JP5265144B2 - Novel process for producing 3-O-substituted-catechin derivatives - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new method for producing a 3-O-substituted-catechin derivative having various acyl groups and alkyl groups substituted to the 3-hydroxy group of the flavan skeleton of catechins. <P>SOLUTION: The method for easily producing a 3-O-substituted-catechin derivative expressed by formula (IV) in high purity and yield comprises the selective introduction of various acyl groups and alkyl groups to the 3-hydroxy group of the flavan skeleton of catechins by selectively protecting only the phenolic hydroxy groups of catechins. <P>COPYRIGHT: (C)2009,JPO&amp;INPIT

Description

  The present invention relates to a novel method for producing 3-O-substituted-catechin derivatives having various acyl groups and alkyl groups substituted on the hydroxyl group at the 3-position in the flavan skeleton of catechins.

The catechins that are representative compounds of the flavan-3-ols that are one type of polyphenol compounds are (−)-epicatechin, (−)-epigallocatechin, or gallic acid esters thereof (−) —. There are four main types: epicatechin gallate and (−)-epigallocatechin gallate.
Catechins are known to have various chemical and physiological activity actions such as an antioxidant action, an antibacterial action, a deodorizing action, a blood cholesterol suppressing action, and an α-amylase activity inhibiting action. Recently, it has been disclosed that 3-acylcatechins have an action of suppressing cervical cancer (Patent Document 1) and an effect of inhibiting DNA synthesis (Patent Document 2). However, since these catechins are poorly soluble substances, it is difficult to develop them as injections, and when considering DPI formulation for the purpose of improving absorption efficiency, a large amount of compounds are required, so that large-scale synthesis is possible. Development of a novel synthesis method of possible 3-O-substituted-catechin derivatives has been desired.

  Catechin is extracted from any of the leaves, stems, xylem, bark, roots, berries, seeds of tea trees belonging to the camellia family with water, hot water, organic solvents, hydrous organic solvents, or mixed solvents thereof. Can be obtained. With regard to purified products of catechins, for example, an extract obtained by extracting tea leaves with the above solvent can be purified to a desired degree using an organic solvent fraction or an adsorption resin (Patent Literature). 3).

  On the other hand, as a method for introducing a substituent into the hydroxyl group at the 3-position in the flavan skeleton of catechins, a production method in which carboxyesterase is allowed to act on an ester compound in the presence of free catechin (Patent Document 4) ), An acyl group introduced into the hydroxyl group at the 3-position of known 3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-ol (Non-patent Document 1), and the resulting 3-acylation The benzyl group which is the protecting group of 3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan is deprotected to give 3-acylated 3 ′, 4 ′, 5,7-tetrahydroxyflavan-3- A method for producing oale (for example, Patent Document 1), a method for synthesizing a catechin derivative using a boron compound (Patent Documents 5 and 6), a method using trifluoroacetic acid and an acid chloride (Non-Patent Document 2), a lipase for The method (Non-patent Document 3) have been disclosed that.

  However, in the conventional synthesis method, for example, when 3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-ol is used, the protecting group of benzyl group is changed to a hydrogen atmosphere, and a catalyst such as palladium is used. In addition to deprotection of the benzyl group, in addition to requiring safety studies, there were problems such as operability such as separation and purification by the generation of by-products and difficulty in mass synthesis due to reproducibility problems. Further, the production method of Patent Document 4 uses an esterase as an enzyme, and thus the operation is complicated.

  In addition, a method is disclosed in which an acyl group is selectively introduced at the 3-position by reacting with an acyl chloride without protecting the phenolic hydroxyl group, but there are many reaction by-products and separation and purification is very complicated. However, it has not been practical for mass synthesis, and there has been a demand for the appearance of an improved production method capable of mass synthesis that is simpler.

The inventors of the present invention selectively recover only the phenolic hydroxyl group by reacting the starting material catechins in which the phenolic hydroxyl group and alcoholic hydroxyl group of the catechins are not protected with a silylating agent in a polar solvent. It was found to be silylated at a rate.
This silylated product, for example, 3 ′, 4 ′, 5,7-tetra-t-butyldimethylsilyl-(+)-catechin is a compound known in the literature (Patent Document 7). (-) Epicatechin is a method in which all hydroxyl groups of gallate are protected with silyl groups, and then reacted with lithium aluminum hydride in a tetrahydrofuran solvent to remove the silyl group only at the 3-position. However, there is no description about directly introducing a silyl protecting group selectively.

JP 2006-249056 A JP 2006-249057 A Japanese Examined Patent Publication No. 1-44422 JP-A-6-279430 JP 57-118580 A Japanese Patent Laid-Open No. 57-12058 US Patent Publication No. 2007-21384 Journal of the Wood Society of Japan, 1991, 37, 488-493 Bioorganic & Medicinal Chemistry Letters, 2000, 10, 1673-1675. Journal of Molecular Catalysis B: Enzymatic, 2000, 10, 577-582.

  Therefore, an object of the present invention is to provide a novel method for producing a 3-O-substituted-catechin derivative in which various acyl groups or alkyl groups are substituted on the hydroxyl group at the 3-position in the flavan skeleton of catechins.

  As a result of intensive studies to solve the above problems, the present inventors have succeeded in selectively protecting only the phenolic hydroxyl group of catechins, which are commercially available starting materials, with a silyl group and are not protected. After selectively introducing an acyl group or an alkyl group into the hydroxyl group at the 3-position, and then deprotecting the silyl group, it was found that the desired 3-O-substituted-catechin derivatives can be obtained in high yield. The present invention has been reached.

  Accordingly, the present invention provides the following formula (I):

(In the formula, Ra represents a hydrogen atom or a hydroxyl group.)
In the presence of a base, the following formula:
AX
(In the formula, A represents a silyl protecting group for a hydroxyl group, and X represents an active residue.)
Wherein the protecting group is selectively introduced into the phenolic hydroxyl group of formula (I):

(Wherein Rc represents a hydrogen atom or a group: OA, and A is the same as defined above)
And then the following formula (V):
RY (V)
[Wherein, R represents an alkyl group having 1 to 22 carbon atoms which may be substituted, or an acyl group represented by an RbC (═O) — group (Rb may be substituted having 1 to 22 carbon atoms. Represents an alkyl group, and Y represents an active residue]
And a compound represented by the following formula (III):

(Wherein A, Ra and R are the same as defined above)
And then deprotecting the compound represented by the following formula (IV):

(Wherein Ra and R are as defined above)
A method for producing a 3-O-acyl or alkyl-substituted catechin derivative represented by the formula:

  More specifically, the present invention is the above production method, wherein A is a silyl protecting group, and particularly the silyl protecting group is a t-butyldimethylsilyl group.

  In addition, the present invention specifically includes the deprotection of the compound of formula (III) to the compound of formula (IV) using tetrabutylammonium fluoride in a solvent in the presence of acetic acid. This is a featured manufacturing method.

  Furthermore, the present invention is a production method in which the induction to the formula (III) is reacted in one pot without isolating the compound of the above formula (II).

  The present invention is also a method for producing an intermediate compound in the above production method, specifically, represented by the formula (II) in which a protecting group is selectively introduced into the phenolic hydroxyl group in the compound of the above formula (I). It is a manufacturing method of a compound, and is also a manufacturing method of the compound shown by Formula (IV).

  According to the production method provided by the present invention, various acyl groups or alkyl groups can be selectively introduced into the hydroxyl group at the 3-position in the flavan skeleton of catechins, and as a result, various 3-O-acyl substitutions or It is possible to provide a method by which 3-O-alkyl-substituted-catechin derivatives can be easily produced with high purity and high yield.

  Specifically, the production method provided by the present invention can be represented by the reaction formula shown below.

[In the above reaction formula, Ra represents a hydrogen atom or a hydroxyl group, Rc represents a hydrogen atom or group: —OA, A represents a silyl protecting group for a hydroxyl group, X represents an active residue, and R represents a carbon number of 1 Represents an optionally substituted alkyl group having ˜22 or an acyl group represented by an RbC (═O) — group (Rb represents an optionally substituted alkyl group having 1 to 22 carbon atoms), Y Represents an active residue]

Hereinafter, terms and steps in the present invention will be described.
In the production method provided by the present invention, catechins (I) used as starting materials include catechin, epicatechin, gallocatechin, epigallocatechin and the like. Natural or synthetic products such as catechin can be obtained by methods known in the literature. It can be obtained from tea plant.
Moreover, it can manufacture from plants other than tea by the same method as in the case of tea.
These catechins are commercially available, and examples thereof include “Polyphenone” manufactured by Mitsui Norin Co., Ltd., “Sunphenon” manufactured by Taiyo Kagaku Co., Ltd., “Theafuran” manufactured by ITO EN Co., Ltd. and the like.

  In the present invention, the substituent “Ra” represents a hydrogen atom or a hydroxyl group. Therefore, specific examples of the 2-position phenyl group in the catechins represented by the formula (I) include 3,4-dihydroxyphenyl, 3,4,5-trihydroxyphenyl, and the like.

The silyl protecting group of the hydroxyl group represented by the substituent "A", main Chirushiriru, ethylsilyl, dimethylsilyl, diethylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tri t- butylsilyl, dimethyl t- butylsilyl, trimethoxysilyl, List silyl protecting groups such as triethoxysilyl, diphenylmethylsilyl, diphenylethylsilyl, diphenylisopropylsilyl, diphenyl t-butylsilyl, triphenylsilyl, triphenoxysilyl, dimethylmethoxysilyl, dimethylphenoxysilyl, methylmethoxyphenylsilyl groups Can do. Among these, t-butyldimethylsilyl group is most preferable.
“X” represents an active residue, and specific examples include an active residue used in a conventional manner such as a halogen atom, triflate, N-methyltrifluoroacetamide, imidazole and the like. Among these, a halogen atom is preferable.

The halogen atom is a halogen such as fluorine, chlorine, bromine or iodine, preferably chlorine, bromine or iodine.
Therefore, as a compound represented by Formula AX, for example, commercially available t-butyldimethylsilyl chloride (represented by Formula: TBDM-X) can be preferably used.

According to the production method of the present invention, for example, by reacting catechins with t-butyldimethylsilyl chloride (TBDM-X) in the presence of a base in a suitable solvent, preferably a specific mixed solvent, phenolic A silyl protecting group can be selectively introduced into the hydroxyl group.
In the catechins of the formula (I), when the substituent Ra is a hydroxyl group, the hydroxyl group is a phenol hydroxyl group, and thus is protected by a silyl protecting group by the above reaction [formula (II) In which the substituent Rc is a group: -OA].

In the production method of the present invention, the following formula (V) reacting with the compound of the formula (II):
RY (V)
For example, in the compound represented by the formula:
Rb (= CO) -Y
As the acyl activated compound represented by the formula, Rb is one having 2 to 22 carbon atoms. Rb may have a plurality of unsaturated bonds on the chain. The unsaturated fatty acid group having 2 to 22 carbon atoms, for example, oleyl, geranyl or saturated fatty acid group is substituted with alkyl having 1 to 4 carbon atoms. The active form which is acyl groups, such as a good isostearoyl, can be mentioned.

  Moreover, as a C1-C22 alkyl group as R in Formula: RY, for example, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a decane group, a lauryl group, a myristyl group, a palmityl group, An unsubstituted alkyl group such as a stearyl group or a behenyl group, or an unsaturated alkyl group having 2 to 22 carbon atoms having a plurality of unsaturated bonds on the chain, such as an oleyl group, a geranyl group, or an alkyl group having 1 to 4 carbon atoms Mention may be made of alkyl groups substituted with groups.

  The group “Y” is an active residue, and the same active residue as the above “X” can be used. Preferably, the above-mentioned halogen atom can be mentioned, and as the halogen atom, chlorine, bromine and iodine are preferable, or an active residue of a commonly used carboxylic acid derivative can be mentioned.

The deprotection of the protecting group of the hydroxyl group derived from the compound of formula (III) to the compound of formula (IV) in the production method of the present invention is carried out by a known method (TW Green, “Protective Groups in Organic Synthesis”, A Wiley-Interscience). New York, 1999, p. 113-148).
Specifically, for example, the compound of formula (III) is treated with a deprotection reagent such as tetrabutylammonium fluoride [tetrahydrofuran (hereinafter referred to as THF) 1M solution] under acidic conditions such as acetic acid, trifluoroacetic acid and hydrochloric acid. This can be done.
The reaction is preferably performed in the presence of a solvent. As such a solvent, any solvent can be used as long as it does not participate in the reaction, and preferably THF, toluene and the like are used. The deprotection reaction proceeds smoothly in the range of −20 ° C. to 100 ° C.

Hereinafter, the production method of the present invention will be described more specifically with the production method of Example 1 described later as a representative example.
The reaction solvents used in the following production steps, such as THF, dichloromethane, ethyl acetate and the like, were those dried by a conventional method unless otherwise specified.
The production method of the present invention is a production method comprising the following three steps. The following are examples of catechins represented by the formula (I):

3 ', 4', 5,7-tetrahydroxy-(+) catechin represented by (2R, 3S) -3 ', 4', 5,7-tetrahydroxyflavan-3-ol (Compound 1) To explain.

  In the production process 1 in the production method of the present invention, (2R, 3S) -3 ′, 4 ′, 5,7-tetra-O— in which TBDMS is selectively introduced as a protecting group into the phenolic hydroxyl group of catechins. This is a step for producing t-butyldimethylsilylflavan-3-ol (compound 2).

  Specifically, (+)-catechin (compound 1) represented by the formula (1) and at least one base selected from the group of imidazole, pyridine, triethylamine, etc., preferably imidazole, are added to a suitable solvent. The mixture is added dropwise under ice cooling with a THF solution of t-butyldimethylsilyl chloride with stirring, and the precipitate formed in the reaction solution is dissolved in dichloromethane and stirred at room temperature for 1 to 20 hours.

Examples of the solvent used in the production step 1 include THF, dichloromethane, a THF-dichloromethane mixed solvent, and ethyl acetate. Preferred is a mixed solvent of THF and THF-dichloromethane, and more preferred is a mixed solvent of THF-dichloromethane.
The content (parts by weight) of THF per 100 parts by weight of the THF-dichloromethane mixed solvent is preferably 37 to 99.9 parts by weight, more preferably 42 to 99.9 parts by weight, still more preferably 60 to 90 parts by weight. Particularly preferred is 70 to 80 parts by weight.

  After completion of the reaction, according to a conventional method, for example, the reaction solvent is removed under reduced pressure, and the residue is extracted by adding dichloromethane, and the organic layer is washed with water and saturated brine, and dried over anhydrous sodium sulfate and the like. After filtration and concentration, the product was separated and purified by silica gel column chromatography (n-hexane: ethyl acetate), and the phenolic hydroxyl group was selectively protected by a silyl group. 3 ′, 4 ′, 5,7-tetra-t- Butyldimethylsilyl-(+)-catechin (compound 2) can be obtained as a colorless liquid.

The amount of the silylating agent represented by the formula: AX used for the introduction reaction (silylation) of the protecting group can be set according to the number of phenolic hydroxyl groups not substituted in the catechins.
The usage amount specifically set is in the range of 1 to 1.1 times the number of hydroxyl groups. For example, in the case of catechin having 4 unsubstituted phenolic hydroxyl groups, the amount of silylating agent used is at least 4 moles. The silylation is preferably performed in a dry state, for example, in a reaction vessel under an atmosphere substituted with a dry inert gas.

The reaction temperature varies depending on the amount of the starting material catechin, the reaction time, the reaction temperature and the like, and is not particularly limited, but it can usually be carried out in the range from ice-cooled to room temperature.
For example, when 4.4 mol of silylating agent is used per 1 mol of catechin, the reaction yield can be obtained with good yield even when the silylated product is isolated and purified. Practically, 4 mol of silylating agent is added to 1 mol of catechin, and the resulting silylated product is further concentrated by, for example, concentrating under reduced pressure and using the residue as it is in the next production step without isolation and purification. The rate can be improved.

Moreover, as a base used for this manufacturing process, the organic or inorganic base which can be used for a normal silylation reaction besides the above-mentioned base can also be used without a restriction | limiting in particular.
Furthermore, as a solvent used in this production process, there is no particular limitation as long as it does not participate in the reaction other than the above-mentioned solvents. For example, chloroform, dichloromethane, ethyl acetate, preferably dichloromethane is used.

In the production process 2, as one of them, an acyl group is introduced into the hydroxyl group at the 3-position of the catechins represented by the formula (II) in which the phenolic hydroxyl group obtained in the production process 1 is protected. Is a step of obtaining a compound represented by
Specifically, for example, a process for producing 3 ′, 4 ′, 5,7-tetra-Ot-butyldimethylsilyl-(+)-catechin-3-myristate (compound 3) will be described.

In this production process 2, first, the 3 ′, 4 ′, 5,7-tetra-Ot-butyldimethylsilyl-(+)-catechin (compound 2) obtained in the production process 1 is converted into dichloromethane or the like. It is carried out by dissolving in a solvent, adding an acyl active such as myristoyl chloride and N, N-dimethylaminopyridine in the presence of a base such as triethylamine under ice cooling, and stirring for example at room temperature for 1 to 5 hours.
After completion of the reaction, extraction is performed with, for example, dichloromethane according to a conventional method, and the organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and silica gel column chromatography (n-hexane: ethyl acetate). The desired 3 ′, 4 ′, 5,7-tetra-Ot-butyldimethylsilyl-(+)-catechin-3-myristate (compound 3) can be obtained.

The base used in this production process is not particularly limited as long as it is an organic or inorganic base that can be used for a normal acylation reaction in addition to the above-mentioned base.
In addition to the polar solvent, the solvent used in this production process is not particularly limited as long as it does not participate in the reaction. For example, ether solvents such as diethyl ether, THF and dioxane; halogenated hydrocarbon solvents such as dichloromethane and chloroform; hydrocarbon solvents such as pentane, hexane, benzene, toluene and xylene; DMF, DMSO and the like are used. Preferably, THF, dioxane, dichloromethane or a mixed solvent thereof is used. The reaction temperature is not particularly limited, but is preferably under ice cooling to room temperature.

This production process 2 is separately represented by the formula (III) in which an alkyl group is introduced into the 3-position hydroxyl group of the catechins represented by the formula (II) in which the phenolic hydroxyl group obtained in the production process 1 is protected. It is also a step of obtaining the prepared compound.
In the production process, for example, the catechins represented by the formula (II) in which the phenolic hydroxyl group protected in the production process 1 is protected are dissolved in a polar solvent such as dimethylformamide, and sodium hydride or potassium hydride is dissolved. By reacting with an alkyl halide in the presence of a base such as
The reaction time varies depending on the amount to be reacted, the solvent, etc., and is not particularly limited, but is usually 1 to 5 hours, and is treated by a method known per se after the completion of the reaction, and the catechins represented by the formula (III) 3- A compound in which an alkyl group is introduced into the hydroxyl group at the position can be obtained.

Subsequently, the protecting group of the phenolic hydroxyl group of the compound represented by the formula (III) thus produced is removed by the production step 3, and the 3-O-acyl or alkyl-substituted catechin represented by the target formula (V) is removed. A derivative is obtained.
Specifically, this production process is performed by, for example, 3 ′, 4 ′, 5,7-tetra-t-butyldimethylsilyl-(+)-catechin-3-myristate (compound 3) obtained in the production process 2. ) Is dissolved in a suitable solvent such as THF, and acetic acid is added. After stirring, tetrabutylammonium fluoride (THF-1M solution) is added with stirring under ice cooling, and the mixture is stirred at room temperature for 1 to 4 hours. Is implemented.

  After the reaction, it is extracted with, for example, diethyl ether according to a conventional method, and the organic layer is washed with 1N hydrochloric acid aqueous solution, water and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, the product is separated and purified by silica gel column chromatography (n-hexane: ethyl acetate), and the concentrated residue is recrystallized using a mixed solution of n-hexane and ethyl acetate to obtain the desired (+)-catechin. -3-Myristate (compound 4) can be obtained.

  The solvent used in the present production process is not particularly limited as long as it does not participate in the reaction in addition to the above-mentioned solvent, and a polar solvent such as acetic acid or THF can be preferably used.

  In addition, the deprotection reaction of the compound in which an alkyl group is introduced into the 3-position hydroxyl group of the catechins represented by the formula (III) can also be performed according to the above method.

In the production method provided by the present invention, only the phenolic hydroxyl group of the starting catechins can be selectively protected, and such a compound can be subjected to subsequent acylation or alkylation without isolation from the reaction system. Can be carried out in a one-pot reaction to obtain a target compound in which the hydroxyl group at the 3-position is acylated or alkylated.
Therefore, it has the advantage that it can be easily produced with high yield and high purity by a smaller number of production steps and reaction operations.

Hereinafter, the present invention will be described in more detail with reference to production examples and test examples. However, the present invention is not limited to this.
The following examples are shown in chemical reaction formulas in FIG.

Example 1:
(Production Process 1) 3 ′, 4 ′, 5,7-Tetra-Ot-butyldimethylsilyl-(+)-catechin; [(2R, 3S) -3 ′, 4 ′, 5,7-tetra- Ot-Butyldimethylsilylflavan-3-ol] (Compound 2):

  (+)-Catechin “(2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-ol” (compound 1) (50 g, 0.172 mol) and imidazole (104.5 g, 1. 519 mol) was dissolved in 200 mL of THF, and a solution of t-butyldimethylsilyl chloride (114.4 g, 0.759 mol) in 100 mL of THF was added dropwise with stirring under ice cooling. The resulting precipitate was dissolved in 100 mL of dichloromethane and stirred at room temperature for 18 hours. After completion of the reaction, THF was evaporated under reduced pressure, dichloromethane was added to the residue for extraction, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, the obtained residue was separated and purified by silica gel column chromatography (n-hexane: ethyl acetate / 10: 1), and 3 ′, 4 ′, 5,7-tetra-t-butyldimethylsilyl- ( +)-Catechin (compound 2) was obtained as a colorless liquid (122.5 g, 0.164 mol, yield 94.6%).

¹ H-NMR (400 MHz, CDCl ₃ ): 6.70 (1H, s), 6.68 (1H, s), 6.67 (1H, s), 5.92 (1H, d, J = 2. 2), 5.78 (1H, d, J = 2.2), 4.45 (1H, d, J = 3.9), 3.81 (1H, m), 2.79 (1H, dd, J = 5.6, 16.4), 2.40 (1H, dd, J = 8.7, 16.2) 0.84-0.56 (36H, m), 0.10-(-0. 19) (24H, m)

(Production Process 2) 3 ′, 4 ′, 5,7-Tetra-Ot-butyldimethylsilyl-(+)-catechin-3-myristate; [(2R, 3S) -3 ′, 4 ′, 5 7 Tetra-Ot-butyldimethylsilylflavan-3-myristoate] (Compound 3):
3 ′, 4 ′, 5,7-tetra-Ot-butyldimethylsilyl-(+)-catechin (compound 2) (73.8 g, 0.099 mol) obtained in the production step 1 was dissolved in 200 mL of dichloromethane. Under ice-cooling, triethylamine (30.0 g, 0.296 mol), myristoyl chloride (36.6 g, 0.148 mol) and N, N-dimethylaminopyridine (50 mg) were added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was extracted with dichloromethane, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, separation and purification by silica gel column chromatography (n-hexane: ethyl acetate / 3: 1), 3 ′, 4 ′, 5,7-tetra-Ot-butyldimethylsilyl-(+)- Catechin-3-myristate (Compound 3) was obtained as a yellow liquid (93.0 g, 0.097 mol, yield 98.3%).

¹ H-NMR (400 MHz, CDCl ₃ ): 6.61 (1H, s), 6.58 (2H, s), 5.94 (1H, d, J = 1.1), 5.76 (1H, d, J = 1.2), 5.07 (1H, d, J = 1.4), 4.80 (2H, d, J = 2.9), 2.54 (1H, dd, J = 5) .1, 16.6), 2.44 (1H, dd, J = 5.9, 16.8), 2.03-1.99 (2H, m) 1.62-0.93 (2H, m 1.62-0.93 (23H, m), 0.72-0.55 (36H, m), 0.06-(-0.11) (24H, m)

(Production Process 3) Production of (+)-catechin-3-myristate (Compound 4):
3 ′, 4 ′, 5,7-tetra-t-butyldimethylsilyl-(+)-catechin-3-myristate (compound 3) (93.0 g, 0.097 mol) obtained in the production step 2 was added to 100 mL of THF. Acetic acid (35.0 g, 0.583 mol) was added and stirred for 5 minutes, and then tetrabutylammonium fluoride (THF-1M solution) (466 mL, 0.466 mol) was added with stirring under ice cooling. Stir at room temperature for 3 hours. After completion of the reaction, the mixture was extracted with diethyl ether, and the organic layer was washed with 1N hydrochloric acid, water and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, the residue is separated and purified by silica gel column chromatography (n-hexane: ethyl acetate / 1: 1), and the concentrated residue is recrystallized using a mixture of n-hexane and ethyl acetate to obtain (+)- Catechin-3-myristate (compound 4) was obtained as a white solid (25.8 g, 0.052 mol, 53.3% yield).

¹ H-NMR (400 MHz, CD ₃ COCD ₃ ): 6.86 (1H, d, J = 2.2), 6.80 (1H, d, J = 8.3), 6.73 (1H, d , J = 8.3), 6.04 (1H, d, J = 2.2), 5.93 (1H, d, J = 2.2), 5.22 (1H, m), 4.95. (2H, d, J = 6.1), 2.80 (1H, dd, J = 5.4, 16.4), 2.60 (1H, dd, J = 7.0, 16.3), 2.22-2.16 (2H, m) 1.46-1.42 (2H, m) 1.32-1.25 (20H, m), 0.93-0.84 (3H, m)

Example 2:
The following compounds were synthesized according to the production steps of Example 1.
A compound in which the substituent R is represented by —C (O) (CH ₂ ) ₈ = (CH ₂ ) ₈ CH ₃ (cis isomer).
(1) Yield of production process 2 (100.0%),
(2) Yield of production process 3 (36.4%) (Acetic acid was added and reacted).
The compound obtained in production step 3 was identified by ¹ H-NMR.

¹ H-NMR (400 MHz, CD ₃ OD): 6.69 (1H, d, J = 2.0), 6.65 (1H, d, J = 4.0), 6.58 (1H, d, J = 2.0), 5.84 (1H, d, J = 2.4), 5.79 (1H, d, J = 2.0), 5.26-5.23 (2H, m), 5.21 (1H, m), 4.74 (1H, m), 2.71 (1H, dd, J = 5.2,16.4), 2.50 (1H, dd, J = 7.2) 16.4), 2.11 (2H, t, J = 3.6) 1.95-1.92 (4H, m), 1.38-1.31 (2H, m), 1.19- 1.04 (20H, m), 0.89-0.78 (3H, m)

Example 3:
The following compounds were synthesized according to the production steps of Example 1.
A compound in which the substituent R is represented by —C (O) (CH ₂ ) ₉ CH ₃ .
(1) Yield of production process 2 (86.9%),
(2) Yield of production process 3 (16.6%) (reacted under the condition without addition of acetic acid).
The compound obtained in production step 3 was identified by ¹ H-NMR.

¹ H-NMR (400 MHz, CD ₃ OD): 7.15 (1H, d, J = 2.0), 7.11 (1H, d, J = 2.7), 7.03 (1H, d, J = 2.0), 6.31 (1H, d, J = 2.4), 6.25 (1H, d, J = 2.4), 5.58-5.53 (1H, m), 5.20 (1H, m), 3.16 (1H, dd, J = 5.4, 16.3), 2.96 (1H, dd, J = 6.9, 16.3), 2.58 -2.50 (2H, m) 1.81-1.74 (2H, m), 1.67-1.48 (14H, m), 1.27-1.20 (3H, m)

  From the results of Examples 2 to 3, in the deprotection step, deprotection is performed more efficiently in the solvent using tetrabutylammonium fluoride (THF-1M solution) in the presence of acetic acid. It turns out that 3-O-acyl-substituted-catechins are obtained.

Example 4: Method for producing 3-O-alkyl-substituted-catechin derivatives (production process 1)
The compound obtained in the production step 1 of Example 1 was used as a starting material.

(Production Process 2) 3 ′, 4 ′, 5,7-Tetra-Ot-butyldimethylsilyl-(+)-catechin-3-tetradecane ether; [(2R, 3S) -3 ′, 4 ′, 5 , 7 Tetra-Ot-butyldimethylsilylflavan-3-tetradecane ether]:
3 ′, 4 ′, 5,7-Tetra-Ot-butyldimethylsilyl-(+)-catechin (3.0 g, 0.004 mol) obtained in the production step 1 was dissolved in 50 mL of DMF, and cooled with ice. 60% NaH (0.250 g, 0.006 mol) and tetradecan chloride (1.191 g, 0.006 mol) were added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, dichloromethane was added, and the organic layer was washed with water and saturated brine. The product obtained from the organic layer and the precipitated solid were not purified, and a black solid was obtained (yield 8.12 g).

(Manufacturing process 3)
To the black solid obtained in the production step 2, 100 mL of THF and acetic acid (3.10 g, 0.052 mol) were added and stirred for 5 minutes, and then tetrabutylammonium fluoride (THF-1M solution) with stirring under ice cooling. (41.3 mL, 0.413 mol) was added and stirred at room temperature for 3 hours. After completion of the reaction, the mixture was extracted with diethyl ether, and the organic layer was washed with 1N hydrochloric acid, water and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, the residue is separated and purified by silica gel column chromatography (n-hexane: ethyl acetate / 1: 1), and the concentrated residue is recrystallized using a mixture of n-hexane and ethyl acetate to obtain (+)- Catechin-3-tetradecane ether was obtained as a black solid (0.447 g, 0.002 mol, yield 50.0% of production steps 2 to 3).

¹ H-NMR (400 MHz, CD ₃ COCD ₃ ): 6.79 (1H, d, J = 2.0), 6.68 (1H, d, J = 2.0), 6.66 (1H, d , J = 1.6), 5.89 (1H, d, J = 2.4), 5.80 (1H, d, J = 2.4), 4.51 (1H, d, J = 7. 2), 3.92 (1H, m), 2.93 (2H, t, J = 8.4), 2.63 (1H, dd, J = 7.6, 16.2), 2.27 ( 1H, dd, J = 8.2, 16.2), 1.37-1.33 (2H, m), 1.21-0.74 (25H, m)

Examples 5-7:
3 ′, 4 ′, 5,7-tetra-Ot-butyldimethylsilyl in accordance with the production process of Example 1 except that the type and combination of reaction solvents were changed in Production Process 1 of Example 1. -(+)-Catechin (compound 2) was prepared.
The results are shown in Table 1.

Example 8: One-pot synthesis (Production steps 1 and 2 are carried out in one pot)
Method for producing 3 ′, 4 ′, 5,7-tetra-Ot-butyldimethylsilyl-(+)-catechin-3-myristate (compound 3):
(+)-Catechin: [(2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-ol] (Compound 1) (50 g, 0.172 mol) and imidazole (104.5 g, 1 .519 mol) was dissolved in 200 mL of THF, and a solution of t-butyldimethylsilyl chloride (114.4 g, 0.759 mol) in 100 mL of THF was added dropwise with stirring under ice cooling. The resulting precipitate was dissolved in 100 mL of dichloromethane and stirred at room temperature for 18 hours (the yield of 3 ′, 4 ′, 5,7-tetra-t-butyldimethylsilyl-(+)-catechin at this time was 94.6%). . Subsequently, triethylamine (17.4 g, 0.172 mol), myristoyl chloride (42.5 g, 0.172 mol) and N, N-dimethylaminopyridine (50 mg) were added under ice cooling, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was extracted with dichloromethane, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, separation and purification by silica gel column chromatography (n-hexane: ethyl acetate / 3: 1), 3 ′, 4 ′, 5,7-tetra-Ot-butyldimethylsilyl-(+)- Catechin-3-myristoate (compound 3) was obtained as a yellow liquid (yield 93%).

From the results of the above examples, examples of the solvent used in the production step 1 include THF, dichloromethane, a THF-dichloromethane mixed solvent, and ethyl acetate.
Preferred is a mixed solvent of THF and THF-dichloromethane, and more preferred is a mixed solvent of THF-dichloromethane.
In the case of a THF-dichloromethane mixed solvent, the content (parts by weight) of THF per 100 parts by weight of the mixed solvent is preferably 37 to 99.9 parts by weight, more preferably 42 to 99.9 parts by weight, Preferably it is 60-90 weight part, Most preferably, it is 70-80 weight part.
The mixed correlation of THF-dichloromethane is shown in FIG.

According to the production method of the present invention, 3-O-substituted-catechin derivatives having various acyl groups and alkyl groups selectively introduced into the hydroxyl group at the 3-position in the flavan skeleton of catechins can be highly purified by a simple production method. And in a yield.
The production method of the present invention is extremely useful industrially because the desired product can be obtained in the production process of the deprotecting group without using a special apparatus such as a conventional reduction facility.

It is the figure which showed Example 1 of this invention with the concrete reaction type | formula. It is a figure which shows the relationship between the solvent used for introduction | transduction of the silyl protecting group in the manufacturing process 1 of this invention, and the yield of a target object. In the figure, the horizontal axis indicates the content of THF relative to 100 parts by weight of the THF-dichloromethane mixed solvent, and the vertical axis indicates the yield (%) of the target product.

Claims (7)

The following formula (I):

(In the formula, Ra represents a hydrogen atom or a hydroxyl group)
In the presence of a base, the following formula:
AX
(In the formula, A represents a silyl protecting group of a hydroxyl group, and X represents an active residue)
Wherein the protecting group is selectively introduced into the phenolic hydroxyl group of formula (I):

(Wherein Rc represents a hydrogen atom or a group: OA, and A is the same as defined above)
And then the following formula (V):
RY (V)
[Wherein, R represents an alkyl group having 1 to 22 carbon atoms which may be substituted, or an acyl group represented by an RbC (═O) — group (Rb may be substituted having 1 to 22 carbon atoms. Represents an alkyl group, and Y represents an active residue]
And a compound represented by the following formula (III):

(Wherein A, Rc and R are the same as defined above)
And then deprotecting the compound represented by the following formula (IV):

(Wherein Ra and R are as defined above)
A method for producing a 3-O-acyl or alkyl-substituted catechin derivative represented by the formula: Formula (II) below:

Wherein A and Rc are the same as defined in claim 1 above.
And a compound represented by the following formula (V):
RY (V)
Wherein R and Y are the same as defined in claim 1 above.
And a compound represented by the following formula (III):

Wherein A, Rc and R are as defined in claim 1 above.
And then deprotecting the compound represented by the following formula (IV):

Wherein Ra and R are as defined in claim 1 above.
A method for producing a 3-O-acyl or alkyl-substituted catechin derivative represented by the formula: The following formula (I):

(In the formula, Ra represents a hydrogen atom or a hydroxyl group)
In the presence of a base, the following formula:
AX
Wherein A and X are the same as defined in claim 1 above.
Wherein the protecting group is selectively introduced into the phenolic hydroxyl group of formula (I):

Wherein A and Rc are the same as defined in claim 1 above.
And then the following formula:
RY
Wherein R and Y are the same as defined in claim 1 above.
It is made to react with the compound represented by following formula (III):

Wherein A, Rc and R are as defined in claim 1 above.
The manufacturing method of the compound represented by these. The following formula (I):

(In the formula, Ra represents a hydrogen atom or a hydroxyl group)
In the presence of a base, the following formula:
AX
Wherein A and X are the same as defined in claim 1 above.
Wherein the protecting group is selectively introduced into the phenolic hydroxyl group of formula (I):

Wherein A and Rc are the same as defined in claim 1 above.
The manufacturing method of the compound represented by these. The process according to claim 1 , wherein the silyl protecting group is a t-butyldimethylsilyl group.   The method according to claim 1 or 2, wherein the deprotection of the compound of formula (III) to the compound of formula (IV) is carried out using tetrabutylammonium fluoride in a solvent in the presence of acetic acid. .   The production method according to claim 1 or 3, wherein the induction to the formula (III) is reacted in one pot without isolating the compound of the formula (II).

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