151476-47-0Relevant academic research and scientific papers
Highly selective hydrolysis of chloropyrimidines to pyrimidones in 12 N hydrochloric acid
Padilla, Amphlett G.,Pearlman, Bruce A.
, p. 921 - 926 (2006)
A chromatography-free process for synthesis of 6-piperazinyl-2,4-bis- pyrrolidinylpyrimidine in isomerically pure form is described. The key step is the purification of a crude 6-chloro-2,4-bis-pyrrolidinylpyrimidine/2-chloro-4, 6-bis-pyrrolidinylpyrimidine isomer mixture (generated by reaction of 2,4,6-trichloropyrimidine with pyrrolidine) by a highly selective acid-catalyzed hydrolysis of the 2-chloro isomer to the pyrimidone. The 2-chloro isomer hydrolyzes 350 times faster than the 6-chloro isomer in 6 N HCl and 1750 times faster in 12 N HCl. To put these rate ratios in perspective, the 2-chloro isomer reacts with amines and alkoxides only ～ 10-17 times faster than does the 6-chloro isomer. A mechanistic investigation using methodological tools developed by Bunnett established that the transition state for hydrolysis of the 6-chloro isomer involves two more molecules of water (each acting as a base) than does the transition state for hydrolysis of the 2-chloro isomer. As the concentration of HCl increases from 3 N to 6 N to 12 N, there are fewer unprotonated water molecules. Thus, the transition state that involves the greater number of unprotonated water molecules (6-chloro-2,4-bis- pyrrolidinylpyrimidine) is expected to be increasingly disfavored with increasing acid concentration, as is observed. The optimized process was run successfully on production scale.
