ABSTRACT
Peter Giannousis1* and John Carlson11 Chemical Development, Novartis Pharmaceuticals Division, IV Summit, New Jersey, 07901-1398
Marius Leimer Chemical Development, Novartis Pharmaceuticals Division, 1 v Basel S WITZERLAND, CH-4001
Key words: piperidine, pipecolic acid, phosphonate, radical carbamoylation, reduction
CGS 19755 (1, (±)-c/ls,-4-phosphonomethyl-2-piperidinecarboxylic acid) is an N-methyl-D-
aspartic acid (NMDA) antagonist, that has been investigated as an antiischemic agent in the
treatment of stroke and head trauma.2 This chapter presents the evolution of the synthetic
processes to prepare this compound from the initial research laboratory-bases synthesis to the
launch-ready multi kilogram pilot plant campaign. A brief explanation of the development
process at the former Ciba-Geigy during the timeframe of the CGS 19755 project is necessary in
order to put the entire effort into perspective. Medicinal chemistry scientists discovered CGS
19755 in 1985 (Scheme 1; retrosynthetic strategy: Scheme 2) .3 After passing several preclinical
screens, the compound was promoted to early development and as a result it was necessary to
prepare very quickly about 300 g of CGS 19755 in a non-GMP Kilo Lab (Scheme 3). Additional
material was subsequently needed to meet the needs of formal development (formulation,
toxicology, clinical, etc.). After some process research, two preparations were carried out under
GMP (Good Manufacturing Practice) in a pilot plant, giving 8 kg and 51 kg respectively (Scheme
4). The project lay dormant for some time, but rekindled interest led us to develop further
improvements. Two similar routes emerged for scale-up evaluation (Schemes 6 and 7). The
selected process was then transferred to a Process Development group for final optimization using
statistical methods. As a result, three parallel campaigns led to the production of a total of 440 kg
of CGS 19755 during 1995. This final process is suitable for further scale-up and registration.
