JP2000198779A - Purification of 3-alkylflavanol derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To purify the subject compound useful as a hair tonic/hair growing agent with a high purity and industrially advantageously by crystallizing a specific alkylflavanol derivative containing a specific impurity in the presence of a base. SOLUTION: This method for purifying 3-alkylflavanol derivative comprises crystallizing a 3-alkylflavanol derivative of formula II (e.g.; trans-3,4'-dimethyl-3- hydroxyflavanone) containing a 3-alkylflavanone derivative of formula I (R1 is a 1-12C alkyl; R2, R3 are each a 1-12C alkyl substitutable with a halogen or the like, H, OH or the like) (e.g.; cis- and trans-3,4'-dimethylflavanone) as an impurity in the presence of a base such as potassium hydroxide in a solvent such as a mixed solvent of isopropyl alcohol with water to purify the objective compound. It is preferable to perform the above crystallization by adding the above aqueous base solution to the solution of the compound of formula II containing the impurity of the formula I and then cooling the solution mixture to approximately at (-)30-30 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD [0001] The present invention relates to the following general formula (1) useful as a hair tonic / hair restorer:

[0002]

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[In the formula, R ¹ represents an alkyl group having 1 to 12 carbon atoms, and R ² and R ^{3 each} represent a halogen atom or an alkyl group having 1 to 12 carbon atoms which may be substituted by an alkoxyl group having 1 to 12 carbon atoms. A 12-alkyl group, a C1-C12 alkoxyl group which may be substituted by a C1-C12 alkoxyl group, a hydrogen atom, a hydroxyl group, a cyano group or a halogen atom. And a method for purifying a 3-alkylflavanonol derivative represented by the formula:

[0004]

2. Description of the Related Art As a method for producing a 3-alkylflavanonol derivative represented by the above general formula (1), which is a compound useful as a hair-growing and hair-growing agent, JP-A-8-15746.
As described in JP-A No. 4 (KOKAI) No. 4, a method of performing a reaction according to the following reaction formula is exemplified.

[0005]

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[Wherein, R ¹ , R ² and R ³ are the same as above]

That is, by reacting o-hydroxyacylbenzenes (4) with benzaldehydes (3), 3
-Alkylflavanones (2), which are then oxidized with hydrogen peroxide and, after column chromatography purification,
A method for obtaining a desired 3-alkylflavanonol derivative (1) by performing crystallization purification is disclosed.

[0008]

However, the above-mentioned production method has a problem that column chromatography is used as a purification method, and it is not suitable for industrial large-scale purification and production. In addition, since the solubility of the starting material, 3-alkylflavanone derivative (2), is lower than that of the target, 3-alkylflavanonol derivative (1), crystallization, which is a purification method generally used in industry, causes oxidation. It was difficult to completely remove the 3-alkylflavanone derivative (2) as a raw material remaining as an impurity after the reaction, and there was a problem that purification was not possible sufficiently. Therefore, an object of the present invention is to provide a method that can advantageously purify and produce a 3-alkylflavanonol derivative (1) without such problems.

[0009]

According to the present invention, there is provided the following general formula (2):

[0010]

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[In the formula, R ¹ represents an alkyl group having 1 to 12 carbon atoms, and R ² and R ^{3 each} represent a halogen atom or an alkyl group having 1 to 12 carbon atoms which may be substituted by an alkoxyl group having 1 to 12 carbon atoms. A 12-alkyl group, a C1-C12 alkoxyl group which may be substituted by a C1-C12 alkoxyl group, a hydrogen atom, a hydroxyl group, a cyano group or a halogen atom. The following general formula (1) containing a 3-alkylflavanone derivative represented by the formula

[0012]

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Wherein R ¹ , R ² and R ³ are the same as defined above, wherein the 3-alkylflavanonol derivative is crystallized in the presence of a base.
An object of the present invention is to provide a method for purifying an alkylflavanonol derivative with high purity.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, a 3-alkylflavanone derivative (2) and a 3-alkylflavanonol derivative (1) are represented by general formulas (2) and (1), respectively. In the formula, R ¹ is preferably a linear or branched alkyl group having 1 to 5 carbon atoms, and particularly preferably a methyl group. R ² and R ³ are preferably a hydrogen atom, a linear or branched alkyl group having 1 to 5 carbon atoms, and particularly preferably a hydrogen atom or a methyl group.

A 3-alkylflavanone derivative (2) and
As the 3-alkylflavanonol derivative (1), the most
Preferred is R in the formula¹And R^ThreeIs a methyl group
R ^TwoIs a hydrogen atom, 3,4'-dimethylflava
Non and 3,4'-dimethyl-3-hydroxyflavano
It is.

The 3-alkylflavanone derivative (2) used as a raw material in the present invention has a trans form and a ci form.
s-isomer is present, and trans-isomer and ci-isomer
Optical isomers exist for each of the s-isomers. In the production method of the present invention, any of these isomers may be used, or a mixture thereof may be used.

The 3-alkylflavanone derivative (2) and the 3-alkylflavanone derivative in the 3-alkylflavanonol derivative (1) containing the 3-alkylflavanone derivative (2) as an impurity used in the crystallization of the present invention. The content of the phenol derivative (1) is preferably such that the 3-alkylflavanone derivative (2) contains about 0.1 to 50% and the 3-alkylflavanonol derivative (1) about 99.9 to 50%. . The 3-alkylflavanone derivative (2)
The 3-alkylflavanonol derivative (1) containing as an impurity includes, in addition to the 3-alkylflavanone derivative (2) and the 3-alkylflavanonol derivative (1), the oxidation of the 3-alkylflavanone derivative (2). Other impurities that may be generated may be included. Examples of the other impurities include benzoic acid, cinnamic acid, salicylic acid, and derivatives of catechol.

The 3-alkylflavanonol derivative (1) containing the 3-alkylflavanone derivative (2) as an impurity used in the crystallization of the present invention is a crude product of the oxidation of the 3-alkylflavanone derivative (2) as described later. The product may be used as it is or may have been subjected to preliminary purification such as washing with water. The 3-alkylflavanonol derivative (1) containing the 3-alkylflavanone derivative (2) as an impurity used for the crystallization of the present invention may be dried,
Further, it may contain a solvent such as water. However, when water is contained, the water content is desirably about 35% or less.

In this purification method, as described above, the method for producing the 3-alkylflavanonol derivative (1) containing the 3-alkylflavanone derivative (2) as an impurity is disclosed in Japanese Patent Application Laid-Open No. 8-157664 or J. Med. Chem. (Journal of Medicinal Chemistry) 33 19
The method described on page 48 (1990) includes a method in which a 3-alkylflavanone derivative (2) is obtained as an intermediate and then oxidized. That is, the 3-alkylflavanone derivative is obtained by condensing an o-hydroxyacylbenzene (4) and a benzaldehyde (3) in the presence of an amine or an inorganic base in accordance with the above reaction formula. A method of obtaining a 3-alkylflavanonol derivative (1) containing a 3-alkylflavanone derivative (2) as an impurity by oxidizing (2) with an organic peroxide or hydrogen peroxide in the presence of a base. .

The post-treatment method after the completion of the oxidation reaction is carried out in accordance with the usual post-treatment method using a peroxide. That is, the remaining organic peroxide is washed away with water, or
After being decomposed with an aqueous solution of sodium hydrogen sulfite if necessary, it is subjected to the crystallization purification of the present invention.

The purification method of the present invention is characterized in that a 3-alkylflavanonol derivative (1) containing a 3-alkylflavanone derivative (2) as an impurity is crystallized in the presence of a base.

As the base used in the crystallization of the present invention, hydrogen at the 3-position of the 3-alkylflavanone derivative (2) as an impurity can be extracted, and the 3-alkylflavanone derivative (2) can be dissolved in a solvent more. Any base capable of forming an α-alkylchalcone derivative having good properties may be used. Among them, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; and metal alkoxides such as sodium methoxide and sodium ethoxide are preferable. Potassium is most preferred. The alkali metal hydroxides such as sodium hydroxide and potassium hydroxide may be used in the form of solids such as flakes and pellets, or in the form of an aqueous solution (for sodium hydroxide and potassium hydroxide, 20 to An aqueous solution of about 50% is commercially available).

The amount of the base used depends on the purity of the 3-alkylflavanonol derivative (1) containing the 3-alkylflavanone derivative (2) used as an impurity, the type and amount of the solvent, and the like. 0.03-1.0 weight times, preferably 0.05-0.5 weight times, more preferably 0.05 times the 3-alkylflavanonol derivative (1) containing the flavanone derivative (2) as an impurity.
Use about 0.3 times by weight.

The solvent used in the crystallization of the present invention may be any solvent capable of dissolving the α-alkylchalcone derivative formed by extracting the 3-position hydrogen of the impurity 3-alkylflavanone derivative (2). methanol,
Ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutyl alcohol, sec-
4 carbon atoms such as butyl alcohol and t-butyl alcohol
The following alcohol-based solvents or mixed solvents of these alcohol-based solvents having 4 or less carbon atoms and water are more preferable, and among them, α- formed by extracting the 3-position hydrogen of the 3-alkylflavanone derivative (2) is preferable. A mixed solvent of isopropyl alcohol and water is most preferable because the solubility of the alkyl chalcone derivative is good.

The amount of the solvent used depends on the purity of the 3-alkylflavanonol derivative (1) containing the 3-alkylflavanone derivative (2) used as an impurity, the type of the solvent, the type and amount of the base, and the like. Generally, it is 1 to 20 times, preferably 1 to 10 times, more preferably 2 to 7 times the weight of the 3-alkylflavanonol derivative (1) containing the 3-alkylflavanone derivative (2) as an impurity.
It is about weight times.

In the crystallization of the present invention, the solvent may or may not contain water, but the case where water is contained is more effective in recovering the target 3-alkylflavanonol derivative (1). Therefore, a solvent containing water is preferably used. When water is used, the amount of water used is determined based on the amount of 3-alkylflavanone derivative (2) as an impurity.
0.01 based on the alkylflavanonol derivative (1)
It is about 1 to 1 times, preferably about 0.05 to 0.5 times, more preferably about 0.05 to 0.3 times. In addition,
When water is contained in the 3-alkylflavanonol derivative (1) containing the 3-alkylflavanone derivative (2) as an impurity used for crystallization, it is not necessary to add water to the crystallization solvent.

At the time of crystallization, the base may be added to the solution of the 3-alkylflavanonol derivative (1) containing the 3-alkylflavanone derivative (2) as an impurity from the beginning. When acted on the 3-alkylflavanonol derivative (1), a side reaction such as trans-cis isomerization may proceed.
3 containing the alkylflavanone derivative (2) as an impurity
-Crystals are formed by adding an aqueous base solution to the solution of the alkylflavanonol derivative (1) for crystallization.

The crystallization temperature is determined by the purity of the 3-alkylflavanonol derivative (1) containing the 3-alkylflavanone derivative (2) used as an impurity, the type of solvent, the type and amount of base, and the method of adding the aqueous base solution. Depends on
When adding an aqueous base solution to a solution of the 3-alkylflavanonol derivative (1) containing the -alkylflavanone derivative (2) as an impurity, the base aqueous solution is preferably added at 0 to 60 ° C, more preferably at 30 to 50 ° C. , And then preferably at -40 to 30C, more preferably at -30 to 30C.
Crystallization is performed by cooling to about 30 ° C. When a base is added from the beginning to a solution of the 3-alkylflavanonol derivative (1) containing the 3-alkylflavanone derivative (2) as an impurity, the solution is preferably heated at 10 to 50 ° C. Is cooled to about −40 to 30 ° C. for crystallization.

By filtering the crystals precipitated by the above operation, the 3-alkylflavanonol derivative (1) can be obtained with high purity. However, in order to remove remaining impurities and the base used in crystallization, Water, alcoholic solvents,
Washing may be performed once or twice or more with a mixed solvent of a water-alcohol solvent or the like and two or more thereof. Preferred examples of the alcohol solvent used here include methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutyl alcohol, and se.
Examples thereof include alcohol solvents having 4 or less carbon atoms such as c-butyl alcohol and t-butyl alcohol, and among them, isopropyl alcohol is more preferable.

The thus-obtained crystals are dried, if necessary, under normal pressure or reduced pressure, whereby the 3-alkylflavanonol derivative (1) can be obtained with high purity.

The 3-alkylflavanonol derivative (1) purified by the method of the present invention is useful as a hair restorer and hair restorer and has high purity. Can be used advantageously.

[0032]

EXAMPLES Reference Example Trans-3,4'-dimethyl-
Preparation of 3-hydroxyflavanone: 1682 g of 2'-hydroxypropiophenone in a flask under a nitrogen atmosphere
(11.2 mol), 4-methylbenzaldehyde 141
3 g (11.76 mol), isopropyl alcohol 33
64 g and 954 g (11.2 mol) of piperidine were charged, and 673 g (11.2 mol) of acetic acid was added dropwise thereto over about 10 minutes. After completion of the dropwise addition, the mixture is further heated at 80 to 90 ° C for 24 hours.
Stirred for hours. Next, the obtained reaction mixture was subjected to 70-75.
After cooling to 0 ° C, 0.25 g of a seed crystal of trans-3,4'-dimethylflavanone was added, cooled to 30 to 40 ° C, 1400 g of ion-exchanged water was added, and further cooled to 0 to 10 ° C. The precipitated crystals are collected by filtration, and the obtained crystals are washed with a 50% isopropyl alcohol aqueous solution and water,
By drying under reduced pressure, 2506 g (yield: 88.7%) of trans-3,4'-dimethylflavanone was obtained. Next, 126.16 g of the trans-3,4'-dimethylflavanone obtained above was placed in a SUS316 reaction tank.
(0.5 mol) and isopropyl alcohol 189.2
4 g and then 50% aqueous potassium hydroxide solution 4
4.88 g (KOH: 0.4 mol) were added. Next, 128.74 g (1.0%) of a 70% aqueous solution of t-butyl hydroperoxide was added to the mixture while stirring at 35 to 50 ° C.
mol) was added dropwise over about 4 hours. After stirring at 40 to 50 ° C. for 1 hour, 8.42 g of a 50% aqueous potassium hydroxide solution
(KOH: 0.15 mol; KO together with initial addition)
H: 0.55 mol) was added dropwise over about 1 hour. After completion of the dropwise addition, the mixture was further stirred at 40 to 50 ° C. for 8 hours. The reaction mixture was then cooled to about 15 ° C., followed by 252.3 of water.
g was further added and cooled to about 5 ° C. The precipitated crystals are collected by filtration, and the obtained crystals are washed with water and dried under reduced pressure.
86.3 g of crude dimethyl-3-hydroxyflavanone
(Yield 64.3%; HPLC purity 82.0%, cis- and trans-3,4-dimethylflavanone 17.4%
Content).

Comparative Example 1 Crystallization and purification of trans-3,4'-dimethyl-3-hydroxyflavanone: Trans-3,4'- containing cis- and trans-3,4'-dimethylflavanone as impurities in a flask. Dimethyl-
10 g of 3-hydroxyflavanone crude product (92.9% of HPLC purity, containing 4.4% of cis- and trans-3,4'-dimethylflavanone) and 50 g of isopropyl alcohol were charged and dissolved by heating. Cooled down. The precipitated crystals were collected by filtration, washed with 10 g of isopropyl alcohol, and dried under reduced pressure (recovery rate: 80%). HPLC analysis of the obtained crystals revealed that 96.3% of trans-3,4'-dimethyl-3-hydroxyflavanone, cis- and trans-3,
It contained 3.1% of 4'-dimethylflavanone.

Comparative Examples 2 to 9 Crystallization was carried out in the same manner as in Comparative Example 1, except that the crystallization / washing solvent isopropyl alcohol was changed to the solvent shown in Table 1.

[0035]

[Table 1]

EXAMPLE 1 Crystallization and purification of trans-3,4'-dimethyl-3-hydroxyflavanone: Trans-3,4'- containing cis- and trans-3,4'-dimethylflavanone as impurities in a flask. Dimethyl-
85.7 g of crude 3-hydroxyflavanone (HPLC
82.0% purity, containing 17.4% of cis- and trans-3,4'-dimethylflavanone) and 257.1 g of isopropyl alcohol, dissolved at about 55 ° C, and cooled to about 40 ° C. , 34.28 g of a 50% aqueous potassium hydroxide solution were added dropwise. After the addition, the mixture was cooled to about 5 ° C., and the precipitated crystals were collected by filtration.
Washing was performed at 8.6 g (this crystallization method was referred to as one method). Then 257.1 g of water, 51.4 g of isopropyl alcohol and 205.7 g of water, and 255.7 g of water for abasic.
Washed sequentially with 1 g (this abasic washing method is referred to as method a)
Thereafter, by drying under reduced pressure, the purified silane-3,4 'is obtained.
-Dimethyl-3-hydroxyflavanone 62.0 g (recovery 72.3%; HPLC purity 100%) was obtained.

Example 2 Crystallization and purification of trans-3,4'-dimethyl-3-hydroxyflavanone: Trans-3,4'- containing cis- and trans-3,4'-dimethylflavanone as impurities in a flask. Dimethyl-
85.7 g of crude 3-hydroxyflavanone (HPLC
Purity 91.8%, containing 7.3% cis- and trans-3,4'-dimethylflavanone), 265.7 g of isopropyl alcohol, and 50% aqueous solution of potassium hydroxide 3
After charging 4.28 g and dissolving by heating, the mixture was cooled to about 20 ° C. Next, the precipitated crystals were collected by filtration, and the obtained crystals were washed with 128.6 g of an aqueous 88% isopropyl alcohol solution (this crystallization method is referred to as two methods). Next, for debasing, the substrate was washed twice with 257.1 g of 20% isopropyl alcohol (this debasing washing method is referred to as method b), and then dried under reduced pressure to obtain purified trans-3,4'-dimethyl-. 69.4 g of 3-hydroxyflavanone (recovery rate: 8
1.0%; HPLC purity 99.7%).

Examples 3 to 18 Except for the conditions shown in Table 2, crystallization was carried out in the same manner as in Example 1 or 2. The crystallization conditions and the base washing conditions were the same as those of the crystallization method 1 or 2 in Example 1 or 2, and the washing method a.
Method b or method b.

[0039]

[Table 2]

[0040]

[Table 3]

[0041]

According to the present invention, a 3-alkylflavanonol derivative (1), which is a compound useful as a hair-growing and hair-growing agent, can be purified with high purity and industrially advantageously.

Continued on the front page (72) Inventor Yoshinori Nishizawa 2606 Kabane-cho, Akaga-cho, Haga-gun, Tochigi Pref. In the Kao Corporation Research Institute 4C062 FF05 FF43

Claims (1)

[Claims] 1. The following general formula (2): [Wherein, R ¹ represents an alkyl group having 1 to 12 carbon atoms;
² and R ³ are a halogen atom or an alkyl group having 1 to 12 carbon atoms which may be substituted by an alkoxyl group having 1 to 12 carbon atoms, or a carbon number which may be substituted by an alkoxyl group having 1 to 12 carbon atoms. 1 to 12 represent an alkoxyl group, a hydrogen atom, a hydroxyl group, a cyano group or a halogen atom. The following general formula (1) containing, as an impurity, a 3-alkylflavanone derivative represented by the following formula: [Wherein, R ¹ , R ² and R ³ are the same as defined above]
A method for purifying a 3-alkylflavanonol derivative, characterized by crystallizing the 3-alkylflavanonol derivative represented by the formula in the presence of a base.