Method for preparing substituted 4-phenyl-4-cyanocylohexanoic acids

Abstract

This invention relates to a method of preparing a compound type where at least one of R′ or R″ is a carbosyl group (I) by treating a compound of formula (II) with a Group I(a) or Group II(a) metal halide, with an aprotic dipolar amide-based solvent and water.

What is claimed is:  
     
         1 . A method for making a compound of formula I  
       
         
           
           
               
               
           
         
         R 1  is —(CR 4 R 5 ) n C(O)O(CR 4 R 5 )mR 6 , —(CR 4 R 5 ) n C(O)NR 4 (CR 4 R 5 ) m R 6 , —(CR 4 R 5 ) n O(CR 4 R 5 ) m R 6 , or —(CR 4 R 5 ) r R 6  wherein the alkyl moieties may be optionally substituted with one or more halogens;  
         m is 0 to 2;  
         n is 1 to 4;  
         r is 0 to 6;  
         R 4  and R 5  are independently selected from hydrogen or a C 1-2  alkyl;  
         R 6  is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC 1-3  alkyl, halo substituted aryloxyC 1-3  alkyl, indanyl, indenyl, C 7-1  polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C 3-6  cycloalkyl, or a C 4-6  cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group;  
         provided that: 
 a) when R 6  is hydroxyl, then m is 2; or  
 b) when R 6  is hydroxyl, then r is 2 to 6; or  
 c) when R 6  is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or  
 d) when R 6  is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6;  
 e) when n is 1 and m is 0, then R 6  is other than H in —(CR 4 R 5 ) n O(CR 4 R 5 ) m R 6 ;  
 
         X is YR 2 , halogen, nitro, NH 2 , or formyl amine;  
         X 2  is O or NR 8 ;  
         Y is O or S(O) m′ ,  
         m′ is 0, 1, or 2;  
         R 2  is independently selected from —CH 3  or —CH 2 CH 3  optionally substituted by 1 or more halogens;  
         R 3  is hydrogen, halogen, C 1-4  alkyl, CH 2 NHC(O)C(O)NH 2 , halo-substituted C 1-4  alkyl, —CH═CR 8′ R 8′ , cyclopropyl optionally substituted by R 8′ , CN, OR 8 , CH 2 OR 8 , NR 8 R 10 , CH 2 NR 8 R 10 , C(Z′)H, C(O)OR 8 , C(O)NR 8 R 10 , or C≡CR 8′   
         R 8  is hydrogen or C 1-4  alkyl optionally substituted by one to three fluorines;  
         R 8′  is R 8  or fluorine;  
         R 10  is OR 8  or R 11 ;  
         R 11  is hydrogen, or C 1-4  alkyl optionally substituted by one to three fluorines;  
         Z′ is O, NR 9 , NOR 8 , NCN, C(—CN) 2 , CR 8 CN, CR 8 NO 2 , CR 8 C(O)OR 8 , CR 8 C(O)NR 8 R 8 , C(—CN)NO 2 , C(—CN)C(O)OR 9 , or C(—CN)C(O)NR 8 R 8 ;  
         R′ and R″ are independently hydrogen or —C(O)OX where X is hydrogen or metal or ammonium cation;  
         which method comprises: 
 a) combining a Group I(a) or Group II(a) metal halide, with an aprotic dipolar amide-based solvent and water and a compound of formula II(a) or II(b),  
                     
  where R 1 , R 3 , X 2  and X are the same as for formula (I)  
 b) heating the combination to a temperature of at least about 60° for several hours, optionally under an inert atmosphere;  
 c) precipitating out a compound of formula (I) by adding a strong base to said combination;  
 d) removing the amide-based solvent and water from said precipitate, and optionally 
 1) purifying further the precipitate, or  
 2) acidifying the precipitate to obtain the free acid.  
 
 
       
     
     
         2 . The process of  claim 1  wherein the product is a compound wherein R 1  is —CH 2 -cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF 2 H; X is YR 2 ; Y is oxygen; X 2  is oxygen; and R 2  is CF 2 H or methyl; and R 3  is CN.  
     
     
         3 . The process of  claim 1  or  2  wherein the Group I(a) or II(a) metal halide is lithium or magnesium halide.  
     
     
         4 . The process of any one of claims  1 - 3  wherein the Group I(a) or II(a) metal halide is lithium bromide or magnesium bromide.  
     
     
         5 . The process of any one of claims  1 - 4  in which the aprotic dipolar amide-based solvent is dimethylformamide, dimethylacetamide, or N-methyl pyrrolidinone.  
     
     
         6 . The process of any one of claims  1 - 5  wherein the Group I(a) or II(a) metal halide is lithium bromide and the amide-based solvent is dimethylformamide.  
     
     
         7 . The process of any one of claim  1 - 6  wherein water is present in an amount greater than 0.1% by weight/weight of the contents of the reaction vessel.  
     
     
         8 . The process of any one of claims  1 - 7  in which the strong base is lithium hydroxide.  
     
     
         9 . The process of any one of claim  1 - 8  wherein the compound of formula II(a) or II(b) is cis-6-[3-(cyclopentyloxy)-4-methoxyphenyl)]-1-oxaspiro[2.5]octane-2,6-dicarbonitrile.  
     
     
         10 . A product of the process of any one of claims  1 - 9  which is cis-lithium-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-1-cyclohexanecarboxylate.  
     
     
         11 . A compound which is cis-lithium-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-1-cyclohexanecarboxylate.  
     
     
         12 . A compositon of matter comprising essentially pure cis-lithium-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-1-cyclohexanecarboxylate.