A new method for N-methylation of indoles using environmentally safe and less toxic methylating reagent, dimethyl carbonate (DMC), has been developed. The effect of various functional groups on the indole ring has been investigated. This method provides the desired product in high yields with high purity and is suitable for large-scale production. This process was used successfully in a 300-gal reactor train for N-methylation of 6-nitroindole.
A Practical Method for N-Methylation of Indoles Using DimethylCarbonate.-The present new method for the N-methylation of indoles is also suitable for large-scale production. Investigations of the selectivity show that esterification occurs slightly faster than N-methylation, while in most cases the dimethylated products are obtained in high yields. It is also shown that the selectivity of N-methylation versus C-methylation could be improved using Bu 4 NBr as phase transfer catalyst even without the presence of any base.
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.
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