CN1219549C

CN1219549C - Skin-permeated absorption-promoting agent and cosmetics thereof

Info

Publication number: CN1219549C
Application number: CNB971226873A
Authority: CN
Inventors: 西坂崇宏; 山崎诚司; 河上恭子; 佐藤弓子; 山本知幸; 中岛淳
Original assignee: Kao Corp
Current assignee: Kao Corp
Priority date: 1996-11-15
Filing date: 1997-11-14
Publication date: 2005-09-21
Anticipated expiration: 2017-11-14
Also published as: TWI238066B; CN1190597A

Abstract

This invention relates to percutaneous absorption promoting agents (a) comprising oils with a solubility parameter delta in a range of 15.7 < delta <= 17.2 as their effective contents, and cosmetic compositions comprising such content (a) and materials (b) having whitening, antiphlogistic and wetting effects. This percutaneous absorption promoting agent is able to promote the percutaneous absorptivity of the effective contents remarkably when they are used on skin externally, and has little stimulation on skin, thus has excellent safety.

Description

Percutaneous absorption enhancer and cosmetics

The present invention is about the percutaneous absorbability of the effective ingredient that can promote external preparation for skin and to the Percutaneous absorption enhancer that zest is low, safety is good of skin and the cosmetics that used this promoter.

In the past, in skin preparations for extenal use such as cosmetics, the composition as by effects such as Transdermal absorption performance moisture-keeping function, whitening function, antiinflammations had used various materials.Yet, because itself having as defence, the outermost horny layer of skin come exogenic foreign body to invade the physiological function of barrier, so just simply relevant material is fitted in the external agent, be can not obtain abundant percutaneous absorbability, can not show the original effect of this composition.Even and show the material of very good effect by Transdermal absorption because the Transdermal absorption performance in horny layer is low, also often can not bring into play its original effect.

Therefore, used Percutaneous absorption enhancers such as dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, methyl decyl sulfoxide in recent years, purpose is to improve the percutaneous absorbability of various materials.Yet these Percutaneous absorption enhancers do not provide satisfied Transdermal absorption facilitation effect, and because erythema etc. is appearred by force and sometimes in skin irritation on skin, so, be not desirable especially aspect its effect, safety, the use.

Therefore, purpose of the present invention just is to provide and shows superior Transdermal absorption facilitation effect, and low to skin irritation, safe Percutaneous absorption enhancer and the cosmetics that used this promoter.

The present inventor has carried out the result of research with keen determination, the oil preparation that discovery has specific solubility parameter has good external preparation for skin composition Transdermal absorption facilitation, and it is low to skin irritation, if this oil preparation and the material with insulation effect, whitening function and antiinflammation are share, just can obtain improving superior cosmetics aspect the coarse effect of skin, whitening effect, the antiinflammatory effect.

That is, the object of the present invention is to provide with solubility parameter δ and be in oil preparation (a-1) in 15.7＜δ≤17.2 scopes as the Percutaneous absorption enhancer of effective ingredient.

The invention provides the oil preparation (a-1) and the δ that are in 15.7＜δ≤17.2 scopes with solubility parameter δ simultaneously and be in the Percutaneous absorption enhancer of the interior oil preparation (a-2) of 17.5≤δ≤21.0 scopes as effective ingredient.

The invention provides a kind of cosmetics simultaneously, it is characterized in that containing one or more the oil preparation of selecting (a) oil preparation (a-1) in solubility parameter δ is in 15.7＜δ≤21.0 scopes; And the material of (b) Pear Power effect, antiinflammation and moisture-keeping function.

In addition the present invention also provide composition (a) be by select the oil preparation that is in from (a-1) solubility parameter δ in 15.7＜δ≤17.2 scopes one or more oil preparation and the oil preparation in (a-2) solubility parameter δ is in 17.5≤δ≤21.0 scopes the above-mentioned cosmetics that combine of one or more the oil preparation selected.

Its solubility parameter of oil preparation (a-1) δ as effective ingredient is in 15.7＜δ≤17.2 scopes in the present invention.Here said solubility parameter is meant the yardstick of the intermiscibility between material, utilize the 3 yuan solubility parameters of following formula (i) by calculating Hansen can in the hope of.And every can (ii)～(iv) the obtaining by calculating formula on the right in the formula, these calculating formulas are to set up according to the molar attraction constant of Van Krevelen.

δ＝(δd ²+δp ²+δh ²) ^1/2 (i)

δ d; Item (disperseing item) by london dispersion force (Fan Dewaerli) derivation

δ p; Item (polarity item) by the molecular polarity derivation

δ h; Item (hydrogen bond item) by the hydrogen bond derivation

δd＝∑F _di/∑V _i (ii)

δp＝(∑F _pi ²) ^1/2/∑V _i (iii)

δh=(∑F _hi/∑V _i) ^1/2 (iv)

F _Di, F _Pi, F _HiMolar attraction constant V _iMolal volume

Though δ d, δ p, δ h can resemble above-mentioned according to the molar attraction constant (F of atomic group _Di, F _Pi, F _Hi), utilize formula (ii)～(iv) to calculate, be the value of determining by people such as Van Krevelen but molar attraction constant uses in the present invention; Molal volume (Vi) usefulness be the bulking value of the atomic group determined by Fedor.

The object lesson that such solubility parameter δ is in the oil preparation (a-1) in 15.7＜δ≤17.2 scopes has: Ethyl arachidonate., ethyl linolenate, isononyl isononanoate, different octyl palmitate, the linoleic acid isopropyl ester, different octyl pelargonate, linoleic acid oil alkene ester, different n-nonanoic acid isotridecyl ester, Ethyl linoleate, the isostearic acid isopropyl ester, sad isocetyl ester, arachic acid oil alkene ester, sad isooctadecane base ester, the different certain herbaceous plants with big flowers ester of trimethylace tonitric, the different certain herbaceous plants with big flowers ester of different n-nonanoic acid, arachic acid is along the docosene ester, oleic acid octyl group dodecyl ester, trimethylace tonitric isooctadecane base ester, isostearyl isostearate, isostearic acid isocetyl ester, arachic acid isooctadecane base ester, arachic acid octyl group dodecyl ester, acid isopropyl, the misery basic dodecyl ester of dimethyl-octa, the sad hexyl certain herbaceous plants with big flowers of dimethyl ester, myristic acid oil alkene ester, the arachic acid stearyl, ethyl oleate, oleic acid certain herbaceous plants with big flowers ester, stearic acid isocetyl ester, octyl stearate, stearic acid octyl group dodecyl ester, Palmic acid isooctadecane base ester, Palmic acid isocetyl ester, octyl palmitate, myristic acid isooctadecane base ester, myristic acid isocetyl ester, myristic acid isotridecyl ester, myristic acid octyl group dodecyl ester, lauric acid isooctadecane base ester, the own ester of isostearic acid, the isostearic acid myristin, the isostearic acid lauryl, the oleic acid stearyl, the oleic acid cetyl ester, isobutyl stearate, the Palmic acid isobutyl ester, isopropyl palmitate, the myristic acid monooctyl ester, the different certain herbaceous plants with big flowers ester of lauric acid, the isostearic acid butyl ester, the heptadecanoic acid monooctyl ester, isopropyl myristate, isoamyl laurate, lauric acid dissident ester, the neopentanoic acid myristin, the heptadecanoic acid isobutyl ester, the Palmic acid lauryl, myristic acid certain herbaceous plants with big flowers ester, ethyl stearte, ethyl palmitate, butyl myristate, lauric acid ethanol, methyl myristate, methyl laurate etc.Wherein, different n-nonanoic acid isotridecyl ester is best.

These oil preparationes (a-1) can be with one or more usefulness that combines.

The oil preparation that the oil preparation of one or more that select the oil preparation of one or more that select the preferred oil preparation (a-1) that uses in solubility parameter δ is in 15.7＜δ≤17.2 scopes among the present invention and the oil preparation (a-2) in solubility parameter δ is in 17.5≤δ≤21.0 scopes combines.

Here the solubility parameter δ that is used as composition (a-2) is in the interior oil preparation of 17.5≤δ≤21.0 scopes to be had: two n-nonanoic acid propylene glycol esters, certain herbaceous plants with big flowers diacid diisopropyl ester, tricaprylin, three certain herbaceous plants with big flowers acid glycerides, diisobutyl adipate, two certain herbaceous plants with big flowers acid DOPCP, two certain herbaceous plants with big flowers acid propylene glycol esters, dihexyl adipate, triacetyl ricinoleic acid glyceride, diisopropyl adipate, decanoin, three isostearic acids, two glyceride, certain herbaceous plants with big flowers two diethyl phthalates, single isostearic acid list myristic acid diglyceride, dibutyl adipate etc.Wherein, single isostearic acid list myristic acid diglyceride is the most desirable.

Composition (a-1) and composition (a-2) combination time spent, (a-1) preferably uses Crodamol TN as composition, preferably uses single isostearic acid list myristic acid diglyceride as composition (a-2).And also can share better with other oil preparation this moment.

Composition (a-1) and composition (a-2) the combination time spent, their weight ratio is in (a-1)/(a-2)=10/1～1/2, particularly is in 10/1～2/1 the scope better.

By share with composition of the present invention (a) " composition (a-1) independent or composition (a-1) and composition (b-1) combination ", as the composition that promotes percutaneous absorbability so long as be used for common skin preparations for extenal use, the composition of its effect of performance after the skin absorbs, not special restriction, for example wetting agent, whitening agent, antiinflammatory, UV absorbent, aminoacid, plant extract, singlet oxygen remover, thiooxidant, blood circulation promoting agent, cholesterol etc.

Wherein, as heat preserving agent (b-1), so long as the not special restriction of usefulness such as common cosmetics.For example saccharide, polyalcohols, amide compound, ceramide type etc.

Specifically, as saccharide, polyalcohols, for example there are ethylene glycol, glycerol, glucose, maltose, maltose alcohol, sucrose, fructose, xylitol, Sorbitol, maltotriose, threose alcohol, erythritol, amylolysis sugar to go back carbinol, Sorbitol, ethylene glycol, 1,4-butanediol, diglycerol, two triglycerols, three four glycerol, 1 that contract, 3-butanediol, propylene glycol, dipropylene glycol, Polyethylene Glycol, 1, ammediol etc.

And as amide compound, fusing point is 0～50 ℃, it is desirable to 10～40 ℃ chemical compound.If the chemical compound beyond this scope, the stable difficulty that cooperates in compositions.

In the present invention, fusing point is to begin temperature with the extrapolated melting point of measuring according to JIS-K7121-1987-9-9.1 (2) to represent.

As such amide compound, sour amide such as isostearic acid amide, different palmitamide, different myristic acid amide are for example arranged, and the amide derivatives of following general formula (1)～(3) expression etc.

(in the formula, R ¹And R ²Identical or different, the expression carbon number be 1～40 can be by hydroxylated alkyl, R ³Representing carbon number is 1～6 straight chain or alkylidene or the singly-bound that side chain is arranged, R ⁴Representing hydrogen atom, carbon number is 1～12 straight chain or the alkoxyl or 2 that side chain is arranged, 3-dihydroxy propoxyl group.But work as R ³When being singly-bound, R ⁴It is hydrogen atom.)

(in the formula, R ¹And R ²Representative and top identical implication, R ^3aRepresenting carbon number is 3～6 straight chain or the alkylidene that side chain is arranged, R ^4aRepresenting carbon number is 1～12 straight chain or the alkoxyl that side chain is arranged.)

(in the formula, R ¹, R ²And R ³Representative and top identical implication, R ^4bRepresenting hydrogen atom, carbon number is 1～12 straight chain or the alkoxyl or 2 that side chain is arranged, the 3-glycidoxy.But work as R ³When being singly-bound, R ^4bIt is hydrogen atom.)

Wherein, in amide derivatives (1), R ¹And R ²Identical or different, represent carbon number be the straight chain of 1-40 or have side chain saturated or undersaturated can be by hydroxylated alkyl.As R ¹, R ²It for example is methyl; ethyl; propyl group; butyl; amyl group; hexyl; heptyl; octyl group; nonyl; decyl; undecyl; dodecyl; tridecyl; myristyl; pentadecyl; cetyl; heptadecyl; octadecyl; nonadecyl; heneicosyl; docosyl; nonacosyl; melissyl; the isostearoyl base; different heptadecyl; the 2-ethylhexyl; 1-ethyl heptyl; the 8-heptadecyl; 8-heptadecene base; 8,11-17 carbon dialkylenes; 2-heptyl undecyl; 9-vaccenic acid base; 1-hydroxyl nonyl; 1-hydroxyl pentadecyl; 2-hydroxyl pentadecyl; 15-hydroxyl pentadecyl; 11-hydroxyl heptadecyl and 11-hydroxyl-8-heptadecene base etc.

As R ¹It is desirable to carbon number is 8～26 straight chain or alkyl or the alkenyl that side chain is arranged, for example octyl group, decyl, dodecyl, myristyl, cetyl, octadecyl, docosyl, melissyl, isostearoyl base, 2-ethylhexyl, 2-heptyl undecyl and 9-vaccenic acid base etc.As R ¹Optimal alkyl is that carbon number is 12～22 straight chain or the alkyl that side chain is arranged, for example dodecyl, myristyl, cetyl, octadecyl, docosyl and the isostearoyl base that has methyl branch.

As R ²It is desirable to carbon number is 9～25 straight chain or alkyl or the alkenyl that side chain is arranged, for example nonyl, undecyl, tridecyl, pentadecyl, heptadecyl, heneicosyl, nonadecyl, different heptadecyl, 1-ethyl heptyl, 8-heptadecyl, 8-heptadecene base, 8,11-17 carbon dialkylenes, 1-hydroxyl nonyl, 1-hydroxyl pentadecyl, 2-hydroxyl pentadecyl, 15-hydroxyl pentadecyl, 11-hydroxyl heptadecyl and 11-hydroxyl-8-heptadecene base etc.Optimal alkyl is that carbon number is 11～21 straight chain or the alkyl that side chain is arranged, for example undecyl, tridecyl, pentadecyl, heptadecyl, heneicosyl and have different heptadecyl of methyl branch etc.

R ³Representing carbon number is 1～6 straight chain or alkylidene or the singly-bound that side chain is arranged, as alkylidene, for example methylene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, 1-methyl ethylidene, 1-methyl propylidene, 2-methyl propylidene, 1,1-dimethyl ethylidene, 1-ethyl ethylidene, 1-methyl butylidene, 2-ethyl propylidene etc.R ³It is desirable to carbon number and be the alkylidene of 1～6 straight chain, it would be desirable methylene, ethylidene, propylidene.

R ⁴Representing hydrogen atom, carbon number is 1～12 straight chain or the alkoxyl or 2 that side chain is arranged, 3-dihydroxy propoxyl group.Alkoxyl is methoxyl group, ethyoxyl, propoxyl group, butoxy, hexyloxy, octyloxy, certain herbaceous plants with big flowers oxygen base, 1-methyl ethoxy and 2-ethyl hexyl oxy etc. for example.R ⁴It is desirable to hydrogen atom, carbon number and be 1～8 alkoxyl and 2,3-dihydroxy propoxyl group.Wherein, it would be desirable hydrogen atom, methoxyl group, ethyoxyl, propoxyl group, butoxy, 1-methyl ethoxy, 2-ethyl hexyl oxy and 2,3-dihydroxy propoxyl group.

As amide derivatives (1) preferably by R ¹, R ², R ³And R ⁴Be to be in the chemical compound that the moiety combinations of above-mentioned ideal range forms respectively.

And in amide derivatives (2), R ¹And R ²Representative and top identical implication, preferably same group.And as R ^3aCan be in amide derivatives (1), list from R ³In illustrative alkylidene remove other group of methylene and ethylidene.R ^3aIt is desirable to carbon number and be the alkylidene of 3～6 straight chain, wherein it would be desirable propylidene.As R ^4aAlkoxyl can list R with amide derivatives (1) ⁴Same group it is desirable to the same group.

R in amide derivatives (3) ¹, R ²And R ³Representative and top identical implication, R ^4hRepresenting hydrogen atom, carbon number is 1～12 straight chain or the alkoxyl or 2 that side chain is arranged, the 3-glycidoxy.As R ¹, R ²And R ³Specifically, can list and the same group of amide derivatives (1), it is desirable to the same group.As R ^4bCarbon number be that the straight chain of 1-12 or the alkoxyl that side chain is arranged can list the R with amide derivatives (1) ⁴Same group it is desirable to hydrogen atom or and R ⁴Same alkoxyl and 2, the 3-glycidoxy.

In these amide derivatives (1)～(3), it is desirable to chemical compound with general formula (1) expression.

Amide derivatives (1) for example can be made by following method for making 1 or method for making 2.

Method for making 1

(in the formula, R ¹, R ²And R ³Representative and top identical implication, R ^4fRepresenting hydrogen atom, carbon number is 1～12 straight chain or the alkoxyl that side chain is arranged.But work as R ³When being singly-bound, R ^4fIt is hydrogen atom.R ⁶, R ⁸, R ¹⁰And R ¹¹Representing carbon number is 1～8 straight chain or the saturated or undersaturated alkyl that side chain is arranged.It is desirable to carbon number is 1～5 straight chain or the alkyl that side chain is arranged, and it would be desirable methyl.R ⁹Represent hydrogen atom, alkali metal atom or COR ⁸Base, R ⁷And R ¹²Represent halogen atom, methanesulfonic acid base, p-methyl benzenesulfonic acid base etc. to break away from base.As R ⁷Being easy to get to calmly sets out can be chlorine atom and bromine atoms, and chlorine atom preferably is as R ¹²Preferably methanesulfonic acid base, the p-methyl benzenesulfonic acid base of setting out is easy to get to calmly.)

Method for making 2

(in the formula, R ¹, R ²And R ⁶～R ¹²Representative and top identical implication, R ^3gRepresenting carbon number is 1～6 straight chain or the alkylidene that side chain is arranged.)

The reaction condition of each operation of method for making 1 and method for making 2 is as follows.

Operation 1)

Make glycidyl ether (7) and amine (8F) or (8G) do not having solvent or at water or at lower alcohols such as methanol, ethanol, isopropyl alcohols, ether series solvents such as oxolane, dioxanes, glycol dimethyl ether, hydrocarbon system such as hexane, benzene,toluene,xylene solvent, or the reaction down in room temperature～150 ℃ in the mixed solvent of above these solvents, can make aminoalcohol derivative (4F) or (4G).

Operation 2)

Make fatty acid ester (9) it is desirable to fatty acid lower alkyl esters such as fatty acid methyl ester, fatty-acid ethyl ester at alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, alkali carbonates such as potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, base catalysts such as alkali metal alcoholates such as Feldalat NM, Sodium ethylate, potassium tert-butoxide exist down, under the decompression of normal pressure～0.001mmHg, room temperature～150 ℃ and aminoalcohol derivative (4F) or (4G) reaction can make amide derivatives (2F) or (2G).The consumption of base catalyst is with respect to aminoalcohol derivative (4F) or (4G) 0.01～0.2 equivalent preferably, if while react and will react the alcohol that generates and remove, reaction can be carried out fast, and this is optimal.

Operation 3)

Amide derivatives (2F) or (2G) also can be by following method manufacturing.Make fatty acyl ammonia not have solvent, or at aminoform, dichloromethane, 1, halogenated hydrocarbons series solvents such as 2-diamino ethane, ether series solvents such as oxolane, dioxanes, glycol dimethyl ether, hydrocarbon system such as hexane, benzene,toluene,xylene solvent, or exist under the condition of (or not existing) at alkali such as tertiary amine such as pyridine, triethylamines in the mixed solvent of above these solvents, ℃ following and aminoalcohol derivative (4F) or (4G) reaction in room temperature～100, convert amide-ester derivant (11F) or (11G) to, carry out operation 4 afterwards);

Operation 4)

At alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, alkali carbonates such as potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, under the alkali conditions such as alkali metal alcoholates such as Feldalat NM, Sodium ethylate, potassium tert-butoxide, amide-ester derivant (11F) or ester group (11G) are carried out hydrolysis selectively just can make amide derivatives (2F) or (2G).

Operation 5)

Make the normal epoxide of 1-20 (12), it is desirable to epoxychloropropane and do not having solvent, or water or tetrahydrofuran, dioxanes, ether series solvents such as glycol dimethyl ether, hexane, benzene, toluene, hydrocarbon system solvents such as dimethylbenzene, or in the mixed solvent of above these solvents, 1～10 normal potassium hydroxide is being arranged, alkali metal hydroxides such as sodium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, alkali carbonates such as potassium carbonate, under the existence of alkaline earth metal carbonates such as calcium carbonate, react with amide derivatives (2F) or (2G) down in room temperature～150 ℃, can make amide derivatives (3F) or (3G).This moment, aspects such as yield were better if react in the presence of alternate transfer catalysts such as trialkyl ammonium carboxylic acid inner salt such as quaternary ammonium salt, dodecyl dimethyl ammonium carboxylic acid inner salt such as Tetrabutylammonium bromide, tetrabutylammonium chloride, cetyltrimethylammonium chloride, cetrimonium bromide, Varisoft TSC, the two four hydroxyalkyl vinyl base stearyl trimethyl ammoniums of chlorination.

Operation 6)

At alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, alkali carbonates such as potassium carbonate, following or the mineral acids such as sulphuric acid, hydrochloric acid of alkali conditions such as alkaline earth metal carbonates such as calcium carbonate, lewis acid such as boron trifluoride, butter of tin, carboxylic acids such as acetic acid, ten tetra-carbonics, 16 carbonic acid, under the sulfonic acid acid conditions such as p-methyl benzenesulfonic acid, or under alkali-sour mixing condition, ℃ carry out water and reaction in room temperature～300, can make amide derivatives (1F) or (1G) to amide derivatives (3F) or (3G).

Operation 7)

Amide derivatives (1F) or (1G) also can obtain by the following method.Promptly, make carboxylic acid derivates (13), preferably lower aliphatic anhydride such as lower aliphatic acid alkali metal salt, acetic anhydride such as lower fatty acid, sodium acetate such as acetic acid are alone or in combination, be with or without tertiary amine base catalysts such as triethylamine in the presence of, react with amide derivatives (3F) or (3G), make it convert ester-acid amide derivant (14F) or (14G) to, carry out operation 8 afterwards);

Operation 8)

At alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, alkali such as potassium carbonate belong to carbonate entirely, alkaline earth metal carbonates such as calcium carbonate, under the alkali conditions such as alkali metal alcoholates such as Feldalat NM, Sodium ethylate, potassium tert-butoxide, amide-ester derivant (14F) or ester group (14G) are carried out hydrolysis selectively, also can make amide derivatives (1F) or (1G).

Operation 9)

Amide derivatives (1F) or (1G) also can obtain by the following method.Promptly, make carbonyl compound (15), preferably lower aliphatic such as acetone, butanone ketone is at mineral acids such as sulphuric acid, hydrochloric acid, phosphoric acid, carboxylic acids such as acetic acid, boron trifluoride, the existence of acid catalysts such as lewis acids such as tetrazotization stannum down and amide derivatives (3F) or (3G) react, make it convert 1 to, 3-dioxolanes-amide derivatives (16F) or (16G) carries out operation 10 afterwards);

Operation 10)

At mineral acids such as sulphuric acid, hydrochloric acid, phosphoric acid, carboxylic acids such as acetic acid under the sulfonic acid acid conditions such as p-methyl benzenesulfonic acid, to (16F) or (16G) carry out ketalization and also can make amide derivatives (1F) or (1G).

Operation 11)

1,3-dioxolanes-amide derivatives (16F) or (16G) also can obtain by the following method.Make glycerol derivatives at potassium hydroxide, alkali metal hydroxides such as sodium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, alkali carbonates such as potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, under the existence of alkali such as alkali metal hydride such as sodium hydride, under condition of no solvent, or at N, dinethylformamide, non-proton property such as dimethyl sulfoxide polar solvent, oxolane, dioxanes, ether series solvents such as glycol dimethyl ether, hexane, benzene, toluene, hydrocarbon system solvents such as dimethylbenzene, or in the mixed solvent of above these solvents, with amide derivatives (2F) or (2G) reaction make.

The amide derivatives that obtains like this (1) can utilize the known method purification.Among the present invention, no matter the purity with amide derivatives (1) is purified to 100%, and the purity of still not carrying out the by-product that contains intermediate product, reaction of special purification is 70～100% mixture, and its effect, performance are all very superior, and also no problem in the safety, can use.Also containing with the hydras in the amide derivatives (1) simultaneously is the solvate of representative.

The amide derivatives (1) that utilizes manufacture method 1 to obtain is exemplified below.

(implication of m and n is as follows: m+n=10～16, m=4～10, n=4～10, have the distribution as the summit with m=7, n=7.)

(m and n represent implication same as described above.) (m and n represent implication same as described above.)

The amide derivatives (1) that utilizes manufacture method 2 to obtain is exemplified below.

(R ²＝C ₁₇H ₃₅+C ₁₅H ₃₁+C ₁₃H ₂₇)

And as the preferably total carbon number of amide compound at the N substituted amide chemical compound more than 30.

In addition, preferably bound water is more than 1 weight % for amide compound, and it is above better to remain on 5 weight %.The content of bound water is tried to achieve as follows: at first measure in add water under the room temperature in sample, make sample can keep the maximum addition of homogeneous phase as combined water, represent the ratio of bound water gross weight with respect to the sample gross weight with percentage rate then, the content of bound water can be tried to achieve by following formula.

In addition, in the wetting agent of composition (A),, except the well-known chemical compound that provides with following general formula (4), also can enumerate the material of the similar ceramide structure of general formula (5) expression as the ceramide type material.

" in the formula, R ⁵And R ⁶Can be identical or different, the expression carbon number is 8～26 straight chain or the saturated or undersaturated alkyl that side chain is arranged.〗

In the general formula (4), R ⁵And R ⁶The alkyl of representative is that carbon number is 8～26 straight chain or the alkyl that side chain is arranged, no matter be saturated or undersaturated can.For example: octyl group; nonyl; decyl; undecyl; dodecyl; tridecyl; myristyl; pentadecyl; cetyl; heptadecyl; octadecyl; nonadecyl; eicosyl; heneicosyl; docosyl; tricosyl; tetracosyl; pentacosyl; cerul; the nonene base; the decene base; dodecenyl succinic; undecenyl; the tridecylene base; the tetradecene base; 15 carbene bases; the hexadecene base; the heptadecene base; the vaccenic acid base; 19 carbene bases; the eicosylene base; the heneicosene base; two dodecenyl succinic; the tricosene base; the tetracosa carbon thiazolinyl; the ppentacosene base; the cerotene base; the nonadiene base; the decadinene base; 12 carbon dialkylenes; 11 carbon dialkylenes; the oleatridecadiene base; 14 carbon dialkylenes; 15 carbon dialkylenes; 16 carbon dialkylenes; 17 carbon dialkylenes; 18 carbon dialkylenes; 19 carbon dialkylenes; 20 carbon dialkylenes; 21 carbon dialkylenes; 22 carbon dialkylenes, two oleatridecadiene bases; the tetracosa carbon dialkylene; 25 carbon dialkylenes; 26 carbon dialkylenes; 2-hexyl decyl; 2-octyl group undecyl; 2-decyl myristyl; isostearoyl base etc.These alkyl also can be replaced by more than one hydroxyl.

R ⁵Be the straight chained alkyl of 15～23 carbon, it is desirable to pentadecyl, heptadecyl and tricosyl, and R ⁶Be the saturated or undersaturated alkyl or the alkenyl of the straight chain of 16～23 carbon, preferably pentadecyl, heptadecyl and 15 carbene bases.

In the ceramide of general formula (4) expression, optimal chemical compound is the R in the general formula (4) ⁵And R ⁶It is the chemical compound of the moiety combinations of above-mentioned ideal range.

" in the formula, R ⁷Representing carbon number is 10～26 straight chain or the saturated or undersaturated alkyl that side chain is arranged, R ⁸Representing carbon number is 9～25 straight chain or the saturated or undersaturated alkyl that side chain is arranged, Y ¹And Z ¹Represent hydrogen atom or hydroxyl, a represents 0 or 1, and c represents 0～4 integer, and b and d represent 0～3 integer.〗

The material of these similar ceramide structures can be according to well-known method manufacturing " for example, Po..J.Chem.52,1059 (1978); With 52,1283 (1978); The spy opens clear 54-117421 communique, with the 54-144308 communique, with the 54-147937 communique, with the 62-228048 communique, with the 63-216852 communique ".

In the general formula (5), as R ⁷The carbon number of representative is 10～26 straight chain or the saturated or undersaturated alkyl that side chain is arranged, and can be above-mentioned R ⁵And R ⁶The carbon number of representative is 10～26 alkyl, as R ⁸The carbon number of representative is that 9～25 straight chain or the saturated or undersaturated alkyl that side chain is arranged also can be R ⁵And R ⁶The carbon number of representative is 10～26 alkyl.

As R ⁷Can be that carbon number is the saturated alkyl of 12～18 straight chain, preferably myristyl, cetyl and octadecyl; As R ⁸Can be that carbon number is the saturated alkyl of 9～18 straight chain, it is desirable to nonyl, pentadecyl and heptadecyl.In the material of the similar ceramide structure of general formula (5) expression, optimal chemical compound is the R in the general formula (5) ⁷And R ⁸It is the chemical compound of the moiety combinations of above-mentioned ideal range.

In addition, as whitening agent (b-2) is the material of Pear Power effect, so long as the material that common skin preparations for extenal use is used is not particularly limited, materials such as the plant extract of L-ascorbic acid and derivant thereof, hydroquinone derivative, kojic acid and derivant thereof, intacellin, Pear Power effect, spiral shell ether compound for example.

Can enumerate the following example.Be not particularly limited as L-ascorbic acid and derivant thereof, for example as the L-ascorbic acid phosphoric acid esters sodium salt of the univalent metal salt of L-ascorbic acid phosphoric acid esters, L-ascorbic acid phosphoric acid esters potassium salt, L-magnesium L-ascorbyl-2-phosphate salt as divalent metal salt, L-ascorbic acid phosphoric acid esters calcium salt, L-ascorbic acid phosphoric acid esters aluminum salt as trivalent metal salt, also has L-ascorbic acid sulfuric ester sodium salt as the univalent metal salt of L-ascorbic acid sulfuric ester, L-ascorbic acid sulfuric ester potassium salt, L-ascorbic acid sulfuric ester magnesium salt as divalent metal salt, L-ascorbic acid sulfuric ester calcium salt, L-ascorbic acid sulfate aluminium salt as trivalent metal salt, L-SODIUM ASCORBATE as the univalent metal salt of L-ascorbic acid, L-ascorbic acid potassium salt, L-ascorbic acid magnesium salt as divalent metal salt, L-ascorbic acid calcium salt, as L-ascorbic acid aluminum salt of trivalent metal salt etc.

Be not particularly limited as the hydroquinone derivative, for example the condensation substance of hydroquinone derivative and sugar, import the condensation substance of alkyl hydroquinone and sugar after a carbon number is 1～4 alkyl etc. to hydroquinone, wherein it would be desirable arbutin.

Be not particularly limited as kojic acid and derivant thereof, for example monoesters such as kojic acid, kojic acid only son acid esters, kojic acid list certain herbaceous plants with big flowers acid esters, kojic acid monopalmitate, kojic acid list stearyl, kojic acid list cinnamate, kojic acid mono benzoate, by diester such as sour dibutyrate, Kojic Acid Dipalmitate, kojic acid octacosyl ester, kojic acid two oily alkene esters.

Can use as the cosmetic material of market sale and the water solublity intacellin that utilizes as intacellin.For example can use with mammiferous Placenta Hominis such as cattle or pig or people etc. through cleaning, operations such as dehematize, pulverizing, lyophilization, extract water soluble ingredient, remove the extract that obtains behind the impurity again.

As the plant extract of Pear Power effect, Chamomile, tea, Anthemis, Flos Caryophylli, Radix Glycyrrhizae, Folium Eriobotryae, Pericarpium Citri junoris, koryo insam, Radix Paeoniae, Fructus Crataegi, Radix Ophiopogonis, Rhizoma Zingiberis Recens, jasmine, Cortex Mori, Cortex Magnoliae Officinalis, Herba Artemisiae Scopariae, catechu, gold, Aloe, Althaea rosea (L.) Cavan. rake for example arranged, embroider the floss chrysanthemum, Fructus Fragariae Ananssae, the peaceful skin of certain herbaceous plants with big flowers, コ Application Off リ-, Herba Rosmarini Officinalis, the extract of hyoscyami etc.

Wherein, chamomile extract is by with the colored water of Chamomile " Matricaria chamomilla L. (Compositae) " or methanol, ethanol, propanol, propylene glycol, 1, hydrophilic organic solvent or the extractions of their mixed solvent such as 3-butanediol, obtain its extracting solution, this extracting solution drying can be obtained exsiccant powder.Also can extract in addition and to obtain by the mixed solvent of hydrophilic organic solvent such as Oleum Ricini, almond oil, liquid paraffin, soybean oil, isopropyl myristate, lower fatty acid triglyceride, intermediate fatty acid triglycercide, Oleum helianthi, two capric acid DOPCP, three decanes or these solvents.Among the present invention, usefulness can combine above-mentioned one or more chamomile extracts.

In relevant chamomile extract, generally all comprise azulene (azulenes), chrysanthemum azulene, umbelliferone, ayapanin, matricin, Flos Matricariae chamomillae, taraxasterol, lupeol, celery glycosides, chromane, spiral shell ether etc.

Here, the best extracting method as chamomile extract has following method.

That is, Chamomile spent drying, chopping.Add three decanes then, stir every now and then from room temperature behind 50 ℃ of dippings, the squeezing separation obtains extracting solution.With behind the extracting liquid filtering as chamomile extract.

And for example be the chemical compound of following general formula (6) expression as the spiral shell ether compound.

" in the formula, wave represents no matter its bonding state is Z or E, any can "

Relevant spiral shell ether compound (6), for example there is the report can be from the Chamomile of Matricaria (pharmacognosy magazine 64 volumes, 384～388 pages, 1992), the spring chrysanthemum of Chrysanthemum (Agric.Biol.Chem.48 volume, the 1367-1369 page or leaf, 1984), Tanacetum, artemisia, several feverfews such as ロィカ Application セマ system genus obtain, and will separate through the chromatography of routine through the composition that solvent extraction, vapor distillation etc. obtains again.

This spiral shell ether compound (6) has melanic generation in the melanocyte of inhibition, the pigmentation that causes owing to outside stimuluss such as ultraviolet is reduced or disappearance, have superior prevention pigmentation and improve effect, simultaneously skin is had whitening function (spy opens flat 7-206657 communique etc.).

As antiinflammatory (b-3) is the material with antiinflammation, so long as the not special restriction that common skin preparations for extenal use is used, for example glycyrrhizic acid and salt thereof, glycyrrhetinic acid and salt thereof, isopropyl aminocaproic acid and salt thereof, allantoin, lysozyme chloride, heal skin ulcer Austria, methyl salicylate, γ-Hi-Z etc. wherein it is desirable to glycyrrhetinic acid, Stearyl glycyrrhetinate, episilon amino caproic acid.

With these compositions (b) be applied to skin after composition (a) mixes, can be very fast by skin absorbs.If be that the composition of purpose then can in depth infiltrate in the skin with the local action, bring into play its superior effect, in blood if be that the composition of purpose is because composition can circulate, so can bring into play same superior effect with the general action.Therefore, composition (a) and composition (b) being combined together can the original effect of remarkable enhancing ingredients (b).

The cooperation ratio of these compositions (b) cannot treat different things as the same because of the difference of its kind, purpose is different in cosmetics of the present invention, roughly is that the composition (a) with respect to 1 weight portion is 0.0001～10 weight portion, preferably 0.01～1 weight portion.

Though the use level of each constituent is different because of the kind of composition (b) in the cosmetics of the present invention, composition (a) generally accounts for 0.001～40 weight % of cosmetics total amount, it is desirable to 0.01～30 weight %.

Wetting agent (b-1) can it is desirable to account for 0.0001～15 weight % in whole compositions with a kind of or with two kinds of usefulness that combine, and is preferably 0.0001～10 weight %, and more preferably 0.0001～5 weight % is just better aspect usability.

The material of Pear Power effect (b-2) can be with a kind of or with two kinds of usefulness that combine, it is desirable to that their weight accounts for 0.0001～15 weight % in whole compositions, be preferably 0.0001～10 weight %, more preferably 0.0001～5 weight % is just better aspect usability.

In addition, when using plant extract, consider from whitening effect and stable aspect, be converted into behind the exsiccant solid constituent that shared ratio is 0.00001～5 weight % in whole composition, 0.0005～3 weight % preferably, be more preferably 0.001～2 weight %, can obtain sufficient whitening effect, moistening effect, prevention pachylosis and improve the effect of skin, usability and stable aspect just better.

Except mentioned component, in the scope of not damaging effect of the present invention, can suitably cooperate pharmaceuticals, external pharmaceuticals, cosmetics etc. such as oil content beyond aforementioned, organic acid, bases, surfactant, UV absorbent, powder body, pigment, dyestuff, anticorrosion and antifungus agent, antioxidant, chelating agen, viscosifier, spice, the water composition of usefulness usually in the cosmetics of the present invention.

Specifically, as oil content, as liquid paraffin, three decanes, higher fatty acids, higher alcohol etc.; As organic acid, as citric acid, lactic acid etc.; As bases, as caustic soda, triethanolamine etc.

And in the surfactant, as hydrophilic surfactant, polyoxyethylene sclerosis Semen Ricini oil or sclerosis Semen Ricini oil derivants such as the surfactant of nonionic such as polyoxyethylene Semen Ricini oil, polyoxyethylene sclerosis Semen Ricini oil, lauric acid polyoxyethylene sclerosis Semen Ricini oil, isostearic acid polyoxyethylene sclerosis Semen Ricini oil, polyoxyethylene sclerosis Semen Ricini oil pyroglutamic acid isostearic acid diester are for example arranged; Polyoxyethylene sorbitan fatty acid esters such as Tween-20, Tween-40, polyoxyethylene sorbitol acid anhydride list stearyl, polyoxyethylene sorbitol acid anhydride list isooctadecane base ester, polyoxyethylene sorbitol acid anhydride four oily alkene esters; The fatty acid ester of polyoxyethylene glycerol such as polyoxyethylene glycerol list stearyl, polyoxyethylene glycerol list isooctadecane base ester, polyoxyethylene glycerol three isooctadecane base esters; Polyoxyethylene alkyl ethers such as polyoxyethylene lauric acid ether, polyoxyethylene hexyl decyl ethers, Polyoxyethylene cetyl ether, polyoxyethylene 8 stearate ether, polyoxyethylene octyl group lauryl ether, polyoxyethylene docosyl ether, polyoxyethylene nonylplenyl ether, polyoxyethylene polyoxypropylene decyl four decyl ethers; The surfactant of polyoxyethylene add-on types such as polyoxyethylene fatty acid ester such as polyoxyethylene monooleate also has polyglycerol alkyl ether, polyglyceryl fatty acid ester, sucrose fatty acid ester etc. in addition.

In addition, as anionic surfactant, it is surfactant that laureth sulfates such as polyoxyethylene lauryl ether sulphuric acid triethanolamine are arranged; Lauroyl is a surfactant for N-acyl amino hydrochlorates such as sodium sarcosinate, lauroyl methylalanine sodium; The phosphate-based surfactants of polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether sodium phosphate, Polyoxyethylene cetyl ether sodium phosphate, two polyoxy vinyl alkyl ether phosphoric acids, three polyoxy vinyl alkyl ether phosphoric acids, two polyoxy ethylene nonylplenyl ether phosphoric acid, polyoxyethylene lauryl ether sodium phosphate, two polyoxyethylene lauryl ether sodium phosphates etc.As amphoteric surfactant, alkyl betaine, alkyl amido betaine etc. are for example arranged, as cationic surfactant, double long-chain alkyl quaternary ammonium salt, single-long-chain alkyl quaternary ammonium salt, double long-chain alkyl polyoxyethylene quaternary ammonium salt, two (hydroxyalkyl) quaternary ammonium salt are for example arranged, the quaternary ammonium salt of amide/ester bond etc. is arranged.

Wherein, the nonionic surfactant of polyoxyethylene add-on type is best, particularly oxirane addition molal quantity be 20～60 better.

As UV absorbent, benzophenone, the 4-tert-butyl group-4 '-methoxyl group-DBM, dimethoxy-cinnamic acid thylhexoic acid glyceride, 2-ethylhexyl-4-methoxy cinnamic acid, p-aminobenzoate, phenyl salicytate etc. are for example arranged.

Cosmetics of the present invention can for example can make any forms such as liquid, water-in-oil type or emulsion oil-in-water, glue, pasty state, solid according to the usual way manufacturing.Especially it is the most handy to make cosmetics for skin such as astringent, emulsion, cream, beautifying liquid.

Of the present inventionly see through the percutaneous absorbability that skin absorption promoter can promote to be engaged in the effective ingredient in the skin preparations for extenal use significantly, and low to skin irritation, and the safety aspect is superior.

Therefore, cosmetics of the present invention are low to skin irritation, usability is good, raising is as the percutaneous absorbability of the material of Carboxymethyl Chitin, whitening function or the antiinflammation of effective ingredient, just can obtain superior pachylosis effect, whitening effect and the antiinflammatory effect improved with lower consumption.

Embodiment

With embodiment the present invention is described below, but the present invention is not subjected to the qualification of these embodiment.Preparation example 1～10th is made according to above-mentioned method for making 1.In addition, the spiral shell ether compound of using among the following embodiment is that the bonding state of the wave part of general formula (6) is representing with spiral shell ether compound Z of Z, is representing with spiral shell ether compound E of E.

Preparation example 1

In the 2 liter of 5 neck flask that has agitating device, Dropping funnel, nitrogen ingress pipe and distilling apparatus, add 3 methoxypropyl amine 743.2g (8.34mol) and ethanol 150ml, under nitrogen atmosphere in 80 ℃ of limit heated and stirred on one side with 3 hours dropping cetyl glycidyl ether 165.9g (0.56mol) in flask.Drip to finish the back in 80 ℃ of restir 12 hours, under reduced pressure add thermal distillation and remove ethanol and superfluous 3 methoxypropyl amine, residue by purification by silica gel column chromatography, is obtained aminoalcohol derivative (4a) 196.5g (yield 91% is with respect to cetyl glycidyl ether) (operation 1).

The rerum natura that obtains aminoalcohol derivative (4a) is as follows.

White solid

Fusing point: 53 ℃

IR(ν _neat，cm ^-1) ；3340，2930，2855，1470，

1310，1120，1065，955，

900，720。

¹H-NMR(CDCl ₃，δ)；

0.88(t，J＝6.3Hz，3H)，

1.25～1.45(m，26H)，

1.45～1.85(m，6H)，2.57～2.76(m，4H)，

3.32(s，3H)，3.38～3.48(m，6H)，

3.77～3.89(m，1H)。

Fused chemical compound (4a) 61.3g (158.1mmol) that operation 1 obtains above adding in the 1 liter of 5 neck flask that has agitating device, Dropping funnel, nitrogen ingress pipe and distilling apparatus and the methanol solution 1.53g (7.91mmol) that contains 28% Feldalat NM stirred 30 minutes in 60 ℃ under nitrogen atmosphere.Then under the same condition with in above-mentioned solution, dripping methyl myristate 38.3g (158.1mmol) in 1 hour.Drip and finish back (80～10Torr) restir 5 hours, end reaction under 60 ℃ of decompressions.With reactant mixture cooling back reuse purification by silica gel column chromatography, obtain amide derivatives (2a) 88.7g (yield 94%) (operation 2).

The rerum natura of the amide derivatives that obtains (2a) is as follows.

White solid

Fusing point: 48 ℃

IR(ν _neat，cm ^-1)；3440，2930，2860，1650，

1625，1470，1225，1210，

1110，950，720.

¹H-NMR(CDCl ₃，δ)；

0.88(br t，J＝6.3Hz，6H)，

1.15～1.95(m，53H)，

2.36(t，J＝7.5Hz，2H)，

3.29～3.5(m，10H)，3.33(s，3H)，

3.85～3.95(m，1H)。

Operation 2 obtains above adding in the 1 liter of 5 neck flask that has agitating device, Dropping funnel, nitrogen ingress pipe and distilling apparatus chemical compound (2a) 94.5g (158.0mmol), Tetrabutylammonium bromide 1.53g (4.74mmol), epoxychloropropane 32.2g (347.6mmol), sodium hydroxide 12.6g (315.0mmol) and toluene 66ml stirred 10 hours in 45 ℃ under nitrogen atmosphere.The reactant mixture that obtains washes with water 3 times in 70 ℃, under reduced pressure adds thermal distillation and removes toluene and superfluous epoxychloropropane, and residue by purification by silica gel column chromatography, is obtained amide derivatives (3a) 94.9g (yield 92%) (operation 5)

The rerum natura of the amide derivatives that obtains (3a) is as follows.

White solid

Fusing point: 38～39 ℃

IR(ν _neat，cm ^-1)；2930，2855，1650，1470，

1425，1380，1210，1120，

905，840，720.

¹H-NMR(CDCl ₃，δ)；

0.88(br t，J＝6.0Hz，6H)，

1.10～1.45(m，46H)，1.45～1.90(m，6H).

2.25～2.48(m，2H)，2.50～2.68(m，1H).

2.70～2.85(m，1H)，3.02～3.20(m，1H).

3.20～4.00(m，13H)，3.32(s，3H).

Operation 5 obtains above adding in 100 milliliters the autoclave that has agitating device chemical compound (3a) 71.3g (109.0mmol), water 11.78g (654.1mmol), sodium hydroxide 0.087g (2.18mmol) and tetradecanoic acid 0.87g (4.36mmol) stirred 6 hours at 160 ℃ in enclosed system.After the reactant mixture cooling, 80 ℃ with after the 2% Sal washing 2 times, by purification by silica gel column chromatography, obtains purpose amide derivatives (1a) 68.3g (yield 93%) (operation 6).

The rerum natura of the amide derivatives that obtains (1a) is as follows.

Colourless transparent liquid

IR(ν _neat，cm ^-1)；3445，2930，2860，1630，

1470，1420，1380，1305，

1210，1120，720.

¹H-NMR(CDCl ₃，δ)；

0.88(br t，J＝6.7Hz，6H)，

1.15～1.44(m，46H)，

1.44～1.95(m，8H)，2.25～2.45(m，2H)，

3.20～3.90(m，16H)，3.33(s，3H).

Operation 5 obtains above adding in the 500 milliliter of 4 neck flask that has agitating device, nitrogen ingress pipe and distilling apparatus chemical compound (3a) 31.0g (47.4mmol), water 11.9g (663.7mmol), sodium acetate 13.6g (165.9mmol) and acetic acid 104.9g (1746.8mmol) stirred 19 hours in 70 ℃ under nitrogen atmosphere.Under reduced pressure add thermal distillation and remove superfluous acetic acid, obtain containing ester-acid amide derivant (14a-1), (14a-2) and mixture (14a-3) (operation 7).

Then, the mixture that does not need to contain the ester-acid amide derivant takes out from flask, to wherein adding 48% sodium hydrate aqueous solution 59.3g (711.2mmol), water 18g and butanols 200ml, stirs 3 hours in 80 ℃ again.Under reduced pressure add thermal distillation and remove butanols, residue is diluted in the toluene of 250ml, in 70 ℃ wash 2 times with water after, under reduced pressure add thermal distillation and remove toluene, residue obtains purpose amide derivatives (1a) 22.3g (yield 70%) (operation 8) by purification by silica gel column chromatography.

Preparation example 2

In the 10 liter of 5 neck flask that has agitating device, Dropping funnel, nitrogen ingress pipe and distilling apparatus, add 3 methoxypropyl amine 4680g (52.5mol) and ethanol 900g, under nitrogen atmosphere in 80 ℃ of limit heated and stirred on one side with 3 hours dropping cetyl glycidyl ether 1045g (3.50mol) in flask.Drip to finish the back in 80 ℃ of restir 1 hour, under reduced pressure add thermal distillation and remove ethanol and superfluous 3 methoxypropyl amine, obtain aminoalcohol derivative (4a) and be the product of main component (operation 1).

In 10 liter of 5 neck flask that above-mentioned (operation 1) obtains is to add sodium hydroxide 9.82g (0.175mol) in the product of main component with chemical compound (2a), is blown into nitrogen, and (stirred 3 hours 60～10Torr) watersides of removing generation in 80 ℃ of limits down in decompression.Under same condition, dripped methyl myristate 882.3g (3.64mol) with 3 hours to the inside while stirring then.The methanol of generation is removed in distillation.After dripping end, be blown into nitrogen again, (60～10Torr) distill the methanol limit of removing generation in 60～45 ℃ of limits stirred 10 hours, and the end reaction obtains amide derivatives (2a) and is the product of main component (operation 2) down in decompression.

In 10 liter of 5 neck flask that above-mentioned (operation 1) obtains is to add Tetrabutylammonium bromide 33.9g (0.105mol), epoxychloropropane 712.5g (7.70mol) and toluene 2100g in the product of main component with chemical compound (2a), be blown into nitrogen, decompression down (150～50Torr) in 45 ℃ while stirring with 2 hours dropping 48% sodium hydrate aqueous solution 1750.0g (21.0mol).After dripping end, under same condition, stirred 10 hours again, finish reaction.With mixture in 70 ℃ wash 4 times with water after, under reduced pressure add thermal distillation and remove toluene and superfluous epoxychloropropane, obtaining with amide derivatives (3a) is the product (operation 5) of main component.

In 10 liter of 5 neck flask that above-mentioned (operation 5) obtains is to add entry 378.2g (21.0mol), 48% sodium hydrate aqueous solution 5.83g (0.07mol) and ten tetra-carbonic 32.0g (0.14mol) in the product of main component with chemical compound (3a), stirs 2.5 days at 100 ℃ under nitrogen atmosphere.Reactant in 80 ℃ with 2% salt washing 3 times after, decompression is thermal dehydration down, obtaining with purpose chemical compound (1a) is the product 2261.5g (operation 6) of main component.This product contains 70% chemical compound (1a), also contains intermediate that useful following formula represents and side-product of reaction etc. in addition.

C ₁₃H ₂₇CO ₂H C ₁₃H ₂₇CO ₂Na

Preparation example 3

Except in the operation 2 of preparation example 1, substituting the methyl myristate with methyl palmitate, carry out operation 1 and 2 same reactions with preparation example 1, obtain amide derivatives (2b) (operation 1 and 2).

The rerum natura that obtains amide derivatives (2b) is as follows.

White solid

Fusing point: 55 ℃

IR(ν _neat，cm ^-1)；3430，2930，2855，1620，

1470，1205，1110，950，

720.

¹H-NMR(CDCl ₃，δ)；

0.88(br t，J＝6.4Hz，6H)，

1.26～1.89(m，57H)，

2.36(t，J＝7.6Hz，2H)，

3.29～3.52(m，10H)，3.33(s，3H)，

3.88～3.95(m，1H).

Except chemical compound (2b) alternative compounds (2a) that in the operation 5 of preparation example 1, obtains with above-mentioned operation 2, carry out the reaction same with the operation 5 of preparation example 1, obtain amide derivatives (3b)

(operation 5).

The rerum natura that obtains amide derivatives (3b) is as follows.

White solid

Fusing point: 44～45 ℃

IR(ν _neat，cm ^-1)；2930，2860，1650，1470，

1425，1380，1210，1120,

910，845，755，720,

¹H-NMR(CDCl ₃，δ)；

0.88(br t.J＝6.7Hz，6H)，

1.15～1.45(m，50H)，1.45～1.73(m，4H)，

1.73～1.90(m，2H)，2.25～2.48(m，2H)，

2.50～2.68(m，1H)，2.70～2.85(m，1H)，

3.00～3.18(m，1H)，3.18～4.00(m，13H)，

3.32(s，3H).

Except chemical compound (3b) alternative compounds (3a) that in the operation 6 of preparation example 1, obtains with above-mentioned operation 5, substitute outside the tetradecanoic acid with hexadecanoic acid, carry out the reaction same with the operation 6 of preparation example 1, obtain amide derivatives (1b) (operation 6).

The rerum natura that obtains amide derivatives (1b) is as follows.

White solid

Fusing point: 33 ℃

IR(ν _neat cm ^-1)；3445，2930，2860，1650，

1630，1470，1420，1380，

1305，1210，1120，1080.

¹H-NMR(CDCl ₃，δ)；

0.88(br t，J＝6.4Hz，6H)，

1.15～1.45(m，50H)，1.45～1.95(m，7H)，

2.25～2.55(m，3H)，3.20～3.92(m，16H)，

3.33(s，3H).

Operation 5 obtains above adding in the 500 milliliter of 4 neck flask that has agitating device, ammonia ingress pipe chemical compound (3b) 34.1g (50.0mmol), acetic anhydride 25.5g (250.0mmol) and triethylamine 25.3g (250.0mmol) stirred 10 hours in 100 ℃ under nitrogen atmosphere.With the reactant heating down, concentrating under reduced pressure, the residue that obtains purification by silica gel column chromatography obtains ester-acid amide derivant (14b) 34.9g (yield 89%) (operation 7).

The rerum natura that obtains ester-acid amide derivant (14b) is as follows.

The brown transparency liquid

¹H-NMR(CDCl ₃，δ)；

0.88(br t，J＝6.4Hz，6H)，

1.26～1.83(m，56H)，2.03～2.20(m，6H)，

2.33(t，J＝7.1Hz，2H)，

3.12～4.35(m，15H)，3.32(s，3H)，

5.04～5.43(m，1H).

Operation 7 obtains above adding in the 200 milliliter of 4 neck flask that has agitating device, nitrogen ingress pipe chemical compound (14b) 33.9g (43.2mmo1), Feldalat NM 28% methanol solution 0.42g (2.16mmol) and methanol 200ml, under nitrogen atmosphere in stirring at room 3.5 hours.With the reactant mixture heating down, concentrating under reduced pressure, the residue that obtains purification by silica gel column chromatography obtains amide derivatives (1b) 16.0g (yield 53%) (operation 8).

Operation 2 obtains above adding in the 3 liter of 4 neck flask that has agitating device, nitrogen ingress pipe chemical compound (2b) 45.2g (72.0mmol), sodium hydroxide 2.86g (119.2mmol) and toluene 800ml stirred 30 minutes in 55 ℃ under nitrogen atmosphere.Add 1 then, 2-isopropylidene dihydroxy-3-tolysulfonyl oxygen base propane 34.8g (121.5mmol) stirred 18 hours in 100 ℃.In ice-cold downhill reaction mixture, add 2-propanol 20ml, after unreacted sodium hydroxide passivation, under the heating, concentrating under reduced pressure.The residue purification by silica gel column chromatography that obtains obtains 1,3-two oxa-s, penta ring-amide derivatives (16b) 51.0g (yield 96%) (operation 11).

1 of acquisition, the rerum natura of 3-two oxa-s, penta ring-amide derivatives (16b) is as follows.

Colourless transparent liquid

¹H-NMR(CDCl ₃，δ)；

0.88(br t，J＝6.4Hz，6H)，

1.20～1.90(m，62H)，

2.36(t，J=7.0Hz，2H)，

3.30～4.25(m，19H).

Operation 11 obtains above adding in the 2 liter of 4 neck flask that has agitating device, nitrogen ingress pipe chemical compound (16b) 51.0g (68.9mmol), toluenesulfonic acid-a water and thing 0.50g (2.63mmol) and methanol 500ml, under nitrogen atmosphere in stirring at room 12 hours.With concentrating under reduced pressure under the reactant mixture heating, the residue that obtains purification by silica gel column chromatography obtains amide derivatives (1b) 41.0g (yield 85%) (operation 10).

Preparation example 4

Except in the operation 2 of preparation example 1, substituting the methyl myristate with methyl laurate, carry out operation 1 and 2 same reactions with preparation example 1, obtain amide derivatives (2c) (operation 1 and 2).

The rerum natura of the amide derivatives that obtains (2c) is as follows.

Colourless transparent liquid

IR(ν _neat，cm ^-1)；3435，2930，2855，1620，

1470，1220，1110，720.

¹H-NMR(CDCl ₃，δ)；

0.88(br t，J＝6.4Hz，6H)，

1.20～1.90(m，49H)，

2.36(t，J＝7.6Hz，2H)，

3.25～3.52(m，10H)，3.33(s，3H)，

3.88～3.95(m，1H).

Except chemical compound (2c) alternative compounds (2a) that in the operation 5 of preparation example 1, obtains with above-mentioned operation 2, carry out the reaction same with the operation 5 of preparation example 1, obtain amide derivatives (3c) (operation 5).

The rerum natura that obtains amide derivatives (3c) is as follows.

Weak yellow liquid

IR(ν _neat，cm ^-1)；2940，2875，1750，1650，

1470，1380，1210，1120，

910，845.

¹H-NMR(CDCl ₃，δ)；

0.88(br t，J＝6.4Hz，6H)，

1.15～1.45(m，42H)，1.45～1.75(m，4H)，

1.75～1.90(m，2H)，2.25～2.50(m，2H)，

2.50～2.68(m，1H)，2.70～2.85(m，1H)，

3.00～3.18(m，1H)，3.18～4.00(m，13H)，

3.32(s，3H).

Except chemical compound (3c) alternative compounds (3a) that in the operation 7 of preparation example 1, obtains with above-mentioned operation 5, carry out operation 7 and 8 same reactions with preparation example 1, obtain purpose product amide derivatives (1c) (operation 7 and 8).

The rerum natura that obtains amide derivatives (1c) is as follows.

Colourless transparent liquid

IR(ν _neat，cm ^-1)；3430，2930，2860，1650，

1630，1470，1380，1260，

1210，1115，1080，795，

720.

¹H-NMR(CDCl ₃，δ)；

0.88(br t，J＝6.7Hz，6H)，

1.15～1.45(m，42H)，1.45～1.97(m，8H)，

2.25～2.45(m，2H)，3.15～3.92(m，16H)，

3.33(s，3H).

Preparation example 5

In the operation 2 of preparation example 1, except the methyl ester of the Le Na Star Network P-70 that makes with flower king (strain) substitutes the methyl myristate, carry out operation 1 and 2 same reactions with preparation example 1, obtain amide derivatives (2d) (operation 1 and 2).The manufacture method of the methyl ester of Le Na Star Network P-70 is under Le Na Star Network P-70 (tetradecanoic acid, hexadecanoic acid, octadecanoid acid are 3: 70: 27 the mixture by weight) reflux of will flower king (strain) making, what have in the presence of the sulfuric acid catalyst with methanol reaction manufacturing.

(A=C ₁₃H ₂₇, C ₁₅H ₃₁, C ₁₇H ₃₅Mixture)

The rerum natura of the amide derivatives that obtains (2d) is as follows.

White solid

Fusing point: 50 ℃

IR(ν _neat，cm ^-1)；3430，2930，2860，1620，

1470，1205，1110，950，

720.

Except chemical compound (2d) alternative compounds (2b) that obtains with above-mentioned operation 2 in the operation 11 of preparation example 3 is reacted, not purification obtain 1,3-two oxa-s, penta ring-amide derivatives (16d), and directly carry out outside the reaction of following operation 10, carry out operation 11 and 10 same reactions with preparation example 3, obtain purpose product amide derivatives (1d) (operation 11 and 10).

(A=C ₁₃H ₂₇, C ₁₅H ₃₁, C ₁₇H ₃₅Mixture)

The rerum natura of the amide derivatives that obtains (1d) is as follows.

White solid

Fusing point: 32 ℃

IR(ν _neat，cm ^-1)；3445，2930，2860，1650，

1630，1470，1380，1210，

1120，1080，720.

Preparation example 6

Except in the operation 1 of preparation example 1, substituting the cetyl glycidyl ether with the octadecyl glycidyl ether, carry out the reaction same with the operation 1 of preparation example 1, obtain aminoalcohol derivative (4e) (operation 1).

The rerum natura of the aminoalcohol derivative that obtains (4e) is as follows.

White solid

Fusing point: 57～58 ℃

IR(ν _neat，cm ^-1)；3340，2930，2855，1470，

1120，960，900，840，

720.

¹H-NMR(CDCl ₃，δ)；

0.88(t，J＝6.3Hz，3H)，

1.25～1.45(m，30H)，1.45～1.85(m，6H)，

2.55～2.75(m，4H)，3.32(s，3H)，

3.35～3.50(m，6H)，3.77～3.89(m，1H).

Except chemical compound (4e) alternative compounds (4a) that in the operation 2 of preparation example 1, obtains with above-mentioned operation 1, carry out the reaction same with the operation 2 of preparation example 1, obtain amide derivatives (2e) (operation 2).

The rerum natura of the amide derivatives that obtains (2e) is as follows.

White solid

Fusing point: 49 ℃

IR(ν _neat cm ^-1)；3440，2930，2860，1650，

1625，1470，1225，1210，

1110，950，720.

¹H-NMR(CDCl ₃，δ)；

0.88(br t，J＝6.3Hz，6H)，

1.15～1.95(m，57H)，

2.36(t，J＝7.5Hz，2H)，

3.30～3.55(m，10H)，3.33(s，3H)，

3.85～3.95(m，1H).

Except chemical compound (2e) alternative compounds (2a) that in the operation 5 of preparation example 1, obtains with above-mentioned operation 2, carry out the reaction same with the operation 5 of preparation example 1, obtain amide derivatives (3e) (operation 5).

The rerum natura of the amide derivatives that obtains (3e) is as follows.

Colourless transparent liquid

IR(ν _neat cm ^-1)；2930，2860，1650，1425，

1380，1260，1210，1120，

910，720.

¹H-NMR(CDCl ₃，δ)；

0.88(br t，J＝6.0Hz，6H)，

1.10～1.45(m，50H)，1.45～1.90(m，6H)，

2.25～2.50(m，2H)，2.50～2.68(m，1H)，

2.70～2.85(m，1H)，3.01～3.20(m，1H)，

3.20～4.00(m，13H)，3.32(s，3H).

Except chemical compound (3e) alternative compounds (3a) that in the operation 7 of preparation example 1, obtains with above-mentioned operation 5, carry out operation 7 and 8 same reactions with preparation example 1, obtain amide derivatives (1e) (operation 7 and 8).

The rerum natura of the amide derivatives that obtains (1e) is as follows.

White solid

Fusing point: 23 ℃

IR(ν _neat，cm ^-1)；3425，2930，2860，1650，

1630，1470，1380，1220，

1210，1120，720.

¹H-NMR(CDCl ₃，δ)；

0.88(br t，J＝6.7Hz，6H)，

1.17～1.45(m，49H)，1.45～1.92(m，8H)，

2.22～2.45(m，2H)，3.20～3.90(m，17H)，

3.33(s，3H).

Preparation example 7

Except chemical compound (4e) alternative compounds (4a) that in the operation 2 of preparation example 1, obtains, substitute the tetradecanoic acid with hexadecanoic acid with the operation 1 of above-mentioned preparation example 6, carry out the reaction same, obtain amide derivatives (2f) (operation 1 and 2) with the operation 2 of preparation example 1.

The rerum natura of the amide derivatives that obtains (2f) is as follows.

White solid

Fusing point: 54～55 ℃

IR(ν _neat，cm ^-1)；3430，2930，2855，1620，

1470，1220，1205，1110，

950，885，720.

¹H-NMR(CDCl ₃，δ)；

0.88(br t，J＝6.4Hz，6H)，

1.25～1.95(m，61H)，

2.36(t，J＝7.6Hz，2H)，

3.29～3.52(m，10H)，3.33(s，3H)，

3.88～3.95(m，1H).

Except in the operation 5 of preparation example 1 with chemical compound (2f) alternative compounds (2a), carry out the reaction same with the operation 5 of preparation example 1, obtain amide derivatives (3f) (operation 5).

The rerum natura that obtains amide derivatives (3f) is as follows.

White solid

Fusing point: 45～47 ℃

IR(ν _neat，cm ^-1)；2930，2860，1650，1470，

1425，1380，1210，1120，

910，845，755，720.

¹H-NMR(CDCl ₃，δ)；

0.88(br t，J＝6.7Hz，6H)，

1.15～1.45(m，54H)，1.45～1.73(m，4H)，

1.73～1.90(m，2H)，2.25～2.48(m，2H)，

2.50～2.68(m，1H)，2.70～2.85(m，1H)，

3.00～3.18(m，1H)，3.18～4.00(m，13H)，

3.32(s，3H).

Except chemical compound (3f) alternative compounds (3a) that in the operation 7 of preparation example 1, obtains with above-mentioned operation 5, carry out operation 7 and 8 same reactions with preparation example 1, obtain purpose product amide derivatives (1f) (operation 7 and 8).

The rerum natura of the amide derivatives that obtains (1f) is as follows.

White solid

Fusing point: 35 ℃

IR(ν _neat，cm ^-1)；3445，2930，2860，1650，

1630，1470，1420，1380，

1305，1210，1120，1080.

¹H-NMR(CDCl ₃，δ)；

0.88(br t，J=6.4Hz，6H)，

1.15～1.45(m，54H)，1.45～1.95(m，7H)，

2.25～2.55(m，3H)，3.20～3.95(m，16H)，

3.33(s，3H).

Preparation example 8

Except in the operation 1 of preparation example 1, substituting the cetyl glycidyl ether with the myristyl glycidyl ether, carry out the reaction same with the operation 1 of preparation example 1, obtain aminoalcohol derivative (4g) (operation 1).

The rerum natura of the aminoalcohol derivative that obtains (4g) is as follows.

White solid

47 ℃ of fusing points

IR(ν _neat，cm ^-1)；3340，2930，2855，1470，

1310，1120，1065，995，

900，720.

¹H-NMR(CDCl ₃，δ)；

0.88(t，J＝6.3Hz，3H)，

1.25～1.45(m，26H)，1.45～1.85(m，6H)，

2.57～2.75(m，4H)，3.32(s，3H)，

3.38～3.48(m，6H)，3.75～3.88(m，1H).

Except chemical compound (4g) alternative compounds (4a) that in the operation 2 of preparation example 1, obtains, substitute the methyl myristate with methyl palmitate with above-mentioned operation 1, carry out the reaction same, obtain amide derivatives (2g) (operation 2) with the operation 2 of preparation example 1.

The rerum natura of the amide derivatives that obtains (2g) is as follows.

White solid

Fusing point: 47 ℃

IR(ν _neat，cm ^-1)；3440，2930，2855，1620，

1470，1205，1110，950，

720.

¹H-NMR(CDCl ₃，δ)；

0.88(br t，J＝6.4Hz，6H)，

1.26～1.89(m，52H)，

2.36(t，J＝7.6Hz，2H)，

3.29～3.52(m，11H)，3.33(s，3H)，

3.88～3.95(m，1H).

Except chemical compound (2g) alternative compounds (2a) that in the operation 5 of preparation example 1, obtains with above-mentioned operation 2, carry out the reaction same with the operation 5 of preparation example 1, obtain amide derivatives (3g) (operation 5).

The rerum natura of the amide derivatives that obtains (3g) is as follows.

Colourless transparent liquid

IR(ν _neat，cm ^-1)；2930，2860，1650，1470，

1425，1380，1210，1120，

910，845，755，720.

¹H-NMR(CDCl ₃，δ)；

0.88(br t，J＝6.7Hz，6H)，

1.15～1.45(m，46H)，

1.45～1.73(m，4H)，1.73～1.90(m，2H)，

2.25～2.50(m，2H)，2.50～2.68(m，1H)，

2.70～2.85(m，1H)，3.00～3.18(m，1H)，

3.18～4.00(m，13H)，3.32(s，3H).

Except chemical compound (3g) alternative compounds (3a) that in the operation 7 of preparation example 1, obtains with above-mentioned operation 5, carry out operation 7 and 8 same reactions with preparation example 1, obtain purpose product amide derivatives (1g) (operation 7 and 8).

The rerum natura of the amide derivatives that obtains (1g) is as follows.

White solid

Fusing point: 27 ℃

IR(ν _neat，cm ^-1)；3445，2930，2860，1650，

1630，1470，1420，1380，

1305，1210，1120，1080，

720.

¹H-NMR(CDCl ₃，δ)；

0.88(br t，J＝6.4Hz，6H)，

1.15～1.45(m，45H)，1.45～1.93(m，7H)，

2.20～2.60(m，3H)，3.20～3.90(m，17H)，

3.33(s，3H).

Preparation example 9

Except in the operation 1 of preparation example 1, substituting the 3 methoxypropyl amine with the 2-methoxyethyl amine, carry out the reaction same with the operation 1 of preparation example 1, obtain aminoalcohol derivative (4h) (operation 1).

The rerum natura of the aminoalcohol derivative that obtains (4h) is as follows.

White solid

Fusing point: 54～55 ℃

IR(ν _neat，cm ^-1)；3430，2920，2855，1470，

1120，1065，900，720.

¹H-NMR(CDCl ₃，δ)；

0.88(t，J=6.3Hz，3H)，

1.25～1.70(m，30H)，2.57～2.76(m，4H)，

3.32(s，3H)，3.38～3.48(m，6H)，3.77～3.89(m，1H).

Except chemical compound (4h) alternative compounds (4a) that in the operation 2 of preparation example 1, obtains, substitute the methyl myristate with methyl palmitate with above-mentioned operation 1, carry out the reaction same, obtain amide derivatives (2h) (operation 2) with the operation 2 of preparation example 1.

The rerum natura of the amide derivatives that obtains (2h) is as follows.

White solid

Fusing point: 51～52 ℃

IR(ν _neat，cm ^-1)；3420，2920，2855，1620，

1470，1110，720.

¹H-NMR(CDCl ₃，δ)；

0.87(t，J＝6.4Hz，6H)，

1.15～1.70(m，55H)，

2.25～2.50(m，2H)，3.20～4.00(m，11H)，

3.34(s，3H).

Except chemical compound (2h) alternative compounds (2a) that in the operation 5 of preparation example 1, obtains with above-mentioned operation 2, carry out the reaction same with the operation 5 of preparation example 1, obtain amide derivatives (3h) (operation 5).

The rerum natura of the amide derivatives that obtains (3h) is as follows.

Colourless transparent liquid

IR(ν _neat，cm ^-1)；2930，2855，1650，1470，

1420，1380，1310，1250，

1190，1120，910，850，720.

¹H-NMR(CDCl ₃，δ)；

0.88(br t，J＝6.4Hz，6H)，

1.13～1.45(m，50H)，1.45～1.70(m，4H)，

2.30～2.50(m，2H)，2.50～2.70(m，1H)，

2.70～2.85(m，1H)，3.00～3.20(m，1H)，

3.20～4.00(m，13H)，3.32(s，3H).

Except chemical compound (3h) alternative compounds (3a) that in the operation 6 of preparation example 1, obtains with above-mentioned operation 5, carry out the reaction same with the operation 6 of preparation example 1, obtain purpose product amide derivatives (1h) (operation 6).

The rerum natura of the amide derivatives that obtains (1h) is as follows.

White solid

Fusing point: 31～32 ℃

IR(ν _neat，cm ^-1)；3450，2930，2860，1630，

1470，1380，1300，1190，

1160，720.

¹H-NMR(CDCl ₃，δ)；

0.88(t，J＝6.4Hz，6H)，

1.15～1.75(m，54H)，2.20～2.45(m，3H)，

3.20～3.90(m，17H)，3.33(s，3H).

Except chemical compound (2h) alternative compounds (2b) that in the operation 11 of preparation example 3, obtains with above-mentioned operation 2, carry out the reaction same with the operation 11 of preparation example 3, obtain 1,3-two oxa-s, penta ring-amide derivatives (16h) (operation 11).

Obtain 1, the rerum natura of 3-two oxa-s, penta ring-amide derivatives (16h) is as follows.

Colourless transparent liquid

¹H-NMR(CDCl ₃，δ)；

0.88(t，J＝6.4Hz，6H)，

1.15～1.70(m，54H)，1.34(s，3H)，

1.40(s，3H)，2.36(t，J＝7.0Hz，2H)，

3.25～4.30(m，19H).

Except chemical compound (16h) alternative compounds (16b) that in the operation 10 of preparation example 3, obtains with above-mentioned operation 11, carry out the reaction same with the operation 11 of preparation example 3, obtain purpose product amide derivatives (1h) (operation 10).

Preparation example 10

Except in the operation 1 of preparation example 1, substituting the 3 methoxypropyl amine with ethamine, carry out the reaction same with the operation 1 of preparation example 1, obtain aminoalcohol derivative (4i) (operation 1).

The rerum natura of the aminoalcohol derivative that obtains (4i) is as follows.

White solid

Fusing point: 60～61 ℃

IR(ν _neat，cm ^-1)；3400，2930，2855，1470，

1310，1110，955，720.

¹H-NMR(CDCl ₃，δ)；

0.88(t，J＝6.4Hz，3H)，

1.11(t，J＝7.2Hz，3H)，

1.15～1.70(m，30H)，2.55～2.80(m，4H)，

3.35～3.53(m，4H)，3.79～3.93(m，1H).

Except chemical compound (4i) alternative compounds (4a) that in the operation 2 of preparation example 1, obtains, substitute the methyl myristate with methyl palmitate with above-mentioned operation 1, carry out the reaction same, obtain amide derivatives (2i) (operation 2) with the operation 2 of preparation example 1.

The rerum natura of the amide derivatives that obtains (2i) is as follows.

White solid

Fusing point: 56 ℃

IR(ν _neat，cm ^-1)；3410，2930，2860，1625，

1470，1380，1305，1245，

1210，1110，950，855，

720.

¹H-NMR(CDCl ₃，δ)；

0.88(t，J＝6.4Hz，6H)，

1.15～1.75(m，57H)，

2.34(t，J＝7.6Hz，2H)，

3.30～3.55(m，9H)，3.85～4.00(m，1H).

Except chemical compound (2i) alternative compounds (2a) that in the operation 5 of preparation example 1, obtains with above-mentioned operation 2, carry out the reaction same with the operation 5 of preparation example 1, obtain amide derivatives (3i) (operation 5).

The rerum natura of the amide derivatives that obtains (3i) is as follows.

Colourless transparent liquid

IR(ν _neat，cm ^-1)；2930，2855，1650，1470，

1425，1380，1210，1120，

905，840，720.

¹H-NMR(CDCl ₃，δ)；

0.88(br t，J＝6.4Hz，6H)，

1.10～1.75(m，57H)，2.25～2.50(m，2H)，

2.50～2.70(m，1H)，2.70～2.85(m，1H)，

3.00～4.00(m，12H).

Except chemical compound (3i) alternative compounds (3a) that in the operation 6 of preparation example 1, obtains with above-mentioned operation 5, carry out the reaction same with the operation 6 of preparation example 1, obtain amide derivatives (1i) (operation 6).

The rerum natura of the amide derivatives that obtains (1i) is as follows.

White solid

Fusing point: 35～36 ℃

IR(ν _neat，cm ^-1)；3445，2930，2860，1630，

1470，1420，1380，1305， 1210，1120，720.

¹H-NMR(CDCl ₃，δ)；

0.88(br t，J＝6.4Hz，6H)，

1.13～1.75(m，57H)，

2.31(t，J＝7.5Hz，2H)，

3.20～3.90(m，16H).

Embodiment 1～10

Provide the cosmetics of composition by conventional method manufacturing table 1, the percutaneous permeability of the amide compound used as wetting agent and the effect of improving pachylosis are estimated.The result is as shown in table 1.

(evaluation methodology)

(1) percutaneous permeability:

A certain amount of cosmetics are coated on the skin surface of clean ュカ Application マィ Network ロ pig, are placed in the thermostatic chamber (temperature: 37 ℃, humidity: saturated).Through behind the certain hour, remove the not infiltration composition that remains in skin surface, extract and reclaim the infiltration composition, utilize HPLC to measure the Transdermal absorption amount of amide compound.The Transdermal absorption amount is represented with the value (μ g/cm2) of per unit area.

(2) improve the effect of pachylosis:

Select the winter buccal 10 conducts of women in 20-50 year of pachylosis take place to accept the experimenter,, ask to be 2 weeks during coating at the different skin preparations for extenal use of left and right sides buccal coating.Yu Erzhou is coated with second day after finishing, and with the naked eye observes the pachylosis situation, by following standard determination.Scoring is represented with meansigma methods.

0: can't see pachylosis

1: slight pachylosis

2: pachylosis

3: more serious pachylosis

4: serious pachylosis

Table 1

Composition (weight %)	Embodiment										Comparative example
	Embodiment										Comparative example	1	2	3	4	5	6	7	8	9	10	1
	Single isostearic acid list myristic acid diglyceride (δ=18.43) the k succinic acid l of a polyoxyethylene octyl group lauryl ether (20EO) b polyoxyethylene hexyl decyl ethers (20EO) c three 25 ℃ of h three decanes (δ=15.7) i different n-nonanoic acid isotridecyl esters of isostearic acid polyoxyethylene hardened castor oil (50EO) d polyoxyethylene hardened castor oil (50EO) e Tween-60 (20EO) f sorbitan stearate g amide derivatives (1a) fusing point (δ=16.56) j 86% glycerine m 1,3-BDO n water o xanthene natural gum	2----1 1-10 2 0.5 10 5 surpluses 0.5	-2---1 1-10 2 0.5 10 5 surpluses 0.5	--2--112 10 2 0.5 10 5 surpluses 0.5	---2-1 1-10 2 0.5 10 5 surplus 0.5	----2 111 10 2 0.5 10 5 surplus 0.5	2----1 1-5 2 0.5 10 5 surpluses 0.5	-2---1 1-5 2 0.5 10 5 surpluses 0.5	--2--11152 0.5 10 5 surpluses 0.5	---2-1 1-5 2 0.5 10 5 surplus 0.5	----2 1 1-5 2 0.5 10 5 surplus 0.5	1	2	3	4	5	6	7	8	9	10	1	-----11 7--0.5 10 5 surplus 0.5
Amide compound is to infiltration capacity (the μ g/cm of horny layer and epidermis after 18 hours ²)		2----1 1-10 2 0.5 10 5 surpluses 0.5	-2---1 1-10 2 0.5 10 5 surpluses 0.5	--2--112 10 2 0.5 10 5 surpluses 0.5	---2-1 1-10 2 0.5 10 5 surplus 0.5	----2 111 10 2 0.5 10 5 surplus 0.5	2----1 1-5 2 0.5 10 5 surpluses 0.5	-2---1 1-5 2 0.5 10 5 surpluses 0.5	--2--11152 0.5 10 5 surpluses 0.5	---2-1 1-5 2 0.5 10 5 surplus 0.5	----2 1 1-5 2 0.5 10 5 surplus 0.5	15.2	14.1	13.5	16.4	15.5	12.9	13.6	12.4	14.7	13.1	3.9	-----11 7--0.5 10 5 surplus 0.5
	Improve the effect of pachylosis	0.4 ±0.2	0.6 ±0.3	0.7 ±0.2	0.4 ±0.2	0.4 ±0.3	0.7 ±0.3	0.8 ±0.1	0.9 ±0.4	0.6 ±0.2	0.7 ±0.3	15.2	14.1	13.5	16.4	15.5	12.9	13.6	12.4	14.7	13.1	3.9	0.3 ±0.5

Show as the result of table 1, cooperated the cosmetics of Percutaneous absorption enhancer of the present invention, any dermal osmosis amount height that all has an amide derivatives, improve the excellent results of pachylosis.And low to the zest of skin, usability is also good.

Embodiment 11～20

Manufacturing table 2 provides the cosmetics of composition according to conventional methods, with embodiment 1 the same evaluating skin permeability and the effect of improving pachylosis.Table 2 has provided the result who estimates.

Table 2

Composition (weight %)	Embodiment										Comparative example
	Embodiment										Comparative example	11	12	13	14	15	16	17	18	19	20	2
	Single isostearic acid list myristic acid diglyceride (δ=18.43) the k succinic acid l of a polyoxyethylene octyl group lauryl ether (20EO) b polyoxyethylene hexyl decyl ethers (20EO) c three 35 ℃ of h three decanes (δ=15.7) i different n-nonanoic acid isotridecyl esters of isostearic acid polyoxyethylene hardened castor oil (50EO) d polyoxyethylene hardened castor oil (50EO) e Tween-60 (20EO) f sorbitan monostearate g amide derivatives (1f) fusing point (δ=16.56) j 86% glycerine m 1,3-BDO n water o xanthene natural gum	2----1 1-10 2 0.5 10 5 surpluses 0.5	-2---1 1-10 2 0.5 10 5 surpluses 0.5	--2--112 10 2 0.5 10 5 surpluses 0.5	---2-1 1-10 2 0.5 10 5 surplus 0.5	----2 111 10 2 0.5 10 5 surplus 0.5	2----1 1-5 2 0.5 10 5 surpluses 0.5	-2---1 1-5 2 0.5 10 5 surpluses 0.5	--2--11152 0.5 10 5 surpluses 0.5	---2-1 1-5 2 0.5 10 5 surplus 0.5	----2 1 1-5 2 0.5 10 5 surplus 0.5	11	12	13	14	15	16	17	18	19	20	2	-----11 7--0.5 10 5 surplus 0.5
Amide compound is to infiltration capacity (the μ g/cm of horny layer and epidermis after 18 hours ²)		2----1 1-10 2 0.5 10 5 surpluses 0.5	-2---1 1-10 2 0.5 10 5 surpluses 0.5	--2--112 10 2 0.5 10 5 surpluses 0.5	---2-1 1-10 2 0.5 10 5 surplus 0.5	----2 111 10 2 0.5 10 5 surplus 0.5	2----1 1-5 2 0.5 10 5 surpluses 0.5	-2---1 1-5 2 0.5 10 5 surpluses 0.5	--2--11152 0.5 10 5 surpluses 0.5	---2-1 1-5 2 0.5 10 5 surplus 0.5	----2 1 1-5 2 0.5 10 5 surplus 0.5	19.5	17.9	15.8	22.4	15.5	18.1	15.4	16.3	18.5	14.6	3.4	-----11 7--0.5 10 5 surplus 0.5
	Improve the effect of pachylosis	0.3 ±0.1	0.4 ±0.2	0.5 ±0.2	0.3 ±0.1	0.6 ±0.2	0.3 ±0.2	0.6 ±0.1	0.5 ±0.2	0.4 ±0.2	0.7 ±0.3	19.5	17.9	15.8	22.4	15.5	18.1	15.4	16.3	18.5	14.6	3.4	3.4 ±0.6

Show as the result of table 2, cooperated the cosmetics of Percutaneous absorption enhancer of the present invention, any dermal osmosis amount height that all has an amide derivatives, improve the excellent results of pachylosis.And low to the zest of skin, usability is also good.

Embodiment 21～22

Manufacturing table 3 provides the cosmetics of composition according to conventional methods, with embodiment 1 the same evaluating skin permeability and the effect of improving pachylosis.Table 3 has provided the result who estimates.

Table 3

Composition (weight %)	Embodiment
Composition (weight %)	Embodiment			21	22
Polyoxyethylene octyl group lauryl ether (20E.O.) D-sorbite diglycerol different n-nonanoic acid isotridecyl ester (δ=18.43) single isostearic acid list myristic acid diglyceride (δ=18.43) succinic acid water xanthene natural gum	2 5-1 1 0.5 aequums 0.5	2-5 11 0.5 aequums 0.5		21	22
	2 5-1 1 0.5 aequums 0.5	2-5 11 0.5 aequums 0.5	Improve the effect of pachylosis	1.1±0.3	1.3±0.4

Show as the result of table 3, cooperated the cosmetics of Percutaneous absorption enhancer of the present invention, any dermal osmosis amount height that all has a wetting agent, improve the excellent results of pachylosis.And low to the zest of skin, usability is also good.

Embodiment 23～32

Manufacturing table 4 and table 5 provide the cosmetics of composition according to conventional methods, with embodiment 1～10 the same percutaneous permeability of estimating as the spiral shell ether compound of whitening agent.Table 4 and table 5 have provided the result who estimates.

Table 4

	Composition (weight %)	Embodiment
		Embodiment						23	24	25	26	27	28
		a b c d e f g h i j k l m n o p	Polyoxyethylene octyl group lauryl ether (20E.O. ^1) polyoxyethylene hexyl decyl ethers (20E.O. ^1) three isostearic acid polyoxyethylene hardened castor oil (50E.O. ^1) polyoxyethylene hardened castor oil (50E.O. ^1) polyoxyethylene sorbitan monostearate (20E.O. ^1) sorbitan monostearate spiral shell ether compound ^The different n-nonanoic acid isotridecyl esters of 2 three decanes (δ=15.7) (δ=16.56) single isostearic acid list myristic acid diglycerides (δ=18.43) acetyl pantoyl ether (δ=22.23) succinic acid 86% glycerine 1,3-BDO water xanthene natural gum	2----1 0.1-10 2-0.5 10 5 surpluses 0.5	-2---1 0.1-10 2-0.5 10 5 surpluses 0.5	--2--1 0.1-10 2-0.5 10 5 surpluses 0.5	---2-1 0.1-10 2-0.5 10 5 surplus 0.5	23	24	25	26	27	28	----2 1 0.1-10 2-0.5 10 5 surplus 0.5	2----1 0.1-5 2-0.5 10 5 surpluses 0.5
Estimate (the spiral shell ether compound is to the infiltration capacity of horny layer and epidermis after 18 hours) μ g/cm ²		a b c d e f g h i j k l m n o p		2----1 0.1-10 2-0.5 10 5 surpluses 0.5	-2---1 0.1-10 2-0.5 10 5 surpluses 0.5	--2--1 0.1-10 2-0.5 10 5 surpluses 0.5	---2-1 0.1-10 2-0.5 10 5 surplus 0.5	0.67	0.62	0.68	0.72	0.75	0.60	----2 1 0.1-10 2-0.5 10 5 surplus 0.5	2----1 0.1-5 2-0.5 10 5 surpluses 0.5

^*1: oxirane addition molal quantity

^*2: the mixture of spiral shell ether compound E/ spiral shell ether compound Z=5/1

Table 5

	Composition (weight %)	Embodiment				Comparative example
		Embodiment				Comparative example		29	30	31	32	3	4
		a b c d e f g h i j k l m n o p	Polyoxyethylene octyl group lauryl ether (20E.O. ^1) the basic decyl ethers (20E.O. of polyoxyethylene ^1) three isostearic acid polyoxyethylene hardened castor oil (50E.O. ^1) polyoxyethylene hardened castor oil (50E.O. ^1) polyoxyethylene sorbitan monostearate (20E.O. ^1) sorbitan monostearate spiral shell ether compound ^The different n-nonanoic acid isotridecyl esters of 2 three decanes (δ=15.7) (δ=16.56) single isostearic acid list myristic acid diglycerides (δ=18.43) acetyl pantoyl ether (δ=22.23) succinic acid 86% glycerine 1,3-BDO water xanthene natural gum	-2---1 0.1-5 2-0.5 10 5 surpluses 0.5	--2--1 0.1-5 2-0.5 10 5 surpluses 0.5	---2-1 0.1-5 2-0.5 10 5 surplus 0.5	----2 1 0.1-5 2-0.5 10 5 surplus 0.5	29	30	31	32	3	4	-----1 0.1 5---0.5 10 5 surpluses 0.5	-----1 0.1 6--2 0.5 10 5 surplus 0.5
Estimate (the spiral shell ether compound is to the infiltration capacity of horny layer and epidermis after 18 hours) μ g/cm ²		a b c d e f g h i j k l m n o p		-2---1 0.1-5 2-0.5 10 5 surpluses 0.5	--2--1 0.1-5 2-0.5 10 5 surpluses 0.5	---2-1 0.1-5 2-0.5 10 5 surplus 0.5	----2 1 0.1-5 2-0.5 10 5 surplus 0.5	0.63	0.74	0.69	0.59	0.18	0.15	-----1 0.1 5---0.5 10 5 surpluses 0.5	-----1 0.1 6--2 0.5 10 5 surplus 0.5

^*1: oxirane addition molal quantity

Show that as the result of table 4 and table 5 cooperated the cosmetics of Percutaneous absorption enhancer of the present invention, any all is the dermal osmosis amount height and the superior product of whitening effect of spiral shell ether compound.Safe in addition, usability is also good.

Embodiment 33～34

Manufacturing table 7 provides the skin-lightening cosmetic of composition according to conventional methods.With regard to these cosmetics, the same percutaneous permeability of testing the spiral shell ether compound with embodiment 1-10 is simultaneously by following method test whitening effect.Table 7 has provided result of the test.

(UV-B being induced the whitening effect test of mottle)

The ultraviolet in the inboard radiation of UV-B of wrist zone once-a-day shone two days on 20 healthy man testees, and irradiation dose is 2 times of amounts of minimum erythema dose, in the continuous coated sample in inductive pigmented spots place, 2 times on the one, was coated with the checking whitening effect one month.

Evaluation is to measure with colour difference meter (シノ Le corporate system, CR-300), calculates L from Munsell value ^*Value is used the Δ Δ L that represents its recovery ^*Value.

Δ Δ L ^*Value defined is as follows.

The L that is tested the position that is tested position and uncoated sample of the coated sample when the sample coating has just begun ^*Value is used L respectively ₀, L ₀, represent, be coated with the L at each position after month continuously ^*Value is used L respectively ₁, L ₁, expression, Δ Δ L ^*Value is represented with following formula.

ΔΔL ^*＝(L ₁-L ₀)-(L _1’-L _0’)

Evaluation is to represent with the meansigma methods of 20 testees' evaluation branch.Table 6 has provided the relation of dividing with criterion of estimating.

Table 6

Evaluation score	Criterion
Evaluation score	Criterion	5 4 3 2 1	1.0≤ΔΔL ^* 0.5≤ΔΔL ^＜1.0 0.2≤ΔΔL ^＜0.5 0≤ΔΔL ^＜0.2 ΔΔL ^＜0

Table 7

	Composition (weight %)	Embodiment 33	Embodiment 34	Comparative example 5
	Composition (weight %)	Embodiment 33	Embodiment 34	Comparative example 5	a b c d e f g h i j k l	Polyoxyethylene hardened castor oil (50 E.O. ^1) sorbitan monostearate spiral shell ether compound ^2The different n-nonanoic acid isotridecyl esters of three decanes (δ=15.7) (δ=16.56) single isostearic acid list myristic acid diglycerides (δ=18.43) lactic acid octyl group dodecyl esters (δ=18.53) succinic acid 86% glycerine 1,3-BDO water xanthene natural gum	21 0.01-6 2-0.5 10 5 surpluses 0.5	21 0.01-6-2 0.5 10 5 surpluses 0.5	21 0.01 8---0.5 10 5 surpluses 0.5
Percutaneous permeability is estimated (the spiral shell ether compound is to the infiltration capacity of horny layer and epidermis after 18 hours) μ g/cm ²		0.59	0.62	0.13	a b c d e f g h i j k l		21 0.01-6 2-0.5 10 5 surpluses 0.5	21 0.01-6-2 0.5 10 5 surpluses 0.5	21 0.01 8---0.5 10 5 surpluses 0.5
		0.59	0.62	0.13	Whitening effect evaluation score (meansigma methods)		4.95	4.98	2.11

Embodiment 35-37

Manufacturing table 8 provides the cosmetics of composition according to conventional methods.The same whitening effect of estimating with embodiment 33-34.Table 8 has provided evaluation result.

Table 8

Composition (weight %)	Embodiment			Comparative example
	Embodiment			Comparative example		35	36	37	6	7
	Polyoxyethylene hardened castor oil (50 E.O. ^1) sorbitan monostearate Radix althaeae roseae extract ^2 Aloe extracts ^3 kojic acids ^The different n-nonanoic acid isotridecyl esters of 4 three decanes (δ=15.7) (δ=16.56) single isostearic acid list myristic acid diglycerides (δ=18.43) succinic acid 86% glycerine 1,3-BDO water xanthene natural gum	21 0.9 62 0.5 105 aequums 0.5	21 0.9 62 0.5 10 5 aequums 0.5	21 1.0 62 0.5 10 5 aequums 0.5	21 0.9 8 0.5 10 5 aequums 0.5	35	36	37	6	7	2118 0.5 10 5 aequums 1.5
Whitening effect evaluation score (meansigma methods)		21 0.9 62 0.5 105 aequums 0.5	21 0.9 62 0.5 10 5 aequums 0.5	21 1.0 62 0.5 10 5 aequums 0.5	21 0.9 8 0.5 10 5 aequums 0.5	4.23	4.06	4.55	2.05	1.98	2118 0.5 10 5 aequums 1.5

^*1: oxirane addition molal quantity

^*2: Off ァ Le コレ Star Network スア Le テア (a ball Off ア Le コス company)

^*3: ァロ-グ-プリキ Star De (a ball Off ァ Le コス company)

^*4: sheet mountain chemical industrial company

Embodiment 38-40

Manufacturing table 9 provides the cosmetics of composition according to conventional methods.Estimate its antiinflammatory effect.Table 9 has provided evaluation result.

(evaluation methodology)

The inboard ultraviolet that uses a UV-B zone of the FS-20SE of Toshiba light irradiation of wrist on 20 healthy man testees, irradiation dose is 2 times of amounts (2MED) of minimum erythema dose, is coated with each cosmetics of 15 μ l afterwards at once, measures the redness (a after 24 hours ^*Be worth) and skin temperature.

Redness is measured with colour difference meter (ミノ Le corporate system, CR-300), calculates a from the Munsell value that obtains ^*Value, a of UV-B irradiation after 24 hours ^*Value and pre-irradiation a ^*Value is compared, and the amount of rising is defined as Δ a ^*Value.And skin temperature is that ( スコジヤパ Application corporate system THI-500) is measured with the radiation thermometer.The result represents with meansigma methods.

Table 9

Composition (weight %)	Embodiment			Comparative example
	Embodiment			Comparative example			38	39	40	8	9	10
	Polyoxyethylene hardened castor oil (50E.O. ^1) sorbitan monostearate spiral shell ether compound ^The different n-nonanoic acid isotridecyl esters of 2 glycyrrhizic acid EACAs, three decanes (δ=15.7) (δ=16.56) single isostearic acid list myristic acid diglycerides (δ=18.43) succinic acid 86% glycerine 1,3-BDO water xanthene natural gum	21 0.1 62 0.5 10 5 aequums 0.5	21 0.1 62 0.5 105 aequums 0.5	21 0.1 62 0.5 10 5 aequums 0.5	21 0.1 8 0.5 10 5 aequums 0.5	21 0.1 8 0.5 105 aequums 0.5	38	39	40	8	9	10	2162 0.5 10 5 aequums 0.5
Δa ^*Value (meansigma methods)		21 0.1 62 0.5 10 5 aequums 0.5	21 0.1 62 0.5 105 aequums 0.5	21 0.1 62 0.5 10 5 aequums 0.5	21 0.1 8 0.5 10 5 aequums 0.5	21 0.1 8 0.5 105 aequums 0.5	3.89	4.06	4.12	4.87	4.69	5	2162 0.5 10 5 aequums 0.5
Δa ^*Value (meansigma methods)	The skin temperature (meansigma methods) of 2MED irradiation after 24 hours	33.1	33.2	33.1	33.8	33.7	3.89	4.06	4.12	4.87	4.69	5	34

^*1: oxirane addition molal quantity

^*2: the mixture of spiral shell ether compound E/Z=5/1

Embodiment 41-45

Provide the skin-lightening cosmetic of composition below making according to conventional methods.

Embodiment 41 (emulsion)

(composition) (weight %)

(1) Palmic acid 1.0

(2) stearic acid 1.0

(3) hexadecanol 1.0

(4) single cetyl sodium phosphate 2.0

(5) the monostearate sorbitan 0.5

(6) glycerol 10.0

(7) ethanol 5.0

(8) spiral shell ether compound Z 0.5

(9) different n-nonanoic acid isotridecyl ester (δ=16.56) 3.0

(10) single isostearic acid list myristic acid diglyceride (δ=18.43) 1.0

(11) lactic acid 2.0

(12) arbutin 3.0

(13) Purified Water surplus

Embodiment 42 (emulsion)

(composition) (weight %)

(1) 1,3 butylene glycol 3.0

(2) glycerol 5.0

(3) hyaluronate sodium 0.2

(4) polyacrylic acid (carbopol; Uncommon corporate system in the Gourde(G)) 0.2

(5) potassium hydroxide 0.06

(6) polyoxyethylene hardened castor oil (40E.O. ^{* 1}) 1.0

(7) α-single Glycerol monoisooctadecyl ether 0.2

(8) the monostearate sorbitan 0.2

(9) spiral shell ether compound Z 0.01

(10) different n-nonanoic acid isotridecyl ester (δ=16.56) 5.0

(11) single isostearic acid list myristic acid diglyceride (δ=18.43) 1.0

(12) succinic acid 1.5

(13) carbamide 2.0

(14) episilon amino caproic acid 1.0

(15) Chamomile (Chamomile extracting solution; One ball Off ァ Le コス corporate system) 5.0

(16) Bovine Placenta extracting solution (PVC オ Off ァ Le コ CP-20; One ball Off ァ Le コス corporate system) 1.0

(17) Purified Water surplus

^*1 oxirane addition molal quantity

Embodiment 43 (cream)

(composition) (weight %)

(1) stearic acid 2.0

(2) different n-nonanoic acid isotridecyl ester (δ=16.56) 7.0

(3) single isostearic acid list myristic acid diglyceride (δ=18.43) 4.0

(4) cholesterol 3.0

(5) hexadecanol 2.0

(6) 2-cetyl L-Arginine phosphate. salt 2.0

(7) polyoxyethylene hardened castor oil (40E.O. ^{* 1}) 0.5

(8) α-single Glycerol monoisooctadecyl ether 0.2

(9) spiral shell ether compound Z 0.01

(10) spiral shell ether compound E 0.01

(11) succinic acid 1.0

(12) kojic acid 1.0

(13) glycerol 5.0

(14) hyaluronate sodium 0.05

(15) polyacrylic acid (carbopol; Uncommon corporate system in the Gourde(G)) 0.5

(16) sodium hydroxide 0.15

(17) Purified Water surplus

^*1 oxirane addition molal quantity

Embodiment 44 (vanishing cream)

(composition) (weight %)

(1) titanium oxide 6.0

(2) silk Muscovitum 8.0

(3) ferrum oxide (red, yellow, black) 1.2

(4) sorbitan fatty acid ester (レオ De-Le MO-6; KAO. Corp. SA's system) 5.0

(5) different n-nonanoic acid isotridecyl ester (δ=16.56) 12.0

(6) single isostearic acid list myristic acid diglyceride (δ=18.43) 3.0

(7) dimethyl polysiloxane (KF96A 6cs; Chemical company of SHIN-ETSU HANTOTAI system) 30.0

(8) spiral shell ether compound Z 0.01

(9) glycerol 2.0

(10) Purified Water surplus

Embodiment 45 (powdery foundation cream)

(composition) (weight %)

(1) titanium oxide 10.0

(2) silk Muscovitum 30.0

(3) Pulvis Talci surplus

(4) potter's clay 5.0

(5) red iron oxide 2.0

(6) yellow iron oxide 2.5

(7) black iron oxide 0.1

(8) polyethylene powders 4.0

(9) different n-nonanoic acid isotridecyl ester (δ=16.56) 1.5

(10) single isostearic acid list myristic acid diglyceride (δ=18.43) 0.6

(11) dimethyl polysiloxane (KF96A 6cs; Chemical company of SHIN-ETSU HANTOTAI system) 12.0

(12) spiral shell ether compound Z 0.01

The percutaneous absorbability of any effective ingredient of skin-lightening cosmetic that is obtained by embodiment 41-45 is all good, and whitening effect is superior, and safe, and usability is also good.

Claims

1. a Percutaneous absorption enhancer is characterized in that, the oil preparation (a-1) and the δ that are in 15.7＜δ≤17.2 scopes with solubility parameter δ are in the interior oil preparation (a-2) of 17.5≤δ≤21.0 scopes as effective ingredient,

The weight ratio (a-1)/(a-2) of described oil preparation (a-1) and described oil preparation (a-2) is 10/1～1/2,

Described oil preparation (a-1) is at least a oil preparation that is selected from three decanes and different n-nonanoic acid isotridecyl ester,

Described oil preparation (a-2) is for being selected from least a oil preparation of single isostearic acid list myristic acid diglyceride and lactic acid octyl group dodecyl ester.

2. cosmetics is characterized in that containing composition (a) and (b),

Described composition (a) comprise (a-1) solubility parameter δ be in 15.7＜δ≤17.2 scopes oil preparation and (a-2) solubility parameter δ be in oil preparation in 17.5≤δ≤21.0 scopes,

Described oil preparation (a-2) is at least a oil preparation that is selected from single isostearic acid list myristic acid diglyceride and lactic acid octyl group dodecyl ester,

Described composition (b) is the material of Pear Power effect, antiinflammation and moisture-keeping function.

3. cosmetics as claimed in claim 2 is characterized in that, described composition (a) is to combine by weight (a-1)/(a-2)=10/1～1/2 by oil preparation (a-1) with (a-2).