Synthesis of cyclohexane derivatives useful as sensates in consumer products

Abstract

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. Preparation schemes for neoisomers of other menthyl derivatives which are useful as coolants, including esters, ethers, carboxy esters and other N-substituted carboxamides are also provided.

What is claimed is: 
     
         1 . A process for preparing specific isomers of menthane derivatives comprising
 (a) derivatizing a starting menthane alcohol to a sulfonate ester or other leaving group,   (b) reacting a menthane alcohol derivative from step (a) with sodium cyanide to obtain a menthane nitrile having opposite stereochemistry at the C-1 position from the starting menthane alcohol and   (c) derivatizing the menthane nitrile obtained in step (b) by
 (i) subjecting the menthane nitrile to hydrolysis conditions comprising hydrogen peroxide and dimethyl sulfoxide to obtain a menthane carboxamide having the same stereochemistry as the nitrile, or 
 (ii) subjecting the menthane nitrile to hydrolysis conditions comprising hydrogen bromide to obtain a menthane carboxylic acid having the same stereochemistry as the nitrile, or 
 (iii) subjecting a (1S,2S,5R)-menthane nitrile to hydrolysis conditions comprising potassium hydroxide to obtain a (1R,2S,5R)-menthane carboxylic acid. 
   
     
     
         2 . The process of  claim 1  wherein l-menthol having 1R,2S,5R configuration is used as the starting menthane alcohol to obtain neoiosmers having 1S,2S,5R configuration, of menthane nitrile, menthane carboxylic acid and menthane carboxamide. 
     
     
         3 . A process for preparing neo-menthane-based derivatives having coolant properties comprising derivatizing a neo-menthane carboxylic acid, a neo-menthane acid chloride or a neo-menthane carboxamide. 
     
     
         4 . A process according to  claim 3 , comprising a reaction between an amino compound and a neo-menthane carboxylic acid or a neo-menthane acid chloride to prepare N-substituted-(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide compounds having coolant properties of general formula 
       
         
           
           
               
               
           
         
         wherein R is selected from linear or branched C1-C8 alkyl, substituted C1-C8 alkyl and substituted or unsubstituted aryl or heteroaryl. 
       
     
     
         5 . A process according to  claim 4 , wherein the amino compound is selected from ethyl amine, tert-butyl amine or glycine ethyl ester to prepare N-ethyl-(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide, N-tert-butyl-(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide and N-ethoxycarbonylmethyl-(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide, respectively. 
     
     
         6 . A process according to  claim 3 , comprising a reaction between an alkyl halide and neo-menthane carboxamide to prepare N-alkyl-(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide compounds having coolant properties. 
     
     
         7 . A process according to  claim 6  wherein the alkyl halide is ethyl iodide to prepare N-ethyl-(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide. 
     
     
         8 . A process according to  claim 3  comprising a reaction between an alcohol and a neo-menthane carboxylic acid or a neo-menthane acid chloride to prepare a neo-menthane carboxy ester. 
     
     
         9 . A process according to  claim 8  wherein the alcohol is 1,2-ethanediol or 1,2,3-propanetriol to prepare (1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxylic acid 2-hydroxyethyl ester (neo-WS-4) and (1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxylic acid 2,3-dihydroxypropyl ester (neo-WS-30) respectively. 
     
     
         10 . A process for preparing intermediates useful for preparation of neo-menthyl derivatives having 1S,2S,5R configuration comprising subjecting neo-menthyl acetate to hydrolysis conditions comprising a base to obtain neo-menthol, wherein neo-menthyl acetate is prepared from l-menthol having 1R,2S,5R configuration by
 (a) reacting l-menthol with tosyl chloride to obtain menthyl tosylate which is then reacted with sodium acetate, or   (b) reacting l-menthol in a medium comprising acetic acid, triphenylphosphine (Ph 3 P) and diethyl azodicarboxylate (EtO 2 C—N═N—CO 2 Et).   
     
     
         11 . A process for preparing neo-menthyl derivatives having 1S,2S,5R configuration comprising derivatizing neo-menthol. 
     
     
         12 . A process according to  claim 11  comprising a reaction between neo-menthol and a derivatizing agent selected from a carboxylic acid, carboxylic acid anhydride, dicarboxylic acid anhydride or carboxylic acid chloride to obtain a neo-menthyl ester having coolant properties. 
     
     
         13 . A process according to  claim 12 , wherein the derivatizing agent comprises one or a mixture of lactic acid, pyruvic acid, succinic acid, 2-acetoxy-propanoic acid chloride, and succinic acid anhydride. 
     
     
         14 . A product for application to the mouth, throat or skin comprising an amount of a neo-menthane derivative selected from a neo-menthyl ester, neo-menthyl ether, neo-menthane carboxy ester or neo-menthane carboxamide, effective to give a cooling sensation to the mouth, throat or skin. 
     
     
         15 . A product according to  claim 14  comprising a blend of a neo-menthyl ester, neo-menthyl ether, neo-menthane carboxy ester or neo-menthane carboxamide compound with a corresponding l-isomer in a ratio ranging from about 1:99 to about 99:1. 
     
     
         16 . A product according to  claim 14  selected from compositions for oral, throat, health and personal care, edible compositions, and flavor or perfume compositions. 
     
     
         17 . A product according to  claim 16  in a form selected from mouthwash, gargle, dentifrice, toothpaste, dental tablet, dental powder, dental solution, chewing gum, dental floss or tape, toothpick, throat lozenge, cough syrup, antacid tablet and digestion aid. 
     
     
         18 . A method of providing a cooling effect to the mouth, throat or skin by applying thereto a product comprising a neo-menthyl ester, neo-menthyl ether, neo-menthane carboxamide or neo-menthane carboxy ester compound.