Patent ID: 6066740
Filing Date: 2000-05-23
Classification: C07D

Abstract:
A method of making a 2-amino-2-imidazoline, guanidine, or 2-amino-3,4,5,6-tetrahydropyrimidine derivative having a general structure: ##STR27## or the tautomers thereof, wherein: (a) R.sub.1 is methyl, ethyl, a methylene group connected to R.sub.2 through a single bond such that R.sub.1 and R.sub.2 form a five-membered ring, or a methylene group connected to R.sub.2 through another methylene group such that R.sub.1 and R.sub.2 form a six-membered ring;(b) R.sub.2 is methyl, ethyl, a methylene group connected to R.sub.1 through a single bond such that R.sub.1 and R.sub.2 form a five-membered ring, or a methylene group connected to R.sub.1 through another methylene group such that R.sub.1 and R.sub.2 form a six-membered ring;(c) Z is an alkyl or a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocycle or heterocycle containing one or more heteroatoms selected from O, N, or S; and(d) R.sub.4 is one or more substituents on Z comprising independently hydrogen, alkoxy, alkylthio, alkyl, alkenyl, amino, carboxyl, cyano, halogen, hydroxy, nitro, and thiol;(e) or a protected form, salt, pharmaceutically-acceptable salt, biohydrolyzable ester, or solvate thereof;which comprises the steps of:(I) preparing an intermediate having the general structure: ##STR28## wherein: (a) R is selected from the group consisting of methyl, ethyl, and benzyl;(b) R.sub.1 is methyl, ethyl, a methylene group connected to R.sub.2 through a single bond such that R.sub.1 and R.sub.2 form a five-membered ring, or a methylene group connected to R.sub.2 through another methylene group such that R.sub.1 and R.sub.2 form a six-membered ring;(c) R.sub.2 is methyl, ethyl, a methylene group connected to R.sub.1 through a single bond such that R.sub.1 and R.sub.2 form a five-membered ring, or a methylene group connected to R.sub.1 through another methylene group such that R.sub.1 and R.sub.2 form a six-membered ring;(d) R.sub.3 is --O--R.sub.5 or --R.sub.6 ;(e) R.sub.5 is selected from the group consisting of allyl, methyl, ethyl, benzyl, tert-butyl and phenyl; and(f) R.sub.6 is selected from the group consisting of methyl, ethyl, tert-butyl, and phenyl;from a thiourea having the general structure: ##STR29## wherein: (a) R.sub.1 is methyl, ethyl, a methylene group connected to R.sub.2 through a single bond such that R.sub.1 and R.sub.2 form a five-membered ring, or a methylene group connected to R.sub.2 through another methylene group such that R.sub.1 and R.sub.2 form a six-membered ring;(b) R.sub.2 is methyl, ethyl, a methylene group connected to R.sub.1 through a single bond such that R.sub.1 and R.sub.2 form a five-membered ring, or a methylene group connected to R.sub.1 through another methylene group such that R.sub.1 and R.sub.2 form a six-membered ring;in a two-step, one-pot reaction by:a) alkylating the thiourea using an alkylating agent to form a 2-thio-substituted-2-imidazoline, 2-thioalkyl-2-guanidine, or 2-thioalkyl-2-pyrimidine;b) acylating the 2-thio-substituted-2-imidazoline, 2-thioalkyl-2-guanidine, or 2-thioalkyl-2-pyrimidine of step (I)(a) with an acylating agent in the presence of a base; and(II) coupling the intermediate of step (I) with an amine or its salts of structure: ##STR30## in the presence of an organic acid.