CN102040636A - Method for synthesizing beta-arbutin by adopting alpha-D-glucose pentaacetate - Google Patents
Method for synthesizing beta-arbutin by adopting alpha-D-glucose pentaacetate Download PDFInfo
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- CN102040636A CN102040636A CN 201010608801 CN201010608801A CN102040636A CN 102040636 A CN102040636 A CN 102040636A CN 201010608801 CN201010608801 CN 201010608801 CN 201010608801 A CN201010608801 A CN 201010608801A CN 102040636 A CN102040636 A CN 102040636A
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Abstract
The invention takes alpha-D-glucose pentaacetate as the raw material to synthesize a key intermediate 4-hydroxyphenyl-beta-glucoside tetraacetate or 4-acetyloxyphenyl-beta-glucoside tetraacetate, thus synthesizing beta-arbutin. The invention develops a new method and new process for synthesizing beta-arbutin by adopting the raw materials or by-products such as alpha-D-glucose pentaacetate and the like.
Description
Technical field
The invention belongs to the exploitation of raw material in synthetic β-arbutin technology, relating to the alpha-D-glucose pentaacetate is that raw material replaces the synthetic β-arbutin of β-D-alpha-glucose pentaacetate, is the by product of synthetic β-D-alpha-glucose pentaacetate as the alpha-D-glucose pentaacetate of new raw material.
Background technology
Arbutin (Arbutin) chemistry 4-hydroxy phenyl-β by name-D-glucopyranoside is to separate the natural active matter that obtains from plant.As far back as nineteen thirty report is just arranged, contain arbutin in the leaf of Rhizoma Seu Herba Bergeniae (Bergenia Crassifolia), in the leaf of bird meal tree (Blueberry), cowberry (Cranberry), black bearberry (Bearberry) and pear tree, find arbutin in succession later on.
The chemosynthesis of many for a long time scholar's research arbutin.1980 mid-nineties 90s were emerged in large numbers a large amount of relevant patents, and generation nineteen ninety rises, and arbutin begins to be used for makeup.Nowadays, arbutin occupies critical role as the skin-whitening agents of makeup in makeup whitening function additive.
Early stage employing glucose is starting raw material, obtains β-D-alpha-glucose pentaacetate (hereinafter to be referred as β-five acetyl sugar) through acetylize, and then through the synthetic arbutin of bromo sugar, this method raw material is expensive, intermediate is unstable, is worthless as production technique.
Helferich in 1938 and Reischel report are with 4-MeC
6H
4SO
3H is a catalyzer, with 4-HOC
6H
4The condensation of OBz and β-five acetyl sugar gets β-benzyl oxy phenyl tetrem acyl glucosides.The latter gets arbutin through hydrolysis.
Because be subjected to the influence of the 2-acetoxyl group anchimeric assistance of β-five acetyl sugar, the chemical activity of β-five acetyl sugar is better than alpha-D-glucose pentaacetate (hereinafter to be referred as α-five acetyl sugar), so all adopt directly synthesis of glycoside of β-five acetyl sugar usually.Its industrial production adopts 3 step synthesis techniques: 1) glucose gets β-five acetyl sugar with the acetic anhydride acetylize; 2) latter and Resorcinol react 4-hydroxy phenyl-beta-glucoside tetraacetate, for convenient crystallization and the purifying of obtaining,, obtain key intermediate 4-acetoxyl group phenyl-beta-glucoside tetraacetate through the acetic anhydride acetylize; 3) latter's ammonia solves product β-arbutin.This has become classical production technique.
The crucial part of this technology is: 1) beta configuration of the intermediate β-five acetyl sugar of arbutin is essential, and its purity and quality are very important, is second to go on foot into the key factor of glycosides quality; 2) acetic anhydride of 6～9 times of the synthetic needs of β-five acetyl sugar, the consumption of acetic anhydride is the key of raw materials cost.Wherein, the synthetic employing sodium acetate of β-five acetyl sugar is a catalyzer, under such condition, obtains β-five acetyl sugar crude product, and after making with extra care, the β of gained-five acetyl sugar yield is 65%,, by product is α-five an acetyl sugar, about 25%.
Above-mentioned present situation and analysis revealed, research and development more are easy to get, more cheap raw material is used for synthetic key intermediate 4-hydroxy phenyl-beta-glucoside tetraacetate or 4-acetoxyl group phenyl-beta-glucoside tetraacetate.Exploitation is very useful with novel method and the novel process that such new raw material synthesizes beta-glucoside, and the low-carbon (LC) that meets in the world simultaneously to be advocated and the policy of cleaner production have very big economic and social benefit.
Summary of the invention
The present invention with the synthetic key intermediate 4-hydroxy phenyl of α-five acetyl sugar-beta-glucoside tetraacetate or 4-acetoxyl group phenyl-beta-glucoside tetraacetate, thereby synthesizes β-arbutin by the careful above-mentioned key issue of having researched and solved.Exploitation is with the sugared such new raw material of α-five acetyl or utilize such by product to synthesize the novel method and the novel process of β-arbutin.
For a long time, many documents are paid close attention to the desired α of various catalyzer acquisition-or the glucide of beta configuration.Usually with various acid as catalyst acquisition α-or the glucosides of beta configuration.Sometimes in specifying configuration, judge by accident.Kurosu etc. obtain alpha-arbutin with microbial fermentation processes, and its proton nmr spectra and the spectrum of β-arbutin are contrasted, and clearly illustrate that, can use
1The coupling constant of 1-H is judged the α of arbutin-or beta configuration among the HNMR, i.e. the J=3.7Hz of alpha-arbutin 1-H, and J=7Hz～9Hz of β-arbutin 1-H.β-the arbutin that obtains in the production, its proton nmr spectra is consistent with The above results.
Because be subjected to the influence of the 2-acetoxyl group anchimeric assistance of β-five acetyl sugar, the chemical activity of β-five acetyl sugar is better than α-five acetyl sugar, so existing production technique all adopts directly synthesis of glycoside of β-five acetyl sugar usually.The acetic anhydride that the synthetic needs of β-five acetyl sugar are 6～9 times, the consumption of acetic anhydride is the key of raw materials cost.Wherein, the synthetic employing sodium acetate of β-five acetyl sugar is a catalyzer, under such condition, obtains β-five acetyl sugar crude product, and after making with extra care, the β of gained-five acetyl sugar yield is 65%,, by product is α-five an acetyl sugar, about 25%.The latter waits to locate as refuse, has greatly increased raw-material consumption and production cost.
β-arbutin synthetic all has the lot of documents report both at home and abroad, and these reports show, it is starting raw material that β-arbutin synthetic adopt glucose more, obtain β-five acetyl sugar through acetylize, and then reaction obtains β-arbutin.But with α-five acetyl sugar is the synthetic β-arbutin of starting raw material, does not see bibliographical information.
The present invention adopts the synthetic β-arbutin of α-five acetyl sugar.α-five acetyl sugar can be the by product of producing β-five acetyl sugar, and also can adopt glucose is starting raw material, obtains through acetylize.Catalyzer is various inorganic or organic Lewis acids (Lewis acid) such as zinc chloride, and appropriate solvent comprises various nonpolar, polar organic solvents such as toluene, or their mixed solvent.Should be appreciated that simultaneously the present invention is not limited to those specific descriptions of being exemplified.
What have feature of the present invention synthesizes key intermediate 4-hydroxy phenyl-beta-glucoside tetraacetate or 4-acetoxyl group phenyl-beta-glucoside tetraacetate with α-five acetyl sugar, thus synthetic β-arbutin, and its synthetic route is as follows.
α-five acetyl sugar (1) derive from β-arbutin produce in the by product of synthetic β-five acetyl sugar, or be starting raw material with glucose, obtain through acetylize.Two kinds of approach resulting α-five acetyl sugar (1) have identical physico-chemical property, 111～112 ℃ of fusing points, [α]
D 20+ 102 (C=1, CHCl
3).α-five acetyl the sugar (1) of two kinds of approach acquisitions is respectively applied for the synthetic then β-arbutin (3) of synthetic key intermediate (2), obtains same result.
According to the present invention, with reactions such as solvent such as toluene, hexane, other solvents or mixed solvent, α-five acetyl sugar (1), Resorcinol, catalyzer zinc chloride or tosic acid, temperature is 30～160 ℃, reaction 1～6h, obtain 4-hydroxy phenyl-beta-glucoside tetraacetate, or the adding acetic anhydride obtains 4-acetoxyl group phenyl-beta-glucoside (2) after condensation reaction is finished.Separate with conventional ammonia and to obtain β-arbutin crude product, the crystal makes β-arbutin (3).
By α-five acetyl sugar (1) synthetic (2) synthetic (3) then, the fusing point of gained compound (2) and (3) and
1Physico-chemical properties such as HMR are with consistent shown in the document, with routine be that the result of the synthetic β of raw material-arbutin gained is consistent with β-five acetyl sugar.(2) 145～146 ℃ of fusing points,
1HMR (400MHz, CDCl
3): δ 7.00 (4H, s, Ph), 5.23-5.27 (1H, m), 5.14-5.18 (1H, m), 5.03-5.04 (1H, m), 4.27-4.30 (1H, m), 4.15-4.18 (1H, m), 3.83-3.85 (1H, m), 2.28 (3H, s, PhOCOCH
3), 2.04-2.07 (12H, m, COCH
3).(3) 199～200 ℃ of fusing points,
1HMR (400MHz, DMSO-d
6): δ 9.61 (1H, S, Ar-OH), 6.87 (2H, d, ArH), 6.67 (2H, d, ArH), 5.25 (1H, d, 2-OH), 5.05 (1H, d, 3-OH), 4.99 (1H, d, 4-OH), 4.65 (1H, d, J=7.4,1-H), 4.56 (1H, t, 6-OH), 3.69 (1H, m, 6-CH), 3.46 (1H, m, 6-CH), 3.24 (1H, m, 3-H), 3.19 (1H, m, 5-H), 3.15 (1H, m, 4-H).
Embodiment
Following examples are to illustrate and unrestricted the present invention.
Embodiment 1 usefulness α-five acetyl sugar (1) synthesizes 4-acetoxyl group phenyl-beta-glucoside tetraacetate (2)
In reaction flask, add toluene 45ml, β-five acetyl sugar (1) 18.8g (0.048mol), Resorcinol 5.5g (0.05mol), zinc chloride 1.8g (0.013mol), reacting by heating 4h.Add acetic anhydride 9.5g (0.093mol), continue reaction 1h, cooling wait solid is fully separated out.Tell organic layer.With 30ml ethyl alcohol recrystallization solid, drying, get 4-acetoxyl group phenyl-beta-glucoside tetraacetate (2) 6.9g, 145～146 ℃ of fusing points,
1HMR (400MHz, CDCl
3): δ 7.00 (4H, s, Ph), 5.23-5.27 (1H, m), 5.14-5.18 (1H, m), 5.03-5.04 (1H, m), 4.27-4.30 (1H, m), 4.15-4.18 (1H, m), 3.83-3.85 (1H, m), 2.28 (3H, s, PhOCOCH
3), 2.04-2.07 (12H, m, COCH
3).
Embodiment 2 usefulness 4-acetoxyl group phenyl-beta-glucoside tetraacetates (2) synthesize β-arbutin (3)
Add methyl alcohol 25ml and (2) 6.9g in reaction flask, be cooled to 5 ℃, feed ammonia, holding temperature is reacted 3h below 10 ℃, and placement is spent the night.Concentrating under reduced pressure adds chloroform 90ml, stirs, and β-arbutin is fully separated out, and the water recrystallization gets product 2.7g.199～200 ℃ of fusing points,
1HMR (400MHz, DMSO-d
6): δ 9.61 (1H, S, Ar-OH), 6.87 (2H, d, ArH), 6.67 (2H, d, ArH), 5.25 (1H, d, 2-OH), 5.05 (1H, d, 3-OH), 4.99 (1H, d, 4-OH), 4.65 (1H, d, J=7.4,1-H), 4.56 (1H, t, 6-OH), 3.69 (1H, m, 6-CH), 3.46 (1H, m, 6-CH), 3.24 (1H, m, 3-H), 3.19 (1H, m, 5-H), 3.15 (1H, m, 4-H), [α]
D 25=-64 ° of (C=3.0, H
2O).
Claims (6)
1. one kind is the novel method and the novel process of the synthetic β-arbutin of raw material with the alpha-D-glucose pentaacetate.
2. method according to claim 1 and technology, raw material alpha-D-glucose pentaacetate can be to produce the by product of β-five acetyl sugar, and also can adopt glucose is starting raw material, obtains through acetylize.
3. according to claim 1 and 2 described technology and raw materials, be the synthetic 4-hydroxy phenyl of raw material-beta-glucoside tetraacetate with the alpha-D-glucose pentaacetate, and then synthetic β-arbutin.
4. according to claim 1 and 2 described technology and raw materials; to be raw material synthetic 4-hydroxy phenyl-beta-glucoside tetraacetate acetylize with the alpha-D-glucose pentaacetate; get 4-acetoxyl group phenyl-beta-glucoside tetraacetate, and then synthetic β-arbutin.
5. according to claim 3 and 4 described technology and raw materials, in the reaction that with the alpha-D-glucose pentaacetate is the synthetic 4-hydroxy phenyl of raw material-beta-glucoside tetraacetate or 4-acetoxyl group phenyl-beta-glucoside tetraacetate, used solvent is for comprising toluene, hexane or various nonpolar, polar organic solvent, or their mixed solvent.
6. according to claim 3 and 4 described technology and raw materials, in the reaction that with the alpha-D-glucose pentaacetate is the synthetic 4-hydroxy phenyl of raw material-beta-glucoside tetraacetate or 4-acetoxyl group phenyl-beta-glucoside tetraacetate, used catalyzer is various inorganic or organic Lewis acids (Lewis acid) such as zinc chloride or tosic acid.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104098622A (en) * | 2013-04-09 | 2014-10-15 | 中国医学科学院药物研究所 | Beta-arbutin crystal IV material and preparation method, composition and use |
| CN104098621A (en) * | 2013-04-09 | 2014-10-15 | 中国医学科学院药物研究所 | Beta-arbutin crystal type III substance, and preparation method, composition and application thereof |
| CN105968149A (en) * | 2016-05-06 | 2016-09-28 | 江西金顿香料有限公司 | Preparation method of beta-arbutin |
| CN107216359A (en) * | 2017-07-24 | 2017-09-29 | 湖北阿泰克生物科技股份有限公司 | A kind of synthetic method of β ursin |
| CN112358514A (en) * | 2020-10-19 | 2021-02-12 | 浙江拓普药业股份有限公司 | Synthesis process of arbutin |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1724551A (en) * | 2005-07-21 | 2006-01-25 | 华东理工大学 | Preparation method of alpha-arbutin |
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| CN1724551A (en) * | 2005-07-21 | 2006-01-25 | 华东理工大学 | Preparation method of alpha-arbutin |
Non-Patent Citations (3)
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| 《ARKIVOC》 20081231 Ivica C. 等 Simple and efficient synthesis of arbutin , 第2期 * |
| 《日用化学工业》 20040831 刘锋 等 熊果苷合成研究进展 第34卷, 第4期 * |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104098622A (en) * | 2013-04-09 | 2014-10-15 | 中国医学科学院药物研究所 | Beta-arbutin crystal IV material and preparation method, composition and use |
| CN104098621A (en) * | 2013-04-09 | 2014-10-15 | 中国医学科学院药物研究所 | Beta-arbutin crystal type III substance, and preparation method, composition and application thereof |
| CN104098621B (en) * | 2013-04-09 | 2023-05-09 | 中国医学科学院药物研究所 | Beta-arbutin crystal III substance, preparation method, composition and application thereof |
| CN104098622B (en) * | 2013-04-09 | 2023-11-03 | 中国医学科学院药物研究所 | Beta-arbutin crystal IV substance, preparation method, composition and application thereof |
| CN105968149A (en) * | 2016-05-06 | 2016-09-28 | 江西金顿香料有限公司 | Preparation method of beta-arbutin |
| CN107216359A (en) * | 2017-07-24 | 2017-09-29 | 湖北阿泰克生物科技股份有限公司 | A kind of synthetic method of β ursin |
| CN112358514A (en) * | 2020-10-19 | 2021-02-12 | 浙江拓普药业股份有限公司 | Synthesis process of arbutin |
| CN112358514B (en) * | 2020-10-19 | 2023-01-31 | 浙江拓普药业股份有限公司 | Synthesis process of arbutin |
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Address after: 101100 No. 6, B District, Yongle Economic Development Zone, Beijing, Tongzhou District Patentee after: Beijing belilles Biotechnology Co., Ltd Address before: 101100 No. 6, B District, Yongle Economic Development Zone, Beijing, Tongzhou District Patentee before: BEIJING BRILLIANCE BIOCHEMICAL Co.,Ltd. |