This invention relates to new intermediates and processes for preparing 5-(4-pyridyl)-6-phenyl-2,3-dihydroimidazo[2,1-b]thiazoles and corresponding thiazines which have activity as inhibitors of the 5-lipoxygenase pathway of arachidonic acid metabolism.
Certain anti-arthritic 5,6-diaryl-2,3-dihydroimidazo[2,1-b]thiazoles are described in U.S. Pat. No. 4,175,127. The method disclosed therein for preparing them includes a ring closure of the corresponding 4,5-diaryl-2-mercaptoimidazole. If the substituents at the 4,5-positions of the 2-mercaptomidazole are different, the position isomers at the 5,6-positions of the end product 2,3-dihydroimidazo-[2,1-b]thiazoles are produced in about equal quantities. In most cases, and certainly with the preparation of the preferred 5-(4-pyridyl)-6-(4-fluorphenyl)-2,3-dihydroimidazo-[2,1-b]thiazole, the position isomers are separated with difficulty, and even the most efficient separation techniques, preferably using column separation, provide less than 50% yield of the preferred isomer. In practical fact, however, overall yields are much lower. The present invention greatly reduces the cost of chemical for the preparation of the biologically active 5-pyridyl-6-aryl compounds.
Direct addition of various organic moieties to a pyridine ring through the use of Grignard reagents or other organometallic salts is known. For example, it is shown by K. Akiba et al., Tetrahedron Letters, 23, 429 (1982), that 4-alkylpyridines can be prepared with high regioselectivity by reacting a 1-acylpyridinium salt with an alkylcopper-boron trifluoride complex. The synthesis of 1-acyl-4-alkyl(or aryl)-1,4-dihydropyridines by reacting the appropriate alkyl or aryl Grignard reagent with 1-acylpyridinium salt, in the presence of cuprous iodide, is shown in Comins, Tetrahedron Letters, 24, 2807 (1983) and Comins et al, J. Org. Chem., 47, 4315 (1982).
Direct addition of imidazo-thiazole or -thiazine moieties to pyridine, however, has not been previously shown by these methods. The fused-ring Grignard reagents necessary for direct addition to the pyridinium salt have heretofore been unavailable. Nor has it been suggested previously that a 6-phenyl-imidazo[2,1-b]thiazole (or the corresponding thiazine), by acting as a nucleophile at its 5-position, could bypass the metallic intermediate entirely and add directly to pyridine, particularly with selectivity for the 4-position. The present invention, however, provides methods by which this direct regiospecific addition of the fused-ring moiety can be effected, either by direct nucleophilic attack or by use of novel Grignard intermediates. Accordingly, the present invention avoids the yield loss resulting from the prior art's production of 5,6-position isomers during ring-closure of the corresponding mercaptoimidazole.