Cooling compounds and compositions

Abstract

[0005] Embodiments of the present invention are directed to cooling compounds and compositions having a unique cooling sensation, as well as various edible, drinkable, and / or cosmetic products containing one or more cooling compounds having the general formula (I): 1 R 2 or CH-CH(CH2OR 8 )CH2OR 9 Selected from R 1 and R 2 are independently CHO, CO2H, CH2CH2OH, CHR 10 OR 11 , and C.H.R. 10 OR 12 R 8 and R 9 are independently H or combine to form a spiroacetal or spiroketal moiety; each R 10 are independently H or CH3, R 11 and R 12 is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkaryl, substituted or unsubstituted aryl or heteroaryl, and substituted or unsubstituted acyl, or R 11 and R 12 combine to form a spiroketal or spiroacetal moiety, R 3 , R 4 , R 5 , and R 6 is independently selected from H, CH3, and CH2CH3; R 7 is selected from H, isopropyl, isopropenyl, and sec-butyl, with the proviso that R 3 , R 4 , R 5 , R 6 , and R 7 Not all of the values ​​are H. TIFF2025500584000086.tif28170

Description

[Technical field]

[0001] The present invention relates to cooling compounds and compositions having a unique cooling perception that provides a pleasant cooling effect to the user without a bitter taste. The present invention also relates to products containing one or more cooling compounds. [Background technology]

[0002] A variety of compounds are known that impart a cooling sensation when ingested or in contact with the body. Perhaps the best known of these compounds is menthol, which presumably acts on cold receptors in nerve endings to provide this cooling effect.

[0003] Because menthol has a strong minty odor and high relative volatility, new compounds have been developed and reported as potential flavorings or odorants useful in various topical and ingestible compositions.For example, U.S. Patent No. 5,009,893 proposes the use of menthol in combination with N-substituted-p-menthane carboxyamide compounds as a cooling agent composition in edible products.

[0004] WO 93 / 23005 proposes a cooling sensate composition for edible or topical products comprising a ketal and a secondary cooling sensate, which may be selected from menthol, carboxamides and mixtures thereof. In addition, this patent application refers to several other references that disclose compounds with a menthol-like flavor, including menthyl carbinol, sugar esters of menthol and various amides. Also, 2,3-p-menthanediol is reported to have a sharp cooling taste.

[0005] DE 2 339 661 A1 discloses fragrance compositions containing menthol or menthol esters of heterocyclic carboxylic acids. A preferred ester is menthyl-2-pyrrolidone-5-carboxylic acid ester.

[0006] DE 2608226 A1 discloses compositions exhibiting a physiological cooling effect. The cooling compounds disclosed include menthol esters of naturally occurring hydroxycarboxylic acids having 2 to 6 carbon atoms esterified with C1-C4 alkyl groups. Menthyl acetate and menthyl lactate are the most preferred cooling compounds of this disclosure.

[0007] WO 97 / 07771 A1 discloses cooling compositions, flavor compositions, and ingestible and topical compositions containing monomenthyl succinate, alkali metal or alkaline earth metal salts of monomenthyl succinate, and mixtures thereof. Secondary cooling agents that may be used in combination with monomenthyl succinate and / or its salts include menthol, carboxamides, ketals, menthyl acetate, menthyl lactate, 3-menthoxypropane-1,2-diol, and mixtures thereof.

[0008] Finally, EP 80148 B1 describes 3-menthoxypropane-1,2-diol, another commercially available compound with cooling properties.

[0009] Thus, a variety of compounds are known to have cooling properties and are useful in a wide variety of products. However, there remains a need to provide new cooling compositions that have improved cooling effect and / or taste. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] U.S. Pat. No. 5,009,893 [Patent Document 2] International Publication No. 93 / 23005 Brochure [Patent Document 3] DE 2339661 A1 [Patent Document 4] DE 2608226 A1 [Patent Document 5] International Publication No. 97 / 07771A1 Brochure [Patent Document 6] European Patent No. 80148B1 Summary of the Invention [Problem to be solved by the invention]

[0011] It is therefore an object of the present invention to provide an improved cooling sensate composition. Another object of the present invention is to provide a cooling sensate composition having a unique cooling sensation and taste. Yet another object of the present invention is to provide a cooling sensate composition comprising two or more cooling agents that can provide complementary cooling sensations and tastes.

[0012] These and other objects of the present invention will become apparent from the detailed description and examples which follow. [Means for solving the problem]

[0013] Certain aspects of the disclosure are set forth in the appended claims. There are further features and advantages of the subject matter described herein. These will become apparent as the present specification proceeds. In this regard, it should be understood that the claims serve as a brief summary of various aspects of the subject matter described herein. The various features described below for the claims and various embodiments may be used in combination or separately. For example, the ranges specified may include their recited endpoints unless expressly excluded. Any particular embodiment need not provide all of the features described above, solve all of the problems, or address all of the issues described above.

[0014] According to an embodiment of the present invention, there is provided a cooling composition comprising (or consisting essentially of) an effective amount of a cooling compound having general formula (I) and an edible, drinkable or cosmetic ingredient, [ka] During the ceremony, Q is CR 1 R 2 or CH-CH(CH2OR 8 )CH2OR 9 Selected from R 1 and R 2 are independently CHO, CO2H, CH2CH2OH, CHR 10 OR 11 , and C.H.R. 10 OR 12 R 8 and R 9 are independently H or combine to form a spiroacetal or spiroketal moiety; each R 10 are independently H or CH3, R 11 and R 12 is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkaryl, substituted or unsubstituted aryl or heteroaryl, and substituted or unsubstituted acyl, or R 11 and R 12 combine to form a spiroketal or spiroacetal moiety, R 3 , R 4 , R 5 , and R 6 is independently selected from H, CH3, and CH2CH3; R 7 is selected from H, isopropyl, isopropenyl, and sec-butyl, with the proviso that R 3 , R 4 , R 5 , R 6 , and R 7 Not all of the A cooling composition is provided.

[0015] Further embodiments of the present invention include product compositions selected from oral care products, nasal care products, toiletries (toiletries, beauty products), pipe tobacco products, chewing tobacco, chewing tobacco products, filters for snuff products, combustible papers and coated sheets, topical products such as chewing gum and chewing gum products, ingestible products, or tobacco products, a topical, ingestible, or tobacco-based product; an effective amount of a cooling composition comprising (or consisting essentially of) a cooling compound having the general formula (I); The present invention relates to a product composition comprising:

[0016] The present invention also relates to the use of cooling compounds having general formula (I) as cooling agents or flavoring agents.

[0017] According to yet another embodiment of the present invention, there is provided a cooling compound having the general formula (I): [ka] During the ceremony, Q is CR 1 R 2 or CH-CH(CH2OR 8 )CH2OR 9 Selected from R 1 are CHO, CO2H, CH2CH2OH, CHR 10 OR 11 R 2 is CHO, CH2CH2OH, and CHR 10 OR 12 R 8 and R 9 are independently H or combine to form a spiroacetal or spiroketal moiety; R 10 is H or CH3, R 11 and R 12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkaryl, substituted or unsubstituted aryl or heteroaryl, and substituted or unsubstituted acyl, or R 11 and R 12 combine to form a spiroketal or spiroacetal moiety, R 3 , R 4 , R 5 , and R 6 is independently selected from H, CH3, and CH2CH3; R 7 is selected from isopropyl, isopropenyl, and sec-butyl; The first condition is R 3 , R 4 , R 5 , R 6 , and R 7 Not all of the numbers are H. The second condition is that Q is CR 1 R 2 and R 1 and R 2 When both are CH2OH, R 7 is not H, R 3 , R 5 , and R 6 Not all of the 4 is not CH3, but R 7 is not isopropyl, The third condition is that Q is CR 1 R 2 and R 1 and R 2 Both are CH2OH, and R 7 is isopropyl or isobutyl, R 3 , R 4 , R 5 , and R 6 at least two of the are CH3 or CH2CH3; The fourth condition is that Q is CR 1 R 2 and R 1 CHR10 OR 11 and R 2 CHR 10 OR 12 and R 10 is H and R 11 and R 12 combine to form a spiroketal or spiroacetal moiety, R 7 When is H, R 3 , R 4 , R 5 , and R 6 At least two of the groups are CH3 or CH2CH3. A cooling compound is provided. [Brief description of the drawings]

[0018] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and, together with the general description of the invention above and the detailed description below, serve to explain the invention.

[0019] [Figure 1] FIG. 1 is a graph showing preliminary comparative cooling intensity over time of several dilute aqueous solutions of compound 1 (((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol) and compound 2 ((7S,10R)-7-isopropyl-3,10-dimethyl-2,4-dioxaspiro[5.5]undecane) versus WS-3™ and WS-5™. [Diagram 2] FIG. 2 is a graph showing the comparative evaluation of compound 1 (((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol) over time against menthol, WS-3™, PHYSCOOL™, and mineral water. [Diagram 3] FIG. 3 is a graph showing the comparative evaluation of Compound 1 (((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol) versus PHYSCOOL™ over a 10 minute period. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In case of conflict, the present specification, including explanations of terms, will control. The singular terms "a," "an," "at least one," and "the" include plural referents unless the context clearly contradicts otherwise. Similarly, the term "or" is intended to include "and" unless the context clearly contradicts otherwise. The term "comprising" means "including." Thus, "comprising A or B" means including A or B, as well as including both A and B.

[0021] According to an embodiment of the present invention, there is provided a cooling composition comprising (or consisting essentially of) an effective amount of a cooling compound having general formula (I) and an edible, drinkable or cosmetic ingredient, [ka] During the ceremony, Q is CR 1 R 2 or CH-CH(CH2OR 8 )CH2OR 9 Selected from R 1 and R 2 are independently CHO, CO2H, CH2CH2OH, CHR 10 OR 11 , and C.H.R. 10 OR 12 R 8 and R 9 are independently H or combine to form a spiroacetal or spiroketal moiety; each R 10 are independently H or CH3, R 11 and R 12is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkaryl, substituted or unsubstituted aryl or heteroaryl, and substituted or unsubstituted acyl, or R 11 and R 12 combine to form a spiroketal or spiroacetal moiety, R 3 , R 4 , R 5 , and R 6 is independently selected from H, CH3, and CH2CH3; R 7 is selected from H, isopropyl, isopropenyl, and sec-butyl, with the proviso that R 3 , R 4 , R 5 , R 6 , and R 7 Not all of the A cooling composition is provided.

[0022] As used herein, "effective amount" means an amount of a cooling compound or cooling composition that imparts a statistically significant cooling effect to a composition or product as determined by one of ordinary skill in the perfumery arts.

[0023] As used herein, "cooling compound" means that the compound is active on the hTRPM8 receptor and provides a cooling effect on the skin and / or mucous membranes. In some cases, the cooling compound may have olfactory chemo-receptor activity, which makes the compound useful as a fragrance molecule. Thus, depending on the unique properties of each cooling compound disclosed herein, the cooling compound may be used as a cooling agent and / or a fragrance agent.

[0024] As used herein, "substituted" and "substituted" mean containing a functional group selected from an ester moiety, an acid moiety, or an alkoxy moiety.

[0025] C1-C6 alkyl means a straight or branched alkyl group containing 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl and hexyl.

[0026] Cycloalkyl is of the formula C n H 2n-1 "cycloalkyl" refers to monocyclic saturated hydrocarbon groups such as (but not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Unless otherwise specified, cycloalkyl groups contain from 3 to 8 carbon atoms.

[0027] Aryl means an aromatic ring containing 5 to 10 carbon atoms, consisting of one ring or several condensed rings. Aryl is preferably phenyl.

[0028] Heteroaryl means a heteroaromatic ring containing 4 to 10 carbon atoms and 1 to 3 heteroatoms selected from O, S or N. Non-limiting examples include pyridinyl, thiophenyl, or furanyl.

[0029] Alkaryl refers to the group Alk-Ar, where Alk is a C1-C6 alkyl and Ar is an aromatic ring. A non-limiting example of alkaryl is benzyl.

[0030] Acyl means a carboxyl moiety containing 1 to 4 carbons. Non-limiting examples include acetyl, propanoyl, butanoyl, or succinyl.

[0031] In one embodiment, in formula (I), Q is CR 1 R 2 whereby the cooling compound in the cooling composition is characterized by having the general formula (II): [ka] In the formula, R 1 ~R 7is the same as defined for formula (I).

[0032] In one embodiment, in formula (I), R 4 is methyl, R 6 is H, whereby the cooling compound in the cooling composition is represented by the general formula (II a ) is characterized in that it has. [ka] In the formula, R 1 , R 2 , R 3 , R 5 , and R 7 is the same as defined for formula (I). In another embodiment, R 1 and R 2 are independently CHO, CH2OR 11 , and CH2OR 12 R 3 and R 5 is independently selected from H and CH3; R 7 is selected from H and isopropyl; R 11 and R 12 is the same as defined for formula (I).

[0033] In one embodiment, in formula (II), R 3 is CH3 and R 4 , R 5 and R 6 are H and R 7 is isopropyl, whereby the cooling compound in the cooling composition is characterized as having the general formula (III): [ka] In the formula, R 1 and R 2 is the same as defined for formula (I). In another embodiment, R 1 and R 2 are independently CHO, CH2OR 11 , and CH2OR 12R 11 and R 12 is the same as defined for formula (I). For example, the cooling compound in the cooling composition is represented by the general formula (IV a ) or (IV b ) may be a stereoisomer. [ka] In one embodiment, the compound of formula (IV a ) and (IV b ) in R 1 and R 2 are each CHO, thereby providing the compounds (2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-dicarboxaldehyde and (2R,5R)-2-isopropyl-5-methylcyclohexane-1,1-dicarboxaldehyde, respectively.

[0034] In another embodiment, the compound of formula (III), (IV a ) or formula (IV b ) in R 1 is CHR 10 OR 11 and R 2 is CHR 10 OR 12 Thus, the cooling compound in the cooling composition is represented by the general formula (V), (V a ) or (V b ) is characterized in that it has. [ka] In the formula, R 10 , R 11 , and R 12 is the same as defined for formula (I). In another embodiment, formula (V), (V a ), or (V b ) in R 10 is H. In a further embodiment, R 10 is H and R 11 and R 12 are combined to form a spiroketal moiety or a spiroacetal moiety CR13 R 14 Thus, the cooling compound in the cooling composition is represented by the general formula (VI), a ), or (VI b ) is provided. [ka] In the formula, R 13 and R 14 is independently selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkaryl, and substituted or unsubstituted aryl or heteroaryl, or R 13 and R 14 combine to form a substituted or unsubstituted cycloalkyl.

[0035] In another embodiment, in formula (I), Q is CH—CH(CHOR 8 )CH2OR 9 whereby the cooling compound in the cooling composition is characterized by having the general formula (VII): [ka] In the formula, R 3 ~R 9 is the same as defined for formula (I).

[0036] In yet another embodiment, in formula (II), R 1 is CHR 10 OR 11 and R 2 is CHR 10 OR 12 and R 10 is H, whereby the cooling compound in the cooling composition is characterized as having the general formula (VIII): [ka] In the formula, R 3 ~R 9 , R 11 and R12 is the same as defined for formula (I). In a further embodiment, R 11 and R 12 are combined to form a spiroketal moiety or a spiroacetal moiety CR 13 R 14 whereby the cooling compound in the cooling composition is characterized by having the general formula (IX): [ka] In the formula, R 13 and R 14 is represented by the formula (VI), a ), and (VI b ) is the same as that defined for

[0037] In a further embodiment, in formula (II), R 3 , R 4 , and R 5 are CH3 and R 6 and R 7 are each H, whereby the cooling compound in the cooling composition is characterized as having the general formula (X): [ka] In the formula, R 1 and R 2 is the same as defined for formula (I). In another embodiment, R 1 and R 2 are independently CHO, CH2OR 11 , and CH2OR 12 R 11 and R 12 is the same as defined for formula (I).

[0038] In another embodiment, in formula (X), R 1 is CHR 10 OR 11 and R 2 is CHR 10 OR 12 and R 10is H, whereby the cooling compound in the cooling composition is characterized as having the general formula (VII). [ka] In the formula, R 11 and R 12 is the same as defined for formula (I). In a further embodiment, R 11 and R 12 are combined to form a spiroketal moiety or a spiroacetal moiety CR 13 R 14 whereby the cooling compound in the cooling composition is characterized as having the general formula (XII): [ka] In the formula, R 13 and R 14 is independently selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkaryl, and substituted or unsubstituted aryl or heteroaryl, or R 13 and R 14 combine to form a substituted or unsubstituted cycloalkyl.

[0039] According to one embodiment, the cooling composition comprises: 1. ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol, 2. (7S,10R)-7-isopropyl-3,10-dimethyl-2,4-dioxaspiro[5.5]undecane, 3. (7S,10R)-7-isopropyl-3,3,10-trimethyl-2,4-dioxaspiro[5.5]undecane, 4. (7S,10R)-3-ethyl-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane, 5. 4-((7S,10R)-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecan-3-yl)-2-methoxyphenol, 6. (7S,10R)-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane, 7. (1S,4R,10S,13R)-1,10-diisopropyl-4,13-dimethyl-7,16-dioxadispiro [5.2.5 9 .2 6 ]Hexadecane, 8. (2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-dicarbaldehyde, 9. ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)bis(methylene) diacetate, 10. (3,3,5-trimethylcyclohexane-1,1-diyl)dimethanol, 11. 3,8,8,10-tetramethyl-2,4-dioxaspiro[5.5]undecane, 12. 3,3,8,8,10-pentamethyl-2,4-dioxaspiro[5.5]undecane, 13. (7S,10R)-3-ethyl-7-isopropyl-3,10-dimethyl-2,4-dioxaspiro[5.5]undecane, 14. (7S,10R)-7-isopropyl-10-methyl-3-propyl-2,4-dioxaspiro[5.5]undecane, 15. (7S,10R)-3,7-diisopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane, 16. (7S,10R)-3-(sec-butyl)-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane, 17. (2S,5R)-2-isopropyl-1,1-bis(methoxymethyl)-5-methylcyclohexane, 18. (7S,10R)-7-isopropyl-10-methyl-3-phenyl-2,4-dioxaspiro[5.5]undecane, 19. (7S,10R)-3,3-diethyl-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane, 20. (3,3-dimethylcyclohexane-1,1-diyl)dimethanol, 21. 4,4'-((((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)bis(methylene))bis(oxy))bis(4-oxobutanoic acid), 22. (7S,10R)-7-isopropyl-3,10-dimethyl-3-phenyl-2,4-dioxaspiro[5.5]undecane, 23. 2-((7S,10R)-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecan-3-yl)pyridine, 24. (7S,10R)-7-isopropyl-10-methyl-3-(thiophen-2-yl)-2,4-dioxaspiro[5.5]undecane, 25. (7S,10R)-7-isopropyl-10-methyl-3-(2-(methylthio)ethyl)-2,4-dioxaspiro[5.5]undecane, 26. 3,8,8-trimethyl-2,4-dioxaspiro[5.5]undecane, 27. (2-(sec-butyl)cyclohexane-1,1-diyl)dimethanol, 28. Ethyl (7S,10R)-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane-3-carboxylate, 29. 2,2'-((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)bis(ethan-1-ol), 30. (2-isopropyl-5,5-dimethylcyclohexane-1,1-diyl)dimethanol, 31. 7-(sec-butyl)-3-methyl-2,4-dioxaspiro[5.5]undecane, 32. ((2S,5R)-1-(hydroxymethyl)-2-isopropyl-5-methylcyclohexyl)methyl acetate, 33. 7-isopropyl-3,10,10-trimethyl-2,4-dioxaspiro[5.5]undecane, 34. 1,1'-((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)bis(ethan-1-ol), 35. 2-((1R,2R,5R)-5-methyl-2-(prop-1-en-2-yl)cyclohexyl)propane-1,3-diol, 36. 2-methyl-5-((1R,2R,5R)-5-methyl-2-(prop-1-en-2-yl)cyclohexyl)-1,3-dioxane, 37. 2-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)propane-1,3-diol, 38. ((2S,5R)-1-((benzyloxy)methyl)-2-isopropyl-5-methylcyclohexyl)methanol, 39. (2S,5R)-1-(hydroxymethyl)-2-isopropyl-5-methylcyclohexane-1-carboxylic acid, 40. (3,3,5,5-tetramethylcyclohexane-1,1-diyl)dimethanol, and combinations and mixtures thereof The cooling compound is selected from the group consisting of:

[0040] In addition to the cooling compounds having the general formulae (I)-(XII), the cooling composition further includes edible, drinkable or cosmetic ingredients, such as those typically used in ingestible or cosmetic products. For example, the edible, drinkable or cosmetic ingredients may include carrier or diluent materials, which may be inert or may contain other active ingredients relevant to its end use. A wide variety of carrier or diluent materials may be employed, including, for example, polar solvents, oils, fats, finely divided solids, maltodextrins, cyclodextrins, gums, natural or synthetic resins, or any other known carrier or diluent materials for cooling or flavoring compositions. In another example, the edible, drinkable or cosmetic ingredients may include flavorings, which may be particularly useful as flavoring compositions in various ingestible (edible or drinkable) compositions and / or compositions intended for contact with the human or animal body (cosmetic products). Flavoring agents may be selected from fruit flavors, e.g., strawberry flavor, herbal oils, e.g., eucalyptus oil, peppermint oil, spearmint oil, and other known flavoring or flavoring oils conventionally used in ingestible compositions and compositions designed to contact the human or animal body, such as flavored syrups (e.g., sorbitol syrup) or other sweet syrups.

[0041] The cooling composition or fragrance may be diluted with a polar solvent, such as, for example, ethyl alcohol, ethyl acetate, propylene glycol, isopropyl alcohol, glycerin, and combinations thereof. The polar solvent acts as a carrier material to aid in incorporating the cooling composition into a product. The edible, potable, or cosmetic ingredient may optionally include one or more additional conventional ingredients selected from the group consisting of colorants, lubricants, thickeners, emulsifiers, plasticizers, and encapsulating agents, such as gums, starches, dextrins, and cyclodextrins.

[0042] Typically, the cooling composition contains 1 wt% to 99 wt% of the cooling compound based on the total weight of the cooling composition. Preferably, the cooling composition contains 5 wt% to 90 wt% of the cooling compound and 10 wt% to 95 wt% of the edible, drinkable or cosmetic ingredient. More preferably, the cooling composition contains 5 wt% to 50 wt% of the cooling compound and 50 wt% to 95 wt% of the edible, drinkable or cosmetic ingredient.

[0043] Further embodiments of the invention include a product composition selected from oral care products, nasal care products, toiletries, pipe tobacco products, chewing tobacco, chewing tobacco products, filters for snuff products, combustible papers and coated sheets, topical products such as chewing gum and chewing gum products, ingestible products, or tobacco products, comprising: a topical, ingestible, or tobacco-based product; an effective amount of a cooling compound having the general formulas (I) to (XII); The present invention relates to a product composition comprising:

[0044] In one embodiment, the cooling compounds of general formulae (I)-(XII) may be used in concentrations as low as 1% by weight based on the total weight of the product composition in which they are incorporated, providing a pleasant cooling sensation, or a long-lasting cooling effect, without the bitter taste expected from many cooling compounds of the prior art. Furthermore, at concentrations up to 1% by weight, the cooling compounds do not develop a strong minty taste in the mouth or throat, as other cooling compounds or cooling agents, such as menthol, exhibit.

[0045] According to embodiments of the present invention, topical products include, but are not limited to, toiletry products such as face creams, talcum powders, hair oils, shampoos, bath oils and bath salts, cosmetic soaps, colognes, antiperspirants, lotions, perfumes, shaving lotions and creams, soaps, creams, dentifrices, mouthwashes, lip balms, hair tonics, and other similar products.

[0046] According to an embodiment of the present invention, the ingestible (e.g., edible, drinkable, etc.) products include, but are not limited to, alcoholic and non-alcoholic beverages, confectionery tablets, hard-boiled candies, chewing gum, chewing gum products, pectin-based candies, chewy candies, cream-centered candies, and confectionery compositions including fondants; carbonated beverages, powdered drink mixes, distilled beverages, mineral waters, baked goods, dairy products, fruit ices, jams, jellies, gelatins, puddings, and animal feed. Furthermore, the cooling compounds of the present invention may enhance the taste of alcohol in alcoholic beverages. As a result, an alcoholic beverage containing the cooling compounds of the present invention may taste as having a higher alcohol content than an alcoholic beverage of the same alcoholic strength that does not contain the cooling compounds.

[0047] According to embodiments of the present invention, tobacco products include, but are not limited to, filters, combustible papers, and coating sheets for chewing tobacco products, snuff products, and pipe tobacco products.

[0048] The selection of cooling compounds within the scope of general formula (I)-(XII) for use in the cooling composition depends, in part, on the solubility characteristics of the compound. For example, the cooling compounds of the present invention are poorly soluble in water and more soluble in oil. Thus, the cooling compounds of the present invention are particularly suited to environments where oil solubility is advantageous, although these cooling compounds can be used in aqueous environments when concentrations below the water solubility limit are employed.

[0049] The most preferred compositions incorporating the cooling compounds and / or cooling sensate compounds of the present invention are compressed confectionery tablets, hard boiled candies, chewing gums, chewy candies, pectin candies, cream-centered candies, fondants, toothpastes, mouthwashes, breath fresheners, alcoholic and non-alcoholic beverages, carbonated beverages, and dry beverage mixes.

[0050] The amount of cooling compound or cooling composition incorporated into each of these proposed product compositions (or end-use compositions) will vary depending on the particular compound, the concentration of the cooling compound in the cooling composition, the degree of cooling effect desired, and the strength of other fragrances in the composition. Typically, the cooling compound having the general formulas (I)-(XII) will comprise 0.001-1.0 wt. % of the end-use composition. More preferably, the cooling compound will comprise 0.005-0.5 wt. % based on the total weight of the end-use composition.

[0051] It has been found that the cooling compounds of the present invention, when ingested, provide a cooling effect in a different region of the mouth and throat than, for example, menthol or carboxamide-based cooling agents. As a result, the cooling compounds of the present invention, when combined with at least one secondary cooling agent, further provide a complementary or synergistic cooling effect. Exemplary but non-limiting secondary cooling agent compounds include carboxamides, ketals, menthyl glutarate, menthyl succinate, menthyl acetate, menthyl lactate, 3-menthoxypropane-1,2-diol, isopulegol, menthol, and mixtures thereof. Thus, according to another embodiment of the present invention, there is provided a cooling composition comprising a cooling compound having the general formula (I)-(XII) in combination with at least one secondary cooling agent. Secondary cooling agents that may be used in combination with the cooling compounds of the present invention include carboxamides, ketals, menthyl glutarate, menthyl succinate, menthyl acetate, menthyl lactate, 3-menthoxypropane-1,2-diol, menthol, and mixtures thereof.

[0052] The carboxamide and ketal cooling sensates are known from the prior art and are described, for example, in U.S. Pat. No. 5,009,893 and WO 93 / 23005, the disclosures of which are incorporated herein by reference. The remaining secondary cooling sensates are known cooling sensates, many of which are commercially available.

[0053] For example, secondary carboxamide cooling agents may be represented by the general formula: [ka] wherein R', when alone, is hydrogen or an aliphatic group containing up to 25 carbon atoms, and R" when alone is hydroxy or an aliphatic group containing up to 25 carbon atoms, with the proviso that when R' is hydrogen, R" may be an aryl group of up to 10 carbon atoms and may be selected from the group consisting of substituted phenyl, phenyl alkyl, substituted phenyl alkyl, naphthyl, substituted naphthyl and pyridyl, and R' and R" taken together with the nitrogen atom to which they are attached represent a cyclic or heterocyclic group of up to 25 carbon atoms.

[0054] Additionally, the secondary carboxamide cooling agent may be represented by the general formula [ka] and mixtures thereof, wherein R' and R" are independently selected from hydrogen, C1-C5 alkyl, or C1-C8 hydroxyalkyl, providing a total of up to 8 carbon atoms, with the proviso that when R' is hydrogen, R" may be an alkylcarboxyalkyl of up to 6 carbon atoms, or R' and R" taken together represent an alkylene group of up to 6 carbon atoms, both ends of which are attached to the amide nitrogen atom, thereby forming a nitrogen heterocycle, the carbon chain of which may optionally be interrupted (interrupted) by oxygen; a is hydrogen or C1-C5 alkyl, R b and R c are each C1-C5 alkyl, with the proviso that (i) R a , R b , and R c together provide a total of at least 5 carbon atoms, preferably 5 to 10 carbon atoms; and (ii) R a If is hydrogen, R b is C2-C5 alkyl, R c is C2-C5 alkyl, R b and R cAt least one of the following is preferably marked in the formula: * ) branched at the α or β position relative to the carbon atom.

[0055] Non-limiting secondary ketal cooling agents include those having the general formula [ka] where R d represents a C2-C6 alkylene group having at least one but not more than three hydroxyl groups; R e and R f or each independently represents a C1-C10 alkyl, a C5-C7 cycloalkyl, preferably cyclohexyl, optionally substituted by 1 to 3 groups selected from the group consisting of hydroxyl, amino, and halogen, and a C6-C12 aryl, preferably phenyl, with the proviso that R e and R f The total number of carbon atoms in is 3 or more, or R e and R f together represent an alkylene group, which is a group R e and R f Together with the carbon atom carrying the group, it forms a 5- to 7-membered ring which may be substituted with a C1-C6 alkyl group.

[0056] Depending on the particular flavor desired, the relative amount of the cooling compound of formula (I)-(XII) to the secondary cooling agent in the cooling composition may vary over a wide range. For example, if the strong minty taste of menthol is desired, a combination of a higher amount of menthol with a relatively lower amount of the cooling compound of the present invention may be desirable. Other promising combinations of the cooling compound of the present invention with secondary cooling agents will be apparent to those skilled in the art.

[0057] When present, the concentration of the secondary cooling agent in the cooling composition is about 0.05% to about 95% by weight, more preferably about 0.1% to about 70% by weight, and most preferably about 0.5% to about 50% by weight, based on the total weight of the cooling composition. Typically, the cooling composition is prepared by mixing the cooling compound having the general formulas (I) to (XII) and the secondary cooling agent in a conventional manner.

[0058] According to yet another embodiment of the present invention, there is provided a cooling compound having the general formula (I): [ka] In the formula, Q is CR 1 R 2 or CH-CH(CH2OR 8 )CH2OR 9 Selected from R 1 are CHO, CO2H, CH2CH2OH, CHR 10 OR 11 R 2 is CHO, CH2CH2OH, and CHR 10 OR 12 R 8 and R 9 are independently H or combine to form a spiroacetal or spiroketal moiety; R 10 is H or CH3, R 11 and R 12 is independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkaryl, substituted or unsubstituted aryl or heteroaryl, and substituted or unsubstituted acyl, or R 11 and R 12 combine to form a spiroketal or spiroacetal moiety, R 3 , R 4 , R 5 , and R 6 is independently selected from H, CH3, and CH2CH3; R 7is selected from isopropyl, isopropenyl, and sec-butyl; The first condition is R 3 , R 4 , R 5 , R 6 , and R 7 Not all of the numbers are H. The second condition is that Q is CR 1 R 2 and R 1 and R 2 When both are CH2OH, R 7 is not H, R 3 , R 5 , and R 6 Not all of the 4 is not CH3, but R 7 is not isopropyl, The third condition is that Q is CR 1 R 2 and R 1 and R 2 Both are CH2OH, and R 7 is isopropyl or isobutyl, R 3 , R 4 , R 5 , and R 6 at least two of the are CH3 or CH2CH3; The fourth condition is that Q is CR 1 R 2 and R 1 CHR 10 OR 11 and R 2 CHR 10 OR 12 and R 10 is H and R 11 and R 12 combine to form a spiroketal or spiroacetal moiety, R 7 When is H, R 3 , R 4 , R 5 , and R 6 At least two of the groups are CH3 or CH2CH3.

[0059] Further contemplated is the use of cooling compounds having general formula (I) as cooling agents or flavoring agents.

[0060] According to one or more embodiments, the cooling compound itself may be further defined by formulas (II)-(XII), where Q and R 1 ~R 14 is defined in formulas (II) to (XII) above, and is limited only by the above four conditions, if applicable.

[0061] Exemplary compounds and compositions within the embodiments of the present invention are illustrated by the following examples. EXAMPLES

[0062] Experimental Procedures for the Examples: Synthesis of Cooling Compounds 1-40.

[0063] Compound 1: ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol [ka] In a 1 L flask, potassium hydroxide (80 g, 1426 mmol) and ethanol (500 ml) are added. After complete solubilization of the KOH, 37% aqueous formaldehyde solution (106 ml, 1426 mmol) is added to the above medium over 15 minutes and the mixture is stirred at room temperature for 30 minutes. (2S,5R)-2-isopropyl-5-methylcyclohexane-1-carbaldehyde (60 g, 357 mmol) (also called menthanal, the synthesis of which is described in the literature) is then added to the medium over 15 minutes and the mixture is then stirred at room temperature for 72 hours. The medium is concentrated and the aqueous phase is extracted with MTBE (300 mL). The organic phase is washed with a saturated solution of NaHCO3 (150 mL) and the aqueous phase is extracted with methyl t-butyl ether (MTBE) (150 mL). The organic phases are combined, washed with brine (100 mL), dried over anhydrous MgSO4, filtered and concentrated. ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (45.93 g, 218 mmol, 61.1% yield) is obtained after distillation (T=122° C., 0.3 mbar) in the form of a very viscous liquid, which crystallizes into a white solid after a few hours at room temperature. 1 H NMR (300MHz, chloroform-d) δ 4.07(d,J=10.4Hz,1H),3.87(d,J=1.0Hz,2H),3.39(d,J=10.4Hz,1H),2.69 (d,J=1.8Hz,2H),2.27-2.15(m,1H),2.05-1.90(m,1H),1.85-1.71(m,1H),1 .67-1.37(m,2H),1.34-1.15(m,1H),1.08(dd,J=12.8,3.5,1.2Hz,1H),0.9 4-0.85(m,6H),0.87-0.76(m,1H),0.74(d,J=6.8Hz,3H),0.70-0.55(m,1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data of the obtained compound. Olfactory description: Almost odorless, refreshing.

[0064] Compound 2: (7S,10R)-7-isopropyl-3,10-dimethyl-2,4-dioxaspiro[5.5]undecane [ka] In a 100 mL flask equipped with a magnetic stirrer and a condenser, ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (5 g, 24.96 mmol), acetaldehyde (2.81 mL, 49.9 mmol) and para-toluenesulfonic acid monohydrate (PTSA) (0.750 g, 3.94 mmol) are added. The medium is left under stirring overnight at ambient temperature. Na2CO3 (0.579 g, 5 mol%) is added to the medium, which is then filtered. (7S,10R)-7-Isopropyl-3,10-dimethyl-2,4-dioxaspiro[5.5]undecane (1.3 g, 23%) is obtained after distillation as a colorless liquid (70 °C, 0.3 mbar; mixture of isomers, two GC peaks 25 / 75). 1 H NMR(300MHz,CDCl3) δ 4.61(q,J=5.2Hz,1H),4.09-3.97(m,2H),3.79-3.68(m,1H),3.51-3.31(m,1H),2.65-2.53(m,1H),2.12-1.93(m,1H),1.84-1.70(m,1H) ),1.63-1.51(m,1H),1.55-1.42(m,2H),1.38-1.20(m,3H),1.25-1.06(m,1H),1.01-0.82(m,7H),0.84-0.71(m,3H),0.71-0.49(m,1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data of the obtained compounds. Olfactory description: refreshing, minty, fruity.

[0065] Compound 3: (7S,10R)-7-isopropyl-3,3,10-trimethyl-2,4-dioxaspiro[5.5]undecane [ka] A 100 mL flask equipped with a magnetic stirrer and a condenser is charged with ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (10 g, 49.9 mmol) melt, acetone (5.80 g, 100 mmol) and PTSA (0.475 g, 2.496 mmol). The medium is left under stirring at ambient temperature overnight. Na2CO3 (0.442 g, 5 mol%) is added to the medium, which is then filtered and concentrated. The liquid obtained is purified by a chromatography column (CombiFlash®, cyclohexane / EtOAc gradient). (7S,10R)-7-Isopropyl-3,3,10-trimethyl-2,4-dioxaspiro[5.5]undecane (1.81 g, 14%) is obtained as a colorless liquid. 1 H NMR(300MHz,chloroform-d) δ 3.89(d,J=11.6Hz,2H),3.60(dt,J=11.7,0.9Hz,1H),3.20-3.10(m,1H),2.29-2.08(m,2H),1.75-1.60(m,1 H),1.49-1.37(m,1H),1.33(s,3H),1.32(s,3H),1.23-1.00(m,1H),0.99-0.60(m,11H),0.58-0.42(m,1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data of the compounds obtained. Odor description: Weak, cool, woody.

[0066] Compound 4: (7S,10R)-3-ethyl-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane [ka] In a 100 mL flask equipped with a magnetic stirrer and a condenser, add ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (7 g, 34.9 mmol), propionaldehyde (5.01 mL, 69.9 mmol) and PTSA (0.332 g, 1.747 mmol). The medium is left under stirring overnight at ambient temperature. Na2CO3 (0.185 g, 5 mol%) is added to the medium, which is then filtered and concentrated. (7S,10R)-3-Ethyl-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane (3.86 g, 44%) is obtained after distillation as a colorless liquid (T = 80-85 °C, 0.3 mbar; two peaks GC 23 / 77). 1 H NMR(300MHz,chloroform-d) δ 4.44-4.29(m,1H),4.10-3.96(m,2H),3.80-3.68(m,1H),3.50-3.32(m, 1H),2.57(ddd,J=13.6,3.4,2.3Hz,1H),2.13-1.93(m,1H),1.83-1.71(m ,1H),1.70-1.58(m,2H),1.57-1.41(m,1H),1.38-1.20(m,1H),1.20-1. 03(m,1H),1.01-0.83(m,11H),0.78(d,J=6.9Hz,3H),0.67-0.49(m,1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data of the compounds obtained. Olfactory description: refreshing, fruity, exotic.

[0067] Compound 5: 4-((7S,10R)-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecan-3-yl)-2-methoxyphenol [ka] Vanillin (1.246 g, 8.19 mmol), trimethyl orthoformate (2.73 mL, 24.96 mmol), PTSA (0.047 g, 0.250 mmol) and then ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (1 g, 4.99 mmol) are added to a 100 mL flask equipped with a magnetic stirrer and a condenser. The medium is left under stirring overnight at ambient temperature. MTBE (50 mL) is added and then the medium is poured into a saturated NaHCO3 (50 mL) solution. The organic phase is washed with NaCl (sat) (100 mL), dried over anhydrous MgSO4, filtered and concentrated. The liquid obtained is purified by chromatography column (CombiFlash®, cyclohexane / EtOAc gradient). 4-((7S,10R)-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecan-3-yl)-2-methoxyphenol (0.53 g, 31%) is obtained as a colorless viscous liquid. 1 H NMR (300 MHz, chloroform-d) δ 7.10-6.91 (m, 2H), 6.94-6.84 (m, 1H), 5.58 (s, 1H), 5.36 (d, J = 10.7 Hz, 1H), 4.27-4.16 (m, 2H), 4.01-3.91 (m, 1H), 3.87 (s, 3H), 3.73-3.50 (m, 1H), 2.81-2.69 (m, 1H) ,2.21-2.01(m,1H),1.81(dt,J=12.4,3.1Hz,1H),1.71-1.46(m,2H),1.45-1.10(m ,2H),1.08-0.98(m,2H),0.98-0.94(m,4H),0.94-0.80(m,4H),0.76-0.55(m,1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data of the compound obtained. Olfactory description: Almost odorless, vanilla.

[0068] Compound 6: (7S,10R)-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane [ka] In a 250 mL three-neck flask equipped with a Dean-Stark trap, ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (10 g, 49.9 mmol), dimethoxymethane (22.34 ml, 250 mmol), cyclohexane (100 ml) and PTSA (0.475 g, 2.496 mmol) are added. The mixture is stirred at reflux overnight. The cooled medium is poured into a saturated NaHCO3 (50 mL) solution, then the organic phase is washed with brine (50 mL), dried over anhydrous MgSO4, filtered and concentrated. (7S,10R)-7-Isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane (7.13 g, 32.9 mmol, 65.9% yield) is recovered after distillation (74° C., 0.4 mbar) as a colorless liquid. 1 H NMR(300MHz,chloroform-d) δ 4.93(d,J=5.9Hz,1H),4.67(d,J=6.0Hz,1H),3.97-3.87(m,2H),3.82(dd,J=11.4,1.3Hz,1H ),3.45-3.29(m,1H),2.43-2.28(m,1H),2.20(p,J=6.9Hz,1H),1.88-1.64(m,1H),1.64-1.3 6(m,2H),1.19(qd,J=13.1,3.5Hz,1H),0.96(dd,J=3.6,1.2Hz,1H),0.91(d,J=5.0Hz,3H),0 .89(d,J=4.3Hz,3H),0.85(dd,J=3.6,1.0Hz,1H),0.80(d,J=6.7Hz,3H),0.67-0.53(m,1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data for the compounds obtained. Olfactory description: Weak, red fruit.

[0069] Compound 7: (1S,4R,10S,13R)-1,10-diisopropyl-4,13-dimethyl-7,16-dioxadispiro[5.2.5 9 .2 6 ]Hexadecane [ka] In a 100 mL three-neck flask equipped with a Dean-Stark trap, ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (2 g, 9.98 mmol), l-menthone (1.540 g, 9.98 mmol), toluene (50 mL) and then PTSA (0.095 g, 0.499 mmol) are added. The mixture is stirred overnight at reflux. The cooled medium is poured into a saturated NaHCO3 (50 mL) solution, then the organic phase is washed with brine (50 mL), dried over anhydrous MgSO4, filtered and concentrated. (1S,4R,10S,13R)-1,10-diisopropyl-4,13-dimethyl-7,16-dioxadispiro[5.2.5 9 .2 6 ]Hexadecane (1.5 g, 4.23 mmol, 42.4% yield) is recovered in the form of a pasty white solid after purification by chromatography column (CombiFlash®, cyclohexane / EtOAc gradient). 1 H NMR(300MHz,chloroform-d) δ 4.35(d,J=11.1Hz,1H),3.89-3.67(m,2H),3.07(dd,J=11.1,2.6Hz,1H),2.79-2.63(m,2H),2.63-2.47(m,1H),2.1 4-1.89(m,1H),1.83-1.66(m,3H),1.58-1.47(m,4H),1.28-1.06(m,3H),0.95-0.87(m,18H),0.81(d,J=6.8Hz,4H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data of the compound obtained. Olfactory description: odorless.

[0070] Compound 8: (2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-dicarbaldehyde [ka] In a 500 mL three-neck flask, TEMPO (0.234 g, 1.498 mmol), ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (15 g, 74.9 mmol), ethyl acetate (100 mL) and sodium bicarbonate (12.58 g, 150 mmol) are added. A solution of potassium bromide (1.782 g, 14.98 mmol) in water (20.00 ml) is then added to the flask. The mixture is vigorously stirred and cooled to 0-5 ° C. 36 ° bleach (116 ml, 187 mmol) is then added dropwise over 20 minutes, keeping the temperature below 15 ° C, and the mixture is then stirred in an ice bath for 30 minutes. The medium is diluted with water (50 mL) and the aqueous phase is extracted with EtOAc (100 mL). The organic phases are combined and then washed with 10% aqueous H2SO4 (30 mL) and saturated Na2SO3 (50 mL) solutions. No residual oxidizing agent is observed in the organic phase by KI / starch test. The organic phase is washed with saturated NaCl (50 mL), dried over anhydrous MgSO4, filtered and concentrated. (2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-dicarbaldehyde (1.5 g, 7.11 mmol, 9.49% yield) is obtained after distillation (T=78-80 °C, 0.4 mbar) as a yellowish liquid with a GC purity of 93%. 1 H NMR (300 MHz, chloroform-d) δ 10.12 (t, J = 0.9 Hz, 1H), 9.64 (s, 1H), 1.96-1.77 (m, 4H), 1.75-1.58 (m, 2H), 1.55-1.34 (m, 1H), 1.12-0.95 (m, 2H), 0.93-0.88 (m, 9H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data of the obtained compound. Olfactory description: refreshing, minty.

[0071] Compound 9: ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)bis(methylene) diacetate [ka] In a 100 mL three-neck flask equipped with a condenser are added ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (10 g, 49.9 mmol), MTBE (30 ml), 4-dimethylaminopyridine (DMAP) (0.610 g, 4.99 mmol), then acetic anhydride (14.13 ml, 150 mmol) is added dropwise. The mixture is stirred at room temperature for 30 minutes. The medium is poured into a mixture of 10% aqueous HCl (30 mL) and ice, then the organic phase is washed with saturated NaHCO3 (30 mL) solution, saturated NaCl (30 mL), dried over anhydrous MgSO4, filtered and concentrated. ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)bis(methylene) diacetate (11.2 g, 38.2 mmol, 77% yield) is recovered after distillation (T=106-108 °C, 0.7 mbar) as a clear colorless liquid. 1 H NMR(300MHz,chloroform-d) δ 4.26(d,J=11.4Hz,1H),4.08-3.97(m,3H),2.06(s,3H),2.03(s,3H),1.99-1.89(m,1H),1.83-1.58(m,2H),1.58-1.42(m,2H) ,1.42-1.11(m,2H),1.01-0.90(m,1H),0.88(d,J=6.9Hz,3H),0.84(d,J=6.4Hz,3H),0.82-0.78(m,1H),0.75(d,J=6.8Hz,3H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data of the compound obtained. Olfactory description: odorless.

[0072] Compound 10: (3,3,5-trimethylcyclohexane-1,1-diyl)dimethanol [ka] In a 250 ml three-neck flask, potassium hydroxide (21.82 g, 389 mmol) and ethanol (162 ml) are added. After complete solubilization of the KOH, 37% aqueous formaldehyde solution (29.0 ml, 389 mmol) is added dropwise at ambient temperature and the mixture is then stirred for 10 min. Then 3,3,5-trimethylcyclohexane-1-carbaldehyde (15 g, 97 mmol) is added dropwise over 30 min and the mixture is stirred overnight at ambient temperature. The medium is concentrated and the aqueous phase is extracted with MTBE (2 x 30 mL). The combined organic phases are washed successively with saturated NaHCO3 (30 mL) solution, then with brine (30 mL), dried over anhydrous MgSO4, filtered and concentrated to give a white solid. After recrystallization from cyclohexane (50 mL) under reflux, (3,3,5-trimethylcyclohexane-1,1-diyl)dimethanol (13.3 g, 67.8 mmol, 69.7% yield) is recovered in the form of a white solid. 1 H NMR(300MHz,chloroform-d) δ 3.85-3.66(m,2H),3.45-3.31(m,2H),3.31-3.01(m,2H),1.72-1.46(m,3H),1.41(ddt,J=12.9,3.6 ,2.1Hz,1H),0.98(s,3H),0.92(s,3H),0.88(d,J=6.4Hz,3H),0.86-0.67(m,2H),0.59-0.46(m,1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data of the compound obtained. Olfactory description: odorless.

[0073] Compound 11: 3,8,8,10-tetramethyl-2,4-dioxaspiro[5.5]undecane [ka] In a 100 mL three-neck flask, add (3,3,5-trimethylcyclohexane-1,1-diyl)dimethanol (8 g, 42.9 mmol), acetaldehyde (7.20 mL, 129 mmol), then PTSA (0.408 g, 2.147 mmol). The mixture is stirred for 3 hours at ambient temperature, then sodium carbonate (0.455 g, 4.29 mmol) is added to the medium. After stirring for 5 minutes, the medium is filtered and then distilled to obtain 3,8,8,10-tetramethyl-2,4-dioxaspiro[5.5]undecane (3.34 g, 15.73 mmol, 36.6% yield) in the form of a colorless liquid (Tb.=54 °C, 0.4 mbar; two GC peaks 60 / 40). 1 H NMR(300MHz,chloroform-d) δ 4.65-4.45(m,1H),4.42-4.14(m,1H),3.51-3.20(m,3H),2.53-2.20(m,1 H),1.62-1.48(m,1H),1.48-1.37(m,1H),1.32(t,J=5.3Hz,3H),1.17-1.0 7(m,1H),1.04(s,2H),0.94(s,2H),0.92(d,J=6.4Hz,2H),0.88-0.85(m, 3H),0.84(s,1H),0.75(ddd,J=19.2,13.2,6.6Hz,1H),0.66-0.40(m,1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data for the compounds obtained. Olfactory description: woody, ambery, fruity.

[0074] Compound 12: 3,3,8,8,10-pentamethyl-2,4-dioxaspiro[5.5]undecane [ka] In a 50 mL two-neck flask, add (3,3,5-trimethylcyclohexane-1,1-diyl)dimethanol (5 g, 26.8 mmol), acetone (7.95 mL, 107 mmol) and PTSA (0.255 g, 1.342 mmol). The mixture is stirred at room temperature for 1 h. Sodium carbonate (0.284 g, 2.68 mmol) is added and the medium is stirred for 5 min, then filtered and distilled. 3,3,8,8,10-Pentamethyl-2,4-dioxaspiro[5.5]undecane (2.7 g, 11.81 mmol, 44.0% yield) is recovered in the form of a clear, colorless liquid (T = 58-62 °C, 0.3 mbar). 1 H NMR(300MHz,chloroform-d) δ 3.92(dd,J=11.7,2.0Hz,1H),3.72(dd,J=11.6,1.5Hz,1H),3.52(d,J=11.4Hz,1H),3.23(dd,J=11.4,2.0Hz,1H),2.24-2.11(m,1H) ),1.81-1.53(m,1H),1.40(d,J=5.3Hz,7H),1.31(dt,J=13.9,2.1Hz,1H),0.95-0.86(m,9H),0.82-0.67(m,2H),0.61-0.44(m,1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data of the compounds obtained. Olfactory description: woody, fruity.

[0075] Compound 13: (7S,10R)-3-ethyl-7-isopropyl-3,10-dimethyl-2,4-dioxaspiro[5.5]undecane [ka] A 50 mL three-neck flask is charged with ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (10 g, 46.9 mmol), PTSA (0.446 g, 2.346 mmol) and butan-2-one (6.77 g, 94 mmol). The medium is stirred overnight at ambient temperature and then transferred to a 250 mL three-neck flask equipped with a Dean-Stark trap. Butan-2-one (6.77 g, 94 mmol) and cyclohexane (100 mL) are added and the mixture is refluxed for 1 h. Water (50 mL) is added and the aqueous phase is extracted with MTBE (2 x 30 mL). The organic phases are combined, washed with saturated NaHCO3 (40 mL) solution, brine (40 mL), dried over anhydrous MgSO4, filtered and concentrated. (7S,10R)-3-Ethyl-7-isopropyl-3,10-dimethyl-2,4-dioxaspiro[5.5]undecane (5.8 g, 21.52 mmol, 45.9% yield) is obtained in the form of a colorless liquid (T = 72-77 °C, 0.4 mbar, two GC peaks 46 / 54). 1 H NMR(300MHz,CDCl3) δ 4.06-3.83(m,2H),3.66(ddd,J=11.8,7.0,1.5Hz,1H),3.29-3.08(m,1H),2.34-2.05(m,2H),1.83-1.57(m ,3H),1.57-1.40(m,2H),1.33(d,J=7.9Hz,3H),1.28-1.02(m,1H),0.99-0.80(m,14H),0.64-0.46(m,1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with expected data for the compounds obtained. Odor description: strong, woody, algae.

[0076] Compound 14: (7S,10R)-7-isopropyl-10-methyl-3-propyl-2,4-dioxaspiro[5.5]undecane [ka] In a 50 mL three-neck flask, ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (10 g, 46.9 mmol), PTSA (0.446 g, 2.346 mmol) and butyraldehyde (13.53 g, 188 mmol) are added. The medium is stirred for 45 minutes at ambient temperature, then sodium carbonate (0.497 g, 4.69 mmol) is added. The mixture is stirred for 5 minutes, then filtered and distilled. (7S,10R)-7-isopropyl-10-methyl-3-propyl-2,4-dioxaspiro[5.5]undecane (9.6 g, 35.1 mmol, 74.8% yield) is recovered as a colorless liquid (T=66° C., 0.5 torr; two GC peaks 82 / 18). 1 H NMR(300MHz,CDCl3) δ 4.44(d,J=5.2Hz,1H),4.07-3.97(m,2H),3.80-3.63(m,1H),3.54-3.31(m,1H),2.89-2.35(m,1H),2.03(septet,J=6.9Hz,1H),1.88-1 .69(m,1H),1.69-1.52(m,3H),1.52-1.36(m,3H),1.36-1.04(m,2H),0.97-0.85(m,10H),0.75(d,J=6.8Hz,3H),0.69-0.52(m,1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with expected data for the compound obtained. Olfactory description: Cheese-like, gluey.

[0077] Compound 15: (7S,10R)-3,7-diisopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane [ka] A 50 mL three-neck flask is charged with ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (10 g, 46.9 mmol), PTSA (0.446 g, 2.346 mmol) and isobutyraldehyde (13.53 g, 188 mmol). The medium is stirred overnight at ambient temperature and then transferred to a 250 mL three-neck flask equipped with a Dean-Stark trap. Cyclohexane (100 mL) is then added and the mixture is refluxed for 1 h. Water (50 mL) is added and the aqueous phase is extracted with MTBE (2 x 30 mL). The combined organic phases are washed with saturated NaHCO3 (40 mL) solution, brine (40 mL), dried over anhydrous MgSO4, filtered and concentrated. (7S,10R)-3,7-Diisopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane (3.4 g, 12.29 mmol, 26.2% yield) is recovered after distillation as a yellowish liquid (Teb = 76 °C, 0.8 torr; two GC peaks 65 / 35). 1 H NMR(300MHz,CDCl3) Major isomer δ 4.18(dd,J=15.0,4.3Hz,1H),4.04(dd,J=11.1,2.8Hz,1H),3.99(d,J=10.9Hz, 1H),3.85-3.66(m,1H),3.49-3.30(m,1H),2.61-2.48(m,1H),2.11-1.93(m,1H) ),1.89-1.65(m,2H),1.65-1.43(m,2H),1.40-1.00(m,3H),1.00-0.92(m,6H), 0.92-0.89(m,3H),0.89-0.86(m,3H),0.78(d,J=7.0Hz,3H),0.65-0.42(m,1H). Trace isomer (characteristic signal) δ 4.35(dd,J=12.0,2.3Hz,1H),2.93-2.70(m,1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data for the compound obtained. Odor description: weak, chocolate.

[0078] Compound 16: (7S,10R)-3-(sec-butyl)-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane [ka] In a 50 mL three-neck flask are added ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (10 g, 46.9 mmol), PTSA (0.446 g, 2.346 mmol) and 2-methylbutanal (16.17 g, 188 mmol). The medium is stirred for 1 hour at ambient temperature and then sodium carbonate (0.497 g, 4.69 mmol) is added. After stirring for 5 minutes, the medium is filtered and distilled. (7S,10R)-3-(sec-butyl)-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane (5.8 g, 20.53 mmol, 44% yield) is recovered as a colorless liquid (T=80° C., 0.4 torr, two GC peaks 15 / 85). 1 H NMR(300MHz,CDCl3) Major isomer δ 4.39-4.19(m,1H),4.09-3.93(m,2H),3.80-3.64(m,1H),3.49-3.29(m,1H),2.63-2.44(m,1H),2.12-1.93(m,1H),1.84-1.68(m,1H), 1.67-1.40(m,3H),1.38-1.04(m,3H),0.97-0.94(m,1H),0.95-0.86(m,12H),0.87-0.83(m,1H),0.83-0.71(m,3H),0.68-0.47(m,1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data for the compound obtained. Odor description: Weak, ethereal.

[0079] Compound 17: (2S,5R)-2-isopropyl-1,1-bis(methoxymethyl)-5-methylcyclohexane [ka] A nitrogen-flushed 250 mL round-bottom flask equipped with a bubbler is charged with sodium hydride (3.51 g, 88 mmol), THF (165 mL), and then a solution of ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (8 g, 39.9 mmol) in THF (35 mL) is added dropwise over 15 min at room temperature. Methyl iodide (6.24 mL, 100 mmol) is then added and the mixture is refluxed overnight. Water (30 mL) is added and the aqueous phase is extracted with MTBE (2 x 50 mL). The organic phase is collected, washed with brine (30 mL), dried over anhydrous MgSO4, filtered and concentrated. (2S,5R)-2-Isopropyl-1,1-bis(methoxymethyl)-5-methylcyclohexane (6.4 g, 25.8 mmol, 64.6% yield) is obtained after distillation (T=60° C., 0.2 mbar) as a colorless liquid. 1 H NMR(300MHz,chloroform-d) δ 3.44(d,J=9.2Hz,1H),3.39(d,J=9.3Hz,1H),3.33(s,3H),3.30(d,J=2.5Hz,3H),3.28-3.20(m,2H),2.03(septet,J=6.9Hz,1H),1. 78-1.60(m,2H),1.60-1.03(m,5H),0.99(d,J=12.8Hz,1H),0.90(d,J=6.9Hz,3H),0.86(d,J=6.5Hz,3H),0.74(d,J=6.8Hz,3H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with expected data for the compound obtained. Odor description: Cool, weak, grapefruit.

[0080] Compound 18: (7S,10R)-7-isopropyl-10-methyl-3-phenyl-2,4-dioxaspiro[5.5]undecane [ka] In a 50 mL three-neck flask are added ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (10 g, 46.9 mmol), PTSA (0.451 g, 2.371 mmol) and benzaldehyde (5.54 g, 52.2 mmol). The medium is stirred for 1 hour at ambient temperature and then sodium carbonate (0.503 g, 4.74 mmol) is added. After stirring for 5 minutes, the medium is filtered and distilled. (7S,10R)-7-Isopropyl-10-methyl-3-phenyl-2,4-dioxaspiro[5.5]undecane (7.8 g, 25.4 mmol, yield 53.6%) is obtained as a colorless viscous oil (T=120° C., 0.6 torr, two GC peaks 26 / 74). 1 H NMR(300MHz,CDCl3) δ 7.61-7.46(m,2H),7.45-7.29(m,3H),5.44(d,J=8.9Hz,1H),4.29-4.17(m,1H),4.05-3.88(m,1H),3.85-3.41(m,2H),2.86-2.67(m,1H) ),2.23-2.03(m,1H),1.89-1.74(m,1H),1.74-1.47(m,2H),1.31-1.19(m,1H),1.10-0.93(m,7H),0.92-0.79(m,4H),0.79-0.60(m,1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with expected data for the compound obtained. Odor description: Weak, almond.

[0081] Compound 19: (7S,10R)-3,3-diethyl-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane [ka] In a 250 mL round-bottom flask equipped with a Dean-Stark apparatus, ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (10 g, 47.4 mmol), PTSA (0.451 g, 2.371 mmol), pentan-3-one (16.34 g, 190 mmol) and cyclohexane (100 mL) are introduced. The mixture is refluxed for 1 h, then cooled, washed with saturated NaHCO3 (40 mL), brine (40 mL), dried over anhydrous MgSO4, filtered and distilled (T = 100 °C, 0.7 torr). (7S,10R)-3,3-diethyl-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane (5.8 g, 20.31 mmol, 42.8% yield) is obtained as a colorless liquid. 1 H NMR(300MHz,CDCl3) δ 3.99-3.82(m,2H),3.64(dd,1H),3.19(dd,1H),2.35-2.16(m,2H),1.81-1.60(m, 5H), 1.54-1.37 (m, 2H), 1.20-1.05 (m, 1H), 0.94-0.79 (m, 17H), 0.61-0.46 (m, 1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data of the compounds obtained. Odor description: Weak, cool, woody.

[0082] Compound 20: (3,3-dimethylcyclohexane-1,1-diyl)dimethanol [ka] In a 100 ml three-neck flask, potassium hydroxide (0.600 g, 10.70 mmol) and ethanol (75 ml) are added. After complete solubilization of the KOH, 37% aqueous formaldehyde solution (0.796 ml, 10.70 mmol) is added dropwise at ambient temperature and the mixture is then stirred for 10 min. 3,3-dimethylcyclohexane-1-carbaldehyde (1 g, 7.13 mmol) is then added dropwise over 30 min and the mixture is stirred for 72 h at ambient temperature. The medium is concentrated and the aqueous phase is extracted with MTBE (2 x 30 mL). The combined organic phases are washed successively with saturated NaHCO3 (30 mL) solution, then with brine (30 mL), dried over anhydrous MgSO4, filtered and concentrated. After purification by chromatography column (CombiFlash®, cyclohexane / EtOAc gradient), (3,3-dimethylcyclohexane-1,1-diyl)dimethanol (0.64 g, 7.13 mmol, 52% yield) is recovered in the form of a white solid. 1 H NMR (300 MHz, chloroform-d) δ 3.67-3.51(m, 4H), 3.06(s, 2H), 1.56-1.42(m, 2H), 1.31-1.17(m, 6H), 0.94(s, 6H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data of the compound obtained. Olfactory description: Almost odorless, solvent.

[0083] Compound 21: 4,4'-((((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)bis(methylene))bis(oxy))bis(4-oxobutanoic acid) [ka] In a 50 ml three-neck flask, ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (5 g, 24.96 mmol), MCH (10 ml), and then succinic anhydride (5.00 g, 49.9 mmol) are added. The mixture is refluxed overnight and then concentrated. 4,4'-((((2R,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)bis(methylene))bis(oxy))bis(4-oxobutanoic acid) (7.25 g, 17.20 mmol, 68.9% yield) is obtained as a viscous oil after purification by chromatography column (CombiFlash®, cyclohexane / EtOAc gradient). 1 H NMR(300MHz,chloroform-d) δ 10.97(s,2H),4.31(d,J=11.4Hz,1H),4.18-3.98(m,4H),2.74-2.53(m,8H),1.99(q,J=6.9Hz,1H),1.84-1.60(m ,2H),1.60-1.40(m,2H),1.40-1.30(m,2H),0.89(d,J=6.8Hz,4H),0.84(d,J=6.4Hz,3H),0.75(d,J=6.8Hz,3H). 13 C NMR and IR (cm -1 ) The data obtained were consistent with the expected data for the compound. Olfactory description: Odorless.

[0084] Compound 22: (7S,10R)-7-isopropyl-3,10-dimethyl-3-phenyl-2,4-dioxaspiro[5.5]undecane [ka] A 50 mL three-neck flask is charged with ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (10 g, 47.4 mmol), PTSA (0.451 g, 2.371 mmol) and acetophenone (6.27 g, 52.2 mmol). The medium is stirred overnight at ambient temperature and then transferred to a 250 mL three-neck flask equipped with a Dean-Stark trap. Cyclohexane (100 mL) is then added and the mixture is stirred overnight at room temperature and then refluxed for 16 hours. The cooled solution is washed with saturated NaHCO3 (40 mL) solution, brine (40 mL), dried over anhydrous MgSO4, filtered and concentrated. (7S,10R)-7-Isopropyl-3,10-dimethyl-3-phenyl-2,4-dioxaspiro[5.5]undecane (3.6 g, 11.21 mmol, 23.6% yield) is recovered after distillation as a viscous colorless liquid (Teb = 97 °C, 0.6 torr; two GC peaks 61 / 39). 1 H NMR(300MHz,CDCl3) Major isomer δ 7.25-7.13(m,4H),7.13-7.00(m,1H),3.93-3.62(m,1H),3.60-3.50(m,1H),3.51-3.0 3(m,1H),3.03-2.62(m,1H),2.62-2.29(m,1H),1.63-1.34(m,1H),1.29(d,J=9.7Hz,3 H),1.24-0.83(m,2H),0.78(d,J=6.9Hz,3H),0.73(d,J=6.4Hz,3H),0.69-0.55(m,2H) ,0.54-0.48(m,3H),0.46-0.35(m,1H),0.30(d,J=6.8Hz,2H),0.20(t,J=12.9Hz,0H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with expected data for the compound obtained. Olfactory description: powdery, vanilla, mimosa.

[0085] Compound 23: 2-((7S,10R)-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecan-3-yl)pyridine [ka] A 50 mL three-neck flask is charged with ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (10 g, 47.4 mmol), PTSA (0.451 g, 2.371 mmol) and picolinaldehyde (5.59 g, 52.2 mmol). The medium is stirred overnight at ambient temperature and then transferred to a 250 mL three-neck flask equipped with a Dean-Stark trap. Cyclohexane (100 mL) is then added and the mixture is refluxed overnight. The cooled solution is washed with saturated NaHCO3 (40 mL) solution, brine (40 mL), dried over anhydrous MgSO4, filtered and concentrated. 2-((7S,10R)-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecan-3-yl)pyridine (4.8 g, 15.76 mmol, 33.2% yield) is recovered after distillation as a viscous yellow liquid (Teb = 110 °C, 0.4 torr; two GC peaks 72 / 28). 1 H NMR(300MHz,CDCl3) Major isomer δ 8.38(tdd,J=5.9,2.4,1.0Hz,1H),7.52(tt,J=7.7,1.6Hz,1H),7.46-7.30(m,1H),7.10-6.99(m,1H),5.28(d,J =2.2Hz,1H),4.27-3.82(m,2H),3.83-3.63(m,1H),3.36(dd,J=10.9,2.7Hz,1H),2.49(ddd,J=13.6,3.4,2.4Hz ,1H),1.62-1.48(m,1H),1.40(dtd,J=12.0,5.7,2.7Hz,1H),1.30(dq,J=13.4,3.5Hz,1H),1.03-0.94(m,1H),0 .94-0.76(m,1H),0.72(td,J=6.9,5.8Hz,7H),0.61(dd,J=6.6,4.2Hz,4H),0.47(ddd,J=14.4,12.5,2.1Hz,1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with expected data for the compound obtained. Olfactory description: green, mimosa.

[0086] Compound 24: (7S,10R)-7-isopropyl-10-methyl-3-(thiophen-2-yl)-2,4-dioxaspiro[5.5]undecane [ka] A 50 mL three-neck flask is charged with ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (10 g, 47.4 mmol), PTSA (0.451 g, 2.371 mmol) and thiophene-2-carbaldehyde (5.85 g, 52.2 mmol). The medium is stirred at ambient temperature for 27 hours. Sodium carbonate (0.503 g, 4.74 mmol) is added, followed by water (15 mL). The organic layer is washed with brine (40 mL), dried over anhydrous MgSO4, filtered and concentrated. (7S,10R)-7-Isopropyl-10-methyl-3-(thiophen-2-yl)-2,4-dioxaspiro[5.5]undecane (3.9 g, 12.37 mmol, 26.1% yield) is recovered after distillation as a yellow liquid (Teb = 70 °C, 0.9 torr; two GC peaks 35 / 65). 1 H NMR(300MHz,CDCl3) Major isomer δ 7.32(dd,J=5.0,1.3Hz,1H),7.21-7.10(m,1H),7.01(dt,J=4.8,3.8Hz,1H),5.70(s,1H) ,4.58-4.13(m,2H),4.03-3.84(m,1H),3.67-3.51(m,1H),2.85-2.67(m,1H),2.10(Septet,J =6.8Hz,1H),1.82(dp,J=12.8,3.4Hz,1H),1.70-1.60(m,1H),1.60-1.50(m,1H),1.23(d dd,J=13.2,4.6,2.5Hz,1H),1.06-0.92(m,7H),0.86(t,J=6.9Hz,4H),0.74-0.59(m,1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data for the compound obtained. Odor description: Weak, green, crust-like.

[0087] Compound 25: (7S,10R)-7-isopropyl-10-methyl-3-(2-(methylthio)ethyl)-2,4-dioxaspiro[5.5]undecane [ka] A 50 mL three-neck flask is charged with ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (10 g, 47.4 mmol), PTSA (0.451 g, 2.371 mmol), 3-(methylthio)propanal (9.88 g, 95 mmol) and cyclohexane (7 mL). The medium is stirred at ambient temperature for 27 hours. The mixture is washed with saturated NaHCO3 (40 mL) solution, brine (40 mL), dried over anhydrous MgSO4, filtered and concentrated. After distillation (Teb=77° C., 0.8 torr) and chromatography column (CombiFlash®, cyclohexane / EtOAc gradient, two GC peaks 41 / 59), (7S,10R)-7-isopropyl-10-methyl-3-(2-(methylthio)ethyl)-2,4-dioxaspiro[5.5]undecane (0.5 g, 1.653 mmol, 3.49% yield) is recovered as a colorless liquid. 1 H NMR(300MHz,CDCl3) Major isomer δ 4.61-4.51(m,1H),4.37-3.93(m,2H),3.77-3.63(m,1H),3.50-3.31(m,1H),2.86-2.40(m,3H),2.10(s,3H),2.01(p,J=6.9Hz,1H),1.97- 1.81(m,2H),1.75(dh,J=12.6,3.1Hz,1H),1.65-1.39(m,1H),1.39-1.18(m,1H),1.18-0.93(m,3H),0.94-0.66(m,9H),0.66-0.43(m,1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with expected data for the compounds obtained. Odor description: metallic, garlic, sardine.

[0088] Compound 26: 3,8,8-trimethyl-2,4-dioxaspiro[5.5]undecane [ka] A 50 mL three-neck flask is charged with (3,3-dimethylcyclohexane-1,1-diyl)dimethanol (8 g, 46.4 mmol), acetaldehyde (6.14 g, 139 mmol) and PTSA (0.442 g, 2.322 mmol). The mixture is stirred at ambient temperature for 17 hours. Sodium bicarbonate (0.5 g) is added and the mixture is filtered and concentrated. 3,8,8-trimethyl-2,4-dioxaspiro[5.5]undecane (9.21 g, 23.72 mmol, 51.1% yield) is recovered after distillation as a colorless liquid (Teb=57° C., 1.2 torr; two GC peaks 53 / 47). 1 H NMR(300MHz,CDCl3) Major isomer δ 4.58(dq,J=6.6,5.0Hz,1H),3.95-3.76(m,2H),3.42-3.23(m,2H),1.73-1.64(m,1H),1.62(s, 1H),1.56-1.47(m,1H),1.46-1.38(m,1H),1.37-1.14(m,6H),1.00-0.97(m,3H),0.87(s,4H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with expected data for the compound obtained. Olfactory description: camphor, purple, cool.

[0089] Compound 27: (2-(sec-butyl)cyclohexane-1,1-diyl)dimethanol) [ka] Potassium hydroxide (17 g, 10.70 mmol) and ethanol (200 ml) are added to a 100 ml three-neck flask. After almost complete solubilization of the KOH, 37% aqueous formaldehyde solution (19.47 ml, 261 mmol) is added dropwise at ambient temperature and the mixture is then stirred for 10 min. 2-(sec-butyl)cyclohexane-1-carbaldehyde) (11 g, 65.4 mmol) is then added dropwise over 30 min and the mixture is stirred for 72 h at ambient temperature. The medium is concentrated and the aqueous phase is extracted with MTBE (2 x 100 ml). The combined organic phases are washed successively with saturated NaHCO3 (150 ml) solution, then with brine (100 ml), dried over anhydrous MgSO4, filtered and concentrated. (2-(sec)butyl)cyclohexane-1,1-diyl)dimethanol (0.9 g, 4.27 mmol, 6.53% yield) is recovered in the form of a colorless liquid after distillation (Teb=119° C., 1 torr) followed by column chromatography (CombiFlash®, cyclohexane / EtOAc gradient). 1 H NMR(300MHz,chloroform-d) δ 4.18-4.03(m,1H),3.98-3.74(m,2H),3.70-3.44(m,1H),3.44-3.27(m,1H),2.32-2.15(m,1H),1.95-1.70(m,2H), 1.69-1.49(m,2H),1.49-1.32(m,1H),1.32-1.06(m,5H),1.06-0.90(m,1H),0.90-0.77(m,5H),0.77-0.66(m,2H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data of the compound obtained. Olfactory description: Almost odorless, solvent.

[0090] Compound 28: Ethyl (7S,10R)-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane-3-carboxylate [ka] A 100 mL three-neck flask equipped with a Dean-Stark trap is charged with ((5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (5 g, 24.96 mmol), 50% ethyl 2-glyoxalate in toluene (10.19 mL, 49.9 mmol), and PTSA (0.237 g, 1.248 mmol). The medium is stirred at ambient temperature for 3 hours and 30 minutes. Toluene (300 mL) is then added and the mixture is refluxed for 1 hour. Sodium carbonate (0.265 g, 2.496 mmol) is added to the cooled solution and stirred for 5 minutes. The solution is filtered and concentrated. After distillation (Teb=100° C., 0.3 mbar) followed by column chromatography (CombiFlash®, cyclohexane / EtOAc gradient), ethyl (10R)-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane-3-carboxylate (0.3 g, 0.992 mmol, 4% yield) is recovered as a colorless liquid (two GC peaks 48 / 52). 1 H NMR(300MHz,CDCl3) δ 4.97(s,0H),4.92(s,1H),4.42-3.80(m,5H),3.62-3.44(m,1H),2.68-2. 45(m,1H),2.00(septet,J=7.0Hz,1H),1.76(dq,J=12.5,2.9Hz,1H),1.63-1. 42(m,2H),1.33(td,J=7.1,3.5Hz,3H),1.27-1.02(m,2H),0.95-0.87(m,5 H),0.84(dd,J=6.5,2.8Hz,3H),0.78(d,J=6.8Hz,2H),0.70-0.54(m,1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data of the compound obtained. Olfactory description: odorless.

[0091] Compound 29: 2,2'-((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)bis(ethan-1-ol) [ka] In a 250 mL three-neck flask under nitrogen at 0° C., add (methoxymethyl)triphenylphosphonium chloride (20.96 g, 61.1 mmol), THF (100 mL) and potassium t-butoxide (6.86 g, 61.1 mmol). The mixture turns red after stirring at room temperature for 30 min. Then, add a solution of (2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-dicarbaldehyde (5 g, 25.5 mmol) in THF (20 ml) over 20 min at 0° C. and stir at room temperature overnight. Add MTBE (100 mL) and 10% aqueous HCl (150 mL). Extract the aqueous phase with MTBE (200 mL). Collect the organic phase, wash with brine (30 mL), dry over anhydrous MgSO4, filter and concentrate. Add cyclohexane (100 mL) and filter off the white precipitate. The filtrate is concentrated and distilled (0.3 mbar, T = 66-80 °C) to give (2S,5R)-2-isopropyl-1,1-bis(2-methoxyvinyl)-5-methylcyclohexane (2.2 g, 4.79 mmol, 18.8% yield) as a yellowish liquid as a mixture of isomers accounting for 55% GC. The product is diluted with THF (40 mL) and 10% aqueous HCl (20 mL) is added. The mixture is stirred at room temperature for 2 h and then poured into MTBE (100 mL). The organic phase is washed with saturated NaHCO3 (50 mL), brine (20 mL), dried over anhydrous MgSO4, filtered and concentrated. After purification by column chromatography (CombiFlash®, cyclohexane / EtOAc gradient), 2,2'-((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)diacetaldehyde (0.3 g, 1.244 mmol, 4.9% yield) is recovered as a yellow oil. The product is diluted with EtOH (20 mL) and sodium borohydride (0.482 g, 12.74 mmol) is added. The mixture is stirred overnight and concentrated. MTBE (30 mL) and 10% aqueous NaOH (20 mL) are added. The organic phase is washed with saturated brine (20 mL), dried over anhydrous MgSO4, filtered and concentrated.After purification by column chromatography (CombiFlash®, cyclohexane / EtOAc gradient), 2,2′-((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)bis(ethan-1-ol) (0.25 g, 1.084 mmol, 4.25% yield) is recovered as a white solid. 1 H NMR(300MHz,CDCl3) δ 3.77-3.58(m,4H),2.15(s,2H),2.06-1.89(m,2H),1.89-1.79(m,1H),1.79-1.69(m,1 H),1.69-1.54(m,1H),1.54-1.45(m,1H),1.45-1.40(m,2H),1.38(d,J=3.3Hz,1H),1. 35-1.31(m,1H),1.30-1.22(m,1H),1.18-1.09(m,1H),1.06-0.94(m,1H),0.90(d,J=6 .9Hz,3H),0.83(d,J=1.9Hz,3H),0.81(d,J=2.2Hz,3H),0.74(dd,J=12.3,4.7Hz,0H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data of the compound obtained. Olfactory description: Almost odorless, solvent.

[0092] Compound 30: (2-isopropyl-5,5-dimethylcyclohexane-1,1-diyl)dimethanol [ka] Potassium hydroxide (7.39 g, 132 mmol) and ethanol (55 ml) are added to a 100 ml three-neck flask. After almost complete solubilization of the KOH, 37% aqueous formaldehyde solution (9.8 ml, 132 mmol) is added dropwise at ambient temperature and the mixture is then stirred for 10 min. 2-Isopropyl-5,5-dimethylcyclohexane-1-carbaldehyde (6 g, 32.9 mmol) (synthesized according to WO2016153011) is then added dropwise over 30 min and the mixture is stirred for 24 h at ambient temperature. One more portion of 37% aqueous formaldehyde solution (9.80 ml, 132 mmol) and potassium hydroxide (7.39 g, 132 mmol) is added and the mixture is stirred for a long time at room temperature. The medium is concentrated and the aqueous phase is extracted with MTBE (2 x 30 mL). The combined organic phases are washed successively with saturated NaHCO3 (30 mL) solution, then with brine (30 mL), dried over anhydrous MgSO4, filtered and concentrated. ((2-isopropyl-5,5-dimethylcyclohexane-1,1-diyl)dimethanol (3 g, 11.20 mmol, 34.0% yield) is recovered in the form of a white solid (mixture of diastereomers 5 / 95) after purification by distillation (P=0.3 mbar, T=120° C.) and chromatography column (CombiFlash®, cyclohexane / EtOAc gradient). 1 H NMR(300MHz,chloroform-d) δ 4.06-3.74(m,3H),3.31(dd,J=10.3,1.8Hz,1H),2.79(s,2H),2.04(dd,J=14.1,2.5Hz,1H),1.99-1.85(m,1H),1.56-1. 45(m,1H),1.45-1.30(m,2H),1.22-1.04(m,3H),1.02(s,3H),0.93(s,3H),0.89(d,J=6.9Hz,3H),0.77(d,J=6.8Hz,3H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data of the compound obtained. Olfactory description: odorless.

[0093] Compound 31: 7-(sec-butyl)-3-methyl-2,4-dioxaspiro[5.5]undecane [ka] A 50 mL three-neck flask is charged with (2-(sec)butyl)cyclohexane-1,1-diyl)dimethanol) (3.6 g, 15.28 mmol), acetaldehyde (2.56 mL, 45.8 mmol) and p-toluenesulfonic acid monohydrate (0.145 g, 0.764 mmol). The mixture is stirred overnight at ambient temperature. Sodium bicarbonate (0.5 g) is added and the mixture is filtered and then concentrated. After distillation (Teb=64° C., 1 torr) and column chromatography (CombiFlash®, cyclohexane / EtOAc gradient), 7-(sec-butyl)-3-methyl-2,4-dioxaspiro[5.5]undecane (0.6 g, 2.60 mmol, 17% yield) is recovered as a colorless liquid (mixture of isomers). 1 H NMR(300MHz,CDCl3) δ 4.65-4.51(m,1H),4.34(ddd,J=15.1,12.0,2.5Hz,0H),4.15-3.93(m,2H),3.82-3.59(m,1H),3.44-3.32(m,1H),2.64-2.50(m ,1H),1.84-1.35(m,6H),1.31(t,J=5.3Hz,3H),1.28-0.95(m,5H),0.95-0.87(m,3H),0.87-0.80(m,2H),0.76(d,J=6.9Hz,1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with expected data for the compound obtained. Olfactory description: Animalic, blackcurrant, amber-like.

[0094] Compound 32: ((2S,5R)-1-(hydroxymethyl)-2-isopropyl-5-methylcyclohexyl)methyl acetate [ka] A 100 mL three-neck flask is charged with ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol (2 g, 9.98 mmol), MTBE (50 mL) and triethylamine (2.087 mL, 14.98 mmol). Acetyl chloride (0.784 g, 9.98 mmol) is added dropwise over 5 min and the mixture is stirred at room temperature for 30 min. Water (20 mL) is added and the organic layer is washed with brine, dried over anhydrous MgSO4, filtered and concentrated. ((2S,5R)-1-(hydroxymethyl)-2-isopropyl-5-methylcyclohexyl)methyl acetate (0.72 g, 2.94 mmol, 29.5% yield) (mixture of diastereomers 59 / 41) is recovered as a colorless sticky oil. 1 H NMR(300MHz,CDCl3) δ 4.32-4.02(m,2H),3.79-3.41(m,2H),2.09(d,J=7.0Hz,3H),2.23-1.91(m,1H),2.01(s,1H),1.93-1.60(m,2H) ),1.60-1.40(m,2H),1.40-1.17(m,2H),0.96-0.82(m,7H),0.80(q,J=3.9Hz,1H),0.75(dd,J=6.8,3.7Hz,3H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data of the obtained compound. Olfactory description: Almost odorless, refreshing.

[0095] Compound 33: 7-isopropyl-3,10,10-trimethyl-2,4-dioxaspiro[5.5]undecane [ka] In a 50 mL three-neck flask, (2-isopropyl-5,5-dimethylcyclohexane-1,1-diyl)dimethanol (1 g, 4.67 mmol), acetaldehyde (1.565 mL, 28.0 mmol) and p-toluenesulfonic acid monohydrate (0.044 g, 0.233 mmol) are added. The mixture is stirred overnight at ambient temperature. Sodium carbonate (0.049 g, 0.467 mmol) is added and the mixture is filtered and then concentrated. After column chromatography (CombiFlash®, cyclohexane / EtOAc gradient), 7-isopropyl-3,10,10-trimethyl-2,4-dioxaspiro[5.5]undecane (0.3 g, 1.211 mmol, 25.9% yield) is recovered as a colorless liquid. 1 H NMR(300MHz,CDCl3) δ 4.61(q,J=5.0Hz,1H),4.18(dd,J=11.3,3.1Hz,1H),3.90(d,J=10.8Hz,1H),3.77-3.55(m,1H) ,3.31(dd,J=10.8,3.1Hz,1H),2.43(dd,J=14.3,2.5Hz,1H),2.01(septet,J=6.9Hz,1H),1.48(dq, J=12.5,3.1Hz,1H),1.43-1.36(m,1H),1.34(d,J=5.1Hz,3H),1.31-1.22(m,1H),1.19-1.06(m, 1H),1.03(s,3H),0.94(s,3H),0.92(d,J=7.0Hz,4H),0.88-0.82(m,1H),0.80(d,J=6.8Hz,3H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with expected data for the compounds obtained. Olfactory description: woody, dirty, amber-like.

[0096] Compound 34: 1,1'-((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)bis(ethan-1-ol) [ka] To a 500 mL three-neck flask under nitrogen is added THF (200 mL) and methylmagnesium chloride 3M in THF (37.8 mL, 113 mmol). A solution of (2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-dicarbaldehyde (10 g, 45.3 mmol) in THF (100 mL) is then added dropwise over 30 min at 0° C. The mixture is stirred for 30 min and poured into a mixture of saturated aqueous NH4Cl (200 mL) and ice. The organic layer is washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. After distillation (P=0.5 mbar, T=104° C.) and recrystallization in cyclohexane (5 mL), 1,1′-((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)bis(ethan-1-ol) (0.3 g, 1.314 mmol, 2.90% yield) is obtained as a white solid. 1 H NMR(300MHz,CDCl3) δ 4.58(dd,1H),4.24(dd,1H),2.24(s,2H),2.16-2.00(m,1H),1.80-1.64(m,2H),1.59-1.46(m,1H),1.40( d,3H),1.39-1.27(m,2H),1.15(d,J=6.5Hz,3H),1.12-1.04(m,1H),0.95-0.83(m,9H),0.82-0.66(m,2H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data of the obtained compound. Olfactory description: Almost odorless, refreshing.

[0097] Compound 35: 2-((1R,2R,5R)-5-methyl-2-(prop-1-en-2-yl)cyclohexyl)propane-1,3-diol [ka] In a 250 mL three-neck flask under nitrogen, add dimethyl 2-((1R,2R,5R)-5-methyl-2-(prop-1-en-2-yl)cyclohexyl)malonate (10 g, 33.5 mmol) (Organic Syntheses, Coll. Vol. 9, p. 310 (1998); Vol. 71, p. 167 (1993)) and MTBE (130 mL). Sodium bis(2-methoxyethoxy)aluminum hydride 70% in toluene (40.2 ml, 141 mmol) is added dropwise while maintaining the temperature below 10° C. The mixture is stirred overnight at ambient temperature. The mixture is carefully poured into a mixture of 10% aqueous HCl (200 mL) and ice. The aqueous phase is extracted with MTBE (2 x 100 mL) and the combined organic phases are washed with saturated aqueous NaHCO3 (100 mL), brine (100 mL), dried over anhydrous MgSO4, filtered and concentrated. After recrystallization in refluxing cyclohexane (10 mL), 2-((1R,2R,5R)-5-methyl-2-(prop-1-en-2-yl)cyclohexyl)propane-1,3-diol (4.4 g, 19.27 mmol, 57.5% yield) is recovered as a colorless liquid. 1 H NMR(300MHz,CDCl3) δ 4.76(s,2H),3.95-3.71(m,2H),3.70-3.53(m,2H),2.90(s,2H),2.02-1.82(m,2H),1.74-1.66(m, 1H),1.65(s,3H),1.62-1.22(m,5H),0.99-0.90(m,1H),0.87(d,J=6.5Hz,3H),0.72-0.53(m,1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data of the compound obtained. Olfactory description: Almost odorless, aromatic.

[0098] Compound 36: 2-Methyl-5-((1R,2R,5R)-5-methyl-2-(prop-1-en-2-yl)cyclohexyl)-1,3-dioxane [ka] In a 50 mL three-neck flask, 2-((1R,2R,5R)-5-methyl-2-(prop-1-en-2-yl)cyclohexyl)propane-1,3-diol (2 g, 9.42 mmol), acetaldehyde (1.245 g, 28.3 mmol) and p-toluenesulfonic acid monohydrate (0.090 g, 0.471 mmol) are added. The mixture is stirred overnight at ambient temperature. Sodium bicarbonate (0.05 g) is added and the mixture is filtered and then concentrated. After column chromatography (CombiFlash®, cyclohexane / EtOAc gradient), 2-methyl-5-((1R,2R,5R)-5-methyl-2-(prop-1-en-2-yl)cyclohexyl)-1,3-dioxane (0.64 g, 2.66 mmol, 28.2% yield) is recovered as a colorless liquid. 1 H NMR(300MHz,CDCl3) δ 4.74(s,2H),4.61-4.46(m,1H),4.00(dq,1H),3.80(dq,1H),3.67(t,J=11.3Hz,1H),3.56(t,J=11.1Hz,1H),2.11-1.95 (m,1H),1.83(td,J=11.6,3.4Hz,1H),1.71-1.52(m,6H),1.41-1.20(m,6H),0.97-0.78(m,4H),0.68(q,J=12.2Hz,1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data of the compound obtained. Olfactory description: Almost odorless, solvent.

[0099] Compound 37: 2-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)propane-1,3-diol [ka] Step 1: Dimethyl 2-((1R,2R,5R)-5-methyl-2-(prop-1-en-2-yl)cyclohexyl)malonate (8 g, 29.8 mmol), methanol (100 mL) and 10% Pd / C (1 g, 0.470 mmol) are added to a 300 mL autoclave. The mixture is stirred at room temperature under H2 (5 bar) for 24 h. The mixture is filtered through Celite and then concentrated. Dimethyl 2-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)malonate (5.9 g, 20.29 mmol, 68.1% yield) is obtained as a colorless liquid after distillation (P=0.3 mbar, T=75° C.). Step 2: To a 250 mL three-neck flask under nitrogen is added dimethyl 2-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)malonate (5 g, 18.49 mmol) and MTBE (71 mL). Sodium bis(2-methoxyethoxy)aluminum hydride 70% in toluene (26.4 ml, 92 mmol) is added dropwise while maintaining the temperature below 10° C. The mixture is stirred overnight at ambient temperature. The mixture is carefully poured into a mixture of 10% aqueous HCl (100 mL) and ice. The aqueous phase is extracted with MTBE (2×50 mL) and the combined organic phase is washed with saturated aqueous NaHCO3 (50 mL), brine (100 mL), dried over anhydrous MgSO4, filtered and concentrated. After recrystallization in refluxing cyclohexane (5 mL), 2-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)propane-1,3-diol (1.8 g, 7.98 mmol, 43.1% yield) is recovered as a colorless liquid. 1H NMR (300MHz, CDCl3) δ 3.94(t,J=9.7Hz,1H),3.87-3.75(m,1H),3.75-3.62(m,2H),3.02(s,2H),2.2 1-2.10(m,1H),2.10-1.94(m,1H),1.74-1.59(m,2H),1.57-1.44(m,1H),1.39- 1.30(m,1H),1.30-1.18(m,1H),1.13-1.01(m,1H),1.00-0.94(m,1H),0.91(d, J=6.8Hz,3H),0.84(d,J=6.5Hz,4H),0.75(d,J=6.9Hz,3H),0.68-0.53(m,1H). 13 C NMR, IR (cm -1 ) and mass spectrometry data were consistent with the expected data of the obtained compound. Olfactory description: Almost odorless, rose-like.

[0100] Compound 38: ((2S,5R)-1-((benzyloxy)methyl)-2-isopropyl-5-methylcyclohexyl)methanol [ka] To a stirred solution of [(2S,5R)-1-(hydroxymethyl)-2-isopropyl-5-methyl-cyclohexyl]methanol (5.0 g, 25.0 mmol) in dry DMF (50 mL, [C] = 0.5 M), sodium hydride (60% in mineral oil, 1.05 g, 26.2 mmol, 1.05 equiv.) was added portionwise at 0 °C, and the resulting mixture was stirred at 0 °C for 1 h. Benzyl bromide (2.90 mL, 24.5 mmol, 0.98 equiv.) was added dropwise at 0 °C, and the resulting mixture was stirred at room temperature for 20 h. Most of the DMF was removed under reduced pressure, and the residue was partitioned between saturated aqueous NH4Cl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue (7.50 g) was purified by flash chromatography on silica gel (CyHex. / EtOAc, 95 / 5) to give [(2S,5R)-1-(benzyloxymethyl)-2-isopropyl-5-methyl-cyclohexyl]methanol (3.90 g, 51% yield) as a colorless oil.1 H NMR (400MHz, CDCl3) δ 7.31-7.36(m,5H), 4.43-4.56(m,2H), 3.50-4.0(m,3H), 3.25-3.36(m,1H), 2.14-2.43(m,2H), 1.91-1.98(m,1H), 1.70-1.78(m,1H), 1.45-1.50(m,2H), 1.10-1.39(m,2H), 0.85-0.89(m,7H), 0.67-0.73(m,3H), 0.60-0.67(m,1H). Mass spectrometry data were consistent with expected data for the compound obtained. Odor description: Almost odorless, solvent.

[0101] Compound 39: (2S,5R)-1-(hydroxymethyl)-2-isopropyl-5-methylcyclohexane-1-carboxylic acid [ka] Step 1: To a stirred solution of [(2S,5R)-1-(benzyloxymethyl)-2-isopropyl-5-methyl-cyclohexyl]methanol (3.18 g, 10.9 mmol) in acetone (36 mL, [C] = 0.3 M), Jones reagent (2.1 M in water, 11.5 mL, 24.1 mmol, 2.2 equiv.) was added dropwise at room temperature and the resulting mixture was stirred for 1 h. The mixture was quenched by slow addition of iPrOH (5 mL), stirred for 30 min, and concentrated under reduced pressure. The residue was dissolved in water and extracted with Et2O (3 x 30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to give (2S,5R)-1-(benzyloxymethyl)-2-isopropyl-5-methyl-cyclohexanecarboxylic acid (3.32 g, 90% yield) as a colorless oil. This crude mixture was used in the next step without further purification. HPLC / MS (acid): m / z (ES+) = 327 (M+Na). + Step 2: To a stirred solution of (2S,5R)-1-(benzyloxymethyl)-2-isopropyl-5-methyl-cyclohexanecarboxylic acid (1.50 g, 4.93 mmol) in dry DMF (16 mL, 0.3 M), potassium carbonate (1.36 g, 9.85 mmol, 2 equiv.) was added dropwise at room temperature followed by benzyl bromide (0.88 mL, 7.39 mmol, 1.5 equiv.) and the resulting mixture was stirred at room temperature for 20 h. Most of the DMF was removed under reduced pressure and the residue was poured into water. The aqueous layer was extracted with Et2O (3×15 mL) and the combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude mixture (2.15 g) was purified by flash chromatography on silica gel (CyHex. / EtOAc, 99 / 1) to give benzyl (2S,5R)-1-(benzyloxymethyl)-2-isopropyl-5-methyl-cyclohexanecarboxylate, 1.73 g (80% yield) as a colorless oil. HPLC / MS (acid): m / z (ES+) = 417 (M+Na). + . Step 3: To a stirred solution of benzyl (2S,5R)-1-(benzyloxymethyl)-2-isopropyl-5-methyl-cyclohexanecarboxylate (1.73 g, 4.38 mmol) in iPrOH (22 mL, 0.2 M) at room temperature under Ar was added 10% palladium on carbon (93 mg, 0.877 mmol, 0.2 equiv). The mixture was flushed with hydrogen and stirred at room temperature under hydrogen atmosphere for 20 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The residue (1.08 g) was purified by flash chromatography on silica gel (CyHex. / EtOAc, 9 / 1 to 1 / 1) to give (2S,5R)-1-(hydroxymethyl)-2-isopropyl-5-methyl-cyclohexanecarboxylic acid (550 mg, 56% yield) as a colorless oil that solidified on standing. 1H NMR (400MHz, CDCl3) δ 4.14-4.17 (d, J = 11.3 Hz, 1H), 4.05-4.08 (d, J = 12 Hz, 1H), 3.68-3.71 (d, J = 12 Hz, 1H), 3.32-3.35 (d, J = 11.2 Hz, 1H), 2.14-2.43 (m, 2H), 1.67-1.86 (m, 4H), 1.55-1.57 (m, 2H), 0.92-0.94 (m, 1H), 0.75-0.92 (m, 9H). Mass spectrometry data were consistent with expected data for the compound obtained. Odor description: Almost odorless.

[0102] Compound 40: (3,3,5,5-tetramethylcyclohexane-1,1-diyl)dimethanol [ka] Potassium hydroxide (0.533 g, 9.51 mmol) and ethanol (10 ml) are added to a 50 ml three-neck flask. After almost complete solubilization of the KOH, 37% aqueous formaldehyde solution (0.71 ml, 9.51 mmol) is added dropwise at ambient temperature and the mixture is then stirred for 30 min. 23,3,5,5-tetramethylcyclohexane-1-carbaldehyde (0.4 g, 2.377 mmol) (synthesized according to WO2010025142) is then added dropwise over 1 min and the mixture is stirred at ambient temperature for 4 days. The medium is concentrated and the aqueous phase is extracted with MTBE (2 x 30 mL). The combined organic phases are washed successively with saturated NaHCO3 (10 mL) solution, then with brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated. After purification by column chromatography (CombiFlash®, cyclohexane / EtOAc gradient), (3,3,5,5-tetramethylcyclohexane-1,1-diyl)dimethanol (0.3 g, 1.498 mmol, 63.0% yield) is recovered in the form of a white solid. 1 H NMR (300 MHz, chloroform-d) δ 3.59(s, 4H), 3.43(s, 2H), 1.22(s, 2H), 1.19(s, 4H), 0.99(s, 12H). 13 C NMR, IR (cm -1) and mass spectrometry data were consistent with the expected data of the obtained compound. Olfactory description: Almost odorless, refreshing.

[0103] In vitro compound evaluation The compounds were evaluated in vitro on CHO-K1 cells expressing the gene encoding the hTRPM8 ion channel (Table 1). Channel activation is determined by fluorescent measurement of extracellular calcium using FLUO-8. Compound activity was measured against icilin, a known hTRPM8 agonist.

[0104] [Table 1]

[0105] Compounds 1-6 were tested and shown to be active against hTRPM8, with certain compounds of the invention (1, 3 and 5) showing greater activation than comparison molecules (Physcool™, WS-5™, WS-3™, l-isopulegol, l-menthol, menthyl lactate).

[0106] Compounds 1-40 were tested against hTRPM8 at 5 μM using WS3 as a reference compound (Table 2).

[0107] [Table 2] * Activity (%) vs. WS3 at 5 μM

[0108] Response curves were generated for compounds 1, 3, 5 and 37, which allowed the determination of EC50 (half maximal effective concentration) values ​​for hTRPM8 and comparison of them with the EC50 values ​​of comparative compounds (Table 3). Compounds 1 and 3 have EC50 values ​​lower than WS-3™ and similar to WS-5™.

[0109] [Table 3]

[0110] In vivo compound evaluation Compounds 1, 2 and 5 of the present invention were sensorily evaluated in plain water by a trained panel. Compound 1 in particular exhibited a cooling sensation in the mouth with both a rapid attack and good persistence. Evaluation was performed against comparative compounds WS-3™ and WS-5™ (Figure 1). These compounds of the present invention appear to behave similarly to the comparative compounds. Equimolar comparative analysis of some compounds of the present invention showed better performance than Physcool™ (Figure 2). Equimolar comparative analysis over 10 minutes with a larger panel shows that compound 1 has a sustained cooling effect similar to Physcool® but with greater intensity (Figure 3).

[0111] Example 1: Chewing gum An unflavored chewing gum paste was prepared using the following formulation: sorbitol (52.4 wt%), gum base (30.0 wt%), maltitol syrup (7.0 wt%), glycerin (5.0 wt%), mannitol (5.0 wt%), soy lecithin (0.4 wt%), acesulfame-K (0.1 wt%), and aspartame (0.1 wt%). The paste was heated using a microwave for 1-2 minutes to soften the mixture. After adding a cooling agent (0.20 wt% of compound 1), the paste was kneaded to homogenize the product. The paste was then stretched using a sheeter, flattened to a thickness of 2 mm, and cut into regular rectangular pieces (12 x 42 mm). The chewing gum pieces were packed into plastic bags and left at room temperature for one week to stabilize them. Comparative chewing gum samples (A-C) were also prepared using 0.26 wt.% PHYSCOOL™, 0.21 wt.% WS-3™, and 0.17 wt.% WS-23™, respectively.

[0112] A chewing gum evaluation protocol was carried out by six trained panelists. In the evaluation, the chewing gum was chewed with the panelists' mouths closed for 10 minutes. The cooling sensation intensity was rated from 0 (not perceptible) to 10 (very strong) at 5 seconds, 15 seconds, 30 seconds, 45 seconds, 1 minute, 1.5 minutes, 2 minutes, and then every minute up to 10 minutes. On average, the panelists found that the chewing gum containing the compound 1 of the present invention has a greater initial cooling sensation intensity and a longer duration than the comparative sample A (PHYSCOOL®). The panelists also found that the compound 1 of the present invention provides a long cooling sensation intensity up to 10 minutes, similar to that provided by the WS-3® of Comparative Example B and the WS-23® of Comparative Example C.

[0113] Although the present invention has been illustrated by the description of one or more embodiments thereof, and the embodiments have been described in considerable detail, it is not intended that the appended claims be restricted or in any way limited to such details. Further advantages and modifications will be readily apparent to those skilled in the art. Therefore, the present invention in its broader aspects is not limited to the specific details, representative products and / or methods and examples shown and described. The various features of the exemplary embodiments described herein may be used in any combination. Accordingly, departures may be made from such details without departing from the scope of the overall inventive concept.

Claims

1. Use of a compound having general formula (I) as a cooling agent or flavoring agent, 【Chemistry 1】 During the ceremony, Q is CR １ R ２ or CH-CH(CH ２ OR ８ ) CH ２ OR ９ and R １ and R ２ are independently CHO, CO ２ H, CH ２ CH ２ OH, CHR １０ OR １１ , and CHR １０ OR １２ and R ８ and R ９ are independently H or combine to form a spiroacetal or spiroketal moiety, and each R １０ are independently H or CH ３ and R １１ and R １２ are independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkaryl, substituted or unsubstituted aryl or heteroaryl, and substituted or unsubstituted acyl, or R １１ and R １２ combine to form a spiroketal or spiroacetal moiety, R ３ , R ４ , R ５ , and R ６ are independently H, CH ３ , and C.H. ２ CH ３ is selected from R ７ is selected from H, isopropyl, isopropenyl, and sec-butyl, with the proviso that R ３ , R ４ , R ５ , R ６ , and R ７ Not all of the use.

2. In formula (I), Q is CR １ R ２ whereby the compound has the general formula (II): 【Chemistry 2】 In the formula, R １ ~R ７ is the same as defined for formula (I) in claim 1 2. The use according to claim 1.

3. In formula (II), R ３ , R ５ , and R ６ are H and R ４ is methyl, and R ７ is isopropyl, whereby the compound has the general formula (III), the formula (IV ａ ), or formula (IV ｂ ) 【Transformation 3】 In the formula, R １ and R ２ is the same as defined for formula (I) in claim 1 3. The use according to claim 2.

4. R １ and R ２ The use according to claim 1, wherein each of

5. In formula (II), R １ is CHR １０ OR １１ and R ２ is CHR １０ OR １２ and R １０ is H, whereby the compound has the general formula (VIII): 【Chemistry 4】 In the formula, R ３ ~R ９ , R １１ , and R １２ is the same as defined for formula (I) in claim 1 3. The use according to claim 2.

6. In formula (VIII), R １１ and R １２ are combined to form a spiroketal or spiroacetal moiety CR １３ R １４ whereby the compound has the general formula (IX): 【Transformation 5】 In the formula, R ３ ~R ６ is the same as defined for formula (I) in claim 1, and R １３ and R １４ are independently selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkaryl, and substituted or unsubstituted aryl or heteroaryl, or R １３ and R １４ combine to form a substituted or unsubstituted cycloalkyl 6. The use according to claim 5.

7. Formula (III), (IV ａ ), and (IV ｂ ) in which R １ is CHR １０ OR １１ and R ２ is CHR １０ OR １２ Thus, the compound is represented by the general formula (V), (V ａ ), or (V ｂ ) 【Transformation 6】 In the formula, R １０ is the same as defined for formula (I) in claim 1, and R １１ and R １２ are independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkaryl, substituted or unsubstituted aryl or heteroaryl, and substituted or unsubstituted acyl; or R １０ is H and R １１ and R １２ are combined to form a spiroketal moiety or a spiroacetal moiety CR １３ R １４ whereby the compound has the general formula (VI), (VI ａ ), or (VI ｂ ) 【Transformation 7】 In the formula, R １３ and R １４ are independently selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkaryl, and substituted or unsubstituted aryl or heteroaryl, or R １３ and R １４ combine to form a substituted or unsubstituted cycloalkyl 4. The use according to claim 3.

8. In formula (II), R ３ , R ４ , and R ５ are each methyl, and R ６ and R ７ are both H, whereby the compound has the general formula (X): 【Transformation 8】 In the formula, R １ and R ２ is the same as defined for formula (I) in claim 1 3. The use according to claim 2.

9. In formula (X), R １ is CHR １０ OR １１ and R ２ is CHR １０ OR １２ and R １０ is H, whereby the compound has the general formula (XI): 【Chemistry 9】 In the formula, R １１ and R １２ is the same as defined for formula (I) in claim 1, or R １１ and R １２ are combined to form a spiroketal moiety or a spiroacetal moiety CR １３ R １４ whereby the compound has the general formula (XII): 【Chemistry 10】 In the formula, R １３ and R １４ are independently selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkaryl, and substituted or unsubstituted aryl or heteroaryl, or R １３ and R １４ combine to form a substituted or unsubstituted cycloalkyl 9. The use according to claim 8.

10. In formula (I), Q is CH—CH(CH ２ OR ８ ) CH ２ OR ９ whereby the compound has the general formula (VII): 【Chemistry 11】 In the formula, R ３ ~R ９ is the same as defined for formula (I) in claim 1 2. The use according to claim 1.

11. The compounds include ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)dimethanol, (7S,10R)-7-isopropyl-3,10-dimethyl-2,4-dioxaspiro[5.5]undecane, (7S,10R)-7-isopropyl-3,3,10-trimethyl-2,4-dioxaspiro[5.5]undecane, (7S,10R)-3-ethyl-7-isopropyl-10-methyl-2,4- Dioxaspiro[5.5]undecane, 4-((7S,10R)-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecan-3-yl)-2-methoxyphenol, (7S,10R)-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane, (1S,4R,10S,13R)-1,10-diisopropyl-4,13-dimethyl-7,16-dioxadispiro[5.2.5] ９ .2 ６ ]hexadecane, (2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-dicarbaldehyde, ((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)bis(methylene) diacetate, (3,3,5-trimethylcyclohexane-1,1-diyl)dimethanol, 3,8,8,10-tetramethyl-2,4-dioxaspiro[5.5]undecane, 3,3,8,8,10-pentamethyl-2,4-dioxaspiro[5.5]undecane, (7S,10R)-3-ethyl-7-isopropyl-3,10-dimethyl-2,4-dioxaspiro[5.5]undecane, (7S,10R)-7-isopropyl-10-methyl-3-propyl-2,4-dioxaspiro[5.5]undecane saspiro[5.5]undecane, (7S,10R)-3,7-diisopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane, (7S,10R)-3-(sec-butyl)-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane, (2S,5R)-2-isopropyl-1,1-bis(methoxymethyl)-5-methylcyclohexane, (7S,10R)-7-isopropyl-10-methyl-3-phenyl-2,4-dioxaspiro[5 .5]undecane, (7S,10R)-3,3-diethyl-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane, (3,3-dimethylcyclohexane-1,1-diyl)dimethanol, 4,4'-((((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)bis(methylene))bis(oxy))bis(4-oxobutanoic acid), (7S,10R)-7-isopropyl-3,10-dimethyl-3-phenyl-2,4-dioxaspiro[5.5]undecane 2-((7S,10R)-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecan-3-yl)pyridine, (7S,10R)-7-isopropyl-10-methyl-3-(thiophen-2-yl)-2,4-dioxaspiro[5.5]undecane, (7S,10R)-7-isopropyl-10-methyl-3-(2-(methylthio)ethyl)-2,4-dioxaspiro[5.5]undecane, 3,8,8-trimethyl-2,4-Dioxaspiro[5.5]undecane, (2-(sec-butyl)cyclohexane-1,1-diyl)dimethanol, ethyl (7S,10R)-7-isopropyl-10-methyl-2,4-dioxaspiro[5.5]undecane-3-carboxylate, 2,2'-((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)bis(ethan-1-ol), (2-isopropyl-5,5-dimethylcyclohexane-1,1-diyl)dimethanol, 7-(sec-butyl)-3-methyl-2,4-dioxaspiro[5.5]undecane, ((2S,5R)-1-(hydroxymethyl)-2-isopropyl-5-methylcyclohexyl)methyl acetate, 7-isopropyl-3,10,10-trimethyl-2,4-dioxaspiro[5.5]undecane, 1,1'-((2S,5R)-2-isopropyl-5-methylcyclohexane-1,1-diyl)bis(ethan-1-ol), 2-((1R,2R,5R)-5-methyl-2-(prop-1-en-2-yl)cyclohexyl)propane-1,3-diol, 2-methyl-5-((1R,2R,5R)-5-methyl-2-(prop-1-en-2-yl)cyclohexyl)-1,3-dioxa The use according to claim 1, wherein the hydroxymethyl-2-isopropyl-5-methylcyclohexyl-2-propane-1-carboxylic acid is selected from the group consisting of methylcyclohexane, 2-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)propane-1,3-diol, ((2S,5R)-1-((benzyloxy)methyl)-2-isopropyl-5-methylcyclohexyl)methanol, (2S,5R)-1-(hydroxymethyl)-2-isopropyl-5-methylcyclohexane-1-carboxylic acid, (3,3,5,5-tetramethylcyclohexane-1,1-diyl)dimethanol, and mixtures thereof.

12. A cooling composition comprising an effective amount of a compound of general formula (I) according to any one of claims 1 to 11 and an edible, drinkable or cosmetic ingredient.

13. 13. The cooling composition of claim 12, further comprising a secondary cooling agent selected from the group consisting of carboxamides, ketals, menthyl glutarate, menthyl succinate, menthyl acetate, menthyl lactate, 3-menthoxypropane-1,2-diol, isopulegol, menthol, and mixtures thereof.

14. 1. A product composition selected from topical products such as oral care products, nasal care products, toiletries, pipe tobacco products, chewing tobacco, chewing tobacco products, filters for snuff products, combustible paper and coated sheets, chewing gum and chewing gum products, ingestible products, or tobacco products, comprising: a topical, ingestible, or tobacco-based product; an effective amount of the cooling composition of claim 12; 1. A product composition comprising:

15. A compound having the general formula (I) according to any one of claims 1 to 11, 【Chemistry 12】 During the ceremony, R ２ is CHO, CH ２ CH ２ OH, and CHR １０ OR １２ is selected from the group consisting of The second condition is that Q is CR １ R ２ and R １ and R ２ Both are CH ２ When OH, R ７ is not H, R ３ , R ５ , and R ６ All of the above do not become H, and R ４ is CH ３ Instead, R ７ is not isopropyl, The third condition is that Q is CR １ R ２ and R １ and R ２ Both are CH ２ OH and R ７ is isopropyl or isobutyl, R ３ , R ４ , R ５ , and R ６ At least two of these are CH ３ or CH ２ CH ３ and The fourth condition is that Q is CR １ R ２ and R １ is CHR １０ OR １１ and R ２ is CHR １０ OR １２ and R １０ is H and R １１ and R １２ combine to form a spiroketal or spiroacetal moiety, R ７ When is H, R ３ , R ４ , R ５ , and R ６ At least two of these are CH ３ or CH ２ CH ３ is compound.

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