Methods of making ureas and guanidines, including terazosin, prazosin, doxazosin, tiodazosin, trimazosin, quinazosin, and bunazosin (exemplary of 2-substituted quinazoline compounds), and meobentine, and bethanidine and intermediates thereof

A method of manufacture of cyclic guanidines of the Formula 1 ##STR83## wherein R is selected from the group consisting of hydrogen and lower alkoxy,

• R.sub.1 and R.sub.2 are selected from lower alkyl,
• n is selected from 1 or 2, and
• R.sub.3 is selected from the group consisting of heterocyclic carbonyl, alkoxy carbonyl, alkyl, alkenyl, and lower alkyl carbonyl,
• comprising carrying out a process of manufacture of the cyclic guanidine selected from the group consisting of the following three processes:
• (a) reacting compound (III) of the formula ##STR84## with a compound of the formula H--N.dbd.C.dbd.O to give compound (IX) of the formula ##STR85## and further reacting compound (IX) in the presence of EP, wherein EP is selected from the group consisting of POCl.sub.3, PCl.sub.5, P.sub.2 O.sub.5, MsCl, and TsCl, to give compound (X) of the formula ##STR86## and further reacting compound (X) in the presence of compound (I) of the formula ##STR87## to give compound (VI) of the formula ##STR88## and further closing a ring to give compound (VII) of the formula ##STR89## wherein --O-EP is the substituent arising out of the reaction of the urea oxygen and EP and is a leaving group substitutable by --NH.sub.2 or an amine;
• and wherein R, R.sub.1, R.sub.2, n and R.sub.3 are selected from the following;
• (i) R is H, R.sub.1 and R.sub.2 are each Me, n is 1, R.sub.3 is selected from the group consisting of ##STR90## (ii) R is OMe, R.sub.1 and R.sub.2 are each Me, n is 1, R.sub.3 is ##STR91## and (iii) R is H, R.sub.1 and R.sub.2 are each Me, n is 2, R.sub.3 is ##STR92## (b) reacting compound (II) of the formula ##STR93## in the presence of EP, wherein EP is selected from the group consisting of POCl.sub.3, PCl.sub.5, P.sub.2 O.sub.5 and TsCl, to give compound (VIII) of the formula ##STR94## wherein --O-EP is the substituent arising from the reaction of the urea oxygen and EP and is a leaving group (substitutable by --NH.sub.2 or an amine) and further reacting compound (VII) in the presence of compound (III) of the formula ##STR95## to give compound (VI') of the formula ##STR96## and further closing a ring to give compound (VII')of the formula ##STR97## and wherein R, R.sub.1, R.sub.2, n and R.sub.3 are selected from the following;
• (i) R is H, R.sub.1 and R.sub.2 are each Me, n is 1, R.sub.3 is selected from the group consisting of ##STR98## (ii) R is OMe, R.sub.1 and R.sub.2 are each Me, n is 1, R.sub.3 is ##STR99## and (iii) R is H, R.sub.1 and R.sub.2 are each Me, n is 2, R.sub.3 is ##STR100## and (c) reacting compound (I) of the formula ##STR101## with a compound of the formula H--N.dbd.C.dbd.O to give compound (II) of the formula ##STR102## and further refluxing compound (II) in the presence of Pyridine and compound (Ill) of the formula ##STR103## to give compound (IV) of the formula ##STR104## and further reacting compound (IV) in the presence of EP', wherein EP' is selected from the group consisting of POCl.sub.3, PCl.sub.5, P.sub.2 O.sub.5 and TsCl, to give compound (V) of the formula ##STR105## and further reacting compound (V) in the presence of NH.sub.3 to give compound (VI') of the formula ##STR106## and further closing a ring to give compound (VII') of the formula ##STR107## wherein --O-EP' is the reaction of the urea oxygen and EP' and is a leaving group (substitutable by --NH.sub.2 or amine)
• and wherein R, R.sub.1, R.sub.2, n and R.sub.3 are selected from the following;
• (i) R is H, R.sub.1 and R.sub.2 are each Me, n is 1, R.sub.3 is selected from the group consisting of ##STR108## (ii) R is OMe, R.sub.1 and R.sub.2 are each Me, n is 1, R.sub.3 is ##STR109## and (iii) R is H, R.sub.1 and R.sub.2 are each Me, n is 2, R.sub.3 is ##STR110##