Process for methylating a hindered nitrogen atom in a polysubsti

Details Process for methylating a hindered nitrogen atom in a polysubsti Process for methylating a hindered nitrogen atom in a polysubsti

1989-11-21

1991-05-07

Raymond, Richard L.

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

540492, 540504, 540514, 540598, 544113, 544198, 544231, 544354, 544357, 544384, C07D24108, C07D24144, C07D24310, C07D24314

Patent

active

050138367

ABSTRACT:
The difficulty of methylating a hindered piperidinyl, piperazinyl, or diazepinyl group with an Eschweiler-Clarke ("E-C") procedure without using a large molar excess (more than double) of formaldehyde is surprisingly found to be non-existent in the case of a diazacycloalkan-2-one group with a hindered N.sup.4 - or N.sup.5 -atom of its NH group which is to be methylated. The N.sup.4 - or N.sup.5 -atom of a polysubstituted diazacycloalkan-2-one group ("DCA") is substantially stoichiometrically converted even when a conventional E-C procedure is starved of HCHO, that is, with a much smaller molar excess of formaldehyde than deemed necessary. The effective molar ratio of NH groups: HCHO in the starved E-C process is in the range from 1:1 to 1:1.5, in the presence of enough formic acid to function both as reactant and solvent not only for a DCA-containing complex amine ("starting amine") to be methylated, but also for the methylated amine (product). Such a starting amine may have one or more DCA substituents which, in turn, may be connected to any other structure. Because this process is starved of at least HCHO, and usually both HCHO and HCOOH, it is referred to herein as the "starved E-C process". Upon completion of the reaction any excess HCOOH is neutralized with aqueous alkali, and the product separates from the reaction mass. Though the starting amine is often substantially soluble in water, it usually becomes substantially insoluble after it is methylated. Less than 5% of product is lost in the aqueous wash.

REFERENCES:
"Methylation of Amines with Formaldehyde", Organic Reactions, vol. V by M. L. Moore, 1952, pp. 323-325, John Wiley & Son, New York.

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