WO2016049966A1 - 取代儿茶素的选择性制备方法及产品 - Google Patents

取代儿茶素的选择性制备方法及产品 Download PDF

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WO2016049966A1
WO2016049966A1 PCT/CN2014/090670 CN2014090670W WO2016049966A1 WO 2016049966 A1 WO2016049966 A1 WO 2016049966A1 CN 2014090670 W CN2014090670 W CN 2014090670W WO 2016049966 A1 WO2016049966 A1 WO 2016049966A1
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catechin
tetraester
reaction
ester
acid
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PCT/CN2014/090670
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English (en)
French (fr)
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刘松柏
洪姗
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浙江大学
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Priority claimed from CN201410522023.9A external-priority patent/CN104311524B/zh
Priority claimed from CN201410521386.0A external-priority patent/CN104311523A/zh
Priority claimed from CN201410521178.0A external-priority patent/CN104311542A/zh
Priority claimed from CN201410523187.3A external-priority patent/CN104292201B/zh
Application filed by 浙江大学 filed Critical 浙江大学
Publication of WO2016049966A1 publication Critical patent/WO2016049966A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
    • C07D311/62—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2 with oxygen atoms directly attached in position 3, e.g. anthocyanidins

Definitions

  • the invention belongs to the field of functional food medicines, and particularly relates to a selective preparation method and product for replacing catechins.
  • Polyphenols are a class of polyhydroxyphenols that are widely found in plants. They have a certain content in the leaves, wood, skin, shell and flesh of the plant body, and the plant and grain epidermis contain higher plant polyphenols. Polyphenols have excellent antioxidant effects, which are the basis of all their physiological activities. A large number of in vivo and in vitro experiments and epidemiological data indicate that the consumption of a certain amount of plant polyphenols has a preventive and inhibitory effect on the disease. Polyphenols have anti-arteriosclerosis, prevention and treatment of cardiovascular diseases such as coronary heart disease and stroke, and anti-inflammatory, anti-allergic and anti-viral effects.
  • catechin is an important natural plant polyphenol which has a rich distribution in tea leaves and the like, and its activity is remarkable, and has recently attracted attention. Studies have shown that catechin has significant anti-oxidation, anti-mutation, anti-radiation, antibacterial and disinfecting effects; it can enhance the function of the immune system and inhibit the growth of fat and cholesterol.
  • Catechin is also known as catechin, tea tannin.
  • the catechins were originally proposed by catechu. It is a colorless crystalline solid; soluble in water; its aqueous solution is easily polymerized into amorphous enamel by heat or in the presence of a mineral acid.
  • the catechin is the most important ingredient in the tea soup.
  • the catechins belong to one of the polyphenols, and because of the bitter taste, they have a greater influence on the taste of the tea.
  • the structure of catechins is as follows:
  • catechins have made great progress in basic and applied research, but due to the presence of multiple hydroxyl groups of catechins, their water solubility is relatively low in fat solubility, thus limiting their presence in oil systems. The application is difficult to achieve an effective antioxidant concentration threshold. In addition, the lower fat solubility also causes the catechin molecules to not easily penetrate the cell membrane lipid bilayer, making it less bioavailable, difficult to reach the target and greatly reducing its desired activity. Due to these problems, it has become a research hotspot to modify the molecular structure of catechin to optimize its physical and chemical properties and biological activity.
  • the existing activity of catechin can be enhanced by molecular modification, and on the other hand, new physiological activity can be introduced by introducing other reactive groups, thereby achieving integration of various activities.
  • the catechin structure modification methods mainly include derivatization methods such as esterification and etherification.
  • Esterification modification is the process of esterifying the hydroxyl groups of certain parts of the catechin molecular structure by biological or chemical synthesis. Although there have been preparation methods of mixed ester catechins, there is no effective method for esterification specifically at specific positions. To further optimize the properties of catechins, develop them Specific esterification methods are essential.
  • the present invention provides a selective preparation method of substituted catechins, by which 3', 4', 5, 7- can be obtained. Tetraester catechin, 3 - ester catechin, 3', 4'-diester catechin, 3-tetrahydropyranyl catechin, and the yield is high.
  • the present invention also provides a substituted catechin compound.
  • a method for preparing 3',4',5,7-tetraester catechins comprising:
  • the catechin is dissolved in tert-butyl methyl ether, an acid anhydride and a tertiary amine are added, and the reaction is stirred, and the reaction is terminated to obtain the above-mentioned 3',4',5,7-tetraester catechin;
  • the 3',4',5,7-tetraester catechin structure is as follows:
  • R is a C 2 -C 4 acyl group.
  • R is a C 2 -C 4 alkanoyl group; more preferably a propionyl group, an acetyl group or a butyryl group; still more preferably a propionyl group or an acetyl group.
  • the reaction solvent is selected from t-butyl methyl ether to ensure high selectivity of the reaction;
  • the acid anhydride is one selected from the group consisting of acetic anhydride, propionic anhydride, and butyric anhydride; further preferably acetic anhydride or propionic anhydride; when the above several acid anhydrides are selected, the yield of the target product is 60%. Above, when acetic anhydride and propionic anhydride are selected, the reaction selectivity is higher, and the yield of the target product is above 70%.
  • the tertiary amine is selected from the group consisting of triethylamine, tripropylamine, tributylamine, N,N- At least one of diisopropylethylamine. Further preferably, the tertiary amine is triethylamine, which ensures high yield and selectivity of the target product, is inexpensive, and is easy to handle.
  • the molar ratio of the catechin, anhydride and tertiary amine is 1:0.5-50:0.5-50 Further preferably, the molar ratio of the catechin, the acid anhydride and the tertiary amine is 1:4.0-6.0:4-12, and the molar ratio range is favorable for sufficient conversion and high selectivity of the raw material.
  • the post-processing comprises:
  • the organic solvent includes one of ethyl acetate, diethyl ether, chloroform, dichloromethane, petroleum ether, n-hexane, and tert-butyl methyl ether. These organic solvents have good solubility properties for the product and are easily removed by evaporation.
  • the present invention also provides a 3',4',5,7-tetraester catechin compound having the following structure:
  • R is propionyl or butyryl.
  • the reaction of the present invention is carried out at room temperature.
  • the invention provides a preparation method of 3-ester catechin, comprising the following steps:
  • R' is an alkanoyl group
  • 3',4',5,7-tetraester catechin reacts with an acylating reagent to form a 3-ester group -3',4',5,7-tetraester catechin
  • the structure of the 3-ester-3',4',5,7-tetraester catechin is as follows:
  • R' is as defined above, and R '' is an alkanoyl group
  • R' and R '' are defined as above.
  • R' is preferably C1-C5
  • the alkanoyl group is more preferably an acetyl group, a propionyl group or a butyryl group.
  • the R '' is preferably C1-C18
  • the alkanoyl group is further preferably an octanoyl group, a dodecanoyl group, a tridecanoyl group or a stearyl group.
  • the acid anhydride is preferably an alkane anhydride, and more preferably acetic anhydride, propionic anhydride or butyric anhydride.
  • these acid anhydrides are used, the selectivity of 3',4',5,7-tetraester catechins is higher, and the yield is higher. More than 70%.
  • the acid anhydride is acetic anhydride and propionic anhydride, and has high selectivity.
  • the tertiary amine is triethylamine, tripropylamine, tributylamine, N,N- At least one of diisopropylethylamine.
  • the tertiary amine is triethylamine, which is inexpensive, easy to handle, and has high selectivity and yield of 3',4',5,7-tetraester catechin.
  • the molar ratio of the catechin, the acid anhydride to the tertiary amine is 1:0.5-50:0.5-50 .
  • the molar ratio of the catechin, anhydride and tertiary amine is 1:4-6:4-12 . This molar ratio range facilitates the full conversion and high selectivity of the feedstock.
  • the post-treatment process in step (1) is preferably:
  • the organic solvent includes one of ethyl acetate, diethyl ether, chloroform, dichloromethane, petroleum ether, n-hexane, and tert-butyl methyl ether, and these organic solvents have better solubility to the product, and Easy to remove by evaporation.
  • the acylating reagent is preferably one of an acid anhydride and an acid chloride. Further preferred is an alkanoyl chloride; still more preferably a C1-C18 The alkane anhydride is more preferably octanoyl chloride, dodecanoyl chloride, tridecanoyl chloride or stearyl chloride.
  • an acid binding agent may be added to ensure rapid and complete reaction.
  • the acid binding agent is pyridine, triethylamine, sodium carbonate, potassium carbonate, sodium hydroxide or the like.
  • step (2) preferably, the 3', 4', 5, 7-
  • the molar ratio of the tetraester catechin, the acylating agent and the acid binding agent (if added) is 1:0.5-50:0.5-50; further preferably 1:1.5-3: 3-6 .
  • the selectivity and yield of the target product are both high.
  • the selective deprotecting agent is an organic amine, and more preferably hydrazine.
  • the 3', 4', 5, 7- The molar ratio of the tetraester catechin to the selective deprotecting agent is 1:1-50; further preferably 1:5-15; still more preferably 1:10-15.
  • the tetraester catechin molecule has high purity and has a good application prospect.
  • the steps of the invention can be carried out at room temperature and are suitable for industrial production.
  • the invention also provides a selective preparation method of 3',4'-diester catechin, comprising:
  • the catechin is dissolved in acetonitrile, the acid chloride and the tertiary amine are added, and the reaction is stirred, and the reaction is terminated to obtain the 3', 4'- Diester catechin; the structure of the 3',4'-diester catechin is as follows:
  • R''' is an acyl group
  • the R ''' is an alkanoyl group or an alkoxy group; more preferably a benzyloxy group or a dodecanoyl group;
  • the acid chloride is one of a chloroformate and an alkyl acid chloride; further preferably benzyl chloroformate or dodecanoyl chloride.
  • the selectivity is high, and the product yield after purification is 70. % The above; further preferred is dodecanoyl chloride, and when the acid chloride is selected, the yield of the purified product is as high as 75%.
  • the tertiary amine is triethylamine, tripropylamine, tributylamine, N,N- At least one of diisopropylethylamine.
  • the use of the above tertiary amine facilitates the acidity of the 3',4'-phenolic hydroxyl group of the catechin to achieve high selectivity of the 3',4'-phenolic hydroxyl group.
  • Further preferred is triethylamine, tripropylamine, N,N-diisopropylethylamine, when the above three tertiary amines are selected, the product has better selectivity and higher yield; and the price is cheap and easy to handle.
  • the use of the acetonitrile as a reaction solvent is advantageous for achieving high selectivity.
  • the molar ratio of the catechin, acid chloride and tertiary amine is 1:0.5-50:0.5-50
  • the molar ratio of the catechin, acid chloride and tertiary amine is 1:2-3:2-4; further preferably 1:2-2.5:2.5-3.5 . This molar ratio range facilitates the full conversion and high selectivity of the feedstock.
  • the post-processing process comprises:
  • the organic solvent includes one or more of ethyl acetate, diethyl ether, chloroform, dichloromethane, petroleum ether, n-hexane, and tert-butyl methyl ether. These organic solvents have good solubility to the product and are easily volatilized. Remove.
  • the chromatographic separation is performed by column chromatography, and the eluent is a mixed solvent of ethyl acetate and petroleum ether;
  • the reaction of the present invention is carried out at room temperature, is low in cost, and is suitable for industrial production.
  • the 3', 4'-diester catechin molecule obtained by the preparation method has high purity and has a good application prospect.
  • the present invention also provides a 3',4'-diester catechin compound having the structure shown in the following formula:
  • R '''' is a benzyloxy group.
  • the invention provides a selective preparation method of 3-tetrahydropyranyl catechin, comprising:
  • the catechin is dissolved in an organic solvent, dihydropyran is added to the acidic catalyst, stirred to carry out the reaction, and the reaction is terminated to obtain the above-mentioned 3-tetrahydropyranylcatechin;
  • the structure of the 3-tetrahydropyranylcatechin is as follows:
  • the acidic catalyst is at least one of p-toluenesulfonic acid, methanesulfonic acid and camphorsulfonic acid. Further preferred is p-toluenesulfonic acid, which has high reactivity, is inexpensive, and is easy to handle.
  • the organic solvent is at least one of tetrahydrofuran, diethyl ether and tert-butyl methyl ether. Further preferred is tetrahydrofuran, the product selectivity is good, the yield is high, and the product yield after purification is More than 70%.
  • the molar ratio of the catechin, dihydropyran and acidic catalyst is 1:0.5-50:0.01-50, further preferably the molar ratio is 1:2-5: 0.05-0.25.
  • the post-processing process comprises:
  • the organic solvent includes one or more of ethyl acetate, diethyl ether, chloroform, dichloromethane, petroleum ether, n-hexane, and tert-butyl methyl ether. These organic solvents have good solubility to the product and are easily volatilized. Remove.
  • the chromatographic separation is performed by column chromatography, and the eluent is a mixed solvent of ethyl acetate and petroleum ether;
  • the reaction of the present invention is carried out at room temperature, is low in cost, and is suitable for industrial production.
  • the 3-tetrahydropyranyl catechin molecule obtained by the preparation method has high purity and has a good application prospect.
  • 3-tetrahydropyranyl group prepared by the invention is used as a protective group, and 3-tetrahydropyranyl catechin can be used for preparing 7-position and 5 A place to replace catechin products.
  • the preparation method of the present invention has a good selectivity, and the yield of the product is as high as 70% or more.
  • the preparation method of the invention is simple in operation, avoids the use of high-cost, highly toxic, highly corrosive reagents, and has mild reaction conditions, avoids the use of high pressure and high temperature conditions, and is suitable for industrial production applications.
  • the catechin (29 mg) was dissolved in tert-butyl methyl ether (10 ml) and propionic anhydride (59 mg) was added. And triethylamine (45 mg), the reaction was stirred at room temperature for 20 hours, and after completion of the reaction, it was extracted with ethyl acetate and purified by chromatography (silica gel column chromatography, eluent solvent ethyl acetate and petroleum ether) After getting 3',4',5,7-tetrapropyl catechin, yield 78%.
  • the catechin 29 mg was dissolved in tert-butyl methyl ether (10 ml), and acetic anhydride (46 mg) was added. N,N-diisopropylethylamine (52 mg), stir the reaction at room temperature 20 After the reaction is completed, the mixture is extracted with ethyl acetate and purified by chromatography (silica gel column chromatography, eluting solvent ethyl acetate and petroleum ether) to give 3',4',5,7-tetraethyl ester Tea, yield 73% .
  • the catechin (29 mg) was dissolved in tert-butyl methyl ether (10 ml) and butyric anhydride (71 mg) was added. And tripropylamine (57 mg), the reaction was stirred at room temperature for 20 hours, and after completion of the reaction, it was extracted with ethyl acetate and purified by chromatography (silica gel column chromatography, eluent ethyl acetate and petroleum ether) get 3',4',5,7-tetrabutyl catechin, yield 62%.
  • the compounds obtained by using Examples 1-3 can be used for the synthesis of 3-ester catechins (the compounds have excellent anticancer activity, See the literature Chemico-Biological Interactions 185 (2010) 182 - 188 ).
  • Catechin (29 mg), propionic anhydride (59 mg) and triethylamine (45 mg) were stirred at room temperature. 20 After the reaction was completed, it was extracted with ethyl acetate and purified by chromatography (eluent ethyl acetate and petroleum ether mixed solvent) to give 3',4',5,7-tetrapropyl catechin (yield 78%). Then with dodecanoyl chloride ( 44 mg ) and pyridine (24 mg) were reacted for 24 hours, and then reacted with hydrazine hydrate (40 mg) for 8 hours. After the reaction was completed, it was extracted with ethyl acetate and purified by chromatography to give 3- Dodecyl catechin 72%.
  • Catechin (29 mg), dihydropyran (25 mg, 2,3-dihydropyran) and p-toluenesulfonic acid (1) (mg) is dissolved in tetrahydrofuran and stirred at room temperature for 2 hours. After the reaction is completed, it is extracted with ethyl acetate and purified by chromatography (eluent is a solvent mixture of ethyl acetate and petroleum ether). Methyl catechin 72%.
  • This compound can be used to prepare 7-acetyl catechin, for example, the following: 3-tetrahydropyranyl catechin (37 mg Benzyl chloroformate (34 mg) and tripropylamine (36 mg) are stirred at room temperature 2 After the reaction is completed, the mixture is evaporated to dryness with ethyl acetate. The obtained solid is dissolved in organic solvent, and acetic anhydride (11 mg) and N,N-diisopropylethylamine (15 mg) are stirred at room temperature.

Abstract

本发明公幵了一种取代儿茶素的制备方法，包括：将儿茶素溶解在有机溶剂中，加入酸酐或酰氯与三级胺，搅拌进行反应，反应结束进行后处理得到所述的3',4',5,7-四酯基儿茶素，或者进一步处理得到3-酯基儿茶素。本发明还公开了一种取代儿茶素化合物。本发明具有如下优点及效果：（1）本发明的制备方法有较好的选择性，产物的产率高达70%以上。（2）本发明的制备方法操作简单，避免采用高成本、高毒性、高腐蚀性的试剂，且反应条件温和，避免采用高压和高温条件，适用于工业化生产应用。

Description

取代儿茶素的选择性制备方法及产品
本发明属于功能食品药品领域，具体涉及一种 取代儿茶素的选择性制备方法及产品 。
多酚是一类广泛存在于植物中的多羟基酚类物质。它们在植物体的叶、木、皮、壳和果肉中均有一定含量，水果、谷物表皮中均含有较高植物多酚。多酚具有优良的抗氧化作用，这是其所有生理活性的基础。大量的体内及体外实验和流行病学资料表明，食用一定量的植物多酚对疾病有预防及抑制作用。多酚具有抗动脉硬化、防治冠心病与中风等心血管疾病及消炎、抗过敏作用和抗病毒作用。随着多酚化学和药理学的发展，人们逐渐认识到多酚是一类具有独特生理活性和药理活性的天然产物。随着当前“ 追求自然 ” 消费观念的兴起，多酚在制药、生化、日化、食品以及精细化工等高科技领域具有广阔的应用前景。儿茶素为一种重要的天然植物多酚在茶叶等中有着丰富的分布，其活性作用显著，近来引人瞩目。研究表明儿茶素具有显著的抗氧化、抗突变、防辐射、抗菌消毒作用；能够增强免疫系统功能，抑制脂肪和胆固醇的增长。
儿茶素又称儿茶精，茶单宁。儿茶素最初由儿茶中提出。为无色结晶形固体；能溶于水；其水溶液受热或在无机酸存在下，容易聚合成无定形鞣质。以儿茶素为茶汤中最主要的成分。儿茶素类属于多元酚类中的一种，因为有苦涩味，所以对茶汤滋味的影响较大。儿茶素结构如下：
Figure 141011782-appb-C000001
近几年，儿茶素在基础和应用研究方面已经取得了较大的进展，但是由于儿茶素多个羟基的存在使得其水溶性较强脂溶性较低，因此限制了其在油脂体系中的应用，难以达到有效的抗氧化浓度阈值。另外较低的脂溶性还导致了儿茶素分子不易透过细胞膜脂双层，使得其生物利用度较低，难以到达靶点而大大降低其应有的活性。由于这些问题，对儿茶素分子结构进行修饰以优化其理化性质和生物活性已成为目前的研究热点。一方面通过分子修饰可以提高儿茶素的已有活性，另一方面还通过引入其他活性基团而引入新的生理活性，实现多种活性的集成。儿茶素结构修饰方法主要有酯化、醚化等衍生化方法。酯化化修饰就是利用生物或化学合成的方法，将儿茶素分子结构某些部位的羟基酯化的过程。目前虽然已有混合酯基儿茶素的制备方法，但是还没有专门针对特定位置进行酯化的有效方法。为了进一步优化儿茶素的性质，开发其 特异性的酯化方法必不可少。
本发明提供了一种 取代 儿茶素的选择性制备方法，利用该方法可以得到 3',4',5,7- 四酯基儿茶素、 3 - 酯基儿茶素、 3',4'- 二酯基儿茶素、 3- 四氢吡喃基儿茶素 纯品，且产率较高。
本发明还提供过了一种 取代 儿茶素化合物。
一种 3',4',5,7- 四酯基儿茶素的制备方法，包括：
将儿茶素溶解在叔丁基甲基醚中，加入酸酐与三级胺，搅拌进行反应，反应结束进行后处理得到所述的 3',4',5,7- 四酯基儿茶素；
所述 3',4',5,7- 四酯基儿茶素结构如下式所示：
Figure 141011782-appb-C000002
上式中： R 为 C2~C4 酰基 。
作为优选，所述的 R 为 C2~C4 烷烃酰基；进一步优选为丙酰基、乙酰基或丁酰基；更进一步优选为丙酰基、乙酰基。
上述制备方法中：
作为优选，反应溶剂选用 叔丁基甲基醚，保证反应具有较高的选择性；
作为优选，所述的酸酐选自乙酸酐、丙酸酐、丁酸酐中的一种；进一步优选为乙酸酐、丙酸酐；选用上述几种酸酐时，目标产物的收率均在 60% 以上，选用乙酸酐、丙酸酐时，反应选择性更高，目标产物的收率均在 70% 以上。
作为优选，所述的三级胺选自三乙胺、三丙胺、三丁胺、 N,N- 二异丙基乙胺中的至少一种。作为进一步优选，所述的三级胺为三乙胺，保证目标产物具有较高的收率和选择性，且价格便宜，易于操作。
作为优选，所述的儿茶素、酸酐和三级胺的摩尔比为 1:0.5-50:0.5-50 ；作为进一步优选：所述的儿茶素、酸酐和三级胺的摩尔比为 1:4.0-6.0:4-12 ，该摩尔比范围有利于原料的充分转化和高选择性。
作为优选，所述的后处理包括：
（ 1 ）将有机溶剂加入到反应完成后的反应体系中，萃取产物到有机相中；
（ 2 ）将萃取后的有机相浓缩，经色谱分离得到 3',4',5,7- 四酯基儿茶素纯品。
后处理过程中，所述的有机溶剂包括乙酸乙酯、乙醚、氯仿、二氯甲烷、石油醚、正己烷、叔丁基甲基醚中的一种。这些有机溶剂对产品的溶解性能较好，并且易于挥发除去。
本发明还提供了一种 3',4',5,7- 四酯基儿茶素化合物，其结构如下：
Figure 141011782-appb-C000003
上式中： R 为丙酰基、丁酰基 。
本发明的反应在室温下进行。
本发明一种提供了一种 3- 酯基儿茶素的制备方法，包括如下步骤：
（ 1 ）儿茶素与酸酐在三级胺作碱和叔丁基甲基醚为溶剂的条件下进行酚羟基选择性酯化反应，反应结束进行后处理得到 3',4',5,7- 四酯基儿茶素；所述的 3',4',5,7- 四酯基儿茶素的结构如下式所示：
Figure 141011782-appb-C000004
上式中： R' 为烷烃酰基；
（ 2 ） 3',4',5,7- 四酯基儿茶素与酰基化试剂反应，生成 3- 酯基 -3',4',5,7- 四酯基儿茶素，所述的 3- 酯基 -3',4',5,7- 四酯基儿茶素的结构如下式所示：
Figure 141011782-appb-C000005
上式中： R' 定义同上， R ''为烷烃酰基；
（ 3 ） 3- 酯基 -3',4',5,7- 四酯基儿茶素用选择性脱保护试剂处理，得到 3- 酯基儿茶素，所述的 3- 酯基儿茶素的结构如下式所示：
Figure 141011782-appb-C000006
上式中： R' 和 R ''定义同上。
上式中，所述的 R' 优选为 C1-C5 的烷烃酰基，进一步优选为乙酰基、丙酰基、丁酰基。
上式中，所述的 R ''优选为 C1-C18 的烷烃酰基，跟进一步优选为辛酰基、十二酰基、十三酰基、硬脂酰基。
步骤（ 1 ）中，作为优选，所述的酸酐为烷烃酸酐，进一步优选为乙酸酐、丙酸酐、丁酸酐。选用这些酸酐时， 3',4',5,7- 四酯基儿茶素 的选择性较高，收率较高，均在 70% 以上。作为更进一步优选，所述的酸酐为乙酸酐和丙酸酐，选择性高。
步骤（ 1 ）中，作为优选，所述的三级胺为三乙胺、三丙胺、三丁胺、 N,N- 二异丙基乙胺中的至少一种。作为优选，所述的三级胺为三乙胺，价格便宜，易于操作，且 3',4',5,7- 四酯基儿茶素选择性和收率均较高。
步骤（ 1 ）中，作为优选，所述的儿茶素、酸酐与三级胺的摩尔比为 1:0.5-50:0.5-50 。为进一步提高目标中间体的选择性，作为进一步优选，所述的儿茶素、酸酐和三级胺的摩尔比为 1:4-6:4-12 。该摩尔比范围有利于原料的充分转化和高选择性。
步骤（ 1 ）中后处理过程优选为：
（ 1 ）将有机溶剂加入到反应完成后的反应体系中，萃取产物到有机相中；
（ 2 ）将萃取后的有机相浓缩，经色谱分离得到纯品。
作为进一步的优选，所述的有机溶剂包括乙酸乙酯、乙醚、氯仿、二氯甲烷、石油醚、正己烷、叔丁基甲基醚中的一种，这些有机溶剂对产品的溶解性能较好，并且易于挥发除去。
步骤（ 2 ）中，作为优选，所述的酰基化试剂为酸酐、酰氯中的一种。进一步优选为烷烃酰氯；更进一步优选为 C1-C18 的烷烃酸酐，更进一步优选为辛酰氯、十二酰氯、十三酰氯、硬脂酰氯。
步骤（ 2 ）中，作为优选，可加入缚酸剂，以保证反应的快速彻底的进行，作为优选，所述的缚酸剂为吡啶、三乙胺、碳酸钠、碳酸钾、氢氧化钠等。
步骤（ 2 ）中，作为优选，所述的 3',4',5,7- 四酯基儿茶素、酰基化试剂与缚酸剂（如果加入）的摩尔比为 1:0.5-50:0.5-50 ；进一步优选为 1:1.5-3 ： 3-6 。选用该摩尔比时，目标产物的选择性和收率均较高。
作为优选，所述的选择性脱保护试剂为有机胺，进一步优选为肼。所述 3',4',5,7- 四酯基儿茶素与选择性脱保护试剂的摩尔比为 1:1-50 ；进一步优选为 1:5-15 ；更进一步优选为 1:10-15 。
该制备方法得到的 3',4',5,7- 四酯基儿茶素分子的纯度高，具有较好的应用前景。本发明的步骤可以在室温下进行，适于工业化生产。
本发明还提供了一种 3',4'- 二酯基儿茶素选择性制备方法，包括：
将儿茶素溶解在乙腈中，加入酰氯与三级胺，搅拌进行反应，反应结束进行后处理得到所述的 3',4'- 二酯基儿茶素；所述 3',4'- 二酯基儿茶素的结构如下式 所示：
Figure 141011782-appb-C000007
上式中， R''' 为酰基；
作为优选，所述的 R '''为烷酰基、烷氧酰基；进一步优选为苄氧酰基、十二烷酰基；
所述的酰氯为氯甲酸酯、烷基酰氯中的一种；进一步优选为氯甲酸苄酯、十二酰氯，选用上述两个酰氯时，选择性高，纯化后的产品收率均在 70% 以上；进一步优选为十二酰氯，选用该酰氯时，纯化后的产品收率高达 75% 。
所述的三级胺为三乙胺、三丙胺、三丁胺、 N,N- 二异丙基乙胺中的至少一种。采用上述三级胺，有利于与儿茶素 3',4'- 酚羟基的酸度匹配，实现 3',4'- 酚羟基的高选择性。进一步优选为三乙胺、三丙胺、 N,N- 二异丙基乙胺，选择上述三种三级胺时，产品选择性较好，产率较高；且价格便宜，易于操作。
所述的乙腈作为反应溶剂有利于实现高选择性。
所述的儿茶素、酰氯和三级胺的摩尔比为 1:0.5-50:0.5-50 ，为进一步提高选择性，作为优选，所述的儿茶素、酰氯和三级胺的摩尔比为 1:2-3:2-4 ；进一步优选为 1:2-2.5:2.5-3.5 。该摩尔比范围有利于原料的充分转化和高选择性。
作为优选，所述的后处理过程包括：
（ 1 ）将有机溶剂加入到反应完成后的反应体系中，萃取产物到有机相中；
（ 2 ）将萃取后的有机相浓缩，经色谱分离得到 3',4'- 二酯基儿茶素纯品。
所述的有机溶剂包括乙酸乙酯、乙醚、氯仿、二氯甲烷、石油醚、正己烷、叔丁基甲基醚中的一种或多种，这些有机溶剂对产品的溶解性能较好，并且易于挥发除去。
所述的色谱分离为柱层析色谱分离，所述的洗脱剂为乙酸乙酯与石油醚混合溶剂；
本发明的反应在室温下进行，成本低，适于工业化生产。
该制备方法得到的 3', 4'- 二酯基儿茶素分子的纯度高，具有较好的应用前景。
本发明还提供了一种 3', 4'- 二酯基儿茶素化合物，其结构如下式所示：
Figure 141011782-appb-C000008
R ''''为苄氧酰基。
本发明提供了一种 3- 四氢吡喃基儿茶素选择性制备方法，包括：
将儿茶素溶解在有机溶剂中，加入二氢吡喃与酸性催化剂，搅拌进行反应，反应结束进行后处理得到所述的 3- 四氢吡喃基儿茶素；所述 3- 四氢吡喃基儿茶素的结构如下式所示：
Figure 141011782-appb-C000009
上述反应过程如下式所示：
Figure 141011782-appb-C000010
作为优选，所述的 3- 四氢吡喃基儿茶素选择性制备方法中，所述的酸性催化剂为对甲基苯磺酸、甲烷磺酸、樟脑磺酸中的至少一种。进一步优选为对甲基苯磺酸，反应活性高，且价格便宜，易于操作。
作为优选，所述的 3- 四氢吡喃基儿茶素选择性制备方法中，所述的有机溶剂为四氢呋喃、乙醚、叔丁基甲基醚中的至少一种。进一步优选为四氢呋喃，产品选择性较好，产率较高，纯化后的产品收率均在 70% 以上。
作为优选，所述的 3- 四氢吡喃基儿茶素选择性制备方法中，所述的儿茶素、二氢吡喃和酸性催化剂的摩尔比为 1:0.5-50:0.01-50 ，进一步优选为摩尔比为 1:2-5:0.05-0.25 。
作为优选，所述的后处理过程包括：
（ 1 ）将有机溶剂加入到反应完成后的反应体系中，萃取产物到有机相中；
（ 2 ）将萃取后的有机相浓缩，经色谱分离得到 3- 四氢吡喃基儿茶素纯品。
所述的有机溶剂包括乙酸乙酯、乙醚、氯仿、二氯甲烷、石油醚、正己烷、叔丁基甲基醚中的一种或多种，这些有机溶剂对产品的溶解性能较好，并且易于挥发除去。
所述的色谱分离为柱层析色谱分离，所述的洗脱剂为乙酸乙酯与石油醚混合溶剂；
本发明的反应在室温下进行，成本低，适于工业化生产。
该制备方法得到的 3- 四氢吡喃基儿茶素分子的纯度高，具有较好的应用前景。
本发明制备的 3- 四氢吡喃基作为保护基团，利用 3- 四氢吡喃基儿茶素可用于制备 7 位和 5 位取代儿茶素产品。
本发明具有如下优点及效果：
（ 1 ）本发明的制备方法有较好的选择性，产物的产率高达 70% 以上。
（ 2 ）本发明的制备方法操作简单，避免采用高成本、高毒性、高腐蚀性的试剂，且反应条件温和，避免采用高压和高温条件，适用于工业化生产应用。
下面结合实施例对本发明作进一步详细的描述，但本发明的实施方式不限于此。
实施例 1
将儿茶素（ 29 mg ）溶解在叔丁基甲基醚（ 10ml ）中，加入丙酸酐（ 59 mg ）和三乙胺（ 45 mg ），在室温下搅拌反应 20 小时，待反应结束后用乙酸乙酯萃取，经色谱纯化（硅胶柱层析，洗脱剂为乙酸乙酯与石油醚混合溶剂）后得到 3',4',5,7- 四丙酯儿茶素，产率 78% 。
结构测定数据 ： 1 H NMR (400 MHz, CDCl3) δ 7.37-7.21 (m, 3 H), 6.61 (d, J = 1.6 Hz, 1 H), 6.56 (d, J = 2.0 Hz, 1 H), 4.74 (d, J = 8.4 Hz, 1 H), 4.02-3.94 (m, 1 H), 2.99 (dd, J = 16.4, 5.6 Hz, 1 H), 2.69-2.52 (m, 9 H), 1.35-1.14 (m, 12 H). 质谱显示加钠分子离子峰 537.11 。这些数据证明了合成物质结构的正确性。
实施例 2
将儿茶素（ 29 mg ）溶解在叔丁基甲基醚（ 10ml ）中，加入乙酸酐（ 46 mg ）和 N,N- 二异丙基乙胺（ 52 mg ），在室温下搅拌反应 20 小时，待反应结束后用乙酸乙酯萃取，经色谱纯化（硅胶柱层析，洗脱剂为乙酸乙酯与石油醚混合溶剂）后得到 3',4',5,7- 四乙酯儿茶素，产率 73% 。
结构测定数据 ： 1 H NMR (400 MHz, DMSO-d6) δ 7.37-7.25 (m, 3H), 6.61 (d, J = 2.8 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 4.87 (d, J = 8.0 Hz, 1H), 4.05-3.95 (m, 1 H), 2.78 (dd, J = 16.4, 5.6 Hz, 1 H), 2.57-2.48 (m, 1 H), 2.30 (s, 3 H), 2.29 (s, 6 H), 2.24 (s, 3 H). 质谱显示加钠分子离子峰 481.03 。这些数据证明了合成物质结构的正确性。
实施例 3
将儿茶素（ 29 mg ）溶解在叔丁基甲基醚（ 10ml ）中，加入丁酸酐（ 71 mg ）和三丙胺（ 57 mg ），在室温下搅拌反应 20 小时，待反应结束后用乙酸乙酯萃取，经色谱纯化（硅胶柱层析，洗脱剂为乙酸乙酯与石油醚混合溶剂）后得到 3',4',5,7- 四丁酯儿茶素，产率 62% 。
结构测定数据 ： 1 H NMR (400 MHz, DMSO) δ 7.39-7.24 (m, 3H), 6.60 (d, J = 2.0 Hz, 1H), 6.58 (d, J = 2.0 Hz, 1H), 4.88 (d, J = 8.0 Hz, 1H), 4.05-3.95 (m, 1 H), 2.77 (dd, J = 16.4, 5.6 Hz, 1 H), 2.63-2.46 (m, 9 H), 1.73-1.59 (m, 8 H), 1.02-0.92 (m, 12 H). 质谱显示加钠分子离子峰 593.17 。这些数据证明了合成物质结构的正确性。
利用实施例 1-3 得到的化合物可用于合成 3- 酯基儿茶素 （ 该类化合物具有很好的抗癌活性 ， 见文献 Chemico-Biological Interactions 185 (2010) 182 - 188 ） 。如下例： 3',4',5,7- 四丙酯儿茶素（ 51 mg ）然后与癸酰氯（ 44 mg ）和吡啶（ 24 mg ）进行反应 24 小时，再与碳酸钾（ 90 mg ）反应 8 小时，待反应结束后用乙酸乙酯萃取，经色谱纯化后得到 3- 癸烷基酯儿茶素 92% 。采用相同的条件， 3',4',5,7- 四丁酯儿茶素也可进行类似的反应，产率约为 93% 左右。
实施例 4
儿茶素（ 29 mg ）、丙酸酐（ 59 mg ）和三乙胺（ 45 mg ）在室温下搅拌反应 20 小时，待反应结束后用乙酸乙酯萃取，经色谱（洗脱剂乙酸乙酯与石油醚混合溶剂）纯化后得到 3',4',5,7- 四丙酯儿茶素（收率为 78% ）。然后与十二酰氯（ 44 mg ）和吡啶（ 24 mg ）进行反应 24 小时，再与水合肼（ 40 mg ）反应 8 小时，待反应结束后用乙酸乙酯萃取，经色谱纯化后得到 3- 十二烷基酯儿茶素 72% 。
结构测定数据 ： 1 H NMR (400 MHz, DMSO) δ 9.35 (s, 1 H), 9.08 (s, 1 H), 8.96 (s, 1 H), 8.90 (s, 1 H), 6.71 (d, J = 1.6 Hz, 1 H), 6.68 (d, J = 8.4 Hz, 1 H), 6.57 (dd, J = 8.4, 2.0 Hz, 1 H), 5.93 (d, J = 2.0 Hz, 1 H), 5.77 (d, J = 2.0 Hz, 1 H), 5.11 (q, J = 6.0 Hz, 1 H), 4.90 (d, J = 6.4 Hz, 1 H), 2.64 (dd, J = 16.4, 5.2 Hz, 1 H), 2.54-2.46 (m, 1 H), 2.17 (td, J = 7.2, 3.2 Hz, 2 H), 1.42-1.33 (m, 2 H), 1.32-1.03 (m, 16 H), 0.86 (t, J = 7.2, 3 H). 质谱显示其中主成分的去氢分子离子峰 470.88 。这些数据证明了合成物质结构的正确性。
实施例 5
儿茶素（ 29 mg ）、乙酸酐（ 46 mg ）和三丙胺（ 57 mg ）在室温下搅拌反应 20 小时，待反应结束后用乙酸乙酯萃取，经色谱纯化后得到 3',4',5,7- 四乙酯儿茶素（收率为 75% ）。然后与辛酰氯（ 24 mg ）和吡啶（ 32 mg ）进行反应 24 小时，再与水合肼（ 40 mg ）反应 8 小时，待反应结束后用乙酸乙酯萃取，经色谱纯化后得到 3- 辛酯儿茶素 75% 。结构检测数据与现有技术一致（ 质谱显示其中主成分的去氢分子离子峰 414.88 ）。
3',4',5,7- 四乙酯儿茶素的 结构测定数据 ： 1 H NMR (400 MHz, DMSO-d6) δ 7.37-7.25 (m, 3H), 6.61 (d, J = 2.8 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 4.87 (d, J = 8.0 Hz, 1H), 4.05-3.95 (m, 1 H), 2.78 (dd, J = 16.4, 5.6 Hz, 1 H), 2.57-2.48 (m, 1 H), 2.30 (s, 3 H), 2.29 (s, 6 H), 2.24 (s, 3 H). 质谱显示加钠分子离子峰 481.03 。
实施例 6
儿茶素（ 29 mg ）、丁酸酐（ 71 mg ）和 N,N- 二异丙基乙胺（ 52 mg ）在室温下搅拌反应 20 小时，待反应结束后用乙酸乙酯萃取，经色谱纯化后得到 3',4',5,7- 四丁酯儿茶素（收率为 74% ）。然后与辛酰氯（ 24 mg ）和吡啶（ 32 mg ）进行反应 24 小时，再与水合肼（ 40 mg ） 反应 8 小时，待反应结束后用乙酸乙酯萃取，经色谱纯化后得到 3- 辛酯儿茶素 70% 。结构检测数据同实施例5。
3',4',5,7- 四丁酯儿茶素 结构测定数据 ： 1 H NMR (400 MHz, DMSO) δ 7.39-7.24 (m, 3H), 6.60 (d, J = 2.0 Hz, 1H), 6.58 (d, J = 2.0 Hz, 1H), 4.88 (d, J = 8.0 Hz, 1H), 4.05-3.95 (m, 1 H), 2.77 (dd, J = 16.4, 5.6 Hz, 1 H), 2.63-2.46 (m, 9 H), 1.73-1.59 (m, 8 H), 1.02-0.92 (m, 12 H). 质谱显示加钠分子离子峰 593.17 。
实施例 7
儿茶素（ 29 mg ）、氯甲酸苄酯（ 40 mg ）和三乙胺（ 30 mg ）在室温下搅拌反应 2 小时，待反应结束后用乙酸乙酯萃取，经色谱纯化后得到 3',4'- 二苄氧羰基酯儿茶素 72% 。
结构测定数据 ： 1 H NMR (400 MHz, DMSO) δ 9.28 (s, 1 H), 9.02 (s, 1 H), 7.48-7.34 (m, 13 H), 5.95 (d, J = 2.4 Hz, 1 H), 5.75 (d, J = 2.4 Hz, 1 H), 5.26 (s, 2 H), 5.25 (s, 2 H), 5.16 (d, J = 5.6 Hz, 1 H), 4.68 (d, J = 8.4 Hz, 1 H), 3.89 (ddd, J = 14.0, 8.4, 5.6 Hz, 1 H), 2.78 (dd, J = 16.4, 5.6 Hz, 1 H), 2.41 (dd, J = 16.0, 8.8 Hz, 1 H) 。 质谱显示其中主成分的加钠分子离子峰 580.85 。这些数据证明了合成物质结构的正确性。
实施例 8
儿茶素（ 29 mg ）、氯甲酸苄酯（ 34 mg ）和三丙胺（ 36 mg ）在室温下搅拌反应 2 小时，待反应结束后用乙酸乙酯萃取，经色谱纯化后得到 3',4'- 二苄氧羰基酯儿茶素 70% 。结构检测数据同实施例 7。
实施例 9
儿茶素（ 29 mg ）、十二酰氯（ 44 mg ）和 N,N- 二异丙基乙胺（ 33 mg ）在室温下搅拌反应 2 小时，待反应结束后用乙酸乙酯萃取，经色谱纯化后得到 3',4'- 二十二酰基酯儿茶素 75% ，结构检测数据与现有技术检测数据一致（ 质谱显示其中主成分的加钠分子离子峰 677.10 ）。
实施例 10
将儿茶素（ 29 mg ）、二氢吡喃（ 25 mg ， 2,3- 二氢吡喃）和对甲基苯磺酸（ 1 mg ）溶于四氢呋喃中，在室温下搅拌反应 2 小时，待反应结束后用乙酸乙酯萃取，经色谱纯化（洗脱剂是乙酸乙酯与石油醚的混合溶剂）后得到 3- 四氢吡喃基儿茶素 72% 。
结构测定数据 ： 1 H NMR (400 MHz, DMSO) δ 9.26 (s, 1 H), 9.25 (s, 1 H), 8.99 (s, 1 H), 8.98 (s, 1 H), 8.91 (s, 1 H), 8.88 (s, 1 H), 8.87 (s, 1 H), 8.80 (s, 1 H), 6.74 (dd, J = 5.6, 1.6 Hz, 2 H), 6.70 (dd, J = 8.0, 2.4 Hz, 2 H), 6.64-6.57 (m, 2 H), 5.92 (d, J = 2.4 Hz, 1 H), 5.91 (d, J = 2.4 Hz, 1 H), 5.74 (d, J = 2.0 Hz, 1 H), 5.72 (d, J = 2.0 Hz, 1 H), 4.87-4.84 (m, 1 H), 4.78 (d, J = 6.8 Hz, 1 H), 4.63 (d, J = 7.6 Hz, 1 H), 4.15-4.08 (m,1 H), 3.96 (d, J = 5.2 Hz, 1 H), 3.85 (d, J = 5.6 Hz, 1 H), 3.64-3.57 (m, 4 H), 2.79-2.66 (m, 2 H), 2.54-2.39 (m, 2 H), 1.80-1.72 (m, 10 H), 1.65-1.59 (m, 2 H). ESI-MS [M-H]- C20H21O7 372.94 。
该化合物用可用于制备 7- 乙酰酯基儿茶素，应用例如下： 3- 四氢吡喃基儿茶素（ 37 mg ）、氯甲酸苄酯（ 34 mg ）和三丙胺（ 36 mg ）在室温下搅拌反应 2 小时，待反应结束后用乙酸乙酯萃取蒸干，将得到的固体利用有机溶剂溶解，加入乙酸酐（ 11 mg ）和 N,N- 二异丙基乙胺（ 15 mg ）在室温下搅拌反应 2 小时，待反应结束后用乙酸乙酯萃取蒸干，然后将得到的固体溶解于甲醇中，加入 5% 钯碳（ 1.4mg ）和三乙基硅烷（ 120 mg ），在室温下搅拌反应 12 小时，再加入稀盐酸反应 12 小时，待反应结束后用乙酸乙酯萃取，经柱层色谱纯化后得到 7- 乙酰酯基儿茶素（收率： 30% ，洗脱剂为氯仿甲醇混合溶剂）。经过核磁和质谱检测，证明 7 位的乙酰氧结构。
实施例 11
将儿茶素（ 29 mg ）、二氢吡喃（ 33 mg ）和甲烷磺酸（ 1 mg ）溶于四氢呋喃中，在室温下搅拌反应 2 小时，待反应结束后用乙酸乙酯萃取，经色谱纯化（洗脱剂是乙酸乙酯与石油醚的混合溶剂）后得到 3- 四氢吡喃基儿茶素 70% 。结构检测数据同实施例 10。
实施例 12
将儿茶素（ 29 mg ）、二氢吡喃（ 30 mg ）和樟脑磺酸（ 1 mg ）溶于四氢呋喃中，在室温下搅拌反应 2 小时，待反应结束后用乙酸乙酯萃取，经色谱纯化（洗脱剂是乙酸乙酯与石油醚的混合溶剂）后得到 3- 四氢吡喃基儿茶素 75% 。结构检测数据同实施例 10 。

Claims (21)

  1. 一种3’,4’,5,7-四酯基儿茶素的选择性制备方法，包括：
    将儿茶素溶解在叔丁基甲基醚中，加入酸酐与三级胺，搅拌进行反应，反应结束进行后处理得到所述的3’,4’,5,7-四酯基儿茶素；
    所述3’,4’,5,7-四酯基儿茶素结构如下式所示：
    Figure 141011782-appb-C000011
    上式中：R为C2～C4酰基。
  2. 根据权利要求1所述的3’,4’,5,7-四酯基儿茶素的选择性制备方法，其特征在于，所述的酸酐为乙酸酐、丙酸酐、丁酸酐。
  3. 根据权利要求1所述的3’,4’,5,7-四酯基儿茶素的选择性制备方法，其特征在于，所述的三级胺为三乙胺、三丙胺、三丁胺、N,N-二异丙基乙胺中的至少一种。
  4. 根据权利要求1所述的3’,4’,5,7-四酯基儿茶素的选择性制备方法，其特征在于，其特征在于，所述的儿茶素、酸酐和三级胺的摩尔比为1:4-6:4-12。
  5. 一种3’,4’,5,7-四酯基儿茶素化合物，其特征在于，其结构如下：
    Figure 141011782-appb-C000012
    上式中： R为丙酰基、丁酰基。
  6. 一种3-酯基儿茶素的制备方法，包括如下步骤：
    （1）儿茶素与酸酐在三级胺作碱和叔丁基甲基醚为溶剂的条件下进行酚羟基选择性酯化反应，反应结束进行后处理得到3’,4’,5,7-四酯基儿茶素；所述的3’,4’,5,7-四酯基儿茶素的结构如下式所示：
    Figure 141011782-appb-C000013
    式中：R’为烷烃酰基；
    （2）3’,4’,5,7-四酯基儿茶素与酰基化试剂反应，生成3-酯基-3’,4’,5,7-四酯基儿茶素，所述的3-酯基-3’,4’,5,7-四酯基儿茶素的结构如下式所示：
    Figure 141011782-appb-C000014
    上式中： R''为烷烃酰基；
    （3）3-酯基-3’,4’,5,7-四酯基儿茶素用选择性脱保护试剂处理，得到3-酯基儿茶素，所述的3-酯基儿茶素的结构如下式所示：
    Figure 141011782-appb-C000015
    。
  7. 根据权利要求6所述的3-酯基儿茶素的制备方法，其特征在于，步骤（1）中，所述的酸酐为乙酸酐、丙酸酐、丁酸酐。
  8. 根据权利要求6所述的3-酯基儿茶素的制备方法，其特征在于，步骤（1）中，所述的三级胺为三乙胺、三丙胺、三丁胺、N,N-二异丙基乙胺中的至少一种。
  9. 根据权利要求6所述的3-酯基儿茶素的制备方法，其特征在于，步骤（1）中，所述的儿茶素、酸酐与三级胺的摩尔比1:4-6:4-12。
  10. 根据权利要求6所述的3-酯基儿茶素的制备方法，其特征在于，步骤（2）中，所述的酰基化试剂为辛酰氯、十二酰氯、十三酰氯、硬脂酰氯。
  11. 根据权利要求6所述的3-酯基儿茶素的制备方法，其特征在于，步骤（2）中，所述的3’,4’,5,7-四酯基儿茶素、酰基化试剂与缚酸剂的摩尔比为1：1.5-3：3-6。
  12. 一种3’,4’-二酯基儿茶素选择性制备方法，包括：
    将儿茶素溶解在乙腈中，加入酰氯与三级胺，搅拌进行反应，反应结束进行后处理得到所述的3’,4’-二酯基儿茶素；所述3’,4’-二酯基儿茶素的结构如下式所示：
    Figure 141011782-appb-C000016
    上式中，R'''为酰基。
  13. 根据权利要求12所述的3’,4’-二酯基儿茶素选择性制备方法，其特征在于，所述的酰氯为氯甲酸苄酯、十二酰氯。
  14. 根据权利要求12所述的3’,4’-二酯基儿茶素选择性制备方法，其特征在于，所述的三级胺为三乙胺、三丙胺、N,N-二异丙基乙胺中的至少一种。
  15. 根据权利要求12所述的3’,4’-二酯基儿茶素选择性制备方法，其特征在于，所述的儿茶素、酰氯和三级胺的摩尔比为1:2-3:2-4。
  16. 一种3’,4’-二酯基儿茶素，其特征在于，其结构如下式所示：
    Figure 141011782-appb-C000017
    R''''为苄氧酰基。
  17. 一种3-四氢吡喃基儿茶素选择性制备方法，包括：
    将儿茶素、二氢吡喃与酸性催化剂与有机溶剂混合，搅拌进行反应，反应结束进行后处理得到所述的3-四氢吡喃基儿茶素；所述3-四氢吡喃基儿茶素的结构如下式所示：
    Figure 141011782-appb-C000018
    。
  18. 根据权利要求17所述的3-四氢吡喃基儿茶素选择性制备方法，其特征在于，所述的酸性催化剂为对甲基苯磺酸、甲烷磺酸、樟脑磺酸中的至少一种。
  19. 根据权利要求17所述的3-四氢吡喃基儿茶素选择性制备方法，其特征在于，所述的有机溶剂为四氢呋喃、乙醚、叔丁基甲基醚中的至少一种。
  20. 根据权利要求17所述的3-四氢吡喃基儿茶素选择性制备方法，其特征在于，所述的儿茶素、二氢吡喃和酸性催化剂的摩尔比为1:2-5:0.05-0.25。
  21. 一种3-四氢吡喃基儿茶素，其特征在于，其结构如下式所示：
    Figure 141011782-appb-C000019
    。
PCT/CN2014/090670 2014-09-30 2014-11-10 取代儿茶素的选择性制备方法及产品 WO2016049966A1 (zh)

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