JPH10204001A - Percutaneous absorption accelerator - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a percutaneous absorption accelerator that contains oily agents having specific solubility parameters as effective components, and has an excellent percutaneous absorption accelerating effect with a low skin irritation and a high safety. SOLUTION: This percutaneous absorption accelerator contains, as effective components, an oily agent (a) which has a solubility parameter σ in the range of 15.7<σ<=17.2 (for example, an arachidonic acid ester, ethyl linolenate, isononyl isononanoate, etc., preferably isotridecyl isononanoate) or a combination of the above-mentioned oily agent (a) with another oily agent (b) which has a solubility parameter σ in the range of 17.5<σ<=21.0 (for example, propylene glycol dinonanoate, diisopropyl cebacate, etc., preferably diglyceryl monoisostearate monomyristate) at a weight ratio of oily agent (a) to oily agent (b) in the range of (10:1)-(1:2), preferably (10:1)-(2:1).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a percutaneous absorption enhancer which promotes the percutaneous absorption of the active ingredient of an external preparation for skin, has low skin irritation, and is excellent in safety.

[0002]

2. Description of the Related Art Conventionally, in external preparations for skin such as cosmetics,
Various substances are used as components that exhibit a moisturizing action, a whitening action, an anti-inflammatory action, and the like by transdermal absorption. However, since the stratum corneum, which is the outermost layer of the skin, originally has a physiological function as a barrier to prevent invasion of foreign substances from outside the body, it is not sufficient to simply mix such a substance in an external preparation. It does not have skin absorbability and cannot show its original function. In addition, many substances that exhibit excellent effects by being absorbed by the skin cannot exhibit their original effects due to low percutaneous absorption in the stratum corneum.

[0003] Therefore, in recent years, transdermal absorption enhancers such as dimethylsulfoxide, dimethylformamide, dimethylacetamide, and methyldecylsulfoxide have been used for the purpose of improving the transdermal absorbability of various substances. But,
These percutaneous absorption enhancers do not provide a satisfactory percutaneous absorption promotion effect, and may cause erythema on the skin due to strong skin irritation. Was not enough.

[0004]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a transdermal absorption enhancer which exhibits an excellent transdermal absorption promoting effect, has low skin irritation and is highly safe.

[0005]

Under such circumstances, the present inventors have conducted intensive studies and as a result, it has been found that an oil having a specific solubility parameter has an excellent transdermal absorption-promoting action and has a skin irritation property. The present invention was found to be low, and the present invention was completed.

That is, the present invention provides a percutaneous absorption enhancer containing an oil agent having a solubility parameter δ in the range of 15.7 <δ ≦ 17.2 as an active ingredient.

[0007]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The oil agent used as an active ingredient in the present invention has a solubility parameter δ of 15.7 <δ.
≦ 17.2. Here, the solubility parameter refers to a measure of compatibility between substances, and is expressed by the following equation (i).
Was calculated by calculating Hansen's three-dimensional solubility parameter using In the formula, each term on the right side is a calculation formula (ii) based on the molar attractive constant of Van Krevelen.
To (iv).

[0008]

Δ = (δd ² + δp ² + δh ² ) ^1/2 (i)

Δd; term due to London's dispersive force (van der Waals force) (dispersion term) δp: term due to molecular polarity (polar term) δh: term due to hydrogen bond (hydrogen bond term)

[0010]

Δd = ΣF _di / ΣV _i (ii) δp = (ΣF _pi ² ) ^1/2 / ΣV _i (iii) δh = (ΣF _hi / ΣV _i ) ^1/2 (iv)

F _di , F _pi , F _hi ; molar attraction constant V _i ; molar volume

Note that δd, δp, and δh can be calculated from the above equations (ii) to (iv) based on the molar attraction constants (F _di , F _pi , F _hi ) of the atomic groups as described above. in the present specification, with respect to the molar attraction constants, using the Van Krevelen Rayori determined value, molar volume (V _i) was used the volume value of a defined group of atoms by Fedor.

When the solubility parameter δ is 15.
Specific examples of the oil agent in the range of 7 <δ ≦ 17.2 include:
Ethyl arachidonate, ethyl linolenate, isononyl isononanoate, octyl isopalmitate, isopropyl linoleate, octyl isoperargonate, oleyl linoleate, isotridecyl isononanoate, ethyl linoleate, isopropyl isostearate, isocetyl octanoate, oleyl eicosanoate, Isostearyl octanoate, isodecyl pivalate, isodecyl isononanoate,
Elsyl eicosanoate, octyl dodecyl oleate,
Isostearyl pivalate, Isostearyl isostearate, Isocetyl isostearate, Isostearyl eicosanoate, Octyldodecyl eicosanoate, Isopropyl oleate, Octyldodecyl dimethyloctanoate, Hexyldecyl dimethyloctanoate, Oleyl myristate, Stearyl eicosanate, Oleic acid Ethyl, decyl oleate, isocetyl stearate, octyl stearate, octyl dodecyl stearate, isostearyl palmitate, isocetyl palmitate,
Octyl palmitate, isostearyl myristate,
Isocetyl myristate, isotridecyl myristate, octyl dodecyl myristate, isostearyl laurate, hexyl isostearate, myristyl isostearate, lauryl isostearate, stearyl oleate, cetyl oleate, isobutyl stearate, isobutyl palmitate, isopropyl palmitate, Octyl myristate, isodecyl laurate, butyl isostearate, octyl pelargonate, isopropyl myristate, isoamyl laurate, isohexyl laurate, myristyl neopentanate, isobutyl pelargonate, lauryl palmitate, decyl myristate, ethyl stearate, palmitate Ethyl, butyl myristate, ethyl laurate, methyl myristate, methyl laurate Le, and the like. Of these, isotridecyl isononanoate is particularly preferred.

These oils can be used alone or in combination of two or more. Further, (a) one or two or more oil agents having a solubility parameter δ in the range of 15.7 <δ ≦ 17.2 and (b) a solubility parameter δ of 17.5 ≦ δ ≦ 21. One or two or more selected from oils in the range of 0 can be used in combination.

The oil agent having a solubility parameter δ in the range of 17.5 ≦ δ ≦ 21.0 used as the component (b) includes propylene glycol dinonanoate, diisopropyl sebacate, glyceryl trioctanoate, glyceryl tricaprate, Diisobutyl adipate, neopentyl glycol dicaprate, propylene glycol dicaprate, dihexyl adipate, glyceryl triacetyl ricinoleate, diisopropyl adipate, glyceryl tricaprate, diglyceryl triisostearate, diethyl sebacate, dimonomyristate monoisostearate Glyceryl, dibutyl adipate and the like can be mentioned. Of these, diglyceryl monomyristate monoisostearate is particularly preferred.

When the components (a) and (b) are used in combination, it is preferable to use isotridecyl isononanoate as the component (a) and diglyceryl monomyristate monoisostearate as the component (b). In addition,
In this case, another oil agent may be used in combination.

When component (a) and component (b) are used in combination, the weight ratio of these components is (a) / (b) =
It is preferably in the range of 10/1 to 1/2, particularly 10/1 to 2/1.

As a component which promotes percutaneous absorption when used in combination with the percutaneous absorption enhancer of the present invention, it is used in ordinary skin external preparations and exerts its effect by being absorbed from the skin. There is no particular limitation as long as it is present, but examples thereof include humectants, whitening agents, anti-inflammatory agents, ultraviolet absorbers, amino acids, plant extracts, singlet oxygen scavengers, antioxidants, blood circulation promoters, sterols and the like.

Among these, the humectant is not particularly limited as long as it is used in ordinary cosmetics and the like, and examples thereof include sugars, polyols, amide compounds, and ceramides. Specifically, sugars and polyols include, for example, glycol, glycerin, glucose, maltose, maltitol, sucrose, fructose, xylitol, sorbitol, maltotriose, threitol, erythritol, amylolytic sugar-reducing alcohol,
Sorbitol, ethylene glycol, 1,4-butylene glycol, diglycerin, triglycerin, tetraglycerin, 1,3-butylene glycol, propylene glycol, dipropylene glycol, polyethylene glycol, 1,3-propanediol and the like can be mentioned.

The amide compound has a melting point of from 0 to 0.
50 ° C, preferably 10 to 40 ° C.
If it is out of this range, it is difficult to stably blend it into the composition. In the present invention, the melting point is JIS-
It is indicated by the extrapolated melting point onset temperature measured according to K7121-1987-9-9.1 (2).

Examples of such amide compounds include acid amides such as isostearic acid amide, isopalmitic acid amide, and isomyristic acid amide, and the following general formulas (1) to (3).

[0022]

Embedded image

(Wherein, R ¹ and R ² are the same or different and each represent an optionally hydroxylated hydrocarbon group having 1 to 40 carbon atoms, and R ³ is a linear or branched chain having 1 to 6 carbon atoms) Represents an alkylene group or a single bond, R ⁴ is a hydrogen atom,
It represents a linear or branched alkoxy group having 1 to 12 carbon atoms or a 2,3-dihydroxypropyloxy group. However, when R ³ is a single bond, R ⁴ is a hydrogen atom. )

[0024]

Embedded image

(Wherein, R ¹ and R ² have the same meanings as described above, R ^3a represents a linear or branched alkylene group having 3 to 6 carbon atoms, and R ^4a represents a straight chain having 1 to 12 carbon atoms. A chain or branched chain alkoxy group is shown.)

[0026]

Embedded image

(Wherein, R ¹ , R ² and R ³ have the same meaning as described above, and R ^4b is a hydrogen atom, a linear or branched alkoxy group having 1 to 12 carbon atoms or 2,3-epoxypropyl Represents an oxy group, provided that when R ³ is a single bond, R ^4b
Is a hydrogen atom. ) And the like.

Among them, in the amide derivative (1), R ¹ and R ² are the same or different and each may be a straight-chain or branched-chain saturated or unsaturated hydrocarbon having 1 to 40 carbon atoms, which may be hydroxylated. Represents a group. As R ¹ and R ² , methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, heneicosyl, docosyl, Nonacosyl, triacontyl, isostearyl, isoheptadecyl, 2
-Ethylhexyl, 1-ethylheptyl, 8-heptadecyl, 8-heptadecenyl, 8,11-heptadecadienyl, 2-heptylundecyl, 9-octadecenyl,
1-hydroxynonyl, 1-hydroxypentadecyl,
2-hydroxypentadecyl, 15-hydroxypentadecyl, 11-hydroxyheptadecyl, 11-hydroxy-8-heptadecenyl and the like.

R ¹ is preferably a linear or branched alkyl or alkenyl group having 8 to 26 carbon atoms, for example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, docosyl, triacontyl, isostearyl, 2-ethylhexyl, 2-heptylundecyl and 9-octadecenyl and the like. Particularly preferred hydrocarbon groups for R ¹ are linear or branched alkyl groups having 12 to 22 carbon atoms, such as dodecyl, tetradecyl, hexadecyl, octadecyl, docosyl and methyl-branched isostearyl groups.

R ² is preferably a straight-chain or branched-chain alkyl or alkenyl group having 9 to 25 carbon atoms, such as nonyl, undecyl, tridecyl, pentadecyl, heptadecyl, heneicosyl, nonacosyl, isoheptadecyl, 1-ethylheptyl, 8- Heptadecyl, 8-heptadecenyl, 8,11-heptadecadienyl, 1-hydroxynonyl, 1-hydroxypentadecyl, 2-hydroxypentadecyl, 15-hydroxypentadecyl,
11-hydroxyheptadecyl and 11-hydroxy-
8-heptadecenyl and the like. Particularly preferred hydrocarbon groups for R ² are linear or branched alkyl groups having 11 to 21 carbon atoms, such as undecyl, tridecyl,
Pentadecyl, heptadecyl, heneicosyl and methyl-branched isoheptadecyl groups.

R^ThreeIs a straight or branched chain having 1 to 6 carbon atoms
Represents an alkylene group or a single bond, as an alkylene group
Is, for example, methylene, ethylene, trimethylene, tetrame
Tylene, pentamethylene, hexamethylene, 1-methyl
Ethylene, 1-methyltrimethylene, 2-methyltrime
Tylene, 1,1-dimethylethylene, 1-ethylethylene
, 1-methyltetramethylene, 2-ethyltrimethyle
And the like. R ^ThreeIs a straight-chain having 1 to 6 carbon atoms
Alkylene groups are preferred, of which methylene, ethylene
And trimethylene are particularly preferred.

R ⁴ represents a hydrogen atom, a linear or branched alkoxy group having 1 to 12 carbon atoms or a 2,3-dihydroxypropyloxy group. Examples of the alkoxy group include methoxy, ethoxy, propoxy, butoxy and hexyloxy. Octyloxy, decyloxy, 1-methylethoxy and 2-ethylhexyloxy.
R ⁴ is preferably a hydrogen atom, an alkoxy group having 1 to 8 carbon atoms and a 2,3-dihydroxypropyloxy group,
Of these, hydrogen atom, methoxy, ethoxy, propoxy,
Butoxy, 1-methylethoxy, 2-ethylhexyloxy and 2,3-dihydroxypropyloxy groups are particularly preferred.

As the amide derivative (1), a compound in which R ¹ , R ² , R ³ and R ⁴ in the general formula are each a group in the above particularly preferred range is particularly preferred.

In the amide derivative (2), R ¹
And R ² have the same meaning as described above, and the same group is preferable. Examples of R ^3a include groups obtained by removing methylene and ethylene from the alkylene groups exemplified for R ³ in the amide derivative (1). R ^3a is preferably a straight-chain alkylene group having 3 to 6 carbon atoms, and among them, trimethylene is particularly preferable. The alkoxy group of R ^4a, include the same groups as R ⁴ in the amide derivative (1), the same groups are preferred.

Further, in the amide derivative (3),
R ¹ , R ² and R ³ have the same meaning as described above, and R ^4b represents a hydrogen atom, a linear or branched alkoxy group having 1 to 12 carbon atoms or a 2,3-epoxypropyloxy group. Specific examples of R ¹ , R ² and R ³ include the same groups as in the amide derivative (1), and the same groups are preferable.
Examples of the linear or branched alkoxy group having 1 to 12 carbon atoms for R ^4b include the same groups as R ⁴ of the amide derivative (1), and include a hydrogen atom, an alkoxy group similar to R ⁴ , and 2,3. -An epoxypropyloxy group is preferred.

Of these amide derivatives (1) to (3), those represented by the general formula (1) are particularly preferred.

The amide derivative (1) can be obtained, for example, by the following production method 1 or production method 2.

[0038]

Embedded image

[0039]

Embedded image

(Wherein R ¹ , R ² and R ³ have the same meanings as described above, and R ^4f represents a hydrogen atom or a linear or branched alkoxy group having 1 to 12 carbon atoms. ^Three
Is a single bond, R ^4f is a hydrogen atom. R ⁶ , R ⁸ ,
R ¹⁰ and R ¹¹ is a hydrocarbon group of a saturated or unsaturated straight-chain or branched-chain having 1 to 8 carbon atoms, preferably a linear or branched alkyl group having 1 to 5 carbon atoms, particularly preferably Is a methyl group. R ⁹ represents a hydrogen atom, an alkali metal atom or a COR ⁸ group, and R ⁷ and R ¹² represent a leaving group such as a halogen atom, a mesylate group or a tosylate group. As R ⁷ , a chlorine atom and a bromine atom, particularly a chlorine atom are preferred from the viewpoint of availability, and the like, and a mesylate group and a tosylate group are preferred as R ¹² from the viewpoint of availability. )

[0041]

Embedded image

[0042]

Embedded image

(In the formula, R ¹ , R ² , R ^{6 to} R ¹² have the same meaning as described above, and R ^3g represents a linear or branched alkylene group having 1 to 6 carbon atoms.)

The reaction conditions in each step of Production Method 1 and Production Method 2 are as follows.

Step 1) Glycidyl ether (7) and amine (8F) or (8G) are used without solvent, or in water or a lower alcohol such as methanol, ethanol or isopropanol, or an ether system such as tetrahydrofuran, dioxane or ethylene glycol dimethyl ether. Producing the amino alcohol derivative (4F) or (4G) by reacting at room temperature to 150 ° C. in a solvent, a hydrocarbon solvent such as hexane, benzene, toluene, xylene, or any mixed solvent thereof. Can be.

Step 2) Amino alcohol derivative (4F)
Or (4G), a fatty acid ester (9), preferably a fatty acid lower alkyl ester such as a fatty acid methyl ester or a fatty acid ethyl ester, or an alkali earth metal hydroxide such as potassium hydroxide or sodium hydroxide; Alkaline catalysts such as alkali metal carbonates such as metal hydroxides and potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, alkali metal alcoholates such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; The amide derivative (2F) or (2G) can be produced by reacting at room temperature to 150 ° C. under reduced pressure of normal pressure to 0.01 mmHg in the presence. At this time, the amount of the basic catalyst used is preferably 0.01 to 0.2 equivalent relative to the amino alcohol derivative (4F) or (4G). Is preferred because it proceeds quickly.

Step 3) Amide derivative (2F) or (2F)
G) is also an amino alcohol derivative (4F) or (4F)
G) fatty acid chloride (10) without solvent or a halogenated hydrocarbon solvent such as chloroform, methylene chloride, 1,2-dichloroethane, tetrahydrofuran,
In the presence of a base such as a tertiary amine such as pyridine or triethylamine in an ethereal solvent such as dioxane or ethylene glycol dimethyl ether, a hydrocarbon-based solvent such as hexane, benzene, toluene or xylene, or an arbitrary mixed solvent thereof. Or in the absence of, room temperature to 10
After reaction at 0 ° C. to convert to amide-ester derivative (11F) or (11G),

Step 4) The ester group is converted to an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide, an alkaline earth metal hydroxide such as calcium hydroxide, an alkali metal carbonate such as potassium carbonate, or calcium carbonate. Can be produced by selective hydrolysis under basic conditions such as alkaline earth metal carbonates such as sodium methoxide, sodium ethoxide, and alkali metal alcoholates such as potassium tert-butoxide. .

Step 5) Amide derivative (2F) or (2F)
G) 1 to 20 equivalents of epoxide (12), preferably epichlorohydrin, without solvent or water or an ether solvent such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, hexane, benzene,
In a hydrocarbon solvent such as toluene or xylene, or an arbitrary mixture thereof, 1 to 10 equivalents of an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide, or an alkaline earth metal water such as calcium hydroxide. Oxides,
Room temperature to 150 ° C. in the presence of an alkali metal carbonate such as potassium carbonate or an alkaline earth metal carbonate such as calcium carbonate
The amide derivative (3F) or (3
G) can be manufactured. At this time, tetrabutylammonium bromide, tetrabutylammonium chloride, hexadecyltrimethylammonium chloride, hexadecyltrimethylammonium bromide,
Stearyltrimethylammonium chloride, bistetraoxyethylene stearylmethylammonium chloride or other quaternary ammonium salts or lauryldimethylcarboxyammonium betaine or other phase transfer catalyst such as betaine is preferable to perform the reaction in terms of yield and the like. .

Step 6) Amide derivative (3F) or (3F)
G) represents an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide, an alkaline earth metal hydroxide such as calcium hydroxide, an alkali metal carbonate such as potassium carbonate, or an alkaline earth metal carbonate such as calcium carbonate. Basic conditions such as salts or mineral acids such as sulfuric acid and hydrochloric acid, Lewis acids such as boron trifluoride and tin tetrachloride, carboxylic acids such as acetic acid, tetradecanoic acid and hexadecanoic acid, and sulfonic acids such as p-toluenesulfonic acid The amide derivative (1F) or (1G) can be produced by hydration at room temperature to 300 ° C. under acidic conditions such as those described above or under a base-acid mixed condition.

Step 7) Amide derivative (1F) or (1F)
G) may be a carboxylic acid derivative (13), preferably a lower fatty acid such as acetic acid, an alkali metal salt of a lower fatty acid such as sodium acetate, or a lower fatty acid anhydride such as acetic anhydride, alone with the amide derivative (3F) or (3G). Alternatively, in combination, the mixture is reacted in the presence or absence of a basic catalyst such as a tertiary amine such as triethylamine to convert it into an ester-amide derivative (14F) or (14G).

Step 8) The ester group is converted to an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide, an alkaline earth metal hydroxide such as calcium hydroxide, an alkali metal carbonate such as potassium carbonate, or calcium carbonate. Can be produced by selective hydrolysis under basic conditions such as alkaline earth metal carbonates such as sodium methoxide, sodium ethoxide, and alkali metal alcoholates such as potassium tert-butoxide. .

Step 9) Amide derivative (1F) or (1F)
G) can also be obtained by adding a carbonyl compound (15), preferably a lower aliphatic ketone such as acetone or methyl ethyl ketone, to a amide derivative (3F) or (3G), a mineral acid such as sulfuric acid, hydrochloric acid or phosphoric acid, or a carboxylic acid such as acetic acid. , Boron trifluoride, tin tetrachloride or the like, and reacted in the presence of an acid catalyst such as a Lewis acid to convert to a 1,3-dioxolane-amide derivative (16F) or (16G).

Step 10) Mineral acids such as sulfuric acid, hydrochloric acid and phosphoric acid,
It can also be produced by deketalization under acidic conditions such as carboxylic acid such as acetic acid and sulfonic acid such as p-toluenesulfonic acid.

Step 11) The 1,3-dioxolan-amide derivative (16F) or (16G) is also converted to the amide derivative (2F) or (2G) by the glycerol derivative (17).
A potassium hydroxide, an alkali metal hydroxide such as sodium hydroxide, an alkaline earth metal hydroxide such as calcium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkaline earth metal carbonate such as calcium carbonate, In the presence of a base such as an alkali metal hydride such as sodium hydride, in the absence of a solvent or an aprotic polar solvent such as N, N-dimethylformamide or dimethyl sulfoxide, or an ether solvent such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether or the like. And hexane, benzene, toluene, xylene and the like, or a mixed solvent thereof, or the like.

The amide derivative (1) thus obtained can be purified by a known method. In the present invention, the effect and performance of a purified product obtained by purifying the amide derivative (1) to a purity of 100% or a mixture having a purity of 70 to 100% containing an intermediate or a reaction by-product without purification is not particularly required. Excellent and safe to use. The amide derivative (1) also includes a solvate represented by a hydrate.

Examples of the amide derivative (1) obtained by the production method 1 include the following.

[0058]

Embedded image

[0059]

Embedded image

Examples of the amide derivative (1) obtained by the production method 2 include the following.

[0061]

Embedded image

The amide compound is particularly preferably an N-substituted amide compound having a total carbon number of 30 or more. Also,
The amide compound contains 1% by weight or more, especially 5% by weight of bound water.
What can hold above is more preferable. Here, the content of bound water is determined by first adding water to a sample at room temperature, measuring the maximum amount of water that can maintain a homogeneous phase, and calculating the amount of bound water, and then calculating the percentage of the total weight of bound water relative to the total weight of the sample. And can be obtained according to the following equation.

[0063]

(Equation 3)

Among the humectants of the component (A), examples of the ceramides include known compounds represented by the following general formula (4) and ceramide-like structural substances represented by the following general formula (5). .

[0065]

Embedded image

Wherein R ⁵ and R ⁶ are the same or different and each represent a straight-chain or branched-chain saturated or unsaturated hydrocarbon group having 8 to 26 carbon atoms.

In the general formula (4), the hydrocarbon groups represented by R ⁵ and R ⁶ are linear or branched having 8 to 26 carbon atoms, and may be saturated or unsaturated. Examples include octyl, nonyl, decyl, dodecyl, undecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicodecyl, heneicosyl, docosyl, tricosyl, tetracosyl, pentacosyl, hexacosyl, nonenyl,
Decenyl, dodecenyl, undecenyl, tridecenyl,
Tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosenyl, tetracosenyl, pentacosenyl, hexacosenyl, nonadienyl, decadienyl, dodecadienyl, pentadienyl, didecadienyl, pentadienyl, didecadienyl, pentadienyl, tridecadienyl , Heptadecadienyl, octadecadienyl, nonadecadiethyl, eicosadienyl, heneicosadenyl, docosadienyl, tricosadienyl, tetracosadenyl, pentacosadenyl, hexacosadenyl, 2-hexyldecyl, 2-octylun Decyl, 2-decyltetradecyl, isostearyl group and the like. These hydrocarbon groups may be substituted by one or more hydroxyl groups.

R ⁵ is preferably a straight-chain alkyl group having 15 to 23 carbon atoms, particularly preferably pentadecyl, heptadecyl and tricosyl groups, and R ⁶ is a straight-chain saturated or unsaturated alkyl or alkenyl group having 15 to 23 carbon atoms. The groups are particularly preferably pentadecyl, heptadecyl and pentadecenyl groups. Among the ceramides represented by the general formula (4), particularly preferred compounds are compounds obtained by combining the case where each of R ⁵ and R ⁶ in the general formula (4) is a group in the above particularly preferred range.

[0069]

Embedded image

[Wherein, R ⁷ represents a linear or branched, saturated or unsaturated hydrocarbon group having 10 to 26 carbon atoms, and R ⁸ represents a linear or branched, saturated or unsaturated hydrocarbon group having 9 to 25 carbon atoms. Represents an unsaturated hydrocarbon group, Y ¹ and Z ¹ represent a hydrogen atom or a hydroxyl group, a represents a number of 0 or 1, c represents an integer of 0 to 4, b and d represent 0 to 3 Indicates an integer)

These ceramide-like structural substances can be prepared by a known method [for example, Polish Journal of Chemistry (Po. J. Chem.) 52 , 1059 (19)
78); 52 , 1283 (1978);
Nos. 117421, 54-144308, 54-147937, 62-228048, and 63-216852].

In the general formula (5), the number of carbon atoms represented by R ⁷ is 1
Examples of the linear or branched saturated or unsaturated hydrocarbon group having 0 to 26 carbon atoms include those having 10 to 26 carbon atoms in R ⁵ and R ^6.
Are exemplified ones, as the linear or saturated or unsaturated hydrocarbon group branched 9 to 25 represented by R ^8, include the carbon number of 10 to 26 in the above R ⁵ and R ⁶ Can be R ⁷ is preferably a straight-chain saturated alkyl group having 12 to 18 carbon atoms, particularly preferably tetradecyl, hexadecyl or octadecyl group, and R ⁸ is preferably a straight-chain saturated alkyl group having 9 to 18 carbon atoms, particularly nonyl, Pentadecyl and heptadecyl groups are preferred. Among the ceramide-like structural substances represented by the general formula (5), a particularly preferable compound is a compound obtained by combining a case where each of R ⁷ and R ^{8 in the} general formula (5) is a group in the above particularly preferable range. It is.

The whitening agent is not particularly limited as long as it is a substance having a whitening effect and can be used in ordinary skin external preparations. For example, L-ascorbic acid and its derivatives, hydroquinone derivatives, kojic acid and its derivatives Derivatives,
Placenta extracts, plant extracts having a whitening effect, spiroether compounds, and the like.

Specifically, ascorbic acid and its derivatives are not particularly limited.
L- which is a monovalent metal salt of ascorbic acid phosphate ester
Sodium ascorbic acid phosphate, potassium L-ascorbic acid phosphate, magnesium divalent metal salt L-ascorbic acid phosphate,
L-ascorbic acid phosphate calcium salt, trivalent metal salt L-ascorbic acid phosphate aluminum salt, L-ascorbic acid sulfate monovalent metal salt L-ascorbic acid sulfate sodium salt, L -Potassium ascorbic acid sulfate, 2
L-ascorbic acid sulfate potassium magnesium salt which is a valent metal salt; L-ascorbic acid sulfate calcium salt which is a trivalent metal salt; L-ascorbic acid sulfate aluminum salt which is a trivalent metal salt; and a monovalent metal salt of L-ascorbic acid. L-ascorbate sodium salt, L-ascorbate potassium salt, divalent metal salt L-ascorbate magnesium salt, L-ascorbate calcium salt, trivalent metal salt L-ascorbate aluminum salt and the like. Can be.

The hydroquinone derivative is not particularly limited, and examples thereof include a condensate of hydroquinone and a sugar, and a condensate of an alkylhydroquinone and a sugar obtained by introducing one alkyl group having 1 to 4 carbon atoms into hydroquinone. Among these, arbutin and the like are preferable.

The kojic acid and its derivatives are not particularly restricted but include, for example, kojic acid, kojic acid monobutyrate, kojic acid monocaprate, kojic acid monopalmitate, kojic acid monostearate, kojic acid monocinnamoate, Examples thereof include monoesters such as kojic acid monobenzoate, diesters such as kojic acid dibutyrate, kojic acid dipalmitate, kojic acid distearate, and kojic acid dioleate.

As the placenta extract, those which are generally marketed as a water-soluble placenta extract and used as cosmetic raw materials can be used. For example, the placenta of mammals such as cows, pigs, and humans can be washed and blood removed. , Crushing, freezing, and the like, and after extracting the water-soluble component, further removing impurities to obtain the same.

Examples of the plant extract having a whitening effect include chamomile, cha, cakkon, clove, licorice,
Loquat, spruce, ginseng, peonies, hawthorn, barley winter, ginger, suegasa, mulberry bark, magnolia, inchenbukaku, asenyaku,
Extracts such as yellow gon, aloe, altea, spiraea, Dutch mustard, kina, comfrey, rosemary, and funnel.

Among these, the chamomile extract is a chamomile [Matricaria chamomilla]
L. (Compositee)] can be obtained as an extract by extracting the flower with water or a hydrophilic organic solvent such as methanol, ethanol, propanol, propylene glycol, 1,3-butylene glycol or a mixture thereof. The extract can be dried and obtained in the form of a dry powder. Extraction with a hydrophilic organic solvent such as castor oil, persic oil, liquid paraffin, soybean oil, isopropyl myristate, lower fatty acid triglyceride, medium fatty acid triglyceride, sunflower oil, neopentyl glycol dicaprate, squalane, or a mixed solvent thereof. Can be obtained. In the present invention, one of the thus obtained chamomile extract
Species or a combination of two or more can be used.

The chamomile extract generally contains azulene, camazulene, umbelliferone, 7-methoxycoumarin, matricin, maticalin, taraxasterol, lupeol, apiin, chroman, spiroether and the like. Here, a preferable method for extracting chamomile includes, for example, the following method.

That is, the chamomile flowers are dried and cut into small pieces. After adding squalane thereto and immersing it from room temperature to 50 ° C. with occasional stirring, the extract is separated by pressing to obtain an extract.
This extract is filtered to obtain a chamomile extract.

Examples of the spiroether compound include those represented by the following general formula (6).

[0083]

Embedded image

[Wherein the wavy line indicates that the bonding state may be either Z or E]

The spiroether compound (6) is, for example, a chamomile of Matricaria spp.
Vol., Pp. 384-388 (1992), Chrysanthemum genus (Agric. Biol. Chem. 48, 13).
67-1369, 1984), the genus Tanacetam,
It has been reported that it can be obtained from several Asteraceae plants such as Artemisia and Leucansemum, and the components obtained by solvent extraction, steam distillation, etc. can be isolated by subjecting them to chromatography as usual. . The spiroether compound (6) suppresses melanin production in melanocytes, reduces or eliminates pigmentation based on external stimuli such as ultraviolet rays, has an excellent effect of preventing and improving pigmentation, and has a skin whitening effect. (JP-A-7-206657, etc.).

The anti-inflammatory agent is not particularly limited as long as it is a substance having an anti-inflammatory effect and is used in ordinary skin external preparations. For example, glycyrrhizic acid and its salts, glycyrrhetinic acid and its salts, isopropylaminocaproic acid And salts thereof, allantoin, lysozyme chloride, guaiazulene, methyl salicylate, γ-oryzanol, and the like. Of these, glycyrrhetinic acid, stearyl glycyrrhetinate, and epsilon aminocaproic acid are preferred.

Examples of ultraviolet absorbers include benzophenone, 4-t-butyl-4'-methoxy-dibenzoylmethane, glyceryl ethyl hexanoate dimethoxycinnamate, 2-ethylhexyl-4-methoxycinnamate,
Examples include aminobenzoic acid esters and phenyl salicylate.

Examples of the amino acid include neutral amino acids such as glycine, serine, cystine, alanine, threonine, cysteine, valine, phenylalanine, methionine, leucine, tyrosine, proline, isoleucine, tryptophan, and hydroxyproline; aspartic acid, asparagine, and glutamine. Acidic amino acids such as glutamic acid; arginine, histidine, basic amino acids such as lysine; and betaines and amino acid derivatives such as acylsarcosine and salts thereof, acylglutamic acid and salts thereof, acyl-β-alanine and salts thereof, glutathione and pyrrolidone carboxylic acid. Acid and its salts, glutatin, carnosine,
Oligopeptides such as gramcigin S, tyrosidine A, and tyrosidine B, and guanidine derivatives and salts thereof described in JP-A-6-228023.

Examples of plant extracts include ashitaba, adzuki bean, avocado, amacha, amachatull, alteca,
Arnica, almond, aloe, apricot, nettle, iris, fennel, turmeric, age, ogon, oubak, ouren, barley, okra, olygi, odorisou, ononis, holland kalashi, oyster, cuckoo, kanokosou, birch, kamare, kamire , Oats, oats, liquorice, raspberries, kiwi, cucumber, kyonin, kukuinuts, gardenia, kumazasa, walnuts, cauliflower, mulberry, guenjo, gentian, gennoshoko, burdock, sesame, wheat, rice, sasanqua, saffron, hawthorn, sansho, shiitake Geo, Shikon, Shiso, Shinanouki, Shimotsukeisou, Peonies, Showa, Shobu, Birch, Watermelon, Horsetail, Stevia, Stevia, Kizuta, Hawthorn, and Elderberry Juniper, yarrow, peppermint, sage, mallow, Sinensis, assembly, soybean, pinch runner, dime, tea,
Clove, cock, evening primrose, camellia, camellia, teuchigurumi, touki, calendula, tonin, spruce,
Corn, doctor, tomato, carrot, garlic, novara, balsam, parsley, naked pearl, adlay,
Mentha, papaya, hamamelis, rose, hinoki, sunflower, loquat, coltsfoot, grape, placenta, hazelnut, loofah, safflower, bodaige, button, hop, macadamia nut, pine, malonier, melissa,
Melilot, peach, bean sprouts, cornflower, palm, eucalyptus, saxifrage, lily, yokunin, mugwort, rye, peanut, lavender, apple, litchi, lettuce, lemon, astragalus, rosemary, roman chamomile, golden cornflower, catalpa, asunaro, holtsou,
Examples include extracts obtained from plants such as Hioki-koshi, pheasant, seng-ki, chickweed, floating grass, sagebrush, ginkgo, kikyo, chrysanthemum, kumazasa, mukuroji and forsythia.

As the singlet oxygen scavenger or antioxidant,
For example, carotenoids such as α-carotene, β-carotene, γ-carotene, lycopene, cributoxanthin, lutein, zeaxanthin, isoseaxanthin, rhodoxanthin, capsanthin, crocetin; 1,4-diazacyclooctane, 2,5-dimethyl Furan, 2-methylfuran, 2,5-diphenylfuran, 1,3-diphenylisobenzofuran, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, histidine, tryptophan, methionine, alanine or an alkyl ester thereof; Tannins such as dibutylhydroxytoluene, butylhydroxyanisole, ascorbic acid, tannic acid, epicatechin, epicarocatechin, epicatechin gallate, epicarocatechin gallate, and flavonoids such as rutin Etc., and the like.

Examples of the blood circulation promoting agent include, for example, those described in
No. 87506, an esterified product of vitamin E described as a vasodilator, a nicotinic acid ester or an orotic acid ester; an esterified product of vitamin E described as a peripheral circulation promoting agent in JP-A-62-195316 , Acetate or succinate; nicotinamide, methyl nicotinate; blood circulation promoting effect is specified in the fragrance journal extra edition No. 6 issued in 1986, the fragrance journal extra edition No. 1 issued in 1979, etc. Extracts, such as Arnica,
Hawthorn, kina, salvia, bodaige, rape, ginseng, ginger, mannenrow, hypericum, ginkgo, melissa, ononis, malonier, assembly, garlic, chamomile, saim, mint, nettle, pepper, ginger, hop, western horse chestnut, lavender, carrot Japanese mustard, kei, pine, senkyu, elderberry, elderberry, ash jelly, button, bayberry, dokudami, kohone, shibugaki, tokinsenka, gubidinsou, gentian, grape, hamabo fu, daidai, yuzu, shobu, natsumikan, hamamelis, merry roto Salmon, peonies, eucalyptus,
Mugwort, emisoso, rice, clara, ginger,
Extracts such as cloves are exemplified.

The sterols include, for example, cholesterol, cholesteryl isostearate, provitamin D
₃ , campesterol, stegmasteranol, stegmasterol, 5-dihydrocholesterol, α-spinasterol, palisterol, crionasterol, γ
-Sitosterol, stegmasterol, salgasterol, apenasterol, ergostanol, sitosterol, corvisterol, chondrilasterol, polyferasterol, haliclonasterol, neosvongosterol, fucosterol, aptostanol,
Ergostadienol, ergosterol, 22-dihydroergosterol, brassicasterol, 24-methylenecholesterol, 5-dihydroergosterol, dehydroergosterol, funggisterol, cholestanol, coprostanol, dimosterol, 7
-Heptocholesterol, latosterol, 22-dehydrocholesterol, β-sitosterol, cholestatrien-3β-ol, coprostanol, cholestanol, ergosterol, 7-dehydrocholesterol,
24-Dehydrocholestazan-3-β-ol, equilenin, equilin, estrone, 17β-estradiol, androst-4-en-3β, 17β-diol, dehydroebiandrosterone, cholesteryl alkenyl succinate (Japanese Unexamined Patent Publication No. No. 294989).

These components are absorbed into the skin promptly by being mixed with the transdermal absorption promoter of the present invention and applied to the skin. If it is a component intended for local action, it penetrates deeply into the skin and exerts an excellent effect, and if it is a component intended for systemic action, the component is transferred to the blood, so the same excellent effect Demonstrate.

The mixing ratio of these components differs depending on the type, purpose, etc., and cannot be said unconditionally.
Generally, 0.0001 to 1 part by weight of the transdermal absorption enhancer
It can be 10 parts by weight, preferably 0.001 to 1 part by weight.

The percutaneous absorption enhancer of the present invention may be used by mixing only the above-mentioned components as appropriate. However, in consideration of the feeling of use, ease of application, safety, etc., it is generally suitable. It is preferable to use it by blending it in a suitable external preparation for skin, for example, a liquid, water-in-oil or oil-in-water emulsion, gel, paste, or solid base.

In this case, the amount of each component varies depending on the kind of the active ingredient and the like, as described above. However, the percutaneous absorption enhancer of the present invention is contained in an amount of 0.001 to 4 per total skin external preparation.
0% by weight, particularly preferably 0.01 to 30% by weight.

[0097] In addition to the above components, the external preparation for skin includes components used in ordinary pharmaceuticals, quasi-drugs, cosmetics, and the like.
For example, other oils, organic acids, alkalis, surfactants, powders, pigments, dyes, preservatives / fungicides, antioxidants, chelating agents, thickeners, fragrances, water, etc. Can be appropriately compounded within a range that does not impair, and can be produced according to a usual method.

[0098]

The percutaneous absorption enhancer of the present invention significantly enhances the percutaneous absorption of the active ingredient incorporated in the external preparation for skin,
Moreover, it has low skin irritation and excellent safety.

[0099]

Next, the present invention will be described with reference to examples, but the present invention is not limited to these examples. In Production Examples 1 to 10, the amide derivative (1) was produced according to the Production Method 1. In the spiroether compounds used in the following examples, those having a bond of Z in the general formula (6) are shown as spiroether compounds Z, and those having a bond state of E as spiroether compounds E.

Production Example 1 743.2 g (8.34 mol) of 3-methoxypropylamine and 15 parts of ethanol were placed in a 2-liter 5-neck flask equipped with a stirrer, a dropping funnel, a nitrogen inlet tube and a distillation apparatus.
Of hexadecyl glycidyl ether 165.9 while heating and stirring at 80 ° C. under a nitrogen atmosphere.
g (0.56 mol) was added dropwise over 3 hours. After completion of the dropwise addition, the mixture was further stirred at 80 ° C. for 12 hours, and then ethanol and excess 3-methoxypropylamine were distilled off by heating under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the amino alcohol derivative (4a). 19
6.5 g (91% yield versus hexadecyl glycidyl ether) were obtained (step 1).

[0101]

Embedded image

The obtained amino alcohol derivative (4a)
Its physical properties are as follows.

Melting point: 53 ° C. IR (ν _neat , cm ⁻¹ ); 3340, 2930, 285
5,1470,1310,1120,1065,95
5,900,720. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (t, J =
6.3 Hz, 3H), 1.25 to 1.45 (m, 26
H), 1.45 to 1.85 (m, 6H), 2.57 to
2.76 (m, 4H), 3.32 (s, 3H), 3.3
8 to 3.48 (m, 6H), 3.77 to 3.89 (m,
1H).

In a 1-liter 5-neck flask equipped with a stirrer, a dropping funnel, a nitrogen inlet tube and a distillation apparatus, 61.3 g (15) of the molten compound (4a) obtained in the above (Step 1) was melted.
8.13 mmol) and 1.53 g (7.91 mmol) of a 28% methanol solution of sodium methoxide were stirred and stirred at 60 ° C. for 30 minutes under a nitrogen atmosphere. Next, 38.3 g (158.1 mmol) of methyl tetradecanoate was added thereto under the same conditions.
Was added dropwise over 1 hour. After completion of the dropwise addition, the mixture is further reduced in pressure (8
The mixture was stirred at 60 ° C. for 5 hours to complete the reaction. After cooling the reaction mixture, the mixture was purified by silica gel column chromatography to obtain the amide derivative (2a).
88.7 g (94% yield) was obtained (Step 2).

[0105]

Embedded image

The physical properties of the obtained amide derivative (2a) are as follows.

Melting point: 48 ° C. IR (ν _neat , cm ⁻¹ ): 3440, 2930, 286
0, 1650, 1625, 1470, 1225, 121
0, 1110, 950, 720. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (br t,
J = 6.3 Hz, 6H), 1.15 to 1.95 (m, 5
3H), 2.36 (t, J = 7.5 Hz, 2H), 3.
29 to 3.55 (m, 10H), 3.33 (s, 3
H), 3.85 to 3.95 (m, 1H).

94.5 g (158.0 mmol) of the compound (2a) obtained in the above (Step 2) and 1.53 g of tetrabutylammonium bromide were placed in a 1-liter 5-neck flask equipped with a stirrer, a nitrogen inlet tube and a distillation apparatus. (4.74mmo
l), 32.2 g (347.6 mmol) of epichlorohydrin
l), 12.6 g (315.0 mmol) of sodium hydroxide
And 66 ml of toluene.
Stirred for 0 hours. The obtained reaction mixture was washed three times with water at 70 ° C., and toluene and excess epichlorohydrin were distilled off by heating under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the amide derivative (3).
a) 94.9 g (92% yield) was obtained (Step 5).

[0109]

Embedded image

The physical properties of the obtained amide derivative (3a) are as follows.

Melting point: 38-39 ° C IR (ν _neat , cm ⁻¹ ); 2930, 2855, 165
0, 1470, 1425, 1380, 1210, 112
0,905,840,720. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (br t,
J = 6.0 Hz, 6H), 1.10 to 1.45 (m, 4
6H), 1.45 to 1.90 (m, 6H), 2.25 to
2.48 (m, 2H), 2.50 to 2.68 (m, 1
H), 2.70 to 2.85 (m, 1H), 3.02 to
3.20 (m, 1H), 3.20 to 4.00 (m, 13
H), 3.32 (s, 3H).

In a 100 ml autoclave equipped with a stirrer, compound (3a) 7 obtained in the above (Step 5) was added.
1.3 g (109.0 mmol), water 11.78 g (65
4.1 mmol), sodium hydroxide 0.087 g (2.1
8 mmol) and 0.87 g (4.36 mmol) of tetradecanoic acid
l) and stirred in a closed system at 160 ° C. for 6 hours.
The reaction mixture was cooled, washed twice with 2% saline at 80 ° C., and then purified by silica gel column chromatography to obtain the desired amide derivative (1a).
3 g (93% yield) was obtained (Step 6).

[0113]

Embedded image

The physical properties of the obtained amide derivative (1a) are as follows.

Colorless transparent liquid IR (ν _neat , cm ⁻¹ ); 3445, 2930, 286
0, 1630, 1470, 1420, 1380, 130
5,1210,1120,720. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (br t,
J = 6.7 Hz, 6H), 1.15 to 1.44 (m, 4
6H), 1.44-1.95 (m, 8H), 2.25-
2.45 (m, 2H), 3.20 to 3.90 (m, 16
H), 3.33 (s, 3H).

In a 500 ml four-necked flask equipped with a stirrer, a nitrogen introducing tube and a distillation apparatus, the above (Step 5) was added.
31.0 g (47.4 mmol) of the compound (3a) obtained in the above, 11.9 g (663.7 mmol) of water, and 13.3 g of sodium acetate.
6 g (165.9 mmol) and acetic acid 104.9 g (174
6.8 mmol) and stirred at 70 ° C. for 19 hours under a nitrogen atmosphere. Excess acetic acid is distilled off by heating under reduced pressure to give ester-
Amide derivatives (14a-1), (14a-2) and (1
A mixture containing 4a-3) was obtained (Step 7).

[0117]

Embedded image

Next, a mixture containing these ester-amide derivatives was added to the flask without removing it from the flask.
59.3 g of 8% aqueous sodium hydroxide solution (711.2 mm
ol), 18 g of water and 200 ml of butanol.
For 3 hours. Butanol is distilled off by heating under reduced pressure.
The residue was diluted with 250 ml of toluene and washed twice with water at 70 ° C. The toluene was distilled off by heating under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 22.3 g (70% yield) of the desired amide derivative (1a) (step 8).

Production Example 2 In a 10-liter 5-necked flask equipped with a stirrer, a dropping funnel, a nitrogen inlet tube and a distillation apparatus, 4680 g (52.5 mol) of 3-methoxypropylamine and ethanol 90
0 g, and while heating and stirring at 80 ° C. under a nitrogen atmosphere, 1045 g of hexadecyl glycidyl ether was added thereto.
(3.50 mol) was added dropwise over 3 hours. After completion of the dropwise addition, the mixture was further stirred at 80 ° C. for 1 hour, and then ethanol and excess 3-methoxypropylamine were distilled off by heating under reduced pressure to obtain a product mainly composed of an amino alcohol derivative (4a) (step). 1).

The product containing the compound (2a) as a main component in a 10-liter 5-neck flask obtained in the above (Step 1) was added to
9.82 g (0.175 mol) of potassium hydroxide was added,
The mixture was stirred for 3 hours under a reduced pressure (60 to 10 Torr) at 80 ° C. while distilling off water generated by blowing in nitrogen. Next, while stirring under the same conditions, methyl tetradecanoate 8 was added thereto.
82.3 g (3.64 mol) were added dropwise over 3 hours.
At this time, generated methanol was distilled off. After the completion of the dropwise addition, the mixture is further blown with nitrogen and under reduced pressure (60 to 10 Torr).
While distilling off the methanol produced at 0-45 ° C, 1
The mixture was stirred for 0 hour to complete the reaction, and the amide derivative (2a)
(Step 2).

The product containing compound (2a) as a main component in a 10-liter 5-neck flask obtained in the above (Step 2) was added to
33.9 g of tetrabutylammonium bromide (0.
105 mol), 712.5 g of epichlorohydrin (7.
70 mol) and 2100 g of toluene, and 1750.0 g of a 48% aqueous sodium hydroxide solution (20.0 g) in a 48% aqueous sodium hydroxide solution while stirring at 45 ° C. under a reduced pressure (150 to 50 Torr) under a nitrogen blow.
1.0 mol) was added dropwise over 2 hours. After completion of the dropwise addition, the mixture was further stirred for 10 hours under the same conditions to complete the reaction. After the reaction mixture was washed four times with water at 70 ° C., toluene and excess epichlorohydrin were distilled off by heating under reduced pressure to obtain a product mainly containing the amide derivative (3a) (Step 5).

The product containing compound (3a) as a main component in a 10-liter 5-neck flask obtained in (Step 5) above was added to
378.2 g (21.0 mol) of water, 5.83 g (0.070 mol) of a 48% aqueous sodium hydroxide solution and 32.0 g (0.14 mol) of tetradecanoic acid were added, and the mixture was stirred at 100 ° C. for 2.5 days under a nitrogen atmosphere. . 80 reaction mixture
After washing three times with 2% saline at 0 ° C., the product was dehydrated by heating under reduced pressure to obtain a product 2 containing the target compound (1a) as a main component.
261.5 g were obtained (step 6). This product contained 70% of the compound (1a), and also contained an intermediate represented by the following formula, a reaction by-product, and the like.

[0123]

Embedded image

[0124]

Embedded image

Production Example 3 Production Example 1 was repeated except that methyl hexadecanoate was used in place of methyl tetradecanoate in Step 2 of Production Example 1.
The reaction was carried out in the same manner as in Steps 1 and 2 of
b) was obtained (steps 1 and 2).

[0126]

Embedded image

The physical properties of the obtained amide derivative (2b) are as follows.

Melting point: 55 ° C. IR (ν _neat , cm ⁻¹ ): 3430, 2930, 285
5,1620,1470,1205,1110,95
0,720. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (br t,
J = 6.4 Hz, 6H), 1.26 to 1.89 (m, 5
7H), 2.36 (t, J = 7.6 Hz, 2H), 3.
29-3.52 (m, 10H), 3.33 (s, 3
H), 3.88-3.95 (m, 1H).

In Step 5 of Production Example 1, compound (2
The reaction was carried out in the same manner as in Step 5 of Production Example 1, except that the compound (2b) obtained in the above (Step 2) was used instead of a).
The amide derivative (3b) was obtained (Step 5).

[0130]

Embedded image

The physical properties of the obtained amide derivative (3b) are as follows.

White solid Melting point: 44 to 45 ° C. IR (ν _neat , cm ⁻¹ ); 2930, 2860, 165
0, 1470, 1425, 1380, 1210, 112
0,910,845,755,720. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (br t,
J = 6.7 Hz, 6H), 1.15 to 1.45 (m, 5
0H), 1.45 to 1.73 (m, 4H), 1.73 to
1.90 (m, 2H), 2.25 to 2.48 (m, 2
H), 2.50 to 2.68 (m, 1H), 2.70 to
2.85 (m, 1H), 3.00 to 3.18 (m, 1
H), 3.18-4.00 (m, 13H), 3.32.
(S, 3H).

In Step 6 of Production Example 1, compound (3
Compound (3b) obtained in the above (Step 5) instead of a)
Was reacted in the same manner as in Step 6 of Production Example 1 except that hexadecanoic acid was used instead of tetradecanoic acid, to obtain the desired amide derivative (1b) (Step 6).

[0134]

Embedded image

The physical properties of the obtained amide derivative (1b) are as follows.

Melting point; 33 ° C. IR (ν _neat , cm ⁻¹ ); 3445, 2930, 286
0, 1650, 1630, 1470, 1420, 138
0, 1305, 1210, 1120, 1080. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (br t,
J = 6.4 Hz, 6H), 1.15 to 1.45 (m, 5
0H), 1.45 to 1.95 (m, 7H), 2.25 to
2.55 (m, 3H), 3.20 to 3.92 (m, 16
H), 3.33 (s, 3H).

In a 500 ml four-necked flask equipped with a stirrer and a nitrogen inlet tube, 34.1 g (50.0 mmol) of the compound (3b) obtained in the above (Step 5), acetic anhydride 2
5.5 g (250.0 mmol) and triethylamine 2
5.3 g (250.0 mmol) were charged and 1
The mixture was stirred at 00 ° C for 10 hours. The reaction mixture was concentrated under reduced pressure while heating, and the obtained residue was purified by silica gel column chromatography to obtain 34.9 g (89%) of the ester-amide derivative (14b) (step 7).

[0138]

Embedded image

The ester-amide derivative (14)
The physical properties of b) are as follows.

Brown transparent liquid ¹ H-NMR (CDCl ₃ , δ); 0.88 (brt,
J = 6.4 Hz, 6H), 1.26 to 1.83 (m, 5
6H), 2.03 to 2.20 (m, 6H), 2.33.
(T, J = 7.1 Hz, 2H), 3.12 to 4.35
(M, 15H), 3.32 (s, 3H), 5.04-
5.43 (m, 1H).

In a 200 ml four-necked flask equipped with a stirrer and a nitrogen inlet tube, 33.9 g (43.2 mmol) of the compound (14b) obtained in the above (Step 7) and 0.42 g of a 28% methanol solution of sodium methoxide. (2.16
mmol) and 200 ml of methanol, and stirred at room temperature for 3.5 hours under a nitrogen atmosphere. While heating the reaction mixture,
The mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 16.0 g (yield 53%) of the target amide derivative (1b) (step 8).

The compound (2) obtained in the above (Step 2) was placed in a 3-liter 4-neck flask equipped with a stirrer and a nitrogen inlet tube.
b) 45.2 g (72.0 mmol), 2.86 g (119.2 mmol) of sodium hydride and 800 ml of toluene were charged, and the mixture was stirred at 55 ° C. for 30 minutes under a nitrogen atmosphere. Next, 34.8 g (121.5 mmol) of 1,2-isopropylidenedioxy-3-tosyloxypropane was added thereto, and the mixture was stirred at 100 ° C. for 18 hours. The reaction mixture was added with 20 ml of 2-propanol under ice cooling to inactivate unreacted sodium hydride, and then concentrated under reduced pressure under heating. The obtained residue was purified by silica gel column chromatography to obtain 51.0 g (96% yield) of a 1,3-dioxolane-amide derivative (16b) (Step 1).
1).

[0143]

Embedded image

The physical properties of the obtained 1,3-dioxolan-amide derivative (16b) are as follows.

Colorless transparent liquid ¹ H-NMR (CDCl ₃ , δ); 0.88 (brt,
J = 6.4 Hz, 6H), 1.20 to 1.90 (m, 6
2H), 2.36 (t, J = 7.0 Hz, 2H), 3.
30-4.25 (m, 19H).

The compound (1) obtained in the above (Step 11) was placed in a 2-liter 4-neck flask equipped with a stirrer and a nitrogen inlet tube.
6b) 51.0 g (68.9 mmol), 0.50 g (2.63 mmol) of tosylic acid monohydrate and 500 ml of methanol
And stirred at room temperature under a nitrogen atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure while heating, and the obtained residue was purified by silica gel column chromatography to give 41.0 g of the desired amide derivative (1b) (yield: 85%).
%) (Step 10).

Production Example 4 A reaction was carried out in the same manner as in Production Example 1 except that methyl dodecanoate was used instead of methyl tetradecanoate in Step 2 of Production Example 1, and the amide derivative (2
c) was obtained (steps 1 and 2).

[0148]

Embedded image

The physical properties of the obtained amide derivative (2c) are as follows.

Colorless transparent liquid IR (ν _neat , cm ^-1 ); 3435, 2930, 285
5,1620,1470,1220,1110,72
0. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (br t,
J = 6.4 Hz, 6H), 1.20 to 1.90 (m, 4
9H), 2.36 (t, J = 7.6 Hz, 2H), 3.
25-3.52 (m, 10H), 3.33 (s, 3
H), 3.88-3.95 (m, 1H).

In Step 5 of Production Example 1, compound (2
Instead of a), the compound (2c) obtained in the above (Step 2)
The reaction was carried out in the same manner as in Step 5 of Production Example 1 except that was used to obtain an amide derivative (3c) (Step 5).

[0152]

Embedded image

The physical properties of the obtained amide derivative (3c) are as follows.

Pale yellow liquid IR (ν _neat , cm ^-1 ); 2940, 2875, 175
0, 1650, 1470, 1380, 1210, 112
0,910,845. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (br t,
J = 6.4 Hz, 6H), 1.15 to 1.45 (m, 4
2H), 1.45 to 1.75 (m, 4H), 1.75 to
1.90 (m, 2H), 2.25 to 2.50 (m, 2
H), 2.50 to 2.68 (m, 1H), 2.70 to
2.85 (m, 1H), 3.00 to 3.18 (m, 1
H), 3.18-4.00 (m, 13H), 3.32.
(S, 3H).

In Step 7 of Production Example 1, compound (3
The reaction was carried out in the same manner as in Steps 7 and 8 of Production Example 1 except that the compound (3c) obtained in the above (Step 5) was used instead of a) to obtain the desired amide derivative (1c) ( Step 7
And 8).

[0156]

Embedded image

The physical properties of the obtained amide derivative (1c) are as follows.

Colorless transparent liquid IR (ν _neat , cm ^-1 ); 3430, 2930, 286
0, 1650, 1630, 1470, 1380, 126
0,1210,1115,1080,795,720. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (br t,
J = 6.7 Hz, 6H), 1.15 to 1.45 (m, 4
2H), 1.45 to 1.97 (m, 8H), 2.25 to
2.45 (m, 2H), 3.15 to 3.92 (m, 16
H), 3.33 (s, 3H).

Production Example 5 In step 2 of Production Example 1, instead of methyl tetradecanoate, Lunac P-70 (manufactured by Kao Corporation) (weight ratio of tetradecanoic acid, hexadecanoic acid, octadecanoic acid: 3: 7)
0:27) under heating and refluxing with methanol in the presence of a sulfuric acid catalyst.
The reaction was carried out in the same manner as in Steps 1 and 2 of Production Example 1 except that the methyl ester of -70 was used, and the amide derivative (2
d) was obtained (steps 1 and 2).

[0160]

Embedded image

The physical properties of the obtained amide derivative (2d) are as follows.

White solid Melting point: 50 ° C. IR (ν _neat , cm ⁻¹ ): 3430, 2930, 286
0,1620,1470,1205,1110,95
0,720.

In Step 11 of Production Example 3, compound (2)
The reaction is carried out using the compound (2d) obtained in the above (Step 2) instead of b), and the obtained 1,3-dioxolan-amide derivative (16d) is purified in the next step 10 without purification.
The reaction was carried out in the same manner as in Steps 11 and 10 of Production Example 3 except that the above reaction was carried out to obtain the desired amide derivative (1d) (Steps 11 and 10).

[0164]

Embedded image

The physical properties of the obtained amide derivative (1d) are as follows.

White solid Melting point: 32 ° C. IR (ν _neat , cm ⁻¹ ); 3445, 2930, 286
0, 1650, 1630, 1470, 1380, 121
0, 1120, 1080, 720.

Production Example 6 The reaction was carried out in the same manner as in Production Example 1, except that octadecyl glycidyl ether was used instead of hexadecyl glycidyl ether. (Step 1).

[0168]

Embedded image

The amino alcohol derivative (4e) obtained
Its physical properties are as follows.

Melting point: 57-58 ° C IR (ν _neat , cm ^-1 ); 3340, 2930, 285
5,1470,1120,960,900,840,7
20. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (t, J =
6.3 Hz, 3H), 1.25 to 1.45 (m, 30
H), 1.45 to 1.85 (m, 6H), 2.55 to
2.75 (m, 4H), 3.32 (s, 3H), 3.3
5 to 3.50 (m, 6H), 3.77 to 3.89 (m,
1H).

In Step 2 of Production Example 1, compound (4
The reaction was carried out in the same manner as in Step 2 of Production Example 1, except that the compound (4e) obtained in the above (Step 1) was used instead of a).
An amide derivative (2e) was obtained (Step 2).

[0172]

Embedded image

The physical properties of the obtained amide derivative (2e) are as follows.

White solid Melting point: 49 ° C. IR (ν _neat , cm ⁻¹ ); 3440, 2930, 286
0, 1650, 1625, 1470, 1225, 121
0, 1110, 950, 720. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (br t,
J = 6.3 Hz, 6H), 1.15 to 1.95 (m, 5
7H), 2.36 (t, J = 7.5 Hz, 2H), 3.
30 to 3.55 (m, 10H), 3.33 (s, 3
H), 3.85 to 3.95 (m, 1H).

In Step 5 of Production Example 1, compound (2
The reaction was carried out in the same manner as in Step 5 of Production Example 1, except that the compound (2e) obtained in the above (Step 2) was used instead of a).
An amide derivative (3e) was obtained (Step 5).

[0176]

Embedded image

The physical properties of the obtained amide derivative (3e) are as follows.

Colorless transparent liquid IR (ν _neat , cm ⁻¹ ); 2930, 2860, 165
0,1425,1380,1260,1210,112
0,910,720. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (br t,
J = 6.0 Hz, 6H), 1.10 to 1.45 (m, 5
0H), 1.45 to 1.90 (m, 6H), 2.25 to
2.50 (m, 2H), 2.50 to 2.68 (m, 1
H), 2.70 to 2.85 (m, 1H), 3.01 to
3.20 (m, 1H), 3.20 to 4.00 (m, 13
H), 3.32 (s, 3H).

In Step 7 of Production Example 1, compound (3
The reaction was carried out in the same manner as in Steps 7 and 8 of Production Example 1 except that the compound (3e) obtained in the above (Step 5) was used instead of a), to obtain an intended amide derivative (1e) ( Step 7
And 8).

[0180]

Embedded image

The physical properties of the obtained amide derivative (1e) are as follows.

Melting point: 23 ° C. IR (ν _neat , cm ⁻¹ ); 3425, 2930, 286
0, 1650, 1630, 1470, 1380, 122
0,1210,1120,720. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (br t,
J = 6.7 Hz, 6H), 1.17 to 1.45 (m, 4
9H), 1.45 to 1.92 (m, 8H), 2.22 to
2.45 (m, 2H), 3.20 to 3.90 (m, 17
H), 3.33 (s, 3H).

Production Example 7 The procedure of Production Example 1 was repeated except that, in place of the compound (4a), the compound (4e) obtained in the step 1 of Production Example 6 was replaced with methyl hexadecanoate instead of methyl tetradecanoate. Was reacted in the same manner as in Step 2 of Production Example 1 to obtain an amide derivative (2f) (Steps 1 and 2).

[0184]

Embedded image

The physical properties of the obtained amide derivative (2f) are as follows.

White solid Melting point: 54 to 55 ° C. IR (ν _neat , cm ⁻¹ ); 3430, 2930, 285
5,1620,1470,1220,1205,111
0,950,885,720. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (br t,
J = 6.4 Hz, 6H), 1.25 to 1.95 (m, 6
1H), 2.36 (t, J = 7.6 Hz, 2H), 3.
29-3.52 (m, 10H), 3.33 (s, 3
H), 3.88-3.95 (m, 1H).

In Step 5 of Production Example 1, compound (2
The reaction was carried out in the same manner as in Step 5 of Production Example 1, except that the compound (2f) was used instead of the a), to give an amide derivative (3f)
Was obtained (step 5).

[0188]

Embedded image

The physical properties of the obtained amide derivative (3f) are as follows.

White solid Melting point: 45 to 47 ° C. IR (ν _neat , cm ⁻¹ ); 2930, 2860, 165
0, 1470, 1425, 1380, 1210, 112
0,910,845,755,720. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (br t,
J = 6.7 Hz, 6H), 1.15 to 1.45 (m, 5
4H), 1.45 to 1.73 (m, 4H), 1.73-
1.90 (m, 2H), 2.25 to 2.48 (m, 2
H), 2.50 to 2.68 (m, 1H), 2.70 to
2.85 (m, 1H), 3.00 to 3.18 (m, 1
H), 3.18-4.00 (m, 13H), 3.32.
(S, 3H).

In Step 7 of Production Example 1, compound (3
The reaction was carried out in the same manner as in Steps 7 and 8 of Production Example 1, except that the compound (3f) obtained in the above (Step 5) was used instead of a), to obtain an intended amide derivative (1f) ( Step 7
And 8).

[0192]

Embedded image

The physical properties of the obtained amide derivative (1f) are as follows.

White solid Melting point; 35 ° C. IR (ν _neat , cm ⁻¹ ); 3445, 2930, 286
0, 1650, 1630, 1470, 1420, 138
0, 1305, 1210, 1120, 1080. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (br t,
J = 6.4 Hz, 6H), 1.15 to 1.45 (m, 5
4H), 1.45 to 1.95 (m, 7H), 2.25 to
2.55 (m, 3H), 3.20 to 3.95 (m, 16
H), 3.33 (s, 3H).

Production Example 8 The reaction was carried out in the same manner as in Production Example 1, except that tetradecyl glycidyl ether was used instead of hexadecyl glycidyl ether. Was obtained (step 1).

[0196]

Embedded image

The obtained amino alcohol derivative (4 g)
Its physical properties are as follows.

Melting point: 47 ° C. IR (ν _neat , cm ⁻¹ ); 3340, 2930, 285
5,1470,1310,1120,1065,99
5,900,720. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (t, J =
6.3 Hz, 3H), 1.25 to 1.45 (m, 26
H), 1.45 to 1.85 (m, 6H), 2.57 to
2.75 (m, 4H), 3.32 (s, 3H), 3.3
8 to 3.48 (m, 6H), 3.75 to 3.88 (m,
1H).

In Step 2 of Production Example 1, compound (4
Compound (4 g) obtained in the above (Step 1) instead of a)
Was reacted in the same manner as in Step 2 of Production Example 1 except that methyl hexadecanoate was used instead of methyl tetradecanoate to obtain an amide derivative (2 g) (Step 2).

[0200]

Embedded image

The physical properties of the obtained amide derivative (2 g) are as follows.

Melting point: 47 ° C. IR (ν _neat , cm ⁻¹ ): 3440, 2930, 285
5,1620,1470,1205,1110,95
0,720. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (br t,
J = 6.4 Hz, 6H), 1.26 to 1.89 (m, 5
2H), 2.36 (t, J = 7.6 Hz, 2H), 3.
29-3.52 (m, 11H), 3.33 (s, 3
H), 3.88-3.95 (m, 1H).

In Step 5 of Production Example 1, compound (2
Instead of a), the compound (2 g) obtained in the above (Step 2)
The reaction was carried out in the same manner as in Step 5 of Production Example 1 except that was used to obtain an amide derivative (3 g) (Step 5).

[0204]

Embedded image

The physical properties of the obtained amide derivative (3 g) are as follows.

Colorless transparent liquid IR (ν _neat , cm ^-1 ); 2930, 2860, 165
0, 1470, 1425, 1380, 1210, 112
0,910,845,755,720. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (br t,
J = 6.7 Hz, 6H), 1.15 to 1.45 (m, 4
6H), 1.45 to 1.73 (m, 4H), 1.73-
1.90 (m, 2H), 2.25 to 2.50 (m, 2
H), 2.50 to 2.68 (m, 1H), 2.70 to
2.85 (m, 1H), 3.00 to 3.18 (m, 1
H), 3.18-4.00 (m, 13H), 3.32.
(S, 3H).

In Step 7 of Production Example 1, compound (3
Instead of a), the compound obtained above (step 5) (3 g)
The reaction was carried out in the same manner as in Steps 7 and 8 of Production Example 1 except for using, to obtain the desired amide derivative (1 g) (Steps 7 and 8).

[0208]

Embedded image

The physical properties of the obtained amide derivative (1 g) are as follows.

Melting point: 27 ° C. IR (ν _neat , cm ⁻¹ ): 3445, 2930, 286
0, 1650, 1630, 1470, 1420, 138
0, 1305, 1210, 1120, 1080, 72
0. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (br t,
J = 6.4 Hz, 6H), 1.15 to 1.45 (m, 4
5H), 1.45 to 1.93 (m, 7H), 2.20 to
2.60 (m, 3H), 3.20 to 3.90 (m, 17
H), 3.33 (s, 3H).

Production Example 9 The reaction was carried out in the same manner as in Production Example 1, except that 2-methoxyethylamine was used in place of 3-methoxypropylamine in the same manner as in Production example 1, and the amino alcohol derivative (4h ) Was obtained (Step 1).

[0212]

Embedded image

The obtained amino alcohol derivative (4h)
Its physical properties are as follows.

White solid Melting point: 54 to 55 ° C. IR (ν _neat , cm ⁻¹ ); 3430, 2920, 285
5,1470,1120,1065,900,720. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (t, J =
6.3 Hz, 3H), 1.25 to 1.70 (m, 30
H), 2.57-2.76 (m, 4H), 3.32.
(S, 3H), 3.38-3.48 (m, 6H), 3.
77-3.89 (m, 1H).

In Step 2 of Production Example 1, compound (4
Compound (4h) obtained in the above (Step 1) instead of a)
Was reacted in the same manner as in Step 2 of Production Example 1 except that methyl hexadecanoate was used instead of methyl tetradecanoate to obtain an amide derivative (2h) (Step 2).

[0216]

Embedded image

The physical properties of the obtained amide derivative (2h) are as follows.

White solid Melting point: 51 to 52 ° C IR (ν _neat , cm ^-1 ); 3420, 2920, 285
5,1620,1470,1110,720. _{^{1 H-NMR (CDCl 3,}} δ); 0.87 (t, J =
6.4 Hz, 6H), 1.15 to 1.70 (m, 55
H), 2.25 to 2.50 (m, 2H), 3.20 to
4.00 (m, 11H), 3.34 (s, 3H).

In Step 5 of Production Example 1, compound (2
The reaction was carried out in the same manner as in Step 5 of Production Example 1, except that the compound (2h) obtained in the above (Step 2) was used instead of a).
An amide derivative (3h) was obtained (Step 5).

[0220]

Embedded image

The physical properties of the obtained amide derivative (3h) are as follows.

Colorless transparent liquid IR (ν _neat , cm ⁻¹ ); 2930, 2855, 165
0, 1470, 1420, 1380, 1310, 125
0, 1190, 1120, 910, 850, 720. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (br t,
J = 6.4 Hz, 6H), 1.13 to 1.45 (m, 5
0H), 1.45 to 1.70 (m, 4H), 2.30 to
2.50 (m, 2H), 2.50 to 2.70 (m, 1
H), 2.70 to 2.85 (m, 1H), 3.00 to
3.20 (m, 1H), 3.20 to 4.00 (m, 13
H), 3.32 (s, 3H).

In Step 6 of Production Example 1, compound (3
The reaction was carried out in the same manner as in Step 6 of Production Example 1 except that the compound (3h) obtained in the above (Step 5) was used instead of a),
The desired amide derivative (1h) was obtained (Step 6).

[0224]

Embedded image

The physical properties of the obtained amide derivative (1h) are as follows.

Melting point; 31 to 32 ° C. IR (ν _neat , cm ⁻¹ ); 3450, 2930, 286
0, 1630, 1470, 1380, 1300, 119
0, 1160, 720. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (t, J =
6.4 Hz, 6H), 1.15 to 1.75 (m, 54
H), 2.20 to 2.45 (m, 3H), 3.20 to
3.90 (m, 17H), 3.33 (s, 3H).

In Step 11 of Production Example 3, compound (2)
The reaction was carried out in the same manner as in Step 11 of Production Example 3 except that the compound (2h) obtained in the above (Step 2) was used instead of b) to obtain a 1,3-dioxolan-amide derivative (16h). (Step 11).

[0228]

Embedded image

The physical properties of the obtained 1,3-dioxolan-amide derivative (16h) are as follows.

Colorless transparent liquid ¹ H-NMR (CDCl ₃ , δ); 0.88 (t, J =
6.4 Hz, 6H), 1.15 to 1.70 (m, 54
H), 1.34 (s, 3H), 1.40 (s, 3H),
2.36 (t, J = 7.0 Hz, 2H), 3.25-
4.30 (m, 19H).

In Step 10 of Production Example 3, compound (1)
The compound (16) obtained in the above (Step 11) in place of 6b)
The reaction was carried out in the same manner as in Step 11 of Production Example 3 except for using h) to obtain the desired amide derivative (1h) (Step 10).

Production Example 10 The reaction was carried out in the same manner as in Production Example 1, except that ethylamine was used in place of 3-methoxypropylamine in Production method 1, and the amino alcohol derivative (4i) was obtained. (Step 1).

[0233]

Embedded image

The obtained amino alcohol derivative (4i)
Its physical properties are as follows.

Melting point: 60-61 ° C IR (ν _neat , cm ^-1 ); 3400, 2930, 285
5,1470,1310,1110,955,720. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (t, J =
6.4 Hz, 3H), 1.11 (t, J = 7.2 Hz,
3H), 1.15 to 1.70 (m, 30H), 2.55
~ 2.80 (m, 4H), 3.35 to 3.53 (m, 4
H), 3.79-3.93 (m, 1H).

In Step 2 of Production Example 1, compound (4
Compound (4i) obtained in the above (Step 1) instead of a)
Was reacted in the same manner as in Step 2 of Production Example 1 except that methyl hexadecanoate was used instead of methyl tetradecanoate to obtain an amide derivative (2i) (Step 2).

[0237]

Embedded image

The physical properties of the obtained amide derivative (2i) are as follows.

White solid Melting point; 56 ° C. IR (ν _neat , cm ⁻¹ ); 3410, 2930, 286
0, 1625, 1470, 1380, 1305, 124
5,1210,1110,950,855,720. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (t, J =
6.4 Hz, 6H), 1.15 to 1.75 (m, 57
H), 2.34 (t, J = 7.6 Hz, 2H), 3.3
0 to 3.55 (m, 9H), 3.85 to 4.00 (m,
1H).

In Step 5 of Production Example 1, compound (2
The reaction was carried out in the same manner as in Step 5 of Production Example 1, except that the compound (2i) obtained in the above (Step 2) was used instead of a).
The amide derivative (3i) was obtained (Step 5).

[0241]

Embedded image

The physical properties of the obtained amide derivative (3i) are as follows.

Colorless transparent liquid IR (ν _neat , cm ^-1 ); 2930, 2855, 165
0, 1470, 1425, 1380, 1210, 112
0,905,840,720. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (br t,
J = 6.4 Hz, 6H), 1.10 to 1.75 (m, 5
7H), 2.25 to 2.50 (m, 2H), 2.50
2.70 (m, 1H), 2.70 to 2.85 (m, 1
H), 3.0-4.00 (m, 12H).

In Step 6 of Production Example 1, compound (3
The reaction was carried out in the same manner as in Step 6 of Production Example 1, except that the compound (3i) obtained in the above (Step 5) was used instead of a).
The desired amide derivative (1i) was obtained (Step 6).

[0245]

Embedded image

The physical properties of the obtained amide derivative (1i) are as follows.

White solid Melting point: 35 to 36 ° C. IR (ν _neat , cm ⁻¹ ); 3445, 2930, 286
0, 1630, 1470, 1420, 1380, 130
5,1210,1120,720. _{^{1 H-NMR (CDCl 3,}} δ); 0.88 (br t,
J = 6.4 Hz, 6H), 1.13 to 1.75 (m, 5
7H), 2.31 (t, J = 7.5 Hz, 2H);
20-3.90 (m, 16H).

Examples 1 to 10 Cosmetics having the composition shown in Table 1 were produced by a conventional method, and the skin permeability and the effect of improving skin roughness of the amide compound used as a humectant were evaluated. Table 1 shows the results.

(Evaluation Method) (1) Skin Permeability: A fixed amount of the cosmetic was applied to the skin surface of a washed Yucatan micropig, and the skin was kept in a constant temperature room (temperature: 37).
℃, humidity: saturated). After a certain period of time, the unpermeated components remaining on the skin surface were removed, and the permeated components were extracted and collected, and the percutaneous absorption of the amide compound was measured by HPLC. The percutaneous absorption was expressed as a value per unit area (μg / cm ² ).

(2) Skin roughening improving effect: Ten women, aged 20 to 50, who have rough skin on their cheeks in winter, are subjected to different skin external preparations on their left and right cheeks for two weeks. 2
The next day after the completion of the weekly application, the rough skin was visually observed and judged according to the following criteria. The score was shown as an average value.

0: No rough skin is recognized 1: Slight rough skin is recognized 2: Skin rough is recognized 3: Severe rough skin is recognized 4: Severe rough skin is recognized

[0252]

[Table 1]

As is evident from the results in Table 1, all the cosmetics containing the percutaneous absorption enhancer of the present invention had a high skin penetration amount of the amide derivative and were excellent in the effect of improving skin roughness. In addition, skin irritation was low and the feeling of use was good.

Examples 11 to 20 Cosmetics having the composition shown in Table 2 were produced by a conventional method.
The skin permeability and the effect of improving skin roughness were evaluated in the same manner as described above. Table 2 shows the results.

[0255]

[Table 2]

As is clear from the results in Table 2, all the cosmetics containing the percutaneous absorption enhancer of the present invention had a high skin penetration amount of the amide derivative and were excellent in the effect of improving skin roughness. In addition, skin irritation was low and the feeling of use was good.

Examples 21 to 22 Cosmetics having the composition shown in Table 3 were produced by a conventional method.
The effect of improving skin roughness was evaluated in the same manner as described above. Table 3 shows the results.

[0258]

[Table 3]

As is evident from the results in Table 3, all the cosmetics containing the percutaneous absorption enhancer of the present invention had an enhanced skin permeation amount of the humectant and were excellent in the effect of improving skin roughness. . In addition, skin irritation was low and the feeling of use was good.

Examples 23 to 32 Cosmetics having the compositions shown in Tables 4 and 5 were produced by a conventional method.
The skin penetration of a spiro ether compound as a whitening agent was evaluated in the same manner as in Examples 1 to 10. Tables 4 and 5 show the results.
Shown in

[0261]

[Table 4]

[0262]

[Table 5]

As is clear from Tables 4 and 5, all of the cosmetics containing the percutaneous absorption enhancer of the present invention have a high skin penetration amount of the spiroether compound and are excellent in whitening effect. Was. Furthermore, the safety was high and the feeling of use was good.

Examples 33 to 34 Whitening cosmetics having the compositions shown in Table 7 were produced by a conventional method. For these whitening cosmetics, the skin penetration of the spiroether compound was tested in the same manner as in Examples 1 to 10, and the whitening effect was tested by the following method. Table 7 shows the results.

(Whitening Effect Test for UV-B-Induced Pigment Spots) The inner arm of 20 healthy male subjects was irradiated with ultraviolet rays in the UV-B region twice the minimum erythema dose once a day for 2 days. The whitening effect by continuously applying the sample to the test site twice a day on the induced pigment spots for one month was examined. The evaluation was performed using a color difference meter (manufactured by Minolta, CR-300), the L ^* value was calculated from the obtained Munsell value, and the ΔΔL ^* value representing the recovery was used. Note that ΔΔL ^*
The values were defined as follows: The sample application test site and the sample uncoated test site of the sample application immediately before the L ^* value, respectively L _0, L _{0 ',} each of the sites in the L ^* values after each successive coating 1 month L _1, L _1', ΔΔL ^* was expressed by the following equation.

[0266]

ΔL ^* = (L ₁ −L ₀ ) − (L _{1 ′} −L _{0 ′} )

The evaluation was shown by the average of the evaluation points of 20 subjects. Table 6 shows the relationship between the evaluation points and the criteria.

[0268]

[Table 6]

[0269]

[Table 7]

Examples 35 to 37 Cosmetics having the compositions shown in Table 8 were produced by a conventional method.
The whitening effect was evaluated in the same manner as in 3-34. Table 8 shows the results.

[0271]

[Table 8]

Examples 38 to 40 Cosmetics having the compositions shown in Table 9 were produced by a conventional method, and their anti-inflammatory effects were evaluated. Table 9 shows the results.

(Evaluation method) UV-B was applied to the inner part of the upper arm of 20 healthy male subjects using a Toshiba FS-20SE lamp.
The region was irradiated once with twice the amount of minimal erythema (2 MED). Immediately after that, 15 μl of each cosmetic was applied and 24
After the time, redness (a ^* value) and skin temperature were measured. Redness was measured using a color difference meter (manufactured by Minolta, CR-300), and the a ^* value was calculated from the obtained Munsell value. UV-
The Δa ^* value was defined as how much a ^* after 24 hours of B irradiation increased from the a ^* value before UV-B irradiation. The skin temperature was measured using a radiation thermometer (Tasco Japan, THI-5).
00). The results were shown as average values.

[0274]

[Table 9]

Continued on the front page (72) Inventor Jun Nakajima 2-1-3 Bunka, Sumida-ku, Tokyo Inside Kao Corporation Research Laboratory (72) Inventor Yumiko 2-1-3 Bunka, Sumida-ku, Tokyo Kao Corporation (72) Inventor Tomoyuki Yamamoto 2-1-3 Bunka, Sumida-ku, Tokyo Kao Corporation Research Laboratory

Claims (3)

[Claims] 1. The method according to claim 1, wherein the solubility parameter δ is 15.7 <δ ≦.
17. A transdermal absorption enhancer containing an oil within the range of 17.2 as an active ingredient. 2. The solubility parameter δ is 15.7 <δ ≦.
An oil agent (a) in the range of 17.2, 17.5 ≦ δ ≦ 2
The percutaneous absorption enhancer according to claim 1, which is a combination of an oil agent (b) in the range of 1.0. 3. The oil agent (a) and (b) are added in a weight ratio of (a) /
The percutaneous absorption enhancer according to claim 2, wherein (b) is a combination in the range of 10/1 to 1/2.