TW201143806A - Zederone related material and synthesis method thereof - Google Patents

Abstract

The present invention provides a zederone related material originating from natural substance, and a synthesis method of precursors useful for synthesizing the zederone related material or intermediates useful for synthesizing the zederone precursors. Specifically, the present invention uses (E)-5-halogenated-4-sorbic acid alkyl ester as an initial substance to synthesize zederone related material, precursors useful for synthesizing the zederone related material or intermediates useful for synthesizing the zederone precursors.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a natural origin oxime epoxy ketone related to a melanin production inhibitory effect and a method for synthesizing the same. [Prior Art] Since the prior art, various external preparations for whitening which improve skin tone, black or chloasma, freckles and the like have been provided. Among the whitening ingredients formulated as an active ingredient of a whitening agent, arbutin or kojic acid, ascorbic acid and derivatives thereof, giutathi〇ne, gum Colloidal sulfur or the like has been used as a well-known substance. In recent years, 4-MSK (4-methoxysulfonic acid potassium salt, 4_meth〇xy salicylic acid) or Rucino® (registered trademark), Magn〇 Iignan (registered trademark), ellagic acid or linoleic acid (Un〇ieic) is used as an active ingredient in a commercially available whitening external preparation. In addition to the above compounds, 'Bear grape leaf extract Or various extracts of animal and plant extracts such as zephyr extract, chamomile extract, mulberry extract, and placenta extract, and sea stagnation are also used as active ingredients of whitening bud (4). However, there are few records indicating these plants and animals. The extract contained in the extract contains the whitening effect of the middle-class ingredients. So far, the bear (4) in the 4-leaf extract has a whitening effect, and in recent years, it has only been exposed: the whitening effect is well known. The condensed-type acid-type substance of the (four) structure in the leaf bean extract has a whitening effect (refer to the patent text. On the other hand, it is also the fact that various whitening ingredients are found in the plant extract of the whitening effect). I48986.doc 201143806 ( For example, refer to Patent Document 2). The zederone shown in the following formula has been confirmed since its existence in Curcuma zedoaria Roscoe (Zingiberaceae 'Gingeraceae: alias Ziphoran) (Non-Patent Document 1), It has been reported many times that the oxime ketone is not only found in zedoary, but also in the genus Curcuma as its related plant, such as C. phaeocaulis or turmeric called Curcuma longa [syn. C Domestica]: an alias of autumn turmeric, Curcuma aromatica SaUsb, and Chloranthus serratus (Chloranthaceae) and the like (see, for example, Non-Patent Documents 2 to 4).

There are many reports that 'the extract of zedoary turmeric and the extract of turmeric exhibit an anti-allergic effect (see Patent Documents 3 to 6) or have a squatting effect (refer to Patent Document 7), and have hair growth. Promoting effect (refer to Patent Reading 8), blood circulation promoting fairy (refer to Patent Document 9), anti-aging or wrinkling effect (refer to the patent literature and other pharmacological effects. However, the applicant of this case has confirmed as turmeric The autumn turmeric of the plant does not have a whitening effect (refer to Patent Document (1), and even if it is a plant extract containing the same (4) epoxy ketone, it does not all play a whitening effect, so it is not the essence of the whitening ingredient of the epoxy ketone. J48986.doc 201143806 Furthermore, the industry has conducted various studies on the mechanism of whitening effect, and found various mechanisms of action. For example, it was found that the c_kit gene is involved in the production of melanin, which is disclosed in the above-mentioned Patent Document ,1, which is 50% (v. /v) Ethanol extracts exert a whitening effect by inhibiting the expression of the c-kit gene. However, even if found as described above The inhibition of the expression of the e_kit gene as a mechanism of action of the extract of the box i_ is not a month as described above, which substance contained in the extract is involved in the inhibition of the expression of the c-kit gene. It is known that the epoxy ketone is known to have antibacterial activity (refer to Non-Patent Document 5), w and has prevention by D_(五)滋滋(Dg山Ctosamine/Hpop〇lysaccharide, D galactosamine/lipid listen The effect of the induced liver disease (refer to Non-Patent Document 6). &, in the above patent, contains an extract of sputum containing a sulphur ketone which promotes skin activation. The essential oil component containing the bismuth epoxy copper exhibits the detoxification function of the liver and the strong diuretic effect, the antibacterial action, and the inhibition of cholesterol. In the above Patent Document 12, it is revealed that (4) the epoxy ketone and the like (4) The class exhibits anti-living habits of disease's. However, the patent literature does not explicitly indicate that the ketone ketone directly exhibits these effects. Moreover, as a substance having anti-inflammatory activity, it is known that it contains展二稀_ (Refer to Non-Patent Document 7), the effect of self-destruction in the sputum and the effect of succulent cancer. 'As a substance against anti-cancer activity, 莪 % % 二烯 _ ( (refer to the non-patent literature) 8) Further, as a substance having an antibacterial action, an antibacterial or an antiviral effect, an anthracycline and an anthraquinone are known (refer to Patent Document 13). 148986.doc 201143806 As described above, I saw a report on the whitening effect of materials such as box epoxies. 'The actual situation is that there is almost no knowledge of the whitening ingredients in the extracts of zedoary turmeric. Under such technical background, the inventor and others directly seek a kind of Unlike the former whitening component, that is, ascorbic acid is easily oxidized and unstable, and various derivatives are currently used, but as a cosmetic material for contacting human skin, a component derived from a natural product is used. Face cystein or sulphur has the disadvantage of producing a characteristic odor or precipitate. Animal and plant extracts and seaweed extracts have insufficient effects or unstable quality. Tannic acid, bearberry bitter with phenolic groups, and tannic acid in Turkey cause coloration in the presence of a base or in the presence of a metal ion, and thus have problems in preparations that have to be considered to maintain their stability. Further, the sesquial vinegar disclosed in the above Patent Document 2 is known to have a characteristic odor, and the stability of the oily compound is not good, so that it is difficult to stably prepare the product. As described above, the whitening components hitherto have some disadvantages, respectively. The inventors of the present invention have made great efforts under the above background art, and as a result, found that the oxime epoxy ketone contained in the extract has a whitening effect, and particularly has a black pigmentation inhibiting effect. [PRIOR ART DOCUMENT] [Patent Document 1] Japanese Patent Laid-Open No. 3650245 [Patent Document 2] Japanese Patent Laid-Open Publication No. Hei 2 No. 5-2〇5〇 [Patent Document 3] Japanese Patent Laid-Open Publication No. SHO-62-108822 [Patent Document 5] Japanese Patent Laid-Open No. SHO 62-108822 [Patent Document 6] Japanese Patent Laid-Open Patent Publication No. JP-A-62-108822 Japanese Laid-Open Patent Publication No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. [Patent Document 10] Japanese Patent Laid-Open Publication No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. Japanese Patent Laid-Open Publication No. 2000-1 19188 [Non-Patent Document] [Non-Patent Document 1] Hiroshi Hikino et al_, Chemical Pharmaceutical Bulletin (1968), 16(6), 1081-1087. [Non-Patent Document 2] Yu-Chi Hou et al., Chinese Pharmaceutical Journal (Taipei) (1997), 49(2), 119-125. [Non-Patent Document 3] Jun Kawabata et al_, Agricultural and Biological Chemistry (1985), 49(5), 1479-1485 〇 [Non-Patent Document 4] Minh Giang Phan et al., Tap Chi Hoa Hoc (2000), 38 (4), 96-99 = " [Non-Patent Document 5] Minh Giang Phan et al., Tap Chi Hoa Hoc - (2000), 38(1), 91-94. [Non-Patent Document 6] Hisashi Matsuda, Chemical Pharmaceutical Bulletin (2001), 49(12), 1558-1566. [Non-Patent Document 7] Η· Makabe et al., Natural Product Research, Part B: Bioactive Natural Products (2006), 20(7), 680-685 o 148986.doc 201143806 [Non-Patent Document 8] Kazuo Watanabe et al ·, Yakugaku Zasshi (1986), 106(12), 1137-1 142. [Non-Patent Document 9] K. Kuramochi et al., Tetrahedron (1999), 55, 7145. [Non-Patent Document 10] PD Howes et al., 〇rg. Syn, Coll. (1988), V〇l 6, P31 〇 [Non-Patent Document 11] E. Wenkert et al., Tetrahedron Lett. (1999), 40, 5171. [Problems to be Solved by the Invention] As described above, the inventors of the present invention have found for the first time that a sulphur-containing ketone derived from a natural product has a melanin production-inhibiting effect, but the synthesis method has not been established at all. Accordingly, there is a need for a method of synthesizing an oxime epoxy ketone precursor useful for the synthesis of steroidal ketones derived from natural sources or an intermediate useful for synthesizing the above-described oxime epoxy ketone precursor. [Technical means for solving the problem] The inventors of the present invention made great efforts under the above background art, and as a result, established an alkyl ketone ketone by using (E)-5-halogenated 4-hexenoic acid alkyl ester as a starting material. Related substances, methods for synthesizing precursors and intermediates for synthesizing the above related substances. [Effects of the Invention] According to the present invention, it is possible to stably obtain a related substance of a sulphuric acid ketone which is derived from a natural substance having a melanin production-inhibiting effect, and a precursor and an intermediate which are useful for synthesizing the above related substances. 148986.doc 201143806 Further, a melanin production inhibitor and an external preparation for skin having the above-mentioned zephyrone ketone related substance or its precursor as an active ingredient can be obtained. Further, a melanin production inhibitor and a skin external preparation containing the above-mentioned zephyrone ketone related substance, an intermediate, and a specific whitening agent as active ingredients can be obtained. [Embodiment] That is, the present invention provides: D] a method for producing a cyclic epoxy ketone compound, which is a formula (6): [Chemical 2]

(6) Those who are not cyclic epoxy ketone compounds, and which include the following steps: (A) Formula (0): [Chemical 3]

Xi^l〇R (.) [wherein, X1 is C1, Br or U is a substitutable Ci~Ci〇's base] The toothed dilute acid S-based S is intended to be reduced a compound, and then, in the presence of an acid catalyst, the aldehyde group of the above aldehyde compound is protected with a substituted alcohol or a substituted C2 diol to form the formula (1): [Chemical 4]

(1)

Can be replaced by C丨~C

[wherein X1 is CBr or I; R1 and R2 are independently alkyl of 148986.doc 201143806, or R1 and r2 together form a acetal compound of a C2~alkylene group which may be substituted; (B) Equation (2): [Chemical 5]

[Formula, wherein R is hydrazine, Li, Na or K], or a salt thereof, at -80 to 25 ° C, preferably _30 to 〇t:, with a strong base and halogenated The acetal compound represented by the formula (1) is subjected to treatment at a temperature of -80 to 25 ° C, preferably -30 ° (at TC, with the treated formula (in the presence of a transition metal catalyst). 2) reacting the furfuryl carboxylic acid or a salt thereof, and then raising the temperature of the reactant to 25 ° C to 150 ° C, preferably 60 to 80 ° C, to produce the formula (3): [Chemical 6]

Wherein R1 and R2 are the same as defined above, and R3 is an acetal compound having a carboxylic acid or a carboxylate as shown by H, Li, ^^ or "; (C) adding the formula (3) The acid or carboxylic acid salt of the acetal compound having a carboxylic acid or a carboxylate is reacted with an electrophilic halogenating agent in an inert gas atmosphere to form a carboxylic acid dentate such that the above carboxylic acid compound and phosphinyl group B The acid ester reacts to form an acetal compound added with phosphinic acid acetate, and then is hydrolyzed and detached by adding the above-mentioned phosphinyl acetic acid acyl acid compound to 148986.doc •10·201143806 The alkoxycarbonyl group is formed into an acetal compound to which a phosphonate is added, and the acetal compound to which the phosphonate is added is subjected to deacetalization under acidic conditions to form the formula (4):

[化7J

Wherein R 4 and R 5 are independently alkyl or aryl of the substituted c丨~c] 2 or R 4 and R 5 are as defined by the C 2 CM alkyl group which may be substituted; An aldehyde compound having a phosphonate; and (D) cyclizing an aldehyde compound having a phosphonate ester represented by the formula (4) to form a formula (5):

The cyclic ketone compound is shown in the item [1], which further comprises the following steps: (E) reacting a cyclic ketone compound represented by the formula (5) with hydrogen peroxide under basic conditions; , generating formula (6): [Chemical 9]

The cyclic epoxy ketone compound shown; 148986.doc 201143806 [3] A method for producing an acetal compound having a carboxylic acid or a carboxylate, which is a formula (2):

[In the formula, R is hydrazine, Li, Na or K] is a sulphonic acid or a salt thereof, and is strongly neutralized and halogenated at -80 to 25 ° C, preferably -30 to 〇 ° C. Zinc is treated, and then in the presence of a transition metal catalyst, the formula (1): [11] R10 OR2 [wherein, X1 is Cl, Br or I'R1 and R2 are independently substituted c The alkyl group of Ci〇, or R1 and R2 together form an acetal compound of a C2~Cw alkyl group which may be substituted, is preferably -30 to 0 ° C at -80 to 25 ° C. (:, reacting with the treated furanyl carboxylic acid of the formula (2) or a salt thereof, and then raising the reactant to 25 C 15 15 C, preferably 60 to 80 C, to form a formula ( 3): [Chemistry 12]

[Formula wherein 'R and R are the same as above' and r3 is the same as the above] is an acetal compound having a slow acid or a carboxylate; [4] a method for producing a cyclic ketone compound, which is a formula ( 4): [Chem. 13] 148986.doc • 12- (4) 201143806 °V〇R4

O' [wherein R4fR5 is independently an alkyl or aryl group of Ci~c 2 which may be substituted, or R4 and R5- is a C2~C24 alkyl group which may be substituted] There is a compound of phosphonic acid S, which is a salt of metal or magnesium. It is preferably a chemical or a toothed town. It is better to be chlorinated in the presence of chlorine and desertification. ): [Chem. 14] Ο

(5) a cyclic ketone compound as shown; and [5] a method for producing a cyclic epoxy ketone compound, which is obtained by the formula (5)

(5) The ring is not in the ring, the compound and hydrogen peroxide are in the alkaline condition. (6): 'The next reaction, the formation [Chemical 16]

(6) The [6] $襄-like epoxy ketone compound acetal compound shown by the formula (丨) is not 148986.doc -13· (1) 201143806 [Chemical 17] I R10 OR2 [wherein, X Is Cl, Br or I ' R and R are independently a substituted a ~ 匸 alkyl, or R 1 and R 2 together form a substituted C 2 ~ C m alkyl]; [7] An acetal compound having a carboxylic acid or a carboxylate represented by the formula (3): wherein R1 and R2 are independently a substituted Ci~CiQ alkane The base, or Ri and R2 together form a replaceable C2 to C2. The extension of the base, or K]; [8] - an aldehyde compound added with a phosphonic acid vinegar, which is represented by the formula (4): [Chem. 19]

Η [^^^ is independently a county or aryl group which can be substituted, or R and R- are substituted C2~C24; [9] - a cyclic compound It is expressed by the formula (7): [Chem. 20], not · 148986.doc 14· 201143806

; and its expression is expressed by equation (6)··

[10]-A cyclic ring I ketone compound [Chemical 21J

(6) = The cyclic epoxy ketone compound (cyclic epoxy ketone compound (6)) shown is the compound (9), and the cyclic ketone compound represented by the formula (5) (_cyclic epoxy ketone compound (6) (iv) precursor. Further, the compound (the compound (1)), the acetal compound of the addition acid or the carboxylate represented by the formula (7) (the addition of the carboxylic acid or the carboxylate (10) (10) and the formula (4) The compound of the sorrel vinegar (:: bismuth compound (4) with phosphonic acid vinegar) is an intermediate useful for synthesizing a cyclic _ compound and a cyclic epoxide (tetra) compound, all of which are new赖之化\物。 、 〇 者 ' 本 ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' The alkyl group of m to η. Further, the "alcohol which can be substituted by c. ~ &" means that the total carbon number of the linear or branched type which may be substituted by a phenyl group or the like may be 〇~p. One of the sterols. The so-called "distillable Cq~Cr diol" means a linear or branched type having a total carbon number of q~r which may be substituted by a stupid group or the like. A non-alcohol. The so-called "c-alkyl group which can be substituted by Cs~ct" refers to a linear or branched type of carbon which may be substituted by a stupid base or the like. The total carbon number is s~t. 148986.doc -15- 201143806 Alkyl group. The term "alkyl or aryl group of Cu~^ which may be substituted" means a linear or branched type which may be substituted by a halogen atom such as fluorine or a phenyl group. The alkyl group having a total carbon number of u to v or an aryl group having a total carbon number of 6 to v which may be substituted with a sulfhydryl group, an ethyl group or the like, an alkyl group such as a ruthenium group or a phenyl group, etc. The present invention further provides a aryl group having a total carbon number of 6 to v. A melanin production inhibitor. The melanin production inhibitor of the present invention is a cyclic oxime compound (5), a cyclic epoxy (tetra) compound (6) or a combination thereof which is synthesized by the method of the present invention as an active ingredient. That is, the present invention provides: 1] a melanin production inhibitor which is of the formula (5): [Chem. 22]

(5) The cyclic ketone compound, formula (6): [Chem. 23]

(6) A combination of a cyclic epoxy ketone compound or a combination thereof as an active ingredient. The invention further provides a cosmetic agent comprising a melanin production inhibitor. The external preparation for skin of the present invention is a cyclic ketone compound (5) or a cyclic epoxy ketone compound which is obtained by the method of the present invention. [12] - A topical preparation for skin, which is of the formula (5): [Chem. 24] J48986.doc •16· 201143806

The cyclic ketone compound shown, the cyclic epoxy ketone compound represented by the formula (6): [b25] bdt) (6), or the like, is an active ingredient. The cyclic oxime compound (5) and the cyclic epoxy compound (6) of the present invention used in the melanin production inhibitor of the present invention and the external preparation for skin are considered to have a high melanin production inhibitory effect as shown in the following examples. Compared with the bear fruit bitterness, it exhibits a fan-fold effect, that is, the use amount of about 1/200 of the bear fruit bitterness can exhibit the same melanin production inhibitory effect. In the external preparation for skin or the like, an effective amount of the cyclic ketone compound (7) and the cyclic ring compound (4) which exert an effective whitening effect are formulated according to the dosage form, and specifically, the amount of the f is adjusted to the skin in a total amount of two or two. The total I of the phase agent is about 〇.〇_01 to about U mass%, preferably about 0.00001 to about 0.01% by mass, and the effect can be obtained by a blending amount of about 0.005 mass%. > The present invention further provides a whitening skin comprising the above-mentioned cyclic ketone compound (5), cyclic epoxy ketone compound (6) or the like, and one or two or more specific whitening agents as active ingredients External preparation. That is, the present invention also provides:

H3J is a skin external preparation for whitening, which is based on formula (5) ·· fization 26J 148986.doc •17- (5) 201143806

Ring-shaped compound represented by formula (6) [Chem. 27]

(6) A cyclic epoxy compound as shown or a combination thereof, or a specific whitening agent of two or more kinds as an active ingredient. The specific whitening agent to be used in the external preparation for skin is not particularly limited as long as it is =:, = the effector, and it is preferred to use soil and its derivatives, face acid, ascorbic acid and its derivatives, :: substance, placenta The extract, -1:::: is not limited to p-benzoic acid (10) #, and (10), for example, p-benzo-yttrium-glucose, p-benzoquinone-β-glucose (bearberry bud), p-dichromate, Benzene: (tetra) seven (four) sugar, p-benzene, etc. a_D-half-p-benzoate-called galactose, bismuth galactose, benzoin-galactose and other hexose sugar m^a_D•ribose, pair Benzene divergence - ribose, p-phenylene wL_ribose, p-phenylene ribose, p-phenylene di-arabinose, p-benzene, _D_arabinose, p-phenylene--arabino-p-benzoquinone _ Arabia Pentose, such as sugar, benzodiazepine, p-benzoic acid, glucosamine, p-benzoquinone 148986.doc -18- 201143806 -α-L-glucosamine, hydroquinone _p_L-glucosamine, Hydroquinone π7, galactoside, hydroquinone 邛_〇_galactosamine, hydroquinone-a_L_galactosamine, hydroquinone-β-L-galactosamine Equivalent amine Glycoside; hydroquinone. Glucuronic acid, hydroquinone-β-D-glucuronic acid, hydroquinone glucuronic acid, hydroquinone glucuronic acid, hydroquinone galacturonic acid, pair Hydroquinone·β_〇•galacturonic acid, hydroquinone galactose age k, phenolic acid glycoside such as stupid quinone _P_L_galactose acid, etc. In the case of the sputum, the vinegar such as acetate, acetate, etc., etc. can be exemplified. Among these, in terms of effects, ease of acquisition, stability, and the like, it is most preferable to be benzodiazepine-β-D-glucose. Further, the ascorbic acid and the derivative thereof are not particularly limited, and examples thereof include L. ascorbic acid monostearic acid vinegar or [ascorbic acid monosodium sulphate monohydrate fatty acid vinegar, L-ascorbic acid monophosphate vinegar or L-ascorbic acid mono- vinegar such as L-ascorbic acid 2-sulfate vinegar, [_ ascorbate glucosamine, etc., ascorbate glucosamine or its salt. Examples of the salt include salts of sodium, potassium, magnesium, ammonium salts, amine acid salts, and triethanolamine. Further, it is not particularly limited as the tranexamic acid and its hydrazine, and for example, a dimer of a tranexamic acid (for example, trans-ice (trans-amino-mercaptocyclohexylcarbonyl) Aminomethylcyclohexyl carboxylic acid, etc., tranexamic acid and p-benzoic acid (for example, trans-terminated methylcyclohexyl decanoic acid 4,-p-phenylene, etc.) Acidic g-form (eg '2_(trans-4_aminomethyl\oxy) 5-hydroxybenzoic acid and its salts, etc.) 'transaminic acid amides (eg 'trans--4 amines' Methylcyclohexyl hydrazine methyl decylamine and its salt, trans (p-methoxybenzylidene) aminomethylcyclohexyl acid and its salt, trans 148986.doc 19 201143806 -4- Methylcyclohexyl tarenic acid and its salts, etc.). Further, 'as a salicylic acid and a derivative thereof, it is not particularly limited, and examples thereof include salicylic acid, 3-methoxysalicylic acid and salts thereof, "oxysalicylic acid and salts thereof, and 5-methoxyl. Further, as the hydrazine, each salt such as sodium, smear, magnesium or triethanolamine may be mentioned. Further, 'm-benzoquinone and a derivative thereof are not particularly limited, and examples thereof include: m-benzene. An alkyl resorcinol such as diphenol or 4-n-butyl resorcinol, or the like, and the like, and examples of the salt include various salts such as sodium, magnesium, and triethanolamine. It is not particularly limited as long as it has a melanin production inhibitory action, and examples thereof include a seed extract of Heilongjiang (He丨a_s L.), a Clematischinensis 〇sbeck extract, and a rose extract (Western Rose). (Rosa centif〇Ua (R〇saceae, Rosaceae or Rose (Rosa Hybrids)), Polygonum striata (Reyn〇utria jap〇nica Houtt. var. japnica) extract, etc. Further, in the present invention, it is also possible to use Natural medicine for any part of the plant, sunflower extract is preferably used From the natural medicine of sunflower seeds, Clematis extract, rose extract, and Polygonum cuspidatum extract are preferably used as a natural medicine derived from the roots 'leaves and petals. The plant extract used may be free of the extract itself. The problem is that the extract is obtained by concentrating the extract, and the powder is prepared by cold-blowing, etc. Further, the preparation method of the plant extract is not particularly limited, and various appropriate methods can be used for the extraction. The extraction solvent is extracted from plants rich in various compounds at a low temperature and/or under heating. 148986.doc -20- 201143806 For example, the following lower alcohols such as a solvent alcohol can be used, and the extraction solvent used in the process is also used. There is no particular limitation, one or two or more: liquid polyol such as water, methanol, ethyl oil, propylene glycol, u-butylene glycol, ketone such as acetone or methyl ethyl hydrazine, ethyl m (tetra) benzyl n, a feed hydrocarbon An ether such as diethion, a halogenated alkane such as dichloromethane or chloroform, etc. Among them, one or a mixture of two or more of water, ethanol and 1,3-butanediol is preferred. Use relative to no The treated or dried plant body is in a weight ratio of about 1 to 1000 times by weight, preferably about 1 〇 to 1 〇〇 times the solvent, above 〇 ° C, preferably 2 (TC ~ 40 °) The extraction is carried out for 1 hour or more, preferably 3 to 7 days. Any part of the plant body can be used for the extraction site, and the whole plant can also be used. For example, 'the seed of sunflower (Helianthus annus L.), clematis (ciematiSChinensis0sbeck) ) roots, western rose (R〇sacentif〇iia (Rosaceae) petals, rose flowers (RosaHybrida (Rosaceae) petals, Polygonum japonica Houtt· var. japnica) 1 mL of a 5 % by weight (v/v) aqueous ethanol solution was added thereto, and the mixture was extracted while stirring at room temperature for 7 days, and filtered to obtain each extract. Each of the extracts was concentrated under reduced pressure, and then lyophilized to obtain an extract. In the external preparation for skin of the present invention, the specific whitening agents are preferably formulated in a total amount of one or more of two or more, preferably more than about 0,01 to 10% by mass. {^ When it is less than about 0.001 mass / 〇, it is difficult to give full play to the effect of the invention of the present invention. On the other hand, even if the blending exceeds about 20% by mass, the correspondingly greater effect is not confirmed. 148986.doc • 21 · 201143806 The melanogenesis inhibitor of the present invention is usually used in various cosmetic bases or external pharmaceutical bases, and is, for example, provided as a skin external preparation including the following: cream, lotion Various make-up materials such as lotion, lotion, facial cleanser, foundation, blush, honey powder and other make-up cosmetics, shampoo 'hair-forming agent' shampoo, moisturizer and other hair cosmetics and soap Other cosmetic materials such as oyster sauce and cologne, as well as suitable for skin and medical external preparations. Examples of the base material for the cosmetic material, the outer layer, and the solid form include various oily materials such as fats and oils, waxes, hydrocarbon oils, higher fatty acids, vinegar oils, and polyoxime oils, water, alcohols, and polyhydric alcohols. Further, in the above cosmetic or medical external preparation, in addition to the above-mentioned base, the following additives may be formulated: an anionic surfactant, a cationic surfactant, an amphoteric surfactant, a nonionic surfactant, and pH adjustment. Agent, various water-soluble polymers, thickeners, ultraviolet absorbers, metal ion blockers (chelators), sugars, amino acids, organic amines, polymer emulsions, vitamins, antioxidants, antioxidants, Humidifiers, anti-(4), antibacterial agents, cell activators, perfumes, pigments or pigments, colorants, preservatives, etc. The dosage form of the cosmetic or the medical external preparation is not particularly limited, and examples thereof include a liquid or emulsion, an ointment, a sol, a gel, a powder, a spray, and the like. By making such a cosmetic or medical material (4) effect. Slave 10, [Examples] 148986.doc • 22· 201143806 Example 1 Synthesis of (E)-2-(4-bromopent-3-enyl)-1,3-dioxolane (1,) [ 28]

In an argon atmosphere, y-5_bromo-4-enoate (0') (284 mg, 1.4 mmol) synthesized according to Non-Patent Document 9 was dissolved in tetrahydrofuran (5 〇mL) and cooled to After -78 C, diisobutylaluminum (丨〇M tetrahydrofuran solution, 1.5 mL, 1.5 mmol) was hydrogenated over 30 minutes, thereby being reduced to the aldehyde (〇a,). After completion of the dropwise addition, the mixture was stirred at -78 C for 2 hours, and then heated to a mixture for 1 hour. Then, hydrochloric acid (1 Μ aqueous solution, 50 mL) was added to terminate the reaction, and the temperature was raised to /m·. After the reaction mixture was taken up to 3 times with benzene, the combined organic layers were washed with saturated brine and then dried over anhydrous magnesium sulfate. The obtained toluene solution was not purified and used in the next reaction. That is, adding ethylene glycol (85〇mg, 13 7 mmol) and pyridinium p-toluenesulfonate (π mg, 〇〇68 mm〇i) to the benzene solution containing aldehyde (〇a'), using Ding history The resulting water was removed by a Dean-Stark trap and heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, water was added, and the combined organic layer was washed twice with ethyl acetate. An organic layer free of anhydrous sulfuric acid was used and concentrated under reduced pressure. Then, it was purified by Shih-Hyhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh The spectrum data of this acid (1') is shown below. 148986.doc -23- 201143806 !H NMR (CDC13): δ=5.86 (tq, J=7.7, 1.3 Hz, 1H), 4.86 (t, J = 4.7 Hz, 1H), 4.12-3.80 (m, 4H) , 2.22 (dd, J=1.2, 1.0 Hz, 3H), 2.15 (brq, J=7.7 Hz, 1H), 1.77-1.70 (m, 2H) ppm ; , 3C NMR (CDCI3): δ=131.15, 1 19.82 , 103.59, 64.92, 32.97, 24.08, 23.09 ppm ; MS (El): m/z 219 [M-H+]. Example 2 (E)-2-(5-(l,3-dioxolan-2-yl)-2-decylpent-2-enyl)-4-methylfuran-3-carboxylic acid ( Synthesis of 3') [29]

2,4-Dimethylfuran-3-carboxylic acid (2') (140 mg, 1.0 mmol) synthesized according to Non-Patent Documents 10 and 11 was dissolved in tetrahydrofuran (5.0 mL) under an argon atmosphere. After cooling to -15 ° C, n-butyllithium (1.6 Μ 炫 《 "solution, 1.25 mL, 2.0 mmol) was added dropwise over 10 minutes. After the end of the addition, at -1 5. After mixing for 1 hour, a solution of zinc chloride (1 36 mg, 1.0 mmol) in tetrahydrofuran (2.0 mL) was added dropwise over 5 minutes at _15. (: further stirring for 1 hour. Then, acetal (1,) (1 10 mg, 〇.50 mmol) and tetrakis(triphenylphosphine) were added dropwise at -15 ° C for 5 minutes (29 mg, After a solution of 0.025 mmol) in tetrahydrofuran (3.0 mL), the mixture was heated to 60 ° C and stirred for 15 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl ester = 5 : 1 to 3 : 1) Purification to obtain a carboxylic acid acetal (3,) (55 mg, 〇2〇mmQi, 39%) as a pale yellow solid. The spectrum of the acid acetal is shown below. *H NMR (CDC13): 6=7.09 (q, J=1.2 Hz, 1H), 5.24 (tq, J=7.2, 1.3 Hz, 1H), 4.85 (t5 J =4.8 Hz, 1H), 3.98-3.81 (m, 4H), 3.69 (s, 2H), 2.19-2.12 (m, 2H), 2.17 (d, J=1.3 Hz, 3H), 1.73-1.66 (m, 2H), 2.17 (d, J=ll Hz, 3H) ppm ; 3C NMR (CDCI3): 5=169.52, 163.03, 138.47, 13 1.72 126.29, 121.41, 1 13.30, 104.16, 64.86, 37.82, 33.73, 22.66 16.02, 10.02 ppm MS (FAB): m/z 281 [M+H+]. Example 3 (E)-2_(4- Synthesis of diethyl 2-(2-methyl-6-oxo-hexan-2-enyl)furan-3-yl)_2-oxoethylethylphosphonate (4,) ]

The acetal acetal (3') (140 mg, 0.50 mmo1) was dissolved in di-hexane (5.0 mL) in an air atmosphere and cooled to (TC. Add 1-148986. Doc •25- 201143806 Gas-Ν,Ν,·2-triethylpropenylamine (79 4, 〇6〇mm〇i), stir for 3 minutes, then stir at room temperature for 12 hours. The vacuum pump was concentrated under reduced pressure to give an oily material (3a,). * The obtained oily substance (4) was purified and used directly in the next reaction. Adding gas to monochloromethane (3. 〇mL) a suspension prepared by dissolving magnesium (47 6 , 〇. 5 〇 mmol), phosphinic acid triacetate 34 5 mg, 〇 6〇mm〇i) and triethylamine (139 pL, 1.0 mmol) , Yu Yu. A solution of the oily substance (3a') in dichloromethane (2. 〇 mL) was added dropwise under stirring, and the mixture was stirred for 3 hrs and then at room temperature for 15 hr. Saturated ammonium was added to the reaction mixture to stop the reaction, and the mixture was extracted twice with dioxane. The organic layer was washed with saturated brine and dried over magnesium sulfate. The obtained oily substance (3b,) was not purified and used directly in the next reaction. Distilled water (9 〇 mg, 5.0 mmol) was added to the oily substance (3b,), and heated in a 120 C oil bath for 2 hours. After cooling to room temperature, water (5.0 mL) was added to the reaction mixture and extracted twice with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated to give an oily material (3) 032 mg. The obtained oily substance (3c') was not directly purified and used in the next reaction. Namely, after dissolving the oily substance (3c1) in tetrahydrofuran (1. 〇 mL), 4 M-hydrochloric acid (100 μί) was added and stirred for 5 hours. After adding a second gas to a reaction solution (5.0 mL), it was washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give crude oil (102 mg). The obtained crude product was purified by a silica gel column chromatography (hexane/ethyl acetate = 1 : 1 to i: 5) to give an oily phosphonate (4,) (17 148986, doc -26 - 8 201143806 mg, 0.046 mmol, 9_2%). *H NMR (CDC13): 5 = 9.75 (t, J = 1.5 Hz, 1H), 7.07 (d, J = 1.3 Hz, 1H), 5.16 (brt, J = 6.0 Hz, 1H), 4.15 (dt, J =14.7, 7.2 Hz, 2H), 3.65 (s, 2H), 3.40 (d, J=22.1 Hz, 2 H), 2.52-2.44 (m, 1H), 2.40-2.32 (m, 1H), 2.20 (s , 3H), 1.64 (s, 3H), 1.31 (t, J=7.1 Hz, 3H) ppm 13C NMR (CDCI3): 5=201.98, 188.37 (d, J=6.9 Hz), 160.86, 138.71, 132.67, 124.99 , 123.10 (d, J=3.1 Hz), 120.05, 62.40, 43.54, 41.38 (d, J=131.2 Hz), 38.04, 20.75, 16.26 (d, J=4.4 Hz), 16.21, 10.56 ppm MS (FAB): m/z 371 [M+H+]. Example 4 (5 £, 9 ugly)-3,10-dimercapto-7,8-dihydrocyclodean[1)]furan-4 (11-ketone-ketone (5) Synthesis [Chem. 31]

Liquefied lithium (0.83 mg, 0_019 mmol) was weighed in a flask, and while being heated by hot air, it was dried under vacuum for 30 minutes under a reduced pressure. " After argon replacement of the flask, acetonitrile (1.0 mL) was sequentially added, Phosphonic acid S (4') (6 mg, 0.016 mmol) in EtOAc (0.5 mL), triethylamine ( 226 EtOAc, A saturated aqueous solution of ammonium sulfoxide was added to the reaction mixture, and the mixture was extracted twice with acetic acid. The combined organic layers were washed with saturated brine to add -27-148986.doc 201143806. The organic layer was dried with anhydrous magnesium sulfate and evaporated. Purification by hydrazine column chromatography (hexane / ethyl acetate = 1 : EtOAc: EtOAc: EtOAc: EtOAc: The spectrum data of the cyclic ketone (5) is shown below. H NMR (CDC13): 6=7.08 (s, 1H), 6.05-5.95 (m, 2H), 5·19-5.10 (m, 1H), 3.72 (s, 2H), 2.72-2.63 (m, 1H) , 2.39-2.28 (m, 1H)S 2.11 (d, J=1.2 Hz, 3H), 2.10-1.82 (m, 2H), 1.25 (s, 3H) ppm ; 3C NMR (CDC13): 6=190.44, 157.60 , 138.76, 138.24, 134.87, 133.40, 129.62, 122.79, 121.98, 41.57, 33.64, 26.94, 16.12, 9.3 8 ppm i MS (El): m/z 216 [M+]. Example 5 (E)-(3R,5S)-9,14-Dimethyl-4,12-dioxa-tricyclo[9·3.〇.〇3'5]14_i(l 1 ), synthesis of 8,13-trien-2-one (6) [32]

After the cyclic ketone (5) (13 mg, 0.06 mmol) was dissolved in tetrahydrofuran (1.5 mL) and methanol (1.5 mL), '3 〇〇 /0 hydrogen peroxide (17 吣, 〇·15 mol) 4 Μ- Aqueous sodium hydroxide solution (6.5 μm, 0.026 mmol) was stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted twice with methylene chloride. The combined organic layers were washed with saturated brine. The organic layer 148986.doc -28 · 201143806 was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purified by hydrazine phosphine Hong, paralyzed by α/7-win column chromatography (hexane/ethyl acetate = 10:1) to obtain cyclic ketone ketone as white 牟m M~" π曰邑 solid (6) (11 mg, 0.047 mmol, 79%) 〇 环 妆 铥 铥 频谱 频谱 频谱 频谱 频谱 频谱 频谱 频谱 频谱 频谱 频谱 频谱 频谱 频谱 频谱 频谱 频谱 频谱 频谱 频谱 频谱 频谱 频谱!H NMR (CDC13) : 6=7.10 1TTN c ’ U (s’ 1Η), 5·53-5.48 (m,1H), 3.74

Hz, 1H), 3.53 (d, J=2.0 (d, J=16.9 Ηζ, 1Η), 3.63 (d, J=i6.9 HZ, 1H), 2.97 (ddd, J=10.2, 3.3, 2 〇HZ , 1H), 2.53-2.39 (m 2H), 2.26-2.19 2.04 (d, J=MHZj3H)>155(s 3H) 1.21-1.07 (m, 1H) ppm C NMR (CDCI3) : 5 = 194.08, 156.05 , 138.20, 13 1.54, 130.31, 122.23, 122.14, 61.54, 59.59, 41.13, 31.57, 23.97, 15.68, 9.37 ppm; MS (El): m/z 232 [M+H+]. Example 6 in sunflower (Helianthus annus) L.) Seeds, dried plants of various roots of Clematischinensis Osbeck, 1 〇g, 5 〇% (v/v) ethanol water> gluten solution 100 mL, and are given at room temperature from time to time. The mixture was extracted for 7 days, and each extract was subjected to hydrazine to obtain each extract. The extracts were concentrated under reduced pressure, followed by lyophilization to obtain an extract. Example 7 Melanin production inhibition test of zephyrone epoxicone precursor [Use Melanin production inhibition test of human melanocytes] (culture of human melanocytes) Human melanocytes (NHEM (Normal Human Epidermal Melanocytes) (Moderately, moderate), 148986.doc -29· 201143806

Kurabo Inc.' Seeded 2.5 x 1 每4 per well in a 12-well culture dish containing Medium 254 medium (containing growth factor HMGS-2) l〇〇〇μί, and added stem cell proliferation factor to the medium ( SCF, final concentration 1 〇 ng / mL), then add the test sample after 4 hours ^ culture it under 3 '3 days, change the medium, add SCF again (final concentration i〇ng / mL), then at 4 After the hour, the test sample was added and cultured at 37 ° C for 4 days. Thereafter, the amount of melanin and the amount of protein were measured according to the following methods. (Quantification of melanin) The medium in the well was removed. After the cells were washed three times with PBS(-) (phosphate buffered saline (-), phosphate buffer (-)) 500 ,, PBS (-) was completely removed. Cell lysate was prepared by adding 4 〇 2 of 2 m〇i/L_Na〇H to the washed cells to dissolve the cells and shaking with a shaker for 30 minutes. The cell blisters were transferred to a 1.5 mL microcentrifuge tube, heated with boiling hot water for 10 minutes, and vigorously stirred with a Voltex mixer. The cell lysate was transferred to a 96-well culture dish, and the absorbance was measured at 4 〇 5 nm. (Quantification of Protein) The cell lysate 4 obtained above was mixed with a solution of BCA (bicinch〇ninic acid) to be mixed at 37 ° C for a minute, and the absorbance was measured at 540 nm. The cyclic ketone (5) and the cyclic epoxy ketone (6) obtained in Examples 4 and 5 were subjected to the melanin production inhibition test described above in terms of black pigment and protein < quantitation. Using PBS (·) as a control product 'Using arbutin _pBS (I) solution as a positive sensation, performing the same test, and calculating the melanin (relative ratio) and protein amount (relative ratio) when the reference substance was set to 〇〇 Check the inhibition of melanin production. 148986.doc 201143806 [Table i] Comparative Example 1 Comparative Example 2 Comparative Example 3 Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 PBS (·) 100 Arbutin 0.01 0.02 Cyclic ketone (5 0.0001 0.001 0.01 Cyclic epoxy ketone (6) 0.0001 0.001 0.01 Melanin amount (%) 100 84.4 68.8 73.2 68.1 55.3 71.9 64.6 54.8 Protein amount (%) 100 80.1 76-5 108.2 110.5 108.8 109.5 112.4 112.1 Melanin production inhibition rate 0 15.6 31.2 26.8 31.9 44.7 28.1 35.4 45.2 [Table 2] Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 Capric acid 0.01 L-ascorbic acid 2-glucoside 0.01 L-ascorbic acid Magnesium phosphate 0.01 Turkey decanoic acid 0.01 tranexamic acid 0.01 Resorcinol 0.01 Sunflower seed extract 0.01 Clematis extract 0.0 Melanin amount (%) 82.1 87.2 85.5 80.6 81.1 80.7 88.2 84.4 Protein amount (%) 100 80.1 76.5 104.7 106.2 106.8 110.1 115.3 Melanin production inhibition rate 17.9 12.8 14.5 19.4 18.9 19.3 11.8 15.6 [ 3] Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Example 20 Example 21 Example 22 Arbutin 0.01 Citrate 0.01 L·Ascorbic acid 2·Glucosamine 0.01 L-Ascorbic acid Phosphoric acid 0.01 Turkey citric acid 1 0.01 tranexamic acid 0.01 stilbene phenol 0.01 to hollyhock seed extract 0.01 Clematis extract 0.01 ketone ketone (5) 0.0001 0.0001 0 0001 0 0001 0.0001 0.0001 0.0001 0.0001 0.0001 cyclic epoxy ketone (6) Melanin amount (%) 68.2 66.6 68 0 64.5 69.0 63.2 69.1 64.5 62.6 Protein amount (%) 85.5 100.8 108 2 107.6 100.1 110.8 95.4 111.3 112.5 Melanin production inhibition rate (%) 31.8 33.4 32 35.5 31 36.8 30.9 35.5 37.4 148986 .doc • 31 · 201143806 [Table 4] Example 23 Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 Example 31 Arbutin 0.01 Tannic acid 0.01 L-ascorbic acid 2-Port Glycoside 0.01 L-ascorbyl phosphate 錤0.01 Turkey 鞣0.01 tranexamic acid 0.01 stupid phenol 0.01 to yin yingxuan extract 0.01 clematis extract 0.01 cyclic ketone (5) cyclic epoxy ketone (6) 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 Melanin S (% 65.8 62.5 66.7 61.9 67.1 60.1 65.5 61.2 61.5 Protein amount (%) 90.4 100.8 107.7 110.4 108.3 105.6 100.5 105.1 103.9 Melanin production inhibition rate (%) 34.2 37.5 33.3 38.1 32.9 39.9 34.5 38.8 38.5 The melanin and protein content of each component are shown in the table. 1 to 4. It has been confirmed that the cyclic ketone (5) and the cyclic epoxy ketone (6) are less toxic to cells than the arbutin which is known to have a whitening effect, and exhibit a whitening effect at a very low concentration. Further, in Comparative Examples 4 to 1 1, in Examples 14 to 31, the cyclic ketone (5) and the cyclic epoxy ketone (6) were combined with a whitening agent to exhibit a synergistic effect and suppress melanin. The generation. (Test method) 20 people who were worried about chloasma or freckles were applied to the face twice a day, and the number of people who felt the whitening effect was judged on the following basis after 2 weeks. The results are shown in the table. 7. (Sample preparation) -32-148986.doc 201143806 [Table 5] Comparative Example 12 Whitening component (% of blending) Comparative Example 13 _ arbutin (7.0) Comparative Example 14 Comparative Example 15 Comparative Example 16 Comparative Example 17 L-ascorbic acid 2 -glucoside (2.0) citric acid (2.0) to hollyhock seed extract (〇.〇5) 莪 环氧 epoxy ketone precursors (relevant %) Example 32 Example 33 Example 34 Example 35 Example 36 Clematis Extract (0.05) Arbutin (7_0) L-ascorbic acid 2-glucoside (2.0) Capric acid (2.0) To the hollyhock seed extract (〇.〇5) Cyclic ketone (5) (0.005 ) cyclic ketone (5) (0.005) cyclic ketone (5) (0.005) cyclic ketone (5) (0.005) Example 37 Example 38 Clematis extract (0.05) Cyclic ketone (3) (0.005) ^ ^1(5)(0.005) Stupid oxycodone (6) (0.005)

Example 42 Example 43 Tomosa seed extract (0.05) &amp; Lingxian extract (0.05) Oxy ketone (6) (0.005) ^ Oxy ketone (6) (0.005) The above sample was used, with 8 masses. /. Then, the quality of the polyoxyethylene coconut sorbitol liver fatty acid vinegar (8), 0.2% by mass of the benzoic acid and the remaining amount of purified water, using a method known per se to prepare lotion As a sample preparation. (Criteria for determination) [Table 6] Glycol, 5 mass. / ◦ ◦ glycerol ◎: effective / more effective total number of people more than 15 〇: effective / more effective total number of people 〇 ~ 14 △: effective / more effective total number of people 5 ~ 9 x: effective / The total number of people who are more effective is 4 or less (result) 148986.doc -33- 201143806 [Table 7] Evaluation Comparative Example 12 X Comparative Example 13 Δ Comparative Example 14 X Comparative Example 15 Δ Comparative Example 16 X Comparative Example 17 X Example 32 〇 Example 33 ◎ Example 34 ◎ Example 3 5 ◎ Example 3 6 ◎ Example 37 ◎ Example 3 8 〇 Example 39 ◎ Example 40 ◎ Example 41 ◎ Example 42 ◎ Example 43 ◎ Table 7 confirms that the cyclic ketone (5) and the cyclic epoxy ketone (6) exhibit an excellent whitening effect at a very low concentration as compared with arbutin which is known to have a whitening effect. Moreover, by combining with a whitening agent, the whitening effect can be effectively exerted. Furthermore, it was confirmed that the skin irritation reaction such as erythema or eczema was not observed in the sample application site of the subject, and it was confirmed that it was safe even in the form of the preparation. Further, it has been confirmed that a more excellent whitening effect can be exhibited by blending the cyclic ketone (5) and the cyclic epoxy ketone (6) with a specific whitening component. Example 44 Hereinafter, a formulation example of the external preparation for skin to which the present invention is applied will be listed. &lt;Formulation Example 1 &gt; lotion (% by mass) cyclic ketone (5) 0.005 148986.doc • 34· 201143806 Polyoxyethylene sorbitan monolaurate (20E.O.) 1.5 1,3-butyl Glycol 5.0 Glycerin 3.0 Preservatives·Antioxidants Appropriate amount of spices Appropriate amount of purified water Total 100.0 &lt;Formulation Example 2&gt; Cosmetic Cream (% by mass) Curcumin Epoxy Ketone 0.02 Cyclic Epoxy Ketone (6) 0.03 Beeswax 2.0 Hard Alcohol 5.0 Stearic acid 8.0 Squalane 10.0 Self-emulsifying glyceryl monostearate 3.0 Polyoxyethylene cetyl ether (20E.O.) 1.0 Propylene glycol 5.0 Potassium hydroxide 0.3 - Preservatives · Antioxidants The remainder of the purified water is 100.0 148986.doc -35- 201143806 &lt;Formulation Example 3&gt; Emulsion (% by mass) Cyclic ketone (5) 0.01 Squalat 8.0 Vaseline 2.0 Beecon 0.5 sorbitan sesquioleate 0.8 Polyoxyethylene oleyl ether (20E.O.) 1.2 Carboxyvinyl polymer 0.2 Propylene glycol 0.5 Potassium hydroxide 0.1 Ethanol 7.0 Preservatives · Antioxidants Appropriate amount of spices Proper amount of purified water Total 100.0 <Formulation Example 4> Beauty liquid (quality %) Cyclic ketone (5) 0.001 Sorbitol 4.0 1,3-butanediol 5.0 Magnesium ascorbyl phosphate 0.5 POE sorbitan monolaurate 0.4 Agar 1.0 Natural gellan gum 0.5 148986.doc •36- 201143806 Trimethyl Glycine 1.0 Preservative appropriate pH adjuster (pH adjusted to 8.0) The remaining part of purified water total 100.0 <Formulation 5> Dressing agent (% by mass) Cyclic epoxy ketone (6) 0.005 莪 环氧 epoxy ketone 0.005 Vinyl acetate resin emulsion 15.0 Polyvinyl alcohol 10.0 Jojoba oil 3.0 Glycerin 5.0 Titanium oxide 8.0 Kaolin 7.0 Ethanol 5.0 Perfume amount of preservative · Antioxidant Appropriate amount of purified water Total 100.0 &lt;Formulation Example 6&gt; Ointment (% by mass) Epoxy ketone 0.005 oxime ring dilute ketone 0.005 148986.doc -37· 201143806 cyclic ketone (5) 0.005 p-dimethylamino benzoate octyl ester 4.0 butyl methoxy phenyl hydrazino methane 4.0 stearyl alcohol 18.0 Lacquered wax 20.0 Monostearate glycerin 0.3 0.3 Vaseline 33.0 Perfume amount of preservative · Antioxidant Appropriate amount of purified water Total 100.0 &lt;Formulation Example 7&gt; Cream Foundation (% by mass) Cyclic Epoxy Ketone (6) 0.001 Epoxy Ketone Ketone 0.001 Talc 5.0 Sericite 8.0 Titanium Oxide 5.0 Color Pigment Appropriate Monoisostearate Polyglycerol 3.0 Polyoxyethylene Hydrogenated Castor Oil 1.5 Heterogeneous Acid isotridecyl ester 10.0 1,3-butanediol 5.0 Antioxidant amount 148986.doc -38- 201143806 Preservative appropriate amount of purified water remaining part. Total 100.0 <Formulation Example 8> Sunscreen cosmetic (% by mass) Ring Epoxy Ketone (6) 0.005 Cyclic Ketone (5) 0.010 Titanium Oxide 10.0 Zinc Oxide 10.0 PEG-9 Polydidecyldecyloxyethyl Polydimethyloxane 1.5 Lauryl PEG-9 Polydidecyl矽 alkoxyethyl polydifluorenyl oxane 1.5 cyclopentanoxane 20.0 polydidecyl fluorenyl 10.0 (polydimethyl methoxy oxane / vinyl poly fluorenyl oxane) crosslinked polymer Cetyl polydimethyl oxane 0.25 glycyrrhetinic acid 0.05 0.05 曱 葡萄糖 glucose-20 1.0 1,3-butanediol 10.0 Sodium chloride amount of antioxidants appropriate amount of preservatives appropriate amount of purified water remaining 100.0 [Industry Availability] 148986.doc -39- 201143806 The invention provides a method for the synthesis of a useful precursor and the correlation was a kind of intermediate (E) -5- Videos of -4-hexenoic acid alkyl ester as a starting material to synthesize the epoxy-one correlation Curcuma was. The correlation between the sputum sulphate and the precursor thereof obtained by the synthesis method of the present invention is excellent in stability and exerts an extremely high whitening effect, and thus can be used as a melanin production inhibitor and a skin external preparation containing the same. The active ingredient β χ can be provided by combining the box epoxide related substance obtained by using the synthetic formula of the present invention and its precursor with a specific whitening component, thereby providing a correlation between the individual preparation of the epoxy ketone. The whitening effect of the skin whitening agent which is superior to the whitening effect of the precursor. BRIEF DESCRIPTION OF THE DRAWINGS A human is a synthetic scheme for synthesizing a compound represented by the formula (5) or the formula (6) by an intermediate represented by the compound of the formula. 148986.doc

Claims (1)

201143806 VII. Patent application scope: , 1 · A method for producing a cyclic epoxy ketone compound, which is based on the formula (6): [Chemical 1] (6) The cyclic epoxy ketone compound shown, and comprising the following steps: (A) Formula (〇): [Chemical 2] (〇) [wherein X1 is a, Br or I, and R is an alkyl group of a C?~c10 which may be substituted], and the alkyl hexenoate is reduced to form a hexamethylene aldehyde compound. And dust, in the presence of an acid catalyst, the substituent of the above acid compound is protected by a substituted C丨~C丨〇 alcohol or a substituted C2~C2Q diol to form a formula ( 1): [Chemical 3] I R10 OR2 χΐΛ^ΧΗ (1) [wherein, X is a, Br or I; R1 and R2 are independently alkyl groups of Ci~Ci〇 which may be substituted, or R and R2 Forming an acetal compound represented by a C2~alkylene group which may be substituted; (B) Formula (2): [Chemical 4] 148986.doc 201143806 OR3 [Formula] R3 is represented by Η, Li, Na or K]. Orydenyl carboxylic acid or a salt thereof, at -80 to 25. (: treated with a strong base and a zinc halide, and then in the presence of a transition metal catalyst, the acetal compound represented by the formula (1) is at -80 to 25. Underarm' and treated (2) The furyl carboxylic acid or its salt shown is reacted, and then the temperature of the reactant is raised to 25. (: ~15 〇. (:, formula (3): [Chemical 5] [wherein, R1 and R2 are the same as defined above, and R3 is an acetal compound having a carboxylic acid or a carboxylate represented by hydrazine, Li, Na or K]; (C) adding the formula (3) a carboxylic acid or a carboxylic acid salt having an acetal compound of a carboxylic acid or a decanoate, which reacts with an electrophilic toothing agent in an inert gas atmosphere to form a tetacid halide, and the above-mentioned tick acid compound and phosphinium group The acetate is reacted to form an acetal compound to which a phosphinyl acetate is added, and then the alkoxycarbonyl group is removed by hydrolyzing and decarboxylation of the above-mentioned phosphatidyl acetate-added compound. An acetal compound having a phosphonate is added, and the above-mentioned acetal compound having a phosphonate added is deacetalized under acidic conditions to give a formula (4): [Chem. 6] I48986.doc 201143806 An alkyl or aryl group of Cl2 wherein R4 and R5 are independently a q group which may be substituted, or R4 and R5 are a C2~Cm alkyl group which may be substituted, and a phosphonic acid is added. An ester aldehyde compound; and (D) cyclizing an aldehyde compound having a phosphonate ester represented by the formula (4) to form a formula (5): A cyclic ketone compound is shown. 2. The method of claim 1, further comprising the step of: (E) reacting a cyclic ketone compound represented by formula (5) with hydrogen peroxide under test conditions to form formula (6): ] A cyclic epoxy ketone compound is shown. A method for producing an acetal compound having a carboxylic acid or a carboxylate, which is a formula (2): [Chemical 9] I48986.doc 201143806 [wherein R3 is represented by H, Li, Na or K]. The sulphuric acid or its salt is treated with a strong base and a zinc halide at -8 0 to 2 5 ° C, and then in the presence of a transition metal catalyst, the formula (1): [Chemical 10] [where X1 is ChBr or 1,! ^ and R2 are independently an alkyl group which may be substituted, or R1 and R2 together form an acetal compound represented by a C2~C2Q alkyl group which may be substituted, at -80 to 25 ° C and The furfuryl carboxylic acid represented by the formula (2) or a salt thereof is treated, and then the reactant is heated to 25 ° C to 150 ° C to produce the formula (3): In the formula, R1 and R2 are the same as defined above, and R3 is the same as defined above, and an acetal compound having a carboxylic acid or a carboxylate is added. 4. A method for producing a cyclic ketone compound, which is a formula (4): [Chemical 12] 148986.doc 201143806 [Formula A, R4 and R1 2 are independently substituted alkyl or aryl of A 5 1 C10 or R and R are substituted c2~c2()$#20 The acid compound of the phosphonic acid vinegar is added to the base compound, and is cyclized under the alkali metal to form the existence of the formula #[13] (5) A cyclic ketone compound as shown. The system (5): 5· a method for producing a cyclic epoxy ketone compound [Chem. 14] X1 R1 and R2 are independent [wherein, X1 is CM, Br or I, and the ground is a replaceable C丨~C丨〇148986.doc 1 : the cyclic ruthenium compound is reacted with chlorine peroxide under test conditions, The cyclic epoxy ketone compound represented by the formula (6): [Chemical Formula 15] 2 is produced. An acetal compound represented by the formula (1): a decyl group of 201143806, or R1 and R2 together forming a C2 to C2G extendable group which may be substituted. An acetal compound added with a carboxylic acid or a carboxylate, which is represented by the formula: [Chem. 17] Ο Wherein R 1 and R 2 are independently a C to C alkyl group; or R 1 and R 2 form a substitutable C; 2 to C m alkyl, R 3 is H, u, Na or K]. An aldehyde compound having a phosphonate added, which is represented by the formula (4): [Chemical Formula 18] 0, 0 V〇R4 I48986.doc (6) (6)201143806 [Chem. 20] 11. A melanin production inhibitor which is of the formula (5): [Chem. 21] The cyclic ketone compound shown, formula (6): [Chem. 22] The cyclic epoxy ketone compound shown or a combination thereof is used as an active ingredient. 12. A skin external preparation, which is of the formula (5): [Chem. 23] The cyclic ketone compound shown, formula (6): [Chem. 24] 148986.doc 201143806 A combination of the selected epoxidized ketone compound or a combination thereof as an active ingredient. 13. A whitening agent for external use of the skin, which is of the formula (5) ·· (5) Equation (6): [Chem. 26] (6) A combination of a cyclic epoxy ketone compound or a combination thereof, and a benzo-glycoside and a derivative thereof, 'facial acid, ascorbic acid and its butyl sulphate, linoleic acid, tranexamic acid and Its derivatives, X Yang s 夂 and its organisms, placenta extract, meta- phenol and its derivatives, plant extracts or two or more specific whitening agent ingredients. e $ 148986.doc