Intermediate compounds in the synthesis of dronabinol

Abstract

Dronabinol, the tetrahydrocannabinol compound which comprises the active constituent of marijuana and is pharmaceutically useful as an antiemetic, is prepared by a process involving reaction of cis-menth-1-ene-3,8-diol with olivetol to form 1,3-dihydroxy-2-[(1R,6R)-6-(2-hydroxyprop-2-yl)-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene; and cyclizing the 1,3-dihydroxy-2-[(1R,6R)-6-(2-hydroxypropr-2-yl)-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene so formed to obtain dronabinol. A novel synthesis of cis-menth-1-ene-3,8-diol is also provided.

1 . Methyl 2-oxy-substituted, 3-carboxylic ester-substituted methylcyclohex-3-enes of the general formula: 
     
       
         
         
             
             
         
       
     
     in which R represents lower (C 1 -C 6 ) acyl, lower alkyl, silyl, hydrogen, lower alkylsulfonyl, arylsulfonyl, lower alkoxysulfonyl or lower alkoxyphosphoryl, and R′ represents hydrogen or lower alkyl. 
   
   
       2 . A compound according to  claim 1  which is methyl 2-acetoxy-4-methylcyclohex-3-ene carboxylate. 
   
   
       3 . 2-hydroxy-4-methylcyclohex-3-ene carboxylic acid. 
   
   
       4 . Cis-2-hydroxy-4-methylcyclohex-3-ene carboxylic acid. 
   
   
       5 . Addition salts of cis-2-hydroxy-4-methylcyclohex-3-ene carboxylic acid and a chiral amine. 
   
   
       6 . An addition salt according to  claim 5  which is the cis-2-hydroxy-4-methylcyclohex-3-ene carboxylic acid 1-phenylethylamine addition salt.