Investigation of the interrelationship between structure, antiulcer activity, and toxicology screening data derived from a series of compounds selected from structure-activity studies directed toward identifying a successor to 3-(cyanomethyl)-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine, Sch 28080 (1), has identified 3-(cyanomethyl)-2,7-dimethyl-8-(phenylmethoxy)imidazo[1,2 -a]pyridine (5), 3-amino-2-methyl-8-(2-phenylethyl)imidazo[1,2-a]pyridine (6), and 3-amino-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyrazine (7). These analogues exhibit a combination of antisecretory and cytoprotective activity in animal models, while eliminating the adverse effects of the prototype 1. One of these, 3-amino-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyrazine, Sch 32651 (7), has a profile meeting all criteria.
A novel prototype condenser has been constructed utilizing a Vigreux column surrounded by a water jacket that is encased in a finned aluminum tube. The results reported demonstrate the possibility of condensing a variety of solvents at low to medium volumes without the need for a continuous flow of water.
Route design and process development
of the small nitrogen heterocycle 2·HCl, a constituent
of AZD5718 (1), is
described. The novel synthetic sequence to 2.HCl involves
a desymmetrizing alkylation of 4-nitropyrazole, a non-cryogenic lithiation-alkoxycarbonylation,
and a global reduction-cyclization. This new synthetic route was implemented
in the manufacture of 2.HCl and was able to deliver over
1000 kg of product with a yield of 77% over the three stages.
An efficient method for the synthesis of disubstituted quinazoline diones with differential N-substitution is reported. A wide range of substitutions on the aromatic and dione rings are tolerated, and the reaction proceeds in high yields under mild conditions.
The process development toward synthesizing a diethanolamine (DEA) boronic ester and the subsequent Suzuki− Miyaura coupling (SMC) is disclosed herein. A one-pot lithiation−borylation−transesterification was successfully developed to isolate the DEA boronic ester as a stable crystalline solid and avoided the formation of boronic acid or pinacol boronic ester analogues, which have poor physical properties and purity profiles. The crystalline DEA boronic ester was also successfully employed in the SMC, and the improved input quality allowed for a simpler and more robust process to be developed with enhanced quality of the isolated intermediate. The borylation and SMC were operated on 60 and 350 kg scales, respectively, and generated 2300 kg of the active pharmaceutical ingredient AZD5718.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.