Process for methylating a hindered nitrogen atom in an inert non aqueous-solvent.

摘要

A process for methylating the N<4> atom of a polysubstituted piperazine or piperazin-2-one ("PSP") is effective despite using a much smaller molar excess of formaldehyde and formic acid than dictated by a conventional Eschweiler-Clarke reaction. Particularly in a complex amine in which the PSP substituent is connected to a triazine ring which in turn may be connected to a N atom of an acyclic polyamine, the molar ratio of NH groups : HCHO : HCOOH is in the range from about 1:1:1 to 1:1.5:1.5, the amount of HCHO and HCOOH being sufficient to methylate at least the @NH groups of said PSP substituent if the complex amine contains terminal -NH groups. The same range of molar ratio is maintained when the total number of NH groups to be methylated includes the terminal -NH groups. The effectiveness of the process is attributed to use of an alkylbenzene solvent in which reaction with only a slight excess of HCHO and HCOOH proceeds apace, and in which solvent the methylated product remains dissolved. The excess HCOOH is neutralized with aqueous alkali. When the solution of methylated product is washed with water, the partition coefficient is at least 0.90 and typically 0.99, so that less than 1% of methylated product is lost in the aqueous wash. More than 90% yield is obtained by harvesting the methylated product from the solvent phase alone. The methylated product is precipitated from the alkylbenzene solution by addition of a precipitating agent, such as heptane. The reaction may be carried out under essentially dry conditions with less than 3% water present; or, it may be carried out under wet conditons (less than 30% water).