Selective hydrolysis of methanesulfonate esters

The pH dependence of the hydrolysis of 4-{2-[(methylsulfonyl)oxy]ethyl}phenyl methanesulfonate, 1, and two carboxylate esters, ethyl 2(S)-ethoxy-3-(4-hydroxyphenyl)propionate, 2 and (2S)-2-ethoxy-3-[4-(2-(4-[(methylsulfonyl)oxy]phenyl)ethoxy)phenyl]propanoate, 3, has been studied with a view to the selective removal of any remaining 1, following coupling with 2 to generate 3 in water at 95 degrees C (Scheme 1). It is shown that reduction of pH from that of the reaction conditions (pH 10) to pH 7-8 has little effect on the hydrolysis of 1, which is dominated by the water rate over this pH range, but reduces the rate of hydrolysis of the carboxylate ester group by 3 orders of magnitude (pH 7). This very strong quantitative difference in the response of the two types of ester group to pH change allows complete removal of I at low pH without measurable loss to the product ester, 3. The conclusions should be generally applicable to the removal of potentially genotoxic alkyl esters of methane sulfonic acid in the presence of carboxylic esters and other base-sensitive groups.