CN104004035A - Preparation method for 5[(2E)-(3,5-dihydroxy phenyl)ethenyl]-2-methoxyphenyl-1-O-beta-D-glucopyranoside - Google Patents
Preparation method for 5[(2E)-(3,5-dihydroxy phenyl)ethenyl]-2-methoxyphenyl-1-O-beta-D-glucopyranoside Download PDFInfo
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Abstract
The invention relates to the field of chemical synthesis, and discloses a preparation method for 5[(2E)-(3,5-dihydroxy phenyl)ethenyl]-2-methoxyphenyl-1-O-beta-D-glucopyranoside. According to the preparation method, the 5[(2E)-(3,5-dihydroxy phenyl)ethenyl]-2-methoxyphenyl-1-O-beta-D-glucopyranoside with only 4'-methylation is obtained through the oriented methylation step and the column chromatography separation and purification step with 5[(2E)-(3,5-dihydroxy phenyl)ethenyl]-2-hydroxyphenyl-1-O-beta-D-glucopyranoside serving as the substrate, wherein the purity is larger than or equal to 99%. The preparation method is simple in step, high in reproducibility and high in product purity and has large-scale industrial application prospects.
Description
Technical field
The present invention relates to the field of chemical synthesis, be specifically related to antioxidant 5-[(2E)-(3,5-dihydroxy phenyl) vinyl] preparation method of-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside.
Background technology
5-[(2E)-(3,5-dihydroxy phenyl) vinyl]-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside, English name β-D-Glucopyranoside, 5-[2-(3,5-dihydroxyphenyl) ethenyl]-2-methoxyph-enyl, (E)-(9CI), its structural formula as shown in Equation 1:
Studies have found that the pharmacological action of this compound, can be used for treating disease.It is this compound in polygonaceae Rheum plant Lhasa rhubarb (formal name used at school Rheum lhasaense), its content in medicinal material only has 0.1%, separating difficulty is very high, only obtains minute quantity product after great many of experiments, is difficult to meet scale operation needs.Therefore, need exploitation 5-[(2E badly)-(3,5-dihydroxy phenyl) vinyl] synthesis technique of-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside, solve this compound and be difficult for the problem obtaining.
Summary of the invention
One provided by the invention is prepared 5-[(2E fast, in a large number)-(3,5-dihydroxy phenyl) vinyl] method of-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside, comprise the following steps:
Step 1: taking mineral alkali as catalyzer, ethanol, acetone mixing solutions are solvent, under methylating reagent effect, hydroxyl to the bent letter stilbene glycosides 4'-position shown in formula I methylates, obtain containing 5-[(2E shown in formula II)-(3,5-dihydroxy phenyl) vinyl] reaction solution of-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside;
Step 2: step 1 gained reaction solution is carried out to forward column chromatography for separation, obtain the 5-[(2E shown in formula II)-(3,5-dihydroxy phenyl) vinyl]-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside;
Substrate is to 5-[(2E)-(3,5-dihydroxy phenyl) vinyl]-2-hydroxy phenyl-1-O-β-D-xylopyranoside contains 3 phenolic hydroxyl groups, 3 phenolic hydroxyl groups have very strong electron supplying capacity, make it have very strong resistance of oxidation, simultaneously owing to there being 3 phenolic hydroxyl groups in molecule, this compound is very unstable, very easily oxidized, be oriented on 4' position, to complete methyl substituted and have technical difficulty.
The present invention adopts combinatorial chemistry to synthesize with column chromatography for separation and obtains 5-[(2E)-(3, 5-dihydroxy phenyl) vinyl]-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside, first control condition is to 5-[(2E)-(3, 5-dihydroxy phenyl) vinyl]-2-hydroxy phenyl-1-O-β-D-xylopyranoside carries out orientation and methylates, to 4 in Quzhazhigan molecular structure ' position HM, and to 3 in its molecular structure, the hydroxyl of 5 is without impact, by column chromatography, synthetics is carried out to forward chromatographic separation more again afterwards, result obtains the target substance of purity >=99%.
Preparation 5-[(2E of the present invention)-(3,5-dihydroxy phenyl) vinyl] method of-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside, with respect to significantly improving product cost purity and quality of chemical synthesis process, obtain the sterling of target compound; Reduce the difficulty of separation and purification simultaneously, greatly increased product production.The method of the invention has strengthened industrialization operability, has improved the yield of product.
As preferably, mineral alkali is salt of wormwood.
As preferably, described methylating reagent is methyl-sulfate, methyl tosylate, methyl iodide, halohydrocarbon, methylcarbonate, monobromethane, diazomethane, one or both combinations of ethyl bromoacetate.Most preferably be methyl iodide.
As preferably, the pH of step 1 methylation reaction is 5-12, and preferably pH is 6-10.
As preferably, step 1 methylation reaction temperature is 20～100 DEG C; More preferably methylation reaction temperature is 40～60 DEG C.
The stationary phase of step 2 column chromatography is silica gel; Moving phase: chloroform-methanol-water.
Mixing solutions is mixed to sample, and forward chromatography separates, and the mixing solutions that moving phase is chloroform-methanol-water, obtains target compound, purity >=99% after separation.
The present invention prepares 5-[(2E)-(3,5-dihydroxy phenyl) vinyl] method of-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside, preferably can realize by following two step process: 5-[(2E)-(3,5-dihydroxy phenyl) vinyl]-2-hydroxy phenyl-1-O-β-D-xylopyranoside be raw material in the mixed solvent of ethanol, acetone, use alkaline, inorganic salts K
2cO
3carry out catalysis, CH
3i is methylating reagent, reacts at 55 DEG C, obtains containing 5-[(2E after 6h)-(3,5-dihydroxy phenyl) vinyl] mixing solutions of-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside.
In the specific embodiment of the present invention, methylating reagent, pH value, solvent and the impact of chromatographic separation condition on preparation method of the present invention are disclosed, result shows that methyl iodide is best to the methylated effect in 4'-position, pH8-10 especially under weak basic condition, and reaction conversion ratio is good; In the mixed solvent of ethanol, acetone, reactant can dissolve completely, fully react; Separate with forward silica gel column chromatography, 30～50 times of silica gel separate ratio, chloroform-methanol-water is as moving phase, regulate Rf in (0.05～0.3), the final sterling 5-[(2E that obtains purity >=99%)-(3,5-dihydroxy phenyl) vinyl]-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside.The method of the invention step is simple, favorable reproducibility, and product purity is high, has large-scale industrial application prospect.
Embodiment
The invention discloses 5-[(2E)-(3,5-dihydroxy phenyl) vinyl] preparation method of-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside, those skilled in the art can use for reference content herein, suitably improve processing parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the present invention.Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described in content of the present invention, spirit and scope or suitably change and combination not departing from, and realizes and apply the technology of the present invention.
The present invention prepares 5-[(2E)-(3,5-dihydroxy phenyl) vinyl] method of-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside, can realize by following two step process:
Step 1: taking mineral alkali as catalyzer, ethanol, acetone mixing solutions are solvent, under methylating reagent effect, hydroxyl to the bent letter stilbene glycosides 4'-position shown in formula I methylates, obtain containing 5-[(2E shown in formula II)-(3,5-dihydroxy phenyl) vinyl] reaction solution of-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside;
Step 2: step 1 gained reaction solution is carried out to forward column chromatography for separation, obtain the 5-[(2E shown in formula II)-(3,5-dihydroxy phenyl) vinyl]-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside;
In order to make those skilled in the art understand better technical scheme of the present invention, below in conjunction with specific embodiment, the present invention is described in further detail.
The selection of embodiment 1 the method for the invention methylating reagent
Take respectively Quzhazhigan substrate 0.01mol (about 4.06g), 30mlDMSO dissolves, adjusting pH is weakly alkaline, add respectively trifluoromethanesulfonic acid methyl esters, methyl-sulfate, methyl halide, methylcarbonate, diazomethane, 48 DEG C of constant temperature, stir, sample reaction monitoring respectively at 4h, 6h, 8h, 12h, 24h, the content of target product in HPLC is respectively:
| Methylating reagent | 4h | 6h | 8h | 12h | 24h |
| Trifluoromethanesulfonic acid methyl esters | 2％ | 4％ | 9％ | 13％ | 15％ |
| Methyl-sulfate | 3％ | 8％ | 12％ | 19％ | 22％ |
| Methyl iodide | 4％ | 10％ | 27％ | 31％ | 33％ |
| Methylcarbonate | 3％ | 9％ | 13％ | 18％ | 20％ |
| Diazomethane | 1％ | 3％ | 3％ | 5％ | 5％ |
Methyl iodide, because its steric effect is very little, is convenient to nucleophilic reagent attack; On the other hand because iodide ion is so that good leavings group effect is more satisfactory.Experimental result shows: methyl iodide is best to the methylated effect in 4'-position.
Embodiment 2 impacts of the method for the invention pH on transformation efficiency
Take respectively Quzhazhigan substrate 0.01mol (about 4.06g), 30mlDMSO dissolves, and methyl iodide is methylating reagent, and 48 DEG C of constant temperature stir, and under different pH, react 12h, and the content of target product in HPLC is respectively:
| PH value | HPLC content |
| 4 | 17％ |
| 5 | 20％ |
| 6 | 24％ |
| 7 | 27％ |
| 8 | 32％ |
| 9 | 32％ |
| 10 | 31％ |
Experimental result shows: under weak basic condition, reaction conversion ratio is better, and pH8～10 are comparatively desirable.
The impact of embodiment 3 the method for the invention reaction solvents
Take respectively Quzhazhigan substrate 0.01mol (about 4.06g), methyl iodide is methylating reagent, and 48 DEG C of constant temperature stir, and are 8 at pH, and reaction 12h, adopts different reagent, and response situation is as follows:
| Reagent | Response situation |
| Methyl alcohol | Solubleness is general, and sedimentation is arranged at bottom |
| Ethanol | Dissolve better, dissolve completely |
| Acetone | Solubleness is general, not as good as methyl alcohol |
| DMSO | Dissolve completely, color is darker |
| Methyl alcohol, acetone | Solvability is bad, has precipitation |
| Ethanol, acetone | Solubleness is moderate, reacts more complete |
Result shows: in the mixed solvent of ethanol, acetone, reactant can dissolve completely, fully react.
Embodiment 4 the method for the invention column chromatographys separate
Through reaction, can generate 30%～35% target substance, all the other are reaction substrate and other impurity, want to obtain sterling target compound, must be by unit operations such as exquisiteness or separation.Because composition is more, find that by crystallization experiment purification effect is unsatisfactory, therefore using forward silica gel column chromatography instead separates, 30～50 times of silica gel separate ratio, chloroform-methanol-water, as moving phase, regulates Rf in [0.05～0.3], finally obtains the sterling 5-[(2E of purity >=99%)-(3,5-dihydroxy phenyl) vinyl]-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside (HPLC, external standard method).
Embodiment 5 products detect
Taking the mixed solution of organic solvent and 0.1% phosphate aqueous solution composition as moving phase, its composition volume content is organic solvent acetonitrile 15%-30%, methyl alcohol 15%-30%, 0.1% phosphate aqueous solution 70%-85%, carry out high performance liquid chromatography, 5-[(2E in analytic sample)-(3,5-dihydroxy phenyl) vinyl] content of-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside.Sampling volume is 10ul, detects wavelength 319nm, 30 DEG C of column chromatography column temperatures, flow rate of mobile phase 1.0ml/min.Final detection result is, 5-[(2E)-(3,5-dihydroxy phenyl) vinyl]-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside purity >=99%.
Embodiment 6 5-[(2E)-(3,5-dihydroxy phenyl) vinyl] impact of-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside on cerebral ischemia/reperfusion injury of rats
1 medicine
1.1 tested medicine preparations
Get respectively water for injection 6ml, heat to 80 DEG C, add 2g hydroxypropyl-beta-cyclodextrin, be stirred to dissolve, add 150mg5-[(2E)-(3,5-dihydroxy phenyl) vinyl]-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside is stirred to dissolve, and adds sodium-chlor 90mg stirring and dissolving, and finally mend and inject water to 10ml, survey work in-process pH values (5.0-6.0), obtain 15mg/ml solution, and dilute successively to obtain 3.75mg/ml solution, for subsequent use.
Positive control drug: Edaravone Injection, source: Nanjing Xianshengdongyuan Pharmaceutical Co., Ltd, lot number: 80-101207
Specification: 5ml:10mg, proterties: colourless or almost colourless clear liquid, for subsequent use.
1.2 reagent
TCC (TTC), Solution on Chemical Reagents in Shanghai company of Chinese Medicine group, lot number: 20120315.Take 1.20g TCC, 0.286g Na
2hPO
412H
2o and 0.027g K
2hPO
4adding distilled water to be dissolved to 100ml keeps in Dark Place.
0.9% sodium chloride injection, lot number 10010792, Shangdong Changfu Jiejing Pharmaceutical Industry Co., Ltd., specification 500ml/ bottle.
Chloral Hydrate, lot number 20081027, Chemical Reagent Co., Ltd., Sinopharm Group, is mixed with 12% concentration with physiological saline when use.
Diameter 0.265mm nylon wire, Japan produces.
Mda (MDA) testing cassete, superoxide-dismutase (SOD) testing cassete, serum lactic dehydrogenase (LDH) testing cassete, glutamic-oxal(o)acetic transaminase (AST) testing cassete, gsh (GSH) testing cassete, above test kit all builds up Science and Technology Ltd. purchased from Nanjing.
2 animals
Strain: SD rat
Source: Shanghai Slac Experimental Animal Co., Ltd.
Sex: male
Body weight: 220-250 gram
Animal conformity certification number: SCXK (Shanghai) 2008-0016
Raise: SPF barrier system is raised, 23 ± 2 DEG C of room temperatures, humidity 40-70%, artificial lighting simulation changes round the clock, ad lib and drinking-water.
3 test groupings
Male SD rat, be divided into 4 groups, be respectively sham operated rats, model group, 5-[(2E)-(3,5-dihydroxy phenyl) vinyl]-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside group (3.75mg/kg) (hereinafter to be referred as tested group) and Edaravone Injection group (5mg/kg), administration volume is 1ml/kg.
4 test methods
4.1 test modelings
By healthy SD rat, according to being divided into 4 groups described in 1.3, after 12% Chloral Hydrate intraperitoneal anesthesia (360mg/kg), lie on the back and be fixed on operating table.Room temperature maintains 25 DEG C of left and right.Cut right side skin of neck, separation, ligation right carotid, external carotid artery and bifurcated artery thereof.Separate right side internal carotid artery (ICA), place bulldog clamp at ICA near-end for line, far-end, arteria carotis communis crotch otch, nylon wire 17～20mm that insertion diameter is 0.265mm, bolt line enters ICA, passes arteria cerebri media (MCA) initiating terminal to arteria cerebri anterior near-end, all blood flows source of blocking-up MCA.Tighten standby line, after 2 hours, sublingual vein gives to extract nylon wire after each group of medicine, makes its blood flow logical again, and ligation, for line skin suture, divides cage to put back in cage operation rat and raises.
4.2 test indexes detect
4.2.1 study of behaviour scoring
Postoperative 24h, carries out study of behaviour scoring by single blind method, and methods of marking is: (1) carries mouse tail built on stilts approximately 1 chi, observes forelimb situation.Normal rat two forelimbs stretch to ground symmetrically.As the offside forelimb of operation occurs that wrist is bent, elbow flexing, shoulder inward turning or existing elbow flexing have again shoulder inward turning person, is designated as respectively 1,2,3,4 point.(2) to side shifting, check the resistance that opposing promotes by pushing away respectively a left side (or right) shoulder on sliding animal horizontalization floor.Normal rat bilateral resistance is obvious, and is symmetry.If when pushing away right shoulder and moving to the left, find resistance descender, according to the difference of decline degree, mark and divide for 1-3.(3) animal two forelimbs are put on a wire netting, observed the muscular tension of two forelimbs.Normal rat two forelimb tension force are obvious and symmetrical.And there is left fore tension force descender, be chosen as 1-3 according to the weight of decline degree and divide.(4) animal has and does not stop to a side person of turn-taking, and counts 1 point.According to above standard marking, 11 points of full marks.
4.2.2 biochemical indicator
Aorta abdominalis blood sampling, centrifugal 15 minutes of 3000rpm, gets serum-20 DEG C freezing preservation.According to the operation of test kit specification sheets, measure MDA, SOD, LDH, AST and GSH.
4.2.3 infarct percentage
After getting brain, be divided into 5 by average crown brain, be put in 1.2%TTC solution, 37 DEG C of incubation 10～15min dyeing.Infarcted region is not painted, and normal cerebral tissue dyes redness.After taking pictures, weigh respectively full brain weight and downright bad part weight, calculating necrotic area weight accounts for the percentage of full brain weight.The statistical analysis of all data is checked with t.
5, test-results is in table 1 and table 2
Table 1 target compound causes the therapeutic action of focal cerebral ischemia in rats-reperfusion injury to line bolt method
Compare with model group: * P<0.05, * * P<0.01
Compare with sham operated rats:
#p<0.05,
##p<0.01
Table 1 shows: rat has obvious study of behaviour defect and cerebral tissue ischemic necrosis after operation, and modeling success is described.Rat behavior is learned to scoring to each given the test agent and brain necrosis percentage all has reducing effect;
Table 2 target compound causes the impact of Cerebral Ischemia Reperfusion Biochemical Indices In Serum on line bolt method
Compare with model group: * P<0.05, * * P<0.01
Compare with sham operated rats:
#p<0.05,
##p<0.01
Table 2 shows: with sham operated rats comparison, in model group serum, MDA content obviously raises, SOD and GSH content obviously reduce (p<0.05), though AST and LDH have certain rising, relatively there is no significant difference (p>0.05) with sham operated rats.Tested medicine can significantly raise SOD and GSH content (p<0.05, with model group comparison) in serum; And significantly reduce MDA content in serum (p<0.05, with model group comparison).
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. a 5-[(2E)-(3,5-dihydroxy phenyl) vinyl] preparation method of-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside, comprise the following steps:
Step 1: taking mineral alkali as catalyzer, taking alcohol, ketone, ether or its mixing solutions as solvent, under methylating reagent effect, hydroxyl to the bent letter stilbene glycosides 4'-position shown in formula I methylates, obtain containing 5-[(2E shown in formula II)-(3,5-dihydroxy phenyl) vinyl] reaction solution of-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside;
Step 2: step 1 gained reaction solution is carried out to forward column chromatography for separation, obtain the 5-[(2E shown in formula II)-(3,5-dihydroxy phenyl) vinyl]-2-p-methoxy-phenyl-1-O-β-D-glucopyranoside;
2. preparation method according to claim 1, is characterized in that, described solvent is ethanol, acetone mixing solutions.
3. preparation method according to claim 1, is characterized in that, described mineral alkali is salt of wormwood.
4. according to the preparation method described in claim 1 or 2 or 3, it is characterized in that, methylating reagent is methyl-sulfate, methyl tosylate, methyl iodide, methylcarbonate, monobromethane, one or both combinations of ethyl bromoacetate described in step 1.
5. according to the preparation method described in claim 1 or 2 or 3, it is characterized in that, methylating reagent is methyl iodide described in step 1.
6. according to the preparation method described in claim 1-5 any one, it is characterized in that, the pH of step 1 methylation reaction is 5-12.
7. according to the preparation method described in claim 1-5 any one, it is characterized in that, the pH of step 1 methylation reaction is 6-10.
8. according to the preparation method described in claim 1-7 any one, it is characterized in that, step 1 methylation reaction temperature is 20～100 DEG C.
9. according to the preparation method described in claim 1-7 any one, it is characterized in that, step 1 methylation reaction temperature is 40～60 DEG C.
10. according to the preparation method described in claim 1-9 any one, it is characterized in that, the stationary phase of step 2 column chromatography is silica gel; Moving phase: chloroform-methanol-water.
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| CN112807319A (en) * | 2021-03-19 | 2021-05-18 | 大连医科大学 | Application of Quzhazhigan in treating ischemia-reperfusion injury of small intestine |
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