The initial process used to prepare cimetidine, while adequate for initial supplies, involved a bottleneck step which required the reduction of an imidazole ester intermediate using lithium aluminum hydride (LAH). The LAH process was difficult and expensive to operate and was threatened by a shortage of LAH supplies. Because of the high dose of cimetidine, cost reductions were essential to make the revolutionary new drug successful in the market. Since cimetidine was anticipated to be a worldwide success, it also would require patent protection around the world, including countries that offered process patent protection only.

To address these issues, Charles Berkoff and Elvin Anderson established a process research effort at the Smith Kline & French R&D facilities in Philadelphia aimed at finding cost-effective, practical, and patentable routes for synthesizing cimetidine. Groups headed by George Wellman and Lee Webb were among the first in the industry to emphasize the search for new synthetic methods instead of optimization of existing processes.

The initial objective was to find alternative routes to an alcohol intermediate. A number of alternate methods of preparing the alcohol were devised and patented, and the most cost-effective method, using sodium in liquid ammonia for the reduction of the ester, was finally implemented. This cleaner, less expensive pathway helped cut tens of millions of dollars per year from the manufacturing cost. Many of the other innovative methods of preparing cimetidine also provided process patent protection and therefore enhanced exclusivity in countries around the globe. This process patent strategy was especially important in Japan, where it was not possible to protect the product any other way.

Manufacturing of cimetidine was begun at Cork, Ireland, where production increased from approximately 18 metric tons in 1976 to about 1000 metric tons by 1982. This dramatic increase in production demand led to further streamlining and perfection of the process. Low-cost cysteamine equivalents were implemented, and the alcohol was eventually acquired from a company that had developed a new manufacturing method employing a hydroxymethylation reaction. The number of operational steps was reduced and the throughput was dramatically improved so that the hundreds of tons of drug substance could be manufactured economically and in an environmentally friendly manner.

Just as the discovery of cimetidine is a landmark in logical drug design, so the discovery and development of efficient synthetic routes to cimetidine is a landmark in process research and development.

Copyright ©2004 American Chemical Society. All Rights Reserved. 1155 16th Street NW, Washington DC 20036
202-872-4600, 800-227-5558