibuprofen of above-mentioned 2,3 benzyl protections are dissolved in the dimethyl formamide; The 4-2 methylamino pyridine that adds catalytic amount stirred after 10 minutes; Add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (EDCI), room temperature lower seal reaction 4 ~ 8 hours.2, the vitamin C of 3 benzyl protections, ibuprofen and EDCI mol ratio are 1 ~ 3:2 ~ 4:1 ~ 3.
3) debenzylation: the vitamin C-ibuprofen ester of 2,3 benzyl protections of above-mentioned product is dissolved in the methanol, adds 5% palladium carbon, under the room temperature in the pure hydrogen environment sealed reaction 24 ~ 48 hours, obtain vitamin C-ibuprofen ester.
Above-mentioned reaction is operation at room temperature all.Above-mentioned product warp
1HNMR,
13CNMR, UV, IR, MS etc. have carried out structural identification.
13CNMR result shows that 2 the C=O chemical displacement values in 170 ppm to 180 ppm places are corresponding with the new carbonyl that forms with the lactonic ring of vitamin C-ibuprofen ester; The chemical shift of phenyl ring carbon is high-visible; 120,155 ppm are for connecting the prosposition carbon geochemistry shift value of OH;
1The HNMR integral result surely closes with target compound hydrogen number except that active hydrogen mutually; UV as a result the absorption maximum of display-object chemical compound at the 225nm place.Fourier infrared spectrophotometer testing result shows that chemical compound has the flexible strong vibration peak of tangible OH base absworption peak and C=O key.The ESI-MS negative electricity is 363 from the molecular ion peak that produces, and proves conclusively to be target compound (molecular weight 364.4).
Have following advantage with respect to prior art the present invention:
1. the present invention has successfully solved ibuprofen first in the low problem of brain giving drugs into nose concentration profile; Employed vitamin C-ibuprofen ester brain targeting targeting index of boiling medicine is high.
2. the simple productive rate of the method for preparing of this targeting prodrug is high, and reactant is cheap and easy to get, and production cost is low.
Description of drawings
Fig. 1 is the synthetic route chart of vitamin C-ibuprofen ester.
Fig. 2 is the stability curve figure of vitamin C-ibuprofen ester in different buffer solution.
Fig. 3 is the stability of vitamin C-ibuprofen ester in blood plasma and brains.
Fig. 4 is IAA and hydrolyzate ibuprofen (IBU) molar concentration change curve thereof in the brains that records after vitamin C-ibuprofen ester (IAA) is hatched in brains.
Fig. 5 be respectively in intravenous injection vitamin C-ibuprofen ester (IAA) and ibuprofen (IBU) the back mouse brain ibuprofen through the time curve.
Fig. 6 be respectively in intravenous injection vitamin C-ibuprofen ester (IAA) and ibuprofen (IBU) the back mice plasma ibuprofen through the time curve.
Fig. 7 be respectively in intravenous injection vitamin C-ibuprofen ester (IAA) and ibuprofen (IBU) the back mouse heart ibuprofen through the time curve.
Fig. 8 be respectively in intravenous injection vitamin C-ibuprofen ester (IAA) and ibuprofen (IBU) the back mouse liver ibuprofen through the time curve.
Fig. 9 be respectively in intravenous injection vitamin C-ibuprofen ester (IAA) and ibuprofen (IBU) the back mice lungs ibuprofen through the time curve.
Figure 10 be respectively in intravenous injection vitamin C-ibuprofen ester (IAA) and ibuprofen (IBU) the back mouse kidney ibuprofen through the time curve.
The specific embodiment
One, vitamin C-ibuprofen ester is synthetic.
1. vitamin C prosposition hydroxyl protection.
In being full of the eggplant-shape bottle of nitrogen, add vitamin C, potassium carbonate and dimethyl sulfoxide, stirring at room makes dissolving, adds behind the bromobenzyl stirring at room 4-5 hour.The mol ratio of vitamin C, potassium carbonate and bromobenzyl is 1:3.2:2.2.Use ethyl acetate extraction behind the reactant liquor thin up.Ethyl acetate layer is through anhydrous sodium sulfate drying, and decompression volatilizes revolves, and gets the glutinous thick liquid of pale brown color.Through silica gel column chromatography (ethyl acetate-petroleum ether, volume ratio 1:1) separate faint yellow oily thing, be the vitamin C of 2,3 benzyl protections through detecting, synthetic route is as shown in Figure 1.
2. 6 bit esterified reactions.
Take by weighing the vitamin C of ibuprofen and 2,3 benzyl protections respectively, add the anhydrous methylene chloride stirring and make dissolving, add 4-dimethylamino naphthyridine (DMAP) and 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (EDCI), reacted 6 hours.2, the mol ratio of the vitamin C of 3 benzyl protections, ibuprofen and EDCI is 1:1.3:1.Washing, decompress filter, filtrating use ethyl acetate extraction, ethyl acetate layer is through anhydrous sodium sulfate drying, reduce pressure volatilize yellow oil.Through silica gel column chromatography (ethyl acetate-petroleum ether, volume ratio 1:6) separate faint yellow oily thing, i.e. vitamin C-the ibuprofen ester of 2,3 benzyl protections, synthetic route is as shown in Figure 1.
3. debenzylation.
Get the vitamin C-ibuprofen ester of 2,3 benzyl protections, add in three mouthfuls of round-bottomed flasks, add dissolve with methanol, gradation adds 5% palladium charcoal rapidly, through three-way valve with the air in the hydrogen exchange device.Reacted 24 hours, decompress filter, filtrate decompression concentrate white solid.Through silica gel column chromatography (ethyl acetate-petroleum ether, volume ratio 1:2) separate light yellow solid, i.e. vitamin C-ibuprofen ester, synthetic route is as shown in Figure 1.
Two, vitamin C-ibuprofen ester structural characterization.
The physical and chemical parameter result who measures above-mentioned target response product is following:
1. fusing point.
Mp:196-199℃。
2.
13C NMR measures.
With CDCl
3Dissolving vitamin C-ibuprofen ester is made into concentration and is about 1mg/mL solution.Use Bruker AvanceIII 400 Plus nuclear magnetic resonance chemical analysers, resolution＜0.3Hz, sensitivity (s/n) ﹥ 300:1, resonant frequency 400MHz working sample.
13C?NMR(400MHz,?CDCl3-d6)?:?17.878(CH3),?21.918(CH3),?29.683(CH),?44.503(CH),?44.545(CH2),?64.089(CH2),?64.279(CH2),?67.056(CH),?120.783(C),?126.694~128.943(CH),?134.913~140.167(C),?156.409(C),?169.087(C),?169.150(C),?174.074(C);
3.
1HNMR measures.
With CDCl3 dissolving vitamin C-ibuprofen ester, be made into concentration and be about 200 μ g/mL solution.Use Bruker AvanceIII 400 Plus, nuclear magnetic resonance chemical analyser, resolution＜0.3Hz, sensitivity (s/n) ﹥ 300:1, resonant frequency 400MHz working sample.
1H?NMR(CDCl3-d6)?:?0.861(CH3),?0.877(CH3),?1.472(CH3),?1.490(CH3),?2.411(CH2),?2.429(CH2),?3.728(CH),?3.745(CH),?4.161(CH2),?4.542(CH),?5.296(CH),?7.057(CH),?7.076(CH),?7.157(CH),?7.177(CH),?7.260(CH).
4. mass spectral analysis.
Compound concentration is about vitamin C-ibuprofen ester methanol solution of 1 μ g/mL, injects mass spectrometer system, optimizes the mass spectrum parameter.ESI?(-)?spray?voltage?2500v?；Sheath?gas?pressure?25；Aux?gas?pressure?5；Capillary?temperature?300；Tube?lens?offset?:-109。At 50 to 500 mass range full scans, the molecular ion peak of 363.19 M-1, conform to target compound molecular weight about 364.
5. infrared spectrum analysis.
Vitamin C-ibuprofen ester is dried down infrared at KBr, after KBr is ground, adopt the KBr pressed disc method to measure, resolution is 4cm-1, and 4000-600cm-1 composes scanning entirely, after the calibration blank, measures.
IR?(KBr,?ν/cm-1)：3443.57（νO-H），2955.70（νC-H）,?2870.44（νC-H）,1733.23（νC=O）,?1601.26（νC=C）,?1601.26（νC=C）,?1461.28（νC=C）,?1207.24（νC-O）, 1172.21（νC-O）,?1120.44（νC-O）,?1062.49（νC-O）,?894.52（δC-H）,759.09（νC-H）.
6. ultraviolet spectral analysis.
Vitamin C-ibuprofen ester is mixed with the methanol solution of 1.0 mg/mL, and 200-800nm full wavelength scanner, the maximum absorption wavelength of chemical compound are 225nm, and be obviously different with the end absorption (190-202 nm) of ibuprofen.
7. differential scanning calorimetric DSC curve.
DSC curve display vitamin C-ibuprofen ester fusing point is consistent with the fusing point test result, is 196-198 ° of C, with 79 ° of C of ibuprofen fusing point and 190～192 ° of C of vitamin C fusing point (decomposition) evident difference is arranged.
Three, the stability experiment of vitamin C-ibuprofen ester in different buffer solution.
Vitamin C-ibuprofen ester is dissolved in pH 2.5, pH 5.0, pH 7.4, pH 8.0 buffer, and 37 ℃ of water-baths were vibrated 24 hours, measured content.The result shows that vitamin C-ibuprofen ester has good stability under neutrallty condition; More stable in acid condition; Alkali condition degraded down is rapid.As shown in Figure 2.
Four, the stability experiment of vitamin C-ibuprofen ester in external blood plasma and brains.
The accurate 1 mL vitamin C-ibuprofen ester (500 μ g/mL) of drawing; Be added to 4mL in the blood plasma and brains (33%) of 37 ℃ of water-bath preheatings; Vortex mixed is inserted after 1 minute in 37 ℃ of shaking baths; In different time (0 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h) sampling, measure vitamin C-ibuprofen ester and ibuprofen concentration in blood plasma and the brains.The result shows (as shown in Figure 3), vitamin C-ibuprofen ester in blood plasma in 1 hour degradation amount be lower than 5 %, prompting vitamin C-ibuprofen ester stability in blood plasma better has time enough to be dispensed into brain.In brains, vitamin C-ibuprofen ester degraded is rapid, 2 hours 50 % that degraded, and degraded in 8 hours points out vitamin C-ibuprofen ester in brains, can be hydrolyzed into former medicine ibuprofen performance curative effect rapidly fully.And, the hydrolysis of vitamin C-ibuprofen ester and the increase of ibuprofen, (as shown in Figure 4) confirms that further vitamin C-ibuprofen ester is an ibuprofen at the catabolite of blood plasma and brains.
Five. distribute in vitamin C-ibuprofen ester mice body and brain targeting research.
1. dosage regimen.
With totally 70 of kunming mices (male and female half and half, body weight 18-22g), be divided into 14 groups at random, 5 every group.Wherein press 2.8 mg/kg dosage tail vein injection ibuprofen solution, other 7 groups of vitamin C-ibuprofen ester solution (vitamin C-ibuprofen ester group is equivalent to ibuprofen 2.8 mg/kg) of injecting 5 mg/kg for 7 groups.Each group is got 5 mices respectively at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h after the administration; Pluck eyeball and get about 0.2 mL of blood and put in heparin sodium moistening and exsiccant centrifuge tube and merge,, get supernatant through centrifugal 10 min of 3500 rpm;-80 ℃ of refrigerators are preserved, and are subsequent use.Disconnected immediately neck was put to death after mice was got blood; In tissues such as the heart of winning 5 mices respectively organizing identical time point on ice rapidly, liver, lung, kidney, brains; With the blood and slime of normal saline flushing organ surface, reuse filter paper blots the normal saline that remains in organ surface, merges, weighs.Each tissue and blood plasma are handled as follows, measure the content of ibuprofen in blood plasma and the tissue with the UPLC-MS/MS method.
2. sample treatment.
Tissue sample is handled: after internal organs were weighed, the accurate respectively normal saline that adds identical weight was processed tissue homogenate, adds 10 μ l EDTA (20.3 mg/mL), 2 μ L BHT (20.9 mg/mL), and mix homogeneously ,-80 ℃ of refrigerators are preserved subsequent use.
The preparation of sample: precision is got blood plasma or tissue homogenate 300 μ L, adds inner mark solution naproxen (692 ng/mL) 20 μ L, and the whirlpool mixing adds 750 μ L ethyl acetate then, and whirlpool mixes 5 min and extracts.Centrifugal 10 min of 4000 rpm get the upper strata ethyl acetate and dry up through nitrogen current.Add 500 μ L, 20% methanol, whirlpool redissolves.Centrifugal 10 min of 10000 rpm get supernatant 2 μ L and inject UPLC-MS/MS appearance (U.S.'s match is silent to fly TSQ Quantum Access MAX), the peak area (As and Ai) of record chromatogram and ibuprofen and naproxen.Calculate the content of ibuprofen in blood plasma and the tissue sample according to linear equation.
3. UPLC-MS/MS method
3.1 chromatographic condition: chromatographic column Agilent proshell-C18 (100 * 2.1 mm, 2.7 μ m), flow velocity 300 μ l/min, sample size 5 μ l, 40 ℃ of column temperatures, gradient elution mobile phase is formed as shown in table 1.
The mobile phase of table 1 gradient elution is formed
3.2 mass spectrum condition
ESI (-): spray voltage 2500V; Sheath gas pressure 25 Psi; Assist gas pressure 5 Psi; 300 ℃ of capillary temperatures.
Quota ion is right: ibuprofen parent ion 205, daughter ion 161; Naproxen parent ion 229, daughter ion 185.
Material in blood plasma and the tissue homogenate does not disturb the separation determination of ibuprofen and naproxen, and the retention time of ibuprofen and naproxen is about 4.1 min and 3.4 min respectively.
4. distribution results in the mice body
Mice is behind tail vein injection vitamin C-ibuprofen ester and ibuprofen, and the concentration of ibuprofen is over time like Fig. 5, shown in Figure 6 in mice plasma, the heart, liver, lung, kidney, the brain.0.25h to 8 hours, the interior concentration of ibuprofen brain was significantly higher than the ibuprofen group behind injection vitamin C-ibuprofen ester, and other tissue concentration is not seen remarkable rising, prompting vitamin C-ibuprofen ester has significant brain targeting.Table 2 and table 3 are respectively behind injection vitamin C-ibuprofen ester and the ibuprofen pharmacokinetic parameter of ibuprofen in the mice body.
Ibuprofen pharmacokinetic parameter in the mice body behind table 2 injection vitamin C-ibuprofen ester
Ibuprofen pharmacokinetic parameter in the mice body behind the table 3 injection ibuprofen
5. targeting property evaluation
AUC in tissue and the blood plasma behind application Kinetic 4.0 pharmacokinetics program statistical method calculating intravenous injection vitamin C-ibuprofen ester and the ibuprofen
0 → ∞, AUC
0 → 8h, AUMC, MRT, etc. parameter, as shown in table 2.According to the total targeting efficient of above calculation of parameter (Overall Targeting Efficiency; TE), targeting index (Targeting Index; TI) and relatively targeting efficient (Relative Overall Targeting Efficiency, RTE), its formula is respectively:
Wherein IAA representes to inject vitamin C-ibuprofen ester group; IBU representes to inject the ibuprofen group; TE representes to organize the distribution percentage rate of Chinese medicine concentration; TI reflection vitamin C-ibuprofen ester and the comparison of ibuprofen solution, in each tissue concentration percentile change degree that distributes, TRE then reflects the relative extent of this change.
The targeting parameter contrast of table 4 vitamin C-ibuprofen ester and ibuprofen solution
Annotate: IAA vitamin C-ibuprofen ester; IBU, ibuprofen; TE, total targeting efficient; TI, the targeting index; RTE, targeting efficient relatively.
Can find out that by result in the table 4 ibuprofen AUC in brain obviously increases targeting index 190.82% behind injection vitamin C-ibuprofen ester; And other organ is not all had tangible targeting property, demonstrate vitamin C-ibuprofen ester brain targeting preferably.
Claims (7)
1. the application of vitamin C-ibuprofen ester in preparation ibuprofen brain targeting preparation.
2. the application of vitamin C-ibuprofen ester in the preparation prodrugs of ibuprofen.
3. the method for preparing of vitamin C-ibuprofen ester is characterized in that comprising the steps:
1) vitamin C prosposition hydroxyl protection reaction: vitamin C, potassium carbonate are dissolved in the dimethyl sulfoxide, stir under the room temperature after 2 hours, add bromobenzyl reaction 3-6 hour; Wherein, vitamin C, potassium carbonate and bromobenzyl mol ratio are 1 ~ 3:2 ~ 5:1 ~ 4;
2) 6 bit esterified reactions: the vitamin C and the ibuprofen of above-mentioned 2,3 benzyl protections are dissolved in the dimethyl formamide; The 4-2 methylamino pyridine that adds catalytic amount stirred after 10 minutes; Add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride, room temperature lower seal reaction 4 ~ 8 hours; Wherein, the mol ratio of the vitamin C of 2,3 benzyl protections, ibuprofen and 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride is 1 ~ 3:2 ~ 4:1 ~ 3;
3) debenzylation: the vitamin C-ibuprofen ester of 2,3 benzyl protections of above-mentioned product is dissolved in the methanol, adds 5% palladium carbon, under the room temperature in the pure hydrogen environment sealed reaction 24 ~ 48 hours, obtain vitamin C-ibuprofen ester.
4. method for preparing as claimed in claim 3 is characterized in that, the reaction temperature of said method for preparing is a room temperature.
5. method for preparing as claimed in claim 3; It is characterized in that described vitamin C 2; 3 hydroxyl protection reactions step are specially: under nitrogen environment; Vitamin C and potassium carbonate at room temperature stirred be dissolved in dimethyl formamide or the dimethyl sulfoxide, add then bromobenzyl stirred 2 hours reactant liquor; Use ethyl acetate extraction behind the above-mentioned reactant liquor thin up, ethyl acetate layer volatilizes through anhydrous sodium sulfate drying, gets the glutinous thick liquid of pale brown color; The glutinous thick liquid of above-mentioned pale brown color separates to such an extent that faint yellow oily thing is the vitamin C of 2,3 benzyl protections through silica gel column chromatography; Wherein, the chromatography media of described silicagel column is that volume ratio is ethyl acetate-petroleum ether of 1:1.
6. method for preparing as claimed in claim 3; It is characterized in that described 6 bit esterified reactions step are specially: the vitamin C and the ibuprofen that take by weighing 2,3 benzyl protections; Add the anhydrous methylene chloride stirring and dissolving; Add 4-dimethylamino naphthyridine and 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride then, react 6 hours reactant; The washing of above-mentioned reactant is filtered, and filtrating is used ethyl acetate extraction, and ethyl acetate layer is through anhydrous sodium sulfate drying, volatilize yellow oil; Above-mentioned yellow oil is separated to such an extent that faint yellow oily thing is the vitamin C-ibuprofen ester of 2,3 benzyl protections through silica gel column chromatography; Wherein, the chromatography media of said silicagel column is that volume ratio is ethyl acetate-petroleum ether of 1:6.
7. method for preparing as claimed in claim 3; It is characterized in that described debenzylation step is specially: get the vitamin C-ibuprofen ester of 2,3 benzyl protections, add dissolve with methanol, in the pure hydrogen environment; Add 5% palladium charcoal, react 24 hours must reactant; Above-mentioned reactant sucking filtration, filtrating concentrate white solid, said white solid separates to such an extent that light yellow solid is vitamin C-ibuprofen ester through silica gel column chromatography, wherein, the chromatography media of said silicagel column is that volume ratio is ethyl acetate-petroleum ether of 1:2.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101550119A (en) * | 2009-05-11 | 2009-10-07 | 江南大学 | Aryl (ethanoic) propanoic acid ascorbyl ester, preparation method thereof and medicament containing same |
| CN101939309A (en) * | 2008-02-06 | 2011-01-05 | 默克专利股份有限公司 | Uva filter based on ascorbic acid derivatives |
-
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101939309A (en) * | 2008-02-06 | 2011-01-05 | 默克专利股份有限公司 | Uva filter based on ascorbic acid derivatives |
| CN101550119A (en) * | 2009-05-11 | 2009-10-07 | 江南大学 | Aryl (ethanoic) propanoic acid ascorbyl ester, preparation method thereof and medicament containing same |
Non-Patent Citations (2)
| Title |
|---|
| MAHMOUD SHEHA: "Pharmocokinetic and ulcerogenic studiesof naproxen prodrugs designed for specific brain delivery", 《ARCHIVES OF PHARMACAL RESEARCH》, vol. 35, no. 3, 31 March 2012 (2012-03-31), pages 523 - 530 * |
| 盛华明等: "新型长春西汀-维生素C缀合物的合成及抗氧化活性", 《药学进展》, vol. 35, no. 4, 30 April 2011 (2011-04-30), pages 169 - 173 * |
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Application publication date: 20121114 |