News Column

Patent Issued for Synthesis of Cyclohexane Derivatives Useful as Sensates in Consumer Products

July 4, 2014



By a News Reporter-Staff News Editor at Health & Medicine Week -- A patent by the inventors Yelm, Kenneth Edward (Hamilton, OH); Bunke, Gregory Mark (Lawrenceburg, IN); Haught, John Christian (West Chester, OH), filed on March 20, 2013, was published online on June 17, 2014, according to news reporting originating from Alexandria, Virginia, by NewsRx correspondents (see also The Procter & Gamble Company).

Patent number 8754259 is assigned to The Procter & Gamble Company (Cincinnati, OH).

The following quote was obtained by the news editors from the background information supplied by the inventors: "Coolants or compounds that have a physiological cooling effect particularly on oral and other mucosal surfaces and skin are common ingredients in a wide variety of consumer products including edible compositions and personal and health care compositions and in flavor or perfume compositions for use in such products. Examples of edible compositions include confectionery, candies, chocolate, chewing gum, beverages and oral medicines. Personal care compositions for application to the skin, hair and mucosal surfaces include lotions or creams, skin cleansers, shampoos and conditioners, wipes and towelettes and cosmetic products such as lipsticks and foundations. A particular class of personal and health care compositions to which the present invention relates is for oral and throat care, which include products in powder, paste or liquid forms and which on being used are retained for a time sufficient to contact the surface and the internal mucous membrane of the oral or nasal cavities or the pharynx. Such products include for example, mouthwashes, dental and throat lozenges, gargles, chewing gum, dentifrice or toothpastes, toothpicks, dental tablets and powders and topical solutions for application in dental treatment, as well as cough-syrups, chewable antacids and digestion promoting preparations.

"The pleasant cooling sensation provided by coolants contributes to the appeal and acceptability of the products. In particular, oral care products such as dentifrices and mouthwashes are formulated with coolants because they provide breath freshening effects and a clean, cool, fresh feeling in the mouth.

"A large number of coolant compounds of natural or synthetic origin have been described. The most well-known compound is menthol, particularly l-menthol, which is found naturally in peppermint oil, notably of Mentha arvensis L and Mentha viridis L. Of the isomers of menthol, the l-isomer occurs most widely in nature and is typically what is referred by the name menthol having coolant properties. L-menthol has the characteristic peppermint odor, has a clean fresh taste and exerts a cooling sensation when applied to the skin and mucosal surfaces. Other isomers of menthol (neomenthol, isomenthol and neoisomenthol) have somewhat similar, but not identical odor and taste, i.e., having disagreeable notes described as earthy, camphor, musty. The biggest difference among the isomers is in their cooling potency. L-menthol provides the most potent cooling, i.e., having the lowest cooling threshold of about 800 ppb, i.e., the concentration where the cooling effect could be clearly recognized. At this level, there is no cooling effect for the other isomers. For example, d-neomenthol is reported to have a cooling threshold of about 25,000 ppb and l-neomenthol about 3,000 ppb. [R. Emberger and R. Hopp, 'Synthesis and Sensory Characterization of Menthol Enantiomers and Their Derivatives for the Use in Nature Identical Peppermint Oils,' Specialty Chemicals (1987), 7(3), 193-201]. This study demonstrated the outstanding sensory properties of l-menthol in terms or cooling and freshness and the influence of stereochemistry on the activity of these molecules.

"Among synthetic coolants, many are derivatives of or are structurally related to menthol, i.e., containing the cyclohexane moiety, and derivatized with functional groups including carboxamide, ketal, ester, ether and alcohol. Examples include the .rho.-menthanecarboxamide compounds such as N-ethyl-.rho.-menthan-3-carboxamide, known commercially as 'WS-3', and others in the series such as WS-5 (N-ethoxycarbonylmethyl-.rho.-menthan-3-carboxamide), WS-12 [N-(4-methoxyphenyl)-.rho.-menthan-3-carboxamide] and WS-14 (N-tert-butyl-.rho.-menthan-3-carboxamide). Examples of menthane carboxy esters include WS-4 and WS-30. An example of a synthetic carboxamide coolant that is structurally unrelated to menthol is N,2,3-trimethyl-2-isopropylbutanamide, known as 'WS-23'. Additional examples of synthetic coolants include alcohol derivatives such as 3-(l-menthoxy)-propane-1,2-diol known as TK-10, isopulegol (under the tradename Coolact P) and .rho.-menthane-3,8-diol (under the tradename Coolact 38D) all available from Takasago; menthone glycerol acetal known as MGA; menthyl esters such as menthyl acetate, menthyl acetoacetate, menthyl lactate known as Frescolat.RTM. supplied by Haarmann and Reimer, and monomenthyl succinate under the tradename Physcool from V. Mane. TK-10 is described in U.S. Pat. No. 4,459,425 to Amano et al. Other alcohol and ether derivatives of menthol are described e.g., in GB 1,315,626 and in U.S. Pat. Nos. 4,029,759; 5,608,119; and 6,956,139. WS-3 and other carboxamide cooling agents are described for example in U.S. Pat. Nos. 4,136,163; 4,150,052; 4,153,679; 4,157,384; 4,178,459 and 4,230,688. Additional N-substituted .rho.-menthane carboxamides include amino acid derivatives such as those disclosed in WO 2006/103401 and in U.S. Pat. Nos. 4,136,163; 4,178,459 and 7,189,760 such as N-((5-methyl-2-(1-methylethyl)cyclohexyl)carbonyl)glycine ethyl ester and N-((5-methyl-2-(1-methylethyl)cyclohexyl)carbonyl)alanine ethyl ester. Menthyl esters including those of amino acids such as glycine and alanine are disclosed e.g., in EP 310,299 and in U.S. Pat. Nos. 3,111,127; 3,917,613; 3,991,178; 5,5703,123; 5,725,865; 5,843,466; 6,365,215; 6,451,844; and 6,884,903. Ketal derivatives are described, e.g., in U.S. Pat. Nos. 5,266,592; 5,977,166 and 5,451,404. Additional agents that are structurally unrelated to menthol but have been reported to have a similar physiological cooling effect include alpha-keto enamine derivatives described in U.S. Pat. No. 6,592,884 including 3-methyl-2-(1-pyrrolidinyl)-2-cyclopenten-1-one (3-MPC), 5-methyl-2-(1-pyrrolidinyl)-2-cyclopenten-1-one (5-MPC), and 2,5-dimethyl-4-(1-pyrrolidinyl)-3(2H)-furanone (DMPF); icilin (also known as AG-3-5, chemical name 1-[2-hydroxyphenyl]-4-[2-nitrophenyl]-1,2,3,6-tetrahydropyrimidine-2-one) described in Wei et al., J. Pharm. Pharmacol. (1983), 35:110-112. Reviews on the coolant activity of menthol and synthetic coolants include H. R. Watson, et al. J. Soc. Cosmet. Chem. (1978), 29, 185-200 and R. Eccles, J. Pharm. Pharmacol., (1994), 46, 618-630.

"Many of the compounds above including menthol have relatively low potency and the duration of the cooling effect is typically short-lived. Thus, it is necessary to include fairly high levels of such compounds when formulating products, which increases cost. In addition, many of these compounds are relatively high cost ingredients since they are expensive to manufacture on an industrial scale. Therefore, compounds with high cooling potency and long lasting sensory effect are highly sought that will require only small amounts for incorporation in a variety of consumer products to provide high impact and long-lasting effect. Such potent and long lasting coolant compounds have recently been described for example in WO 2005/049553A1 to Givaudan including .rho.-menthane carboxamides substituted at the N-position with an aryl moiety bearing certain substituents. Examples include N-(4-cyanomethylphenyl)-.rho.-menthanecarboxamide; N-(4-sulfamoylphenyl)-.rho.-menthanecarboxamide; N-(4-cyanophenyl)-.rho.-menthanecarboxamide; N-(4-acetylphenyl)-.rho.-menthanecarboxamide, N-(4-hydroxymethylphenyl)-.rho.-menthanecarboxamide and N-(3-hydroxy-4-methoxyphenyl)-.rho.-menthanecarboxamide. In particular, an isomer having the same configuration as l-menthol, i.e., N-[4-(cyanomethyl)phenyl]-(1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarbo- xamide, has been commercialized by Givaudan under the trade name Evercool 180 (also referred to as G-180), supplied as a solution in a flavor oil such as spearmint or peppermint [Chemical & Engineering News (2007), 85(39), pp. 95-98]. This material has been demonstrated to provide intense and long-lasting cooling effect and useful for incorporation in personal care products such as dentifrice and mouthwash as described in commonly assigned U.S. Application No. 61/003,863, filed Nov. 20, 2007.

"Similar to other commercially available synthetic coolants, the new Givaudan Evercool (G-180) coolant is a relatively expensive ingredient. It is believed that this is due to the high cost of producing, purifying and solubilizing the material. Givaudan's proposed synthetic route for the Evercool material as described in WO 2005/049553A1 involves reacting a menthane acid chloride with an aminobenzyl cyanide, the latter believed to be a relatively expensive raw material. Thus in one aspect, the present invention provides an alternate synthesis pathway for preparing menthane carboxamide derivatives utilizing significantly less expensive raw materials while achieving good yield. Additionally, methods of purifying and solubilizing coolant compounds are provided which facilitate incorporation of the coolants into a wide variety of consumer products."

In addition to the background information obtained for this patent, NewsRx journalists also obtained the inventors' summary information for this patent: "The present invention provides synthetic routes for preparing various isomers of cyclohexane-based coolants, such as menthyl esters and menthanecarboxamide derivatives, in particular those substituted at the amide nitrogen, for example with an aromatic ring or aryl moiety. Such structures have high cooling potency and long lasting sensory effect, which make them useful in a wide variety of consumer products. One synthetic route involves a copper catalyzed coupling of a primary menthanecarboxamide with an aryl halide, such reaction working best in the presence of potassium phosphate and water. Using this synthetic route, specific isomers can be prepared including the menthanecarboxamide isomer having the same configuration as l-menthol and new isomers such as a neoisomer having opposite stereochemistry at the carboxamide (C-1) position. The neoisomer unexpectedly has potent and long lasting cooling effect. Neoisomers of other derivatives including menthyl esters, menthyl ethers, menthanecarboxy esters and other N-substituted menthanecarboxamides are also prepared and demonstrated to be useful as coolants."

URL and more information on this patent, see: Yelm, Kenneth Edward; Bunke, Gregory Mark; Haught, John Christian. Synthesis of Cyclohexane Derivatives Useful as Sensates in Consumer Products. U.S. Patent Number 8754259, filed March 20, 2013, and published online on June 17, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8754259.PN.&OS=PN/8754259RS=PN/8754259

Keywords for this news article include: Esters, Dentistry, Dentifrices, Cyclohexanes, Hydrocarbons, Cycloparaffins, Carboxylic Acids, Organic Chemicals, The Procter & Gamble Company.

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