ACYL TRANSFER REACTIONS OF PIVALYLPHENYLEPHRINE AND ANALOGUES IN NONPOLAR SOLVENTS: STERIC DEPENDENCY OF THE REACTIO

Acyl transfer reactions responsible for the degradation of Pivalylphenylephrine (3-trimethyl acetoxy-(alpha)-{(methylamino)methyl} benzene methanol, PPE) were studies in nonpolar solvent such as isooctane at elevated temperatures. Initial rates were determined by following the disappearance of PPE as well as appearance of the degradation products. Phenylephrine (3-hydroxy-(alpha)-{(methylamino)methyl} benzene methanol, PE) and the O-pivalyl derivative of PPE (trimethyl acetic acid ester of 3-trimethyl acetoxy-(alpha)-{(methylamino)methyl} benzene methanol, DIESTER) were identified as the major degradation products of the initial reaction. No detectable amounts of the expected product, i.e., the N-pivalyl derivative of PPE could be determined. It was also observed that N-pivalyl PPE rearranged under similar conditions to form DIESTER and the rate of its appearance was determined to be much faster than that observed during the degradation of PPE. Because of the observed rates of these reactions and their apparent complexity it was not possible to determine whether the formation of DIESTER (from PPE) involved an initial aminolysis reaction followed by a N(--->)O pivalyl transfer or a direct transesterification reaction. However, it was confirmed that DIESTER was thermodynamically more stable than the N-pivalyl derivative of PPE.;It was postulated that the steric interaction between the bulky t-butyl group of the acyl moiety and the N-methyl group was responsible for the formation of DIESTER and not the N-pivalyl derivative. This postulate was further substantiated with the studies of reactions between phenethanolamines and phenyl esters such as acetates and pivalates. Also, the N(--->)O acyl transfer studies of several N- and O- acyl derivatives of pseudoephedrine and N-methylphenethanolamine showed that the N-acyl derivatives with bulky acyl moiety such as N-pivalyl, N-adamantane carboxyl and N-2,2-dimethyl valeryl-rearranged completely to the corresponding O-acyl derivatives relieving the ground state steric strain in the process.;The N(--->)O pivalyl transfer was further investigated to determine the effect of solvent, temperature and bifunctional catalysts on the transfer reaction. The rate of the rearrangement decreased with the increase in the polarity of the solvent. The bifunctional catalysts such as benzoic acid and 2-pyridone substantially increased the rate of the transfer reaction.;The N(--->)O pivalyl transfer was also observed under basic (pH 10) aqueous conditions. The equilibrium constant for the pivalyl rearrangement was determined to be 2.26 for the pseudoephedrine system.