Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C43/00—Ethers; Compounds having groups, groups or groups
  • C07C43/02—Ethers
  • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
  • C07C43/04—Saturated ethers
  • C07C43/13—Saturated ethers containing hydroxy or O-metal groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C43/00—Ethers; Compounds having groups, groups or groups
  • C07C43/02—Ethers
  • C07C43/18—Ethers having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring
  • C07C43/188—Unsaturated ethers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C43/00—Ethers; Compounds having groups, groups or groups
  • C07C43/02—Ethers
  • C07C43/18—Ethers having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring
  • C07C43/196—Ethers having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring containing hydroxy or O-metal groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• the present invention relates to a cyclohexanol derivative, a cooling sensation agent and a cooling sensation composition containing the same, a method for producing the derivative and an intermediate thereof.
• the present invention relates to a novel cyclohexanol derivative having a cooling action, and a cooling sensation agent and a cooling sensation composition containing the derivative. Further, the present invention relates to a method for producing the above-mentioned cyclohexanol derivative and a novel benzylcyclohexyl ether derivative which is an intermediate for the method.
• heart-strength oil and £ -menthol a main component of heart-strength oil
• menthol has a sufficient cooling sensation, it is crystalline, and when used in the form of a certain composition, it crystallizes in the base, especially when incorporated into a shipping agent or tape. There was a problem that a new dissolving agent had to be added to reduce the release of other drugs. Further, as is well known, since menthol has a strong odor, it often impairs its elegant scent when added to cosmetics and the like.
• JP-A-47-16647, JP-A-47-16649, JP-A-58-888334, JP-A-61-194404 discloses a menthol derivative
• Japanese Patent Application Laid-Open Nos. 589-193454 and 58-95194 describe a tricyclic compound.
• tricyclic amides and the like are disclosed as cooling sensation agents in Japanese Unexamined Patent Publication (Kokai) No. 60-136654.
• these were improved in terms of aroma they were often much less powerful than £ -menthol in terms of cooling sensation. Therefore, conventional cooling sensation agents other than menthol can provide a cooling sensation to the mucous membrane in the oral cavity, which is said to have high sensitivity to the cooling sensation agent, but are sufficient as a cooling sensation agent for skin with low sensitivity. It was not satisfactory.
• the present invention is useful in developing various preparations such as cosmetics, oral preparations, and pharmaceuticals for oral mucosa and skin, etc., which has: (1) a sufficient refreshing action, (2) no peppermint odor, 3 Does not sublime at room temperature, ⁇ ⁇ ⁇ Does not crystallize in the base, 5 Develops compounds with excellent properties such as good compatibility with various bases, and cooling sensation agents and compositions using the compounds It is intended for. Disclosure of the invention
• the present inventors have conducted intensive studies to achieve the above object, and as a result, the novel cyclohexanol derivative represented by the following structural formula has a cooling sensation action comparable to that of menthol, and only the oral mucosa
• the present inventors have found that they have sufficient activity on the skin and have excellent properties such as almost no odor as compared with menthol and heart-strength oil, and have reached the present invention.
• cyclohexanol derivative of the present invention has the following general formula (1)
• R represents a linear or branched alkyl group having 0.1 to 5 carbon atoms.
• cyclohexanol derivative of the present invention is a compound described at the end of the literature, which was first discovered by the present inventors, and its formal name is 2- (2-alkoxy-1-methylethyl) -15-methylcyclohexane.
• Xanol 2- (2-alkoxy-1-methylethyl) -15-methylcyclohexane.
• R represents a linear or branched alkyl group having 1 to 5 carbon atoms
• a methyl group, an ethyl group, an is0-propyl group, a tert-butyl group and an n-pentyl group are preferred, and a methyl group is particularly preferred.
• the cooling sensation agent of the present invention comprises a cyclohexanol derivative represented by the general formula (1). It contains. That is, since the cyclohexanol derivative of the present invention itself acts as a cooling sensation agent, the cooling sensation agent of the present invention may be composed of only the above-mentioned cyclohexanol derivative. It may be a combination.
• the cyclohexanol derivative may be used alone or in a mixture of a plurality of stereoisomers, and may be represented by the general formula (la). It is preferred to use the cyclohexanol derivative alone.
• the cyclohexanol derivative of the present invention has many applications as a cooling sensation agent to pharmaceuticals, quasi-drugs, foods, cosmetics, etc., and various cooling sensation compositions containing such derivatives are available. Obtained by the present invention. That is, the cool sensation composition of the present invention contains the cyclohexanol derivative represented by the general formula (1).
• the cooling sensation composition of the present invention the above-mentioned cyclohexanol derivative was blended as a cooling sensation agent to give a cooling effect.
• Ointments, creams, gels, lotions, molding cataplasms Pharmaceutical products such as tapes, oral preparations, etc.
• Cosmetics such as powders, hair tonics, shampoos, lipsticks,
• Mouth cleaners such as toothpastes, (4) Chewing gum, candy, frozen desserts, soft drinks, etc. Foods and the like can be mentioned.
• the other components used in the cooling sensation composition of the present invention are not particularly limited, and can be appropriately formulated by using in combination with known bases, drugs and the like. Further, as long as the cooling action of the cyclohexanol derivative is not impaired, a preservative, an antioxidant, a fragrance, a coloring agent, a surfactant, and the like can be added to the cooling composition of the present invention. Furthermore, when the cooling composition according to the present invention is various preparations such as pharmaceuticals and cosmetics, a known drug as a medicinal component can be appropriately compounded.
• the content of the cyclohexanol derivative in the cooling composition of the present invention is not particularly limited, but is preferably in the range of 0.001 to 10% by weight when used.
• the cooling sensation agent and the cooling sensation composition of the present invention containing such a derivative are almost all accompanied by hearty odor. It can give a sufficient cooling effect to the skin and the like without using it, and is excellent in the continuity of the action and the rapid effect.
• the cyclohexanol derivative of the present invention can be synthesized, for example, using isopulegol as a raw material according to the following reaction formula.
• R represents a linear or branched alkyl group having 1 to 5 carbon atoms.
• isopulegol (2) and sodium borohydride are used as a solvent selected from getyl ether, tetrahydrofuran, diglyme and the like. Dissolve and add drop-wise boron trifluoride etherate to obtain a mixture. After 1 to 2 hours, water is added to the above mixture, and an aqueous solution of sodium hydroxide and aqueous hydrogen peroxide are further added, followed by sufficient stirring. The reaction product obtained is extracted with ether or the like, and then the solvent is distilled off to obtain the diol (7).
• the diol (7) is dissolved in a solvent selected from dimethylformamide, dimethylsulfoxide, dimethoxetane, tetrahydrofuran, etc., and sodium hydride, silver oxide, barium oxide, sodium hydroxide, triethylamine, potassium carbonate
• a base selected from sodium amide, etc.
• the corresponding alkyl halide is added dropwise in an equimolar amount, and the mixture is reacted at a temperature in the range of 110 ° C to 100 ° C for several hours to tens of hours.
• the desired cyclohexanol compound (1) can be obtained.
• the cyclohexanol derivative of the present invention can be used not only as a mixture of several kinds of stereoisomers but also as one of them. Can be obtained as a single stereoisomer.
• reaction in the method of the present invention is represented by the following reaction formula.
• R represents a linear or branched alkyl group having 1 to 5 carbon atoms.
• (—) monoisopulegol (2a) and metallic sodium or sodium hydride are converted into toluene, The reaction is carried out at a reflux temperature for 3 to 24 hours in a benzene solvent such as xylene to form a salt.
• benzyl halide selected from benzyl chloride, benzylpromide, etc. is added dropwise under heating. After maintaining the reflux temperature for 1 to 12 hours after completion of the dropwise addition, the reaction is terminated. After cooling the above reaction solution, water is added and the mixture is stirred, and the organic phase is separated.
• the solvent is recovered and distilled under reduced pressure to obtain the compound (3a).
• the solvent is preferably used in an amount of (1) about 1 to 10 times by weight based on one isopulegol.
• metal sodium Or, sodium hydride and benzyl halide are each preferably used in an amount of about 1 to 2 times as much as (-) monoisopregol.
• the obtained compound (3a) can be led to the compounds (4a, 4b) by a hydrogenation / hydrogen peroxide oxidation reaction under various conditions well known to those skilled in the art. That is, the compound (3a) is converted by diborane (borane-THF complex, borane-methylsulfide complex, etc.), diisopinocamphenylborane, 9-borabicyclo [3.3.1] nonane (9-BBN), disiamylborane, etc.
• a novel compound (4a, 4b) can be obtained in good yield by adding a B-H bond to the internal olefin and oxidizing it with hydrogen peroxide.
• sodium borohydride and various acids are added to the inside or outside of the reaction system with THF, getyl ether, dimethyloxetane, etc.
• the diborane is generated by reacting in an organic solvent selected from the following. That is, the compound (3a) is dissolved in an organic solvent (preferably tetrahydrofuran) in an amount of preferably 0.5 to 20 times by weight, more preferably 1 to 10 times by weight, and the compound (3a) is dissolved inside or outside the system.
• the diborane is preferably prepared using 1 to 1.5 times the molar amount of sodium borohydride and preferably 1 to 1.5 times the molar amount of sodium borohydride with respect to (3a). generate. Continue stirring so that the temperature inside the container does not exceed 40 ° C, and stir well for 1 to 3 hours after the end of diborane generation. Subsequently, a 3 M aqueous solution of sodium hydroxide is added to the above reaction solution preferably in an amount of about 1 to 2 times the weight of the compound (3a), and the same amount of 30% aqueous hydrogen peroxide is added to the reaction solution at a temperature of 4%. Gently drop the solution not to exceed 0 ° C.
• reaction solution is stirred at room temperature for 0.5 to 3 hours, and the organic phase is separated. Further, the reaction product is extracted from the aqueous phase using tetrahydrofuran and added to the previously separated organic phase. After the organic phase is dried, the solvent is distilled off to obtain a mixture of the crystalline compound (4a) and the liquid compound (4b).
• compound (4a) is formed preferentially over compound (4b), and compound (4a) crystallizes while compound (4b) is liquid. By washing with such an insoluble solvent, compound (4a) can be easily obtained as a single substance.
• Compound (4a) is derived into compound (5a) by an alkylating agent such as a methylating agent in the presence of a base in an organic solvent.
• an alkylating agent such as a methylating agent in the presence of a base in an organic solvent.
• the organic solvent for example, N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dioxane, dimethoxetane and the like can be used, and it is preferably about 1 to 20 times by weight, more preferably about 1 to 20 times by weight the compound (4a).
• an amount of about 2 to 10 times by weight is used.
• sodium hydride and potassium tert-butoxide are particularly preferred, but the kind is not limited as long as the alkylation proceeds.
• alkylating agent alkyl iodide, alkyl chloride, alkyl bromide, dialkyl sulfate and the like are preferable, and about 1-2 mol per 1 mol of compound (4a) is used as an appropriate amount.
• the reaction product is poured into water, neutralized, extracted with an appropriate solvent, and then the organic layer is washed with water, dried and concentrated to obtain a compound (5a), which is a novel compound described in the end of the literature. Can be obtained.
• the compound (5a) may be purified by, for example, vacuum distillation or column chromatography.
• the reaction from compound (5a) to compound (la) is carried out in a solvent selected from ethanol, methanol, acetic acid, dioxane, cyclohexane and the like, using a debenzylating agent such as palladium carbon as a catalyst, sulfuric acid, hydrochloric acid,
• a debenzylating agent such as palladium carbon as a catalyst, sulfuric acid, hydrochloric acid
• an acid such as acetic acid or perchloric acid as a cocatalyst
• the cyclohexanol derivative of the present invention represented by the general formula (la) is obtained.
• the solvent to be used is preferably used in an amount of about 1 to 20 times by weight, more preferably about 2 to 5 times by weight, relative to the compound (5a).
• the acid concentration is preferably in the range of 0.1 to 2 N. If the acid concentration is less than the lower limit, the reaction does not tend to proceed rapidly. If the acid concentration exceeds the upper limit, side reactions other than the intended reaction are likely to occur.
• the use amount of the debenzylating agent is preferably 1 to 10% by weight based on the compound (5a). This reaction may be carried out at normal pressure, but is preferably carried out under a pressure of about 2 to 5 kgcm2.
• the cyclohexanol derivative of the present invention represented by the general formula (la) is produced by the method of the present invention, the compound represented by the general formulas (4a) and (5a) is used as an intermediate. It has been found by the present inventors that the compound is an effective new compound. Therefore, the present invention also relates to an intermediate for producing a cyclohexanol derivative.
• the novel benzylcyclohexyl ether derivative of the present invention will be described below.
• the benzylcyclohexyl ether derivative of the present invention has the following general formula (6a)
• X represents H or a linear or branched alkyl group having 1 to 5 carbon atoms.
• the benzylcyclohexyl ether derivative of the present invention is very useful as an intermediate for industrially and efficiently producing the cyclohexanol derivative of the present invention represented by the general formula (la). Things. BEST MODE FOR CARRYING OUT THE INVENTION
• a lotion having the above composition was prepared. Applying this lotion to the skin gave a refreshing menthol-like feel.
• Formulation 3 Skin lotion (% by weight) Ethanol 20.0 Propylene glycol 5.0 Glycerin 4.5 Methyl parahydroxybenzoate 0.1 Perfume 0.2 Purified water 70. 0 (1R, 2S, 5R) 1 2- (2-ethoxy-1-methylethyl) 0.2 2- 5-methylcyclohexanol
• the above components were mixed to prepare a skin lotion. When used on the skin, it was not irritating and gave the skin a refreshing refreshing sensation.
• Formulation 4 Toothpaste (% by weight) Hydrogen phosphate phosphate 50.0 Carboxymethylcellulose 1.0 Sodium lauryl sulfate 2.0 Glycerin 25.0 Saccharin 0.2 Fragrance 0.8
• Formulation 7 Ointment (% by weight) White petrolatum 76.0 Glycerin monostearate 10.0 Tallow 10.0 Silicone oil 1.0
• Formulation Example 8 cataplasm (wt 0/0) Gelatin 5.0 Sorbitol 1 0.0 carboxymethylcellulose 3.5 glycerol 25.0 kaolin 7.0 sodium polyacrylate 3. 0 (1R, 2S, 5R ) -2- (2-Methoxy-1-methylethyl) 0.5-1 5-Methylcyclohexanol
• Purified water 50.5 The above components were heated and mixed to form a paste, which was spread on a base fabric to prepare a poultice. It gave skin the same cool sensation as menthol.
• Formulation example 10 Lotion (% by weight) Ethanol 59.0 Purified water 35.0 Propylene glycol 5.0
• a lotion having the above composition was prepared. When this lotion was applied to the skin, it gave a refreshing menthol-like refreshing feeling.
• Formulation example 1 Hair tonic (% by weight) Ethanol 52.0 Hohopa's oil 0.4 Polyoxetylene sonolebitan 1.2 Lalate
• Formulation example 1 Skin lotion (% by weight) Ethanol 20.0 Propylene glycol 5.0 Glycerin 4.5 Methyl parahydroxybenzoate 0.1 Perfume 0.2 Purified water 70. 0
• the above components were mixed to prepare a skin lotion. When used on the skin, it was not irritating and gave the skin a refreshing refreshing sensation.
• Formulation Example 1 5 Cream (% by weight) Liquid paraffin 1 0.0 Medium-chain fatty acid triglyceride 5.0 Polyethylene glycol monostearate 3.0 Glycerin 5.0 Carboxyvinyl polymer 1.0 Diisopropanolamine 0.4 Paraoxy Methyl benzoate 0.2
• Formulation Example 16 Ointment (% by weight) White Pserine 76.0 Glycerin monostearate 100 Tallow 10 0 Silicone oil 1.0
• Purified water 46.0 The above components were mixed by heating to form a paste, which was spread on a base cloth to prepare a poultice. It gave skin the same cool sensation as menthol.
• Formulation Example 1 8 Pap agent (% by weight) Gelatin 6.0 Polyvinyl alcohol 3 Methoxyethylene maleic anhydride copolymer 2 Glycerin 30 Violin 5 Sodium polyacrylate 2
• Purified water 50.5 The above components were heated and mixed to form a paste, which was spread on a base fabric to prepare a poultice. It gave skin the same cool sensation as menthol.
• Formulation Example 1 9 cataplasms (wt 0/0) Gelatin 6.0 polyvinyl alcohol 3.5 Main Tokishiechiren maleic anhydride copolymer 2.5 Glycerin 30.0 Kaolin 5.0 Sodium polyacrylate 2.0
• Purified water 50.5 The above components were heated and mixed to form a paste, which was spread on a base fabric to prepare a poultice. It gave skin the same cool sensation as menthol.
• Comparative Example 1 poultice (wt 0/0) Gelatin 5.0 Sorbitol 1 0.0 Kano levo carboxymethyl cell Honoré loin 3.5 Glycerin 25.0 Kaolin 7.0 polyacrylic Sansoichida 3.0 one menthol 0. 5 Black mittens 1.0 Purified water 45.0 A paste was prepared by heating and mixing the above components to form a paste, and a poultice was prepared. In this comparative example, crotamiton was used as a menthol solubilizer.
• a paste was prepared by heating and mixing the above components to form a paste on a base cloth.
• the composition of Comparative Example 1 was the same as the composition of Comparative Example 1 except that crotamiton, a solubilizing agent for menthol, was omitted.
• Liquid paraffin phosphorus 10.0 Medium-chain fatty acid triglyceride 5.0 Polyethylene glycol monostearate 3.0 Glycerin 50 0 Rubiboxyl vinyl polymer 10 0 Diisopropanolamine 0 4 Methyl paraoxybenzoate 0 2-Menthol 2.0 Purified water Remaining amount The above components were mixed to prepare a cream.
• the cream of this comparative example was formulated with the exception that (1R, 2S, 5R, 8R) —2- (2-methoxy-1-methylethyl) -15-methylcyclohexanol was replaced with menthol. Same as Example 15. Test example 1
• the 2- (2-alkoxy-1-methylethyl) -5-methylcyclohexanol of the present invention imparts a sufficient cooling sensation to not only the oral mucosa but also the skin, and is almost odorless as compared with menthol. Furthermore, it has excellent characteristics that it can be stably dissolved in various bases without requiring a dissolving agent.
• the cyclohexanol derivative of the present invention may be used in the form of ointments, creams, gels, lotions, molded cataplasms, tapes, internal medicines, etc., powders, hair tonics, shampoos, lipsticks, and other cosmetics, toothpastes, Usually mixed with mouthwash, chewing gum, candy, frozen desserts, soft drinks and other foods
• the cool sensation composition of the present invention which is odorless and has a refreshing cooling action is obtained.
• (1R, 2S, 5R, 8R) —2- (2-methoxy-1-methylethyl) -15-methylcycloalkyl is particularly preferable among the cyclohexanol derivatives of the present invention. It is possible to efficiently produce a single hexanol in a short process using (-) one isopulegol as a starting material. Therefore, the method of the present invention is an industrially extremely useful method for producing the cyclohexanol derivative of the present invention.
• the benzylcyclohexyl ether derivative of the present invention is an extremely useful intermediate for efficiently producing the cyclohexanol derivative of the present invention by the above-mentioned method of the present invention.

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• Chemical & Material Sciences (AREA)
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• Fats And Perfumes (AREA)
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• 1993
  • 1993-10-28 DK DK93923658.4T patent/DK0667330T3/da active
  • 1993-10-28 EP EP93923658A patent/EP0667330B1/en not_active Expired - Lifetime
  • 1993-10-28 US US08/433,375 patent/US5756857A/en not_active Expired - Lifetime
  • 1993-10-28 WO PCT/JP1993/001562 patent/WO1994010117A1/ja active IP Right Grant
  • 1993-10-28 CA CA002147883A patent/CA2147883C/en not_active Expired - Lifetime
  • 1993-10-28 KR KR1019950701667A patent/KR950704222A/ko active Granted
  • 1993-10-28 ES ES93923658T patent/ES2105338T3/es not_active Expired - Lifetime
  • 1993-10-28 DE DE69312953T patent/DE69312953T2/de not_active Expired - Lifetime
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  • 1993-10-28 JP JP6510890A patent/JP2770081B2/ja not_active Expired - Lifetime
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