On the Kolbe-Schmitt synthesis of pharmacologically useful salicylates: carboxylation of 2,4-di-t-butylphenol and identification and reduction of the formation of 2,2'-dihydroxy-3,3',5,5'-tetra-t-butylbiphenyl in the synthesis of 3,5-di-t-butylsalicylic acid.

The initial yield of 3,5-di-t-butylsalicylic acid obtained via Kolbe-Schmitt carboxylation of the potassium salt of 2,4-di-t-butylphenol was less than 1% and was accompanied by a 65% yield of 2,2'-dihydroxy-3,3',5,5'- tetra-t-butylbiphenyl, a dimer of the 2,4-di-t-butylphenol formed by ortho coupling of phenoxide radicals. Formation of this dimer was decreased to 8%, and the yield of 3,5-di-t-butylsalicylic acid was increased to 68% by optimizing reaction time and temperature and decreasing the amount of oxygen present during carboxylation. This modification of the Kolbe-Schmitt reaction conditions may be generally helpful in the synthesis of all pharmacologically useful salicylates.