April 23, 2012
Use less tin catalyst in a diol monotosylation reaction. M. J. M. A. Guillaume and Y. L. Lang describe the use of low concentrations of n-Bu2SnO as a catalyst for monotosylating (adding one p-toluenesulfonyl [Ts] group to) diols. It is often necessary to use stoichiometric amounts of n-Bu2SnO in such reactions, which requires expensive methods for removing tin compounds from the products—especially from active pharmaceutical intermediates.
The process claimed by the inventors uses tin acetal 1, which is prepared from n-Bu2SnO and ethylene glycol in refluxing toluene (see Figure 1). The water formed in the reaction is removed as an azeotrope with the solvent. The crude product is isolated in 93% yield and can be purified by recrystallization from toluene.
The inventors regioselectively monotosylated several diols with catalytic amounts of 1. The formation of 3 from 2 (Figure 2) is specifically described in the patent, but the end use of 3 is not mentioned.
Amounts of 1 from 0.005 to 0.1 mol% were used to catalyze the reaction. When 0.05–0.1 mol% 1 is used, the conversion of 2 to 3 is 97%. The selectivity to 2 is >99.1% with 0.05 mol% 1. [Tertiary amines are added to the reaction mixture in some examples, but their function is not clear.—Ed.]
The inventors report that product 3 is recovered in solution and used in the next step, but they do not mention what the next step entails. Nor is the isolation of pure 3 discussed.
One example is the production of 3 on a pilot-plant scale with 0.1 mol% n-Bu2SnO and a stoichiometric amount of i-Pr2NEt. The yield of 3 is 80%, demonstrating that the improved process gives high yields with much lower levels of the tin compound. (Janssen Pharmaceutica [Beerse, Belgium]. US Patent 8,143,432, March 27, 2012; Keith Turner)