CN103193767A - Preparation method of 1,6,7-trihydroxy-3-methoxyl xanthone-2-C-beta-D-glucopyranoside - Google Patents
Preparation method of 1,6,7-trihydroxy-3-methoxyl xanthone-2-C-beta-D-glucopyranoside Download PDFInfo
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Abstract
The invention relates to the field of chemical synthesis, and specifically disclose a preparation method of 1,6,7-trihydroxy-3-methoxyl xanthone-2-C-beta-D-glucopyranoside. According to the method, mangiferin is adopted as a raw material, and 3-methoxyl mangiferin is prepared through boric acid esterification, selective methylation, and hydrolysis reactions. The method provided by the invention has the advantages of short synthesis route, high product yield, low-toxic safe reagent, low production cost, and suitability for large-scale industrial productions.
Description
Technical field
The present invention relates to the field of chemical synthesis, specifically disclose a kind of preparation 1,6, the method for the two benzene pyrrones of 7-trihydroxy--3-methoxyl group-2-C-β-D-glucopyranoside.
Background technology
3-methoxyl group Mangiferin, full name 1,6, the two benzene pyrrones of 7-trihydroxy--3-methoxyl group-2-C-β-D-glucopyranoside, claim homomangiferin again, be C-glycoside xanthone compound, be present in Anacardiaceae plant mango (Mangifera indica L.), the almond plants such as (Mangifera persiciformis C.) that its structural formula is suc as formula shown in the I:
The method of obtaining 3-methoxyl group Mangiferin at present mainly contains following three kinds:
(1) plant extract method.From plants such as mango, almond, extract earlier and obtain the Mangiferin crude product, the Mangiferin crude product is further separated obtaining 3-methoxyl group Mangiferin again.Adopt column chromatography technology as people such as Masakazu Aritomi, from the Mangiferin crude product, separate obtained homomangiferin (Masakazu Aritomi and Toshio kawasaki.A mangiferin Monomethyl Ether from Mangifera indicaL[J] .Chem Pharm Bull, 18 (11): 2224-2234).Because the content of 3-methoxyl group Mangiferin in plant is very low, extract, separate comparatively difficulty, so this method cost is very high, is difficult to mass production.
(2) total synthesis method.Zhongtao Wu etc. has reported a kind of with 2, and the 4-dimethoxybenzoic acid is starting raw material, through the 3-methoxyl group Mangiferin of ten step prepared in reaction.(Zhongtao?Wu，Guo?Wei，Gaoyan?Lian，et?a1.Synthesis?of?Mangiferin，Isomangiferin，andHomomangiferin[J].J?Org?Chem，2010，75，5725-5728)。The advantage of this method is not rely on plant resources, but that shortcoming is reaction scheme is long, and yield is low, and total recovery does not possess industrialization value less than 1%.
(3) semisynthesis.It is raw material with the Mangiferin that MasakazuAritomi etc. have reported a kind of, through the method for selective methylation prepared in reaction 3-methoxyl group Mangiferin.(Masakazu?Aritomi?and?Toshio?kawasaki.A?mangiferin?Monomethyl?Ether?from?Mangifera?indica?L[J].Chem?Pharm?Bull，18(11)：2224-2234)。The advantage of this method is that raw material is easy to get, and reactions steps is short; But also there is significant disadvantage in this method, and namely methylating reagent toxicity is big, dangerous high, and the poor selectivity of reaction needs the method separated product with column chromatography, and yield is not high, has only 20%～30%.
Therefore seek more economically, efficiently, the method for preparing 3-methoxyl group Mangiferin of environmental protection becomes the target of our research.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of 3-methoxyl group Mangiferin of high yield, be applicable to large-scale industrial production.
For achieving the above object, the technical solution used in the present invention is as follows:
A kind of structural formula for preparing is suc as formula the method for compound shown in the I, compound shown in the formula II and boric acid generation esterification obtain compound shown in the formula III, compound shown in the formula III and methylating reagent carry out the selective methylation reaction and obtain compound shown in the formula IV under alkaline condition, compound shown in the formula IV issues the reaction of unboiled water solution at acidic conditions and obtains compound shown in the formula I.
Reaction formula of the present invention is as follows:
As preferably, the mol ratio of described formula II compound and boric acid is 1.0: 1.0～3.0.
As preferably, the reaction solvent of described esterification is dimethyl formamide, methyl alcohol, dimethyl sulfoxide (DMSO) or 1,4-dioxane, more preferably methyl alcohol.
As preferably, the temperature of reaction of described esterification is 0～50 ℃, and the time is 0.5～2.0 hour.
As preferably, described methylating reagent is diazomethane, methyl iodide, methyl-sulfate or methylcarbonate, more preferably methylcarbonate.
As preferably, the equivalence ratio of described formula III compound and described methylating reagent is 1.0: 3.0～5.0.
As preferably, described alkaline condition is provided by sodium hydroxide, potassium hydroxide or salt of wormwood.
As preferably, the equivalence ratio of described formula III compound and described alkali is 1.0: 1.0～3.0.
As preferably, the reaction solvent of described selective methylation reaction is dimethyl formamide, methyl alcohol, dimethyl sulfoxide (DMSO) or 1,4-dioxane.
As preferably, the temperature of reaction of described selective methylation reaction is not for being higher than the reflux temperature of reaction solvent, and the reaction times is 8.0～24.0 hours.
As preferably, the reaction solvent of described selective methylation reaction is methyl alcohol, and temperature of reaction is 50～60 ℃.
As preferably, described acidic conditions is provided by sulfuric acid or hydrochloric acid, and acid concentration is 0.5～1.0mol/L.
As preferably, the temperature of reaction of described hydrolysis reaction is 0～50 ℃, and the reaction times is 3.0～8.0 hours.
Compared with prior art, major advantage of the present invention is as follows:
(1) production cost is low, the product yield height.It is raw material that the present invention adopts Mangiferin, and raw material is easy to get, cost is low; Adopt boric acid as esterifying reagent 6,7 hydroxyl to be protected, increased substantially selectivity and the product yield of reaction, its yield reaches more than 90%, and prior art only 20%～30%;
(2) safety, environmental protection.The present invention adopts the methylcarbonate of nontoxic pollution-free as methylating reagent first, has overcome to pollute the shortcoming big, that toxicity is big with methyl halide, diazomethane and methyl-sulfate as methylating reagent in the past.
(3) simple to operate, do not need separation and purification can obtain the high purity target product.The prior art reaction preference is relatively poor, and the product magazine is many, needs to adopt the column chromatography method separated product of very complicated, waste time and energy production cost height, reaction preference height of the present invention, impurity is few, does not need to adopt column chromatography can obtain purity 98% above simplification compound.
The present invention has great application value and economic benefit for the preparation of 3-methoxyl group Mangiferin provides a new synthetic method efficiently.
Embodiment
The invention discloses a kind of preparation method of 3-methoxyl group Mangiferin, those skilled in the art can use for reference this paper content, suitably improve processing parameter and realize.Special needs to be pointed out is that all similarly replace and change apparent to those skilled in the art, they all are regarded as being included in the present invention.Method of the present invention is described by preferred embodiment, and the related personnel obviously can change or suitably change and combination methods and applications as herein described in not breaking away from content of the present invention, spirit and scope, realizes and use the technology of the present invention.
In order to make those skilled in the art understand technical scheme of the present invention better, the present invention is described in further detail below in conjunction with specific embodiment.
Of particular note, room temperature described in following examples is 20 ℃, and described concentrating carried out under 32 ℃ of reduced pressure.
The preparation of compound shown in the embodiment 1 formula IV
Take by weighing 4.22g (0.01mol) formula II compound and 1.24g (0.02mol) boric acid and be dissolved in the N of 200ml, in the dinethylformamide, stirred 1 hour under the room temperature.In reaction solution, add 1.76g (0.02mol) salt of wormwood, 3.60g (0.04mol) methylcarbonate, with this mixture heating up, the backflow stirring reaction is put cold after 10 hours, concentration of reaction solution has yellow solid to separate out, and filters deionized water wash, dry, get 3.81g yellow powder shape solid, be compound shown in the formula IV, product yield is 85.6%.
1H?NMR(DMSO)：δ13.68(s，2H)，δ7.08(s，2H)，δ6.62(s，2H)，δ6.32(s，2H)，δ5.35(s，2H)，δ4.96(d，2H)，δ3.85(s，6H)，δ3.79～3.40(m，18H)。
The preparation of compound shown in the embodiment 2 formula IV
Take by weighing 4.22g (0.01mol) formula II compound and 1.24g (0.02mol) boric acid is dissolved in the dimethyl sulfoxide (DMSO) of 200ml, stirred 1 hour under the room temperature.In reaction solution, add 1.76g (0.02mol) salt of wormwood, 3.60g (0.04mol) methylcarbonate, with this mixture heating up, back flow reaction is put cold after 10 hours, concentration of reaction solution has yellow solid to separate out, and filters deionized water wash, dry, get 3.74g yellow powder shape solid, be compound shown in the formula IV, product yield is 84.0%.
1H?NMR(DMSO)：δ13.68(s，2H)，δ7.08(s，2H)，δ6.62(s，2H)，δ6.32(s，2H)，δ5.35(s，2H)，δ4.96(d，2H)，δ3.85(s，6H)，δ3.79～3.40(m，18H)。
The preparation of compound shown in the embodiment 3 formula IV
Take by weighing 4.22g (0.01mol) formula II compound and 1.24g (0.02mol) boric acid is dissolved in 1 of 200ml, in the 4-dioxane, stirred 1 hour under the room temperature.In reaction solution, add 1.76g (0.02mol) salt of wormwood, 3.60g (0.04mol) methylcarbonate, with this mixture heating up, little backflow stirring reaction is put cold after 10 hours, concentration of reaction solution has yellow solid to separate out, and filters deionized water wash, dry, get 3.93g yellow powder shape solid, be compound shown in the formula IV, product yield is 88.3%.
1H?NMR(DMSO)：δ13.68(s，2H)，δ7.08(s，2H)，δ6.62(s，2H)，δ6.32(s，2H)，δ5.35(s，2H)，δ4.96(d，2H)，δ3.85(s，6H)，δ3.79～3.40(m，18H)。
The preparation of compound shown in the embodiment 4 formula IV
Take by weighing 4.22g (0.01mol) formula II compound and 1.24g (0.02mol) boric acid is dissolved in the anhydrous methanol of 200ml, stirred 1 hour under the room temperature.In reaction solution, add 1.76g (0.02mol) salt of wormwood, 5.04g (0.04mol) methyl-sulfate, with this mixture heating up to 50 ℃, stirring reaction is put cold after 10 hours, concentration of reaction solution has yellow solid to separate out, and filters deionized water wash, dry, get 3.97g yellow powder shape solid, be compound shown in the formula IV, product yield is 89.2%.
1H?NMR(DMSO)：δ13.68(s，2H)，δ7.08(s，2H)，δ6.62(s，2H)，δ6.32(s，2H)，δ5.35(s，2H)，δ4.96(d，2H)，δ3.85(s，6H)，δ3.79～3.40(m，18H)。
The preparation of compound shown in the embodiment 5 formula IV
Take by weighing 4.22g (0.01mol) formula II compound and 1.24g (0.02mol) boric acid is dissolved in the anhydrous methanol of 200ml, stirred 1 hour under the room temperature.In reaction solution, add 1.76g (0.02mol) salt of wormwood, 5.68g (0.04mol) methyl iodide, with this mixture heating up to 50～60 ℃, stirring reaction is put cold after 10 hours, concentration of reaction solution has yellow solid to separate out, and filters deionized water wash, dry, get 4.03g yellow powder shape solid, be compound shown in the formula IV, product yield is 90.6%.
1H?NMR(DMSO)：δ13.68(s，2H)，δ7.08(s，2H)，δ6.62(s，2H)，δ6.32(s，2H)，δ5.35(s，2H)，δ4.96(d，2H)，δ3.85(s，6H)，δ3.79～3.40(m，18H)。
The preparation of compound shown in the embodiment 6 formula IV
Take by weighing 4.22g (0.01mol) formula II compound and 1.24g (0.02mol) boric acid is dissolved in the anhydrous methanol of 200ml, stirred 1 hour under the room temperature.In reaction solution, add 1.76g (0.02mol) salt of wormwood, 3.60g (0.04mol) methylcarbonate, with this mixture heating up to 60 ℃, stirring reaction is put cold after 10 hours, concentration of reaction solution has yellow solid to separate out, and filters deionized water wash, dry, get 4.09g yellow powder shape solid, be compound shown in the formula IV, product yield is 91.9%.
1H?NMR(DMSO)：δ13.68(s，2H)，δ7.08(s，2H)，δ6.62(s，2H)，δ6.32(s，2H)，δ5.35(s，2H)，δ4.96(d，2H)，δ3.85(s，6H)，δ3.79～3.40(m，18H)。
The preparation of embodiment 7 3-methoxyl group Mangiferins
Take by weighing that compound dissolution is in 100ml shown in each gained formula of 8.90g (0.01mol) embodiment 1-6 IV, in the dilute hydrochloric acid of 0.5mol/L, stirring reaction is 5 hours under the room temperature, has a large amount of particulate state yellow solids to separate out, and filters, and it is neutral that deionized water wash to filtrate is.Drying gets 8.70g yellow powder shape solid, is target product 3-methoxyl group Mangiferin, the total recovery 91.7% of product; It is 98.3% that high performance liquid chromatography (HPLC) area normalization method is measured 3-methoxyl group Mangiferin purity.
1H?NMR(DMSO)：δ13.68(s，1H)，δ10.80(s，1H)，δ9.91(d，1H)，δ7.39(s，1H)，δ6.89(s，1H)，δ6.64(s，1H)，δ4.64(dd，1H)，δ4.01(t，1H)，δ3.88(d，3H)，δ3.70(d，1H)，δ3.05～3.41(m，4H)；
13CNMR(DMSO)：δ：179.5，165.5，164.3，161.5，160.7，156.9，154.4，151.0，144.1，111.9，108.5，102.7，101.9，90.7，82.0，79.2，72.9，70.9，61.8，56.5；HRMS(ESI)：C
20H
19O
11[M-1]435。
The above only is preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle 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 (13)
1. one kind prepares structural formula suc as formula the method for compound shown in the I, it is characterized in that, compound shown in the formula II and boric acid generation esterification obtain compound shown in the formula III, compound shown in the formula III and methylating reagent carry out the selective methylation reaction and obtain compound shown in the formula IV under alkaline condition, compound shown in the formula IV issues the reaction of unboiled water solution at acidic conditions and obtains compound shown in the formula I.
2. preparation method as claimed in claim 1 is characterized in that, the mol ratio of described formula II compound and boric acid is 1.0: 1.0～3.0.
3. preparation method as claimed in claim 1 or 2, the reaction solvent that it is characterized in that described esterification is dimethyl formamide, methyl alcohol, dimethyl sulfoxide (DMSO) or 1,4-dioxane.
4. as each described preparation method of claim 1-3, the temperature of reaction that it is characterized in that described esterification is 0～50 ℃, and the time is 0.5～2.0 hour.
5. preparation method as claimed in claim 1 is characterized in that, described methylating reagent is diazomethane, methyl iodide, methyl-sulfate or methylcarbonate.
6. as claim 1 or 5 described preparation methods, it is characterized in that the equivalence ratio of described formula III compound and described methylating reagent is 1.0: 3.0～5.0.
7. preparation method as claimed in claim 1 is characterized in that, described alkaline condition is provided by sodium hydroxide, potassium hydroxide or salt of wormwood.
8. as claim 1 or 7 described preparation methods, it is characterized in that the equivalence ratio of described formula III compound and described alkali is 1.0: 1.0～3.0.
9. preparation method as claimed in claim 1 is characterized in that, the reaction solvent of described selective methylation reaction is dimethyl formamide, methyl alcohol, dimethyl sulfoxide (DMSO) or 1,4-dioxane.
10. as claim 1 or 9 described preparation methods, it is characterized in that the temperature of reaction of described selective methylation reaction is not for being higher than the reflux temperature of reaction solvent, the reaction times is 8.0～24.0 hours.
11. preparation method as claimed in claim 1 is characterized in that, the reaction solvent of described selective methylation reaction is methyl alcohol, and temperature of reaction is 50～60 ℃.
12. preparation method as claimed in claim 1 is characterized in that, described acidic conditions is provided by sulfuric acid or hydrochloric acid, and acid concentration is 0.5～1.0mol/L.
13., it is characterized in that the temperature of reaction of described hydrolysis reaction is 0～50 ℃ as claim 1 or 12 described preparation methods, the reaction times is 3.0～8.0 hours.
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| WO2022220512A1 (en) * | 2021-04-13 | 2022-10-20 | 알리아드바이오파마 주식회사 | Selective mtorc2 inhibitor and uses thereof |
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| WO2008061480A1 (en) * | 2006-11-24 | 2008-05-29 | Hainan Deze Drug Research Co., Ltd | Novel mangiferin calcium salts, the method for its preparation and its use |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2022220512A1 (en) * | 2021-04-13 | 2022-10-20 | 알리아드바이오파마 주식회사 | Selective mtorc2 inhibitor and uses thereof |
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