A systematic study on hippuric acid substituents was performed in order to better understand the influence of stereoelectronic factors on the Erlenmeyer reaction rate. In addition, two reaction systems were evaluated: Hünig’s base solvent free conditions and catalytic sodium acetate in 2-methyl-THF. The effect on reaction rate of electron withdrawing and electron donating groups are reported. Specifically, the study led to the conclusion that stereoelectronic factors have significant influence in one of our key Erlenmeyer reaction by affecting its reaction rate.
An exothermic decomposition was observed during a metalation/acylation of 3,4-difluoroanisole (5), resulting in a significant thermal hazard. The lithiated anion 6 was found to decompose exothermically at temperatures above −47 °C showing an adiabatic temperature rise at a peak rate of 120 °C/min. A literature search revealed similar observations for metalation/acylation in analogous aromatic difluoro compounds. This sequence of reactions was evaluated thermochemically. Control experiments at −55 °C over 2 h indicated anion 6 was stable at temperatures below −55 °C under dilute reaction concentrations. This runaway hazard could be addressed using MgCl2 to stabilize the reactive species and thereby decrease its decomposition rate. Thermochemical experiments suggested MgCl2 forms a weak interaction with lithiated species 6, rather than via complete lithium−magnesium exchange. The process was successfully piloted on a multikilo scale by use of MgCl2 as an additive.
Many oxidation reactions can be hazardous when run on large scale. The manufacturing process for the production of R411, a developmental compound indicated for the treatment of asthma, includes the oxidation of 2-chloro-6-methylbenzaldehyde to the corresponding carboxylic acid. The use of sodium chlorite in this transformation was efficient and economical, but there were safety concerns regarding the use of hydrogen peroxide to scavenge unwanted hypochlorite, which was generated as a byproduct of the reaction. During the development of the R411 manufacturing process, an inherently safer oxidation system was discovered using a stoichiometric quantity of dimethyl sulfoxide (DMSO) as scavenger. The new process provided equivalent yields and purities to the hydrogen peroxide procedure, thus maintaining the economic viability of the process. The developed process was demonstrated in fixed equipment on a 300 gal scale.
The development of a nonaqueous process for the synthesis of 3-amino-pentan-1,5-diol is described. Beginning with dimethyl acetone-1,3-dicarboxylate, a telescoped sequence of reductive amination, Boc protection, sodium borohydride reduction, and acidic resin-mediated deprotection generates the title compound. The key to this efficient process is the telescoped deprotection, purification and nonaqueous isolation of the 3-amino-pentan-1,5diol. The process involves four optimized chemical reactions using two solvents in 89% overall yield and 97-98 area % purity.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
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.