JPH10130191A - 2-acetyl carboxylic acid ester derivative and production of 2-ketone compounds from the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new acetyl carboxylic acid ester derivative useful as an intermediate for synthesizing amine derivatives expressing remarkable actions on the prevention of skin aging, such as the improvement of conification, the prevention and improvement of the pigmentation of skin, by reacting a halogenated alcohol derivative with a 2-acetyl carboxylic acid ester. SOLUTION: A 2-acetyl carboxylic acid ester derivative of formula III [R<1> is H, benzyl; R<2> is a lower alkyl; (n) is an integer of 8-12], e.g. 2-acetyl-12- hydroxydodecanoic acid methyl ester. The compound of formula III is obtained by reacting one mole of a halogenated alcohol derivative of formula I (X is chlorine, bromine or iodine) with 1-10 moles of a 2-acetyl carboxylic acid ester of formula II in the presence of a base such as sodium hydroxide or sodium methoxide. The reaction is carried out in a solvent such as dimethylformamide, toluene or methanol at a reacting temperature of 50-150 deg.C in the presence of a phase transfer catalyst such as n-tetrabutyl ammonium chloride. The compound of formula III is hydrolyzed and subsequently decarbonated to produce a 2-ketone compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a 2- (2-amino) amine derivative useful as a synthetic intermediate having an excellent anti-aging effect.
Acetyl carboxylic acid ester derivative and 2 using the same
-It relates to a process for producing ketones.

[0002]

2. Description of the Related Art The epidermis, which is the outermost layer of the skin, prevents loss of water and various components from the living body and controls the homeostasis of the living body. In addition, it has a barrier function to protect the body from physical and chemical stimuli (temperature, humidity, etc.) from the outside world, as well as various bacteria, and its physiological functions are very important for the vital activities of living organisms. . The keratinocytes forming the epidermis form healthy epidermis having the above-mentioned physiological functions by performing cell proliferation and keratinization (differentiation) in a well-balanced manner.

However, factors such as excessive stimulation from the external environment (such as ultraviolet rays) and changes in physiological functions (such as age-related skin aging and diseases) that act on the living body and the body cause this cell proliferation and keratinization. A loss of balance prevents healthy epidermis formation. In particular, sites that are routinely exposed to stimuli such as ultraviolet rays, such as the face and hands, are often in a state of excessive proliferation and insufficient keratinization. As a result, epidermal thickening and parakeratosis are induced, and as a result, various vulnerable skin troubles such as dry skin or oily skin and dandruff are caused. Further, it is considered that various skin troubles such as pigmentation and the like occur due to the onset of acne due to the formation of keratosis and the delay of melanin metabolism. In order to improve such skin troubles and maintain healthy skin, it is conceivable to eliminate or reduce the causative substances and events, or to add and apply certain components. Conventionally, prevent skin problems,
The main method of improvement is to apply a synthetic or natural moisturizing component to prevent the skin from drying out and increase the moisturizing ability of the skin by applying a moisturizing component or to promote the blood circulation of the skin by applying a blood circulation promoting agent. Attempts have been made to improve.

[0004] In addition, pigmentation on spots, freckles, and skin after sunburn occurs, increases, and hardly disappears due to aging of the skin with aging, which is a problem for middle-aged and elderly people. Although the mechanism of the occurrence of these pigmentation diseases has not yet been clarified, it is thought that the mechanism of melanin synthesis in epidermal melanocytes was enhanced by the action of sunlight, particularly ultraviolet rays and melanocyte stimulating hormones. To restore the acquired pigment (ie melanin) deposits to normal skin color, for example, vitamin C
Attempts have been made to improve with (L-ascorbic acid) derivatives, isoflavone derivatives (JP-A-58-225004), p-hydroxycinnamic acid derivatives (JP-A-59-196813) and the like.

[0005] However, the above methods have various problems in terms of the effectiveness in preventing and improving various skin troubles, the persistence of the effects, and the stability and safety of drugs. That is, since these methods generally rehydrate the epidermis, especially the surface of the keratin, or supplement a part of the moisturizing component, the effect is temporary, permanent and permanent. Fundamental skin improvement could not be expected. At present, there is no known substance which has a substantial effect of preventing or improving pigmentation. Therefore, skin parakeratosis, epidermal thickening,
It has been desired to develop a substance that has a remarkable inhibitory effect on lipid metabolism abnormalities and the like, has an effect of preventing skin aging having an effect of preventing and improving pigmentation of the skin, and an effect of improving skin troubles caused by abnormal keratinization. .

The present inventors have found that a specific amine derivative has a remarkable effect on the prevention of skin aging, such as improvement of keratinization and prevention / improvement of skin pigmentation, and have previously filed a patent application (Japanese Patent Application Laid-Open No. 5-205). 194185, JP-A-6-271450, etc.). Of the compounds disclosed in the specifications of these applications,
The following formula (A)

[0007]

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(Where a and b are a + b = 11-1)
7, a = 4 to 10, b = 5 to 11, and a number having a distribution with a = 7 and b = 8 as vertices. In particular, the amine derivative [compound (1g) in JP-A-5-194195] has excellent effects such as excellent keratinization and prevention / improvement of skin pigmentation. This amine derivative (A)
Uses isostearyl alcohol, which is obtained by reducing isostearic acid, a by-product when producing dimer acid from beef tallow and soybean oil, as a raw material, so methyl branching occurs mainly at various positions on the main chain. Is a mixture of compounds having the formula:

The present inventors have paid attention to the fact that, although this is a mixture, it has excellent keratinization, prevention / improvement of skin pigmentation, etc., and searches for the active ingredient in this amine derivative (A). Embarked on. As a result, it was found that the compound group (B) having the following structure had a high keratinizing effect by fractionation by HPLC and structure determination by GC-MS.

[0010]

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[In the above general formula, R ^b is a total of 17 carbon atoms and represents an alkyl group having one methyl group as a substituent between the 7th and 15th positions.] The amine derivative (B) is an amine derivative (A) contains only about 3%.

Therefore, the present inventors further synthesized and evaluated individual compounds contained in the amine derivative (B) and searched for various peripheral compounds. As a result, the amine derivative represented by the following general formula (C) was obtained. It has been found to have extremely excellent keratinization improvement, skin pigmentation prevention and improvement effects, and skin troubles caused by abnormal keratinization.

[0013]

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[Wherein R ³ represents a hydrogen atom or a carbon atom which may be substituted by one or more hydroxy groups.
3 represents an alkyl group; m represents an integer of 0 to 11;
Represents an integer of 8 to 12]

The amine derivative (C) can be produced, for example, according to the following reaction formula (a).

[0016]

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Wherein R ³ , m and n are the same as above. However, in the above reaction, the reaction between a Grignard reagent prepared from a halide having 8 or more carbon atoms and a ketone is a side reaction. There is a problem that the yield is low because the aldol reaction proceeds easily.

Accordingly, an object of the present invention is to provide a method and an intermediate for producing an amine derivative (C) which are industrially advantageous.

[0019]

Means for Solving the Problems In view of such circumstances, the present invention has made intensive studies and found that the amine derivative (C) can be industrially advantageously produced according to the following reaction formula via the following general formula (1). The present inventors have found that they can be manufactured and completed the present invention.

[0020]

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[In the formula, X represents a chlorine atom, a bromine atom or an iodine atom, and R ¹ , R ² , R ³ , m and n are the same as those described above.]

That is, the present invention provides a 2-acetylcarboxylic acid ester derivative (1) represented by the general formula (1) and a compound represented by the general formula (2) characterized by hydrolyzing and decarboxylating the derivative. -To provide a method for producing ketones.

[0023]

BEST MODE FOR CARRYING OUT THE INVENTION The 2-acetylcarboxylic ester derivative of the present invention is represented by the general formula (1), wherein R ¹ represents a hydrogen atom or a benzyl group.
Examples of the lower alkyl group represented by R ² include a methyl group, an ethyl group, a linear or branched propyl, butyl, pentyl, and hexyl group, with a methyl group or an ethyl group being preferred. Further, n in the general formula (1)
Is an integer of 8 to 12, but 9 or 10 is particularly preferred.

The compound (1) of the present invention is, for example, a halogenated alcohol derivative represented by the aforementioned general formula (4),
By reacting 1 to 10 equivalents of 2-acetylcarboxylic acid ester (3), compound (1) of the present invention can be obtained. In addition, the 2-acetyl carboxylic acid ester (3) used here can be easily obtained as an industrial raw material. Specifically, compound (4) is added to compound (3), mixed to form a solution, and a base may be added thereto. Examples of the base used herein include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium hydride, sodium methoxide, sodium ethoxide and the like. Among them, sodium methoxide, sodium ethoxide and alcohols thereof Solutions are preferred. The amount of the base used is 0.1 to 5 equivalents to the halogenated alcohol,
In particular, it is preferable to use 1 to 3 equivalents. As the solvent used for this reaction, various solvents such as dimethylformamide, tetrahydrofuran, 1,4-dioxane, toluene, xylene, methanol, ethanol, and propanol can be used. Particularly, dimethylformamide,
Methanol and ethanol are preferred. The temperature of this reaction is preferably 0 to 150 ° C, particularly preferably 50 to 150 ° C. Further, in order to increase the reaction rate, a phase transfer catalyst such as n-tetrabutylammonium bromide, n-tetrabutylammonium hydrogensulfate, methyl-β-cyclodextrin or the like is added to the halogenated alcohol by 1 to 2
0% by weight may be used.

The ω-chloro-1-alkanol and ω-chloro-1-benzyloxyalkane represented by the general formula (4) can be produced, for example, by the following method. Reacting 1, ω-alkanediol and hydrochloric acid in the presence of a solvent such as sulfuric acid or phosphoric acid, and xylene,
ω-Chloro-1-alkanol is obtained. Then this ω-
Chloro-1-alkanol and benzyl chloride,
By reacting in the presence of a base and tetra-n-butylammonium bromide, ω-chloro-1-benzyloxyalkane can be obtained.

By hydrolyzing and decarboxylating the compound (1) of the present invention, 2-ketones represented by the formula (2) can be produced. The hydrolysis can be performed by a general method using a base or an acid. Examples of the base include sodium hydroxide, potassium hydroxide, sodium methoxide, and sodium ethoxide, and examples of the acid include sulfuric acid and hydrochloric acid. Is done. As the solvent, it is preferable to use water, methanol, ethanol, or the like, and the reaction temperature is preferably in the range of 20 to 150 ° C. In addition, decarboxylation can also be carried out by a conventional method. For example, when a base is used for hydrolysis, it can be carried out by adding an acid to make it neutral to acidic, and then heating it to 50 to 150 ° C. . Acids or bases used for decarboxylation include those used for hydrolysis.

The compound (2) thus obtained is
When the reaction is carried out according to the above reaction formula (b), an amine derivative (C) having an excellent effect of improving skin trouble can be obtained.

[0028]

Industrial Applicability When the 2-acetylcarboxylic ester derivative (1) of the present invention is used as an intermediate for synthesizing the amine derivative (C), the aldol reaction which is a side reaction in the Grignard reaction hardly progresses, and industrial An amine derivative can be advantageously produced. According to the method of the present invention, 2-ketones can be easily produced.

[0029]

The present invention will be described below in more detail with reference to examples, but the present invention is not limited to these examples.

Examples 1 to 3 Methyl 2-acetyl-12-hydroxydodecanoate (1-1,2-1,3-1)
Manufacturing of

[0031]

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Example 1 50 ml-2 equipped with a reflux condenser and a 10 ml-dropping funnel
Methyl acetoacetate (1-
3) 1.02 g (8.8 mmol), 1.03 g (4.3 mmol) of 10-bromo-1-decanol (1-4) and 3 ml of dimethylformamide were added, and the mixture was stirred under ice cooling for 20 minutes.
To this, 1.67 g (8.8 mmol) of a methanol solution of 28% sodium methoxide was added dropwise. After stirring at 60 ° C. for 6 hours, the mixture was left to cool, added with 20 ml of water, extracted with chloroform, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product which was subjected to silica gel chromatography. And purified to give the title compound (1-1).
68 g (58% yield) were obtained.

Example 2 30 ml-2 equipped with a reflux condenser and a 10 ml dropping funnel
Methyl acetoacetate (2-
3) 0.98 g (8.4 mmol), 1.0 g (4.2 mmol) of 10-bromo-1-decanol (2-4) and 3 ml of dimethylformamide were added, and the mixture was stirred for 10 minutes under ice-cooling. 5 ml of a suspension of 0.37 g (8.4 mmol) of sodium chloride in dimethylformamide was added dropwise over 30 minutes. After stirring at 60 ° C. for 3 hours, the mixture was allowed to cool, 15 ml of water was added, extracted with chloroform, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product which was subjected to silica gel chromatography. Then, 0.77 g (yield 67%) of the title compound (2-1) was obtained.

Example 3 200 equipped with a reflux condenser and two 10 ml dropping funnels
Under a nitrogen atmosphere, 3.61 g (90.2 mol) of sodium hydride (60%) and 20 ml of dimethylformamide were placed in a 3-neck flask and stirred under ice cooling with 10-bromo-1-decanol (3-4). ) 5.21 g (22.0
After stirring for 10 minutes, 10.5 g (90.4 mmol) of methyl acetoacetate (3-3) was added dropwise over 30 minutes. After stirring at 60 ° C. for 3 hours, the mixture was allowed to cool,
After addition of 00 ml, extraction with chloroform was performed, followed by drying over anhydrous magnesium sulfate, filtration and concentration under reduced pressure. The resulting crude product was purified by silica gel chromatography to give the title compound (3-1) 3. 24 g (54% yield) were obtained. The physical properties of the obtained compound are as follows.

Properties: pale yellow oil ¹ H-NMR (CDCl ₃ , δ) 1.08-1.95 (18H, m), 2.22 (3H, s), 3.41 (1H, t, J = 7 Hz), 3.
55-3.70 (3H, m), 3.72 (3H, s) IR (NaCl, cm ^-1 ) 3432, 2932, 2860, 1744, 1718, 1438, 1362, 1246, 12
06, 1154, 1052.

Example 4 Preparation of 13-hydroxy-2-tridecanone (4-2)

[0037]

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In a 30 ml two-necked flask equipped with a reflux condenser, 0.62 g (2.3 mmol) of methyl 2-acetyl-12-hydroxydodecanoate (4-1) and 0.28 g (6.9 mmol) of sodium hydroxide were added. , Ethanol: water = 1: 1
5 ml of the solution was added and stirred at 80 ° C. for 2 hours. After cooling the reaction solution to room temperature, 0.76 g of 50% H ₂ SO ₄ aqueous solution
(3.8 mmol) was added slowly to generate gas. After the foaming had ceased, the mixture was stirred at 80 ° C. for 30 minutes, allowed to cool, added with 20 ml of water, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and subsequently with a saturated saline solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, and the crude product obtained was purified by silica gel chromatography to give the title compound (4-2) 0.4
4 g (89% yield) were obtained. The physical properties of the obtained compound are as follows.

¹ H-NMR (CDCl ₃ , δ) 1.16-1.70 (19H, m), 2.13 (3H, s), 2.41 (2H, t, J = 7 Hz), 3.
63 (2H, t, J = 6Hz) IR (KBr, cm ^-1 ) 3360, 2924, 2856, 1706, 1472, 1380, 1064.

Example 5 13-benzyloxy-2-
Production of Tridecanone (5-2)

[0041]

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Preparation of 10-chloro-1-benzyloxydecane (5-4)

[0043]

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In a 3-neck 1000 ml flask equipped with a 300 ml-dropping funnel, a reflux condenser, and a mechanical stirrer, 320.0 g (1.84 mol) of 1,10-decanediol was added.
l), xylene 1600 ml, sulfuric acid 3.2 g (32 mmol)
And heated to 82-87 ° C. with stirring. After 1468.9 g (15 mol) of hydrochloric acid (36%) was added dropwise over 3 hours, the mixture was further heated and stirred for 14 hours under the same conditions. After cooling to room temperature, it was left still and the lower layer was discarded. After sequentially washing with water, an aqueous solution of sodium hydrogen carbonate and water, the solution was concentrated under reduced pressure to obtain 361.8 g of a crude product. Next, 500 ml-3 ports 3 equipped with a dropping funnel, a reflux condenser, and a mechanical stirrer
475.4 g (3.7) of benzyl chloride was placed in an L flask.
5 mol), 470.0 g of a 48% aqueous sodium hydroxide solution
(5.6 mol) and 1.9 g (5.9 mmol) of tetra-n-butylammonium bromide were added, and 361.8 g of the crude product from the previous step was added dropwise with stirring over 30 minutes, and then 30 to 35 for 12 hours. Heated to ° C. Water and hexane were added, and the lower layer was discarded, washed with saturated saline, dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 523.8 g of a crude product. This was purified by distillation to obtain 450 g (yield 86%) of the title compound (5-4). The physical properties of the obtained compound are as follows.

Properties: colorless oil ¹ H-NMR (CDCl ₃ , δ) 1.20-1.86 (16H, m), 3.54 (2H, t, J = 6.7 Hz), 3.53 (2H, t, J =
6.7Hz), 4.50 (2H, s), 7.20-7.38 (5H, m) IR (NaCl, cm- ¹ ) 2932, 2860, 1456, 1104, 734, 696.

Preparation of methyl 2-acetyl-12-benzyloxidedecanoate (5-1)

[0047]

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In a 3-neck 2 L flask equipped with a reflux condenser and a mechanical stirrer, 318.0 g (1.12 mol) of 10-chloro-1-benzyloxydecane (5-4) and methyl acetoacetate (5-3) 246. 3g (2.12mo
l), 161.3 g (1.17 mol) of potassium carbonate, 35.3 g (0.21 mol) of potassium iodide, and 318.0 g of N, N-dimethylformamide were added thereto, and stirred.
Heated to 5-80 ° C. After 10 hours, cool to room temperature,
318 g of water was added and extracted with toluene. After washing with a saturated saline solution, it was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was purified by a silica gel column, and 277.2 g of the title compound (5-1) (68% yield).
I got The physical properties of the obtained compound are as follows.

Properties: colorless oil ¹ H-NMR (CDCl ₃ , δ) 1.12-1.95 (18H, m), 2.22 (3H, s), 3.35-3.51 (3H, m), 3.7
2 (3H, s), 4.50 (2H, s), 7.18-7.38 (5H, m) IR (NaCl, cm ^-1 ) 2932, 2860, 1746, 1720, 1456, 1360, 1244, 1204, 11
44, 734, 698.

Preparation of 13-benzyloxy-2-tridecanone (5-2) In a 3-neck 2 L flask equipped with a reflux condenser and a mechanical stirrer, methyl 2-acetyl-12-benzyloxidedecanoate (5-1) was prepared. 0 g (0.55 mol), 1
242.8 g of a 0% NaOH aqueous solution was added, and the mixture was stirred at room temperature for 14 hours. Next, 65.4 g of a 50% H ₂ SO ₄ aqueous solution was added, and the mixture was heated to 45 to 50 ° C. One hour later, the mixture was cooled to room temperature, added with 318 g of water, and extracted with toluene.
After washing with a saturated saline solution, the crude obtained by concentration under reduced pressure was purified by a silica gel column to give the title compound (5
-2) 131.0 g (78% yield) was obtained. The physical properties of the obtained compound are as follows.

Properties: colorless oil ¹ H-NMR (CDCl ₃ , δ) 1.20-1.70 (18H, m), 2.13 (3H, s), 2.41 (2H, t, J = 7.3 Hz),
3.46 (2H, t, J = 6.6Hz), 4.50 (2H, s), 7.20-7.38 (5H, m) IR (NaCl, cm ^-1 ) 2932, 2860, 1720, 1456, 1362, 1102, 734, 696 .

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07C 49/213 C07C 49/213 69/716 69/716 Z (72) Inventor Yoshiaki Fujikura 2606 Kabanecho, Kaga-cho, Haga-gun, Tochigi Pref. Inside the company research laboratory

Claims (2)

[Claims] 1. The following general formula (1): [Wherein, R ¹ represents a hydrogen atom or a benzyl group, R ² represents a lower alkyl group, and n represents an integer of 8 to 12]. 2. The following general formula (2) wherein the 2-acetyl carboxylic acid ester derivative according to claim 1 is hydrolyzed and decarboxylated. [Wherein R ¹ and n are the same as those described above].