Process for the preparation of imidazoles useful in angiotensin II antagonism

A process for preparing a product of the formula ##STR27## wherein:

• R.sup.1 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl;
• R.sup.2 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl or --(CH.sub.2).sub.m Z(CH.sub.2).sub.n R.sup.3, each of which is unsubstituted or substituted with 1 or 2 groups selected from halo and --CO.sub.2 R.sup.1 ;
• or aryl or aralkyl, each of which is unsubstituted or substituted with 1 or 2 groups selected from halogen, lower alkoxy, lower alkyl and nitro;
• R.sup.3 is hydrogen, alkyl, cycloalkyl, lower alkenyl or lower alkynyl;
• Z is O, NR.sup.4 or S;
• R.sup.4 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl or aralkyl;
• m is an integer from 0 to 5;
• and
• n is an integer from 1 to 5;
• and wherein the process comprises:
• step (a) reacting a ketone of the formula ##STR28## with a nitrogenic acid, nitrite or nitrate in the presence of an acid to form a hydroxyimino compound of the formula ##STR29## step (b) reacting the hydroxyimino compound with an aldehyde of the formula
• R.sup.2 --CHO
• and an ammonium compound selected from ammonia, ammonium halide and ammonium hydroxide to form an N-hydroxyimidazole of the formula ##STR30## and further comprising step (c) reacting the N-hydroxyimidazole from step (b) with a reducing agent selected from titanium trichloride and zinc in the presence of a buffer to form a product of the formula ##STR31## step (d) reacting the N-hydroxyimidazole from step (b) with ##STR32## in the presence of a coupling agent in an organic solvent to form a product of the formula ##STR33## wherein:
• L is halogen;
• W is --CH.sub.2 -- or --O--CH.sub.2 --;
• X is N, ##STR34## R.sup.5 is hydrogen ##STR35## R.sup.6 is hydrogen, halogen, haloalkyl, alkyl, aryl, cycloalkyl, cycloalkylalkyl, aralkyl or ##STR36## R.sup.7 is hydrogen, alkyl, aryl, aralkyl, cycloalkyl or cycloalkylalkyl;
• R.sup.8 is alkyl, --NR.sup.13 R.sup.14 or ##STR37## R.sup.9 is hydrogen, cycloalkyl, --(CH.sub.2).sub.p C.sub.6 H.sub.5, --OR.sup.11 or --NR.sup.15 R.sup.16 ;
• R.sup.10 is hydrogen, alkyl or phenyl;
• R.sup.11 is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, a 5- to 7-membered carbocyclic ring that may have another 5- to 7-membered carbocyclic ring fused thereto, ##STR38## R.sup.12 is --CN, --NO.sub.2 or --CO.sub.2 R.sup.1 ;
• R.sup.13 and R.sup.14 are independently hydrogen, benzyl or together are alkylene or alkenylene, forming a 4- to 7-membered saturated, unsaturated or aromatic ring with the nitrogen atom to which they are attached;
• R.sup.15 and R.sup.16 independently are hydrogen, alkyl, phenyl, benzyl, .alpha.-methylbenzyl or together with the nitrogen atom to which they are attached form a ring of the formula ##STR39## Q is NR.sup.7, O or CH.sub.2 ;
• R.sup.17 is hydrogen, alkyl, cycloalkyl, aryl or arylalkyl and R.sup.18 is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl or alkoxy, or together R.sup.17 and R.sup.18 are --(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 --, --CH.dbd.CH-- or ##STR40## and t is 0 or 1;
• or
• step (c) and step (d);
• and "coupling agent" refers to an alkali metal disilazane, carbonate or bicarbonate.