A series of 4(3H)-quinazolinones structurally related to 2-methyl-3-o-tolyl-4(3H)-quinazolinone (methaqualone, 3) were synthesized and evaluated for anticonvulsant activity. Preliminary screening of these compounds revealed that 2-[2-oxo-2-(4-pyridyl)ethyl]-3-aryl-4(3H)-quinazolinones 6l and 8i, 8k, and 8p-r having a single ortho substituent on the 3-aryl group had the most promising anticonvulsant activity. Compounds 6l and 8i possessing 3-o-tolyl and 3-o-chlorophenyl groups, respectively, showed good protection against MES- and scMet-induced seizures, combined with relatively low neurotoxicity after intraperitoneal administration in mice. They also exhibited low toxicity in tests for determining the mean hypnotic dose (HD50) and the median lethal dose (LD50). Although these compounds were markedly more potent as anticonvulsants when administered orally in mice and rats, they were also more neurotoxic. This neurotoxicity was particularly acute in oral tests with rats, which resulted in marginal protective indices. In drug differentiation tests, compound 6l was ineffective against seizures induced by bicuculline, picrotoxin, and strychnine, while 8i showed some protection against picrotoxin-induced seizures.
This review includes the preparation
and properties of various
organolithiums, which are commercially available, up to manufacturing
scale. The interdependent properties, such as pyrophoricity, solubility,
stability, and aggregation, are tabulated and discussed. These properties
have a direct bearing on their chemical reactivity and requirements
for safe handling and storage. Extensive guidance for storage, use,
analysis, and disposal of these organolithium solutions is also provided.
Over the last several decades, research directed at optimization of reactions involving organolithium reagents has led to the recognition that a variety of experimental parameters may affect the outcome and viability of such reactions. Investigation of the factors that influence organolithium-mediated reactions on a large scale is a requirement for development of a feasible and practical process. This contribution critically reviews selected examples, taken from the literature, in which adjustment of the reaction medium, order of addition, temperature, the presence of additives, and judicious choice of base, substrate and/or electrophile resulted in optimization of processes involving organolithium reactions.
IntroductionThe innovative realm for a process chemist is the opportunity to optimize a chemical process that is to be scaled from milligrams to metric tons. Organolithium methodology most often involves a sequential protocol: lithiation of substrate followed by coupling of the resulting lithiated substrate with an electrophile. Optimization of organolithium methodology requires attention to several key experimental parameters. For the purpose of the discussion that follows, these experimental parameters are grouped into four general areas: the reaction medium, the reaction procedure, the reagents, and substrateelectrophile compatibility. Clearly, these experimental parameters are interrelated: a change in one parameter affects the others. Thus, optimization requires the evaluation of tradeoffs. The examples that follow illustrate how such tradeoffs are assessed.
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