Understanding and Control of Dimethyl Sulfate in a Manufacturing Process: Kinetic Modeling of a Fischer Esterification Catalyzed by H₂SO₄

Abstract

The formation and fate of monomethyl sulfate (MMS) and dimethyl sulfate (DMS) were studied by proton NMR for a sulfuric acid catalyzed esterification reaction in methanol. The kinetic rate constants for DMS and MMS were determined at 65 °C by fitting time-dependent experimental data to a model using DynoChem. In refluxing methanol, sulfuric acid was converted to monomethyl sulfate (MMS) in nearly quantitative yield within 45 min. Once formed, the MMS underwent a reversible esterification reaction to form DMS. Dimethylsulfate reacted with methanol to regenerate MMS and form dimethyl ether. A byproduct of the esterification reaction was water, which further consumed DMS through hydrolysis. On the basis of derived rate constants, in refluxing methanol, DMS would not be expected to exceed 4 ppm in the reaction mixture at equilibrium. In the presence of the carboxylic acid substrate, DMS was not detected in the reaction mixture. The reaction pathways of this system have been systematically investigated, and the results of this study will be presented.

Round Granules of Dimethyl Fumarate by Three-in-One Intensified Process of Reaction, Crystallization, and Spherical Agglomeration in a Common Stirred Tank

“…However, the larger amount of sulfuric acid used in esterification could raise the level of side products such as MMS and DMS . Due to the genotoxic nature of DMS, its maximum daily intake level should not exceed 1.5 μg per person per day, and the risk of creating MMS and DMS must be carefully evaluated.…”

Handling Hydrogen Peroxide Oxidations on a Large Scale: Synthesis of 5-Bromo-2-nitropyridine

“…As already mentioned, after the oxidation reaction, the product was isolated by directly adding the reaction mixture into water (20 w/w with respect to 5-bromo-2-aminopyridine), followed by the addition of isopropanol (8.5 v/w with respect to 5-bromo-2-aminopyridine). The solid obtained was isolated by filtration, washed with water until the rinsing was at neutral pH, and followed by final isopropanol rinsing (0.63 v/w).…”

Case Studies in the Applicability of Drug Substance Design Spaces Developed on the Laboratory Scale to Commercial Manufacturing

“…Using a carefully designed series of 1 H NMR experiments, all of the rate constants for the formation and degradation of monomethyl sulfate (MMS) and DMS were determined. 5 Interestingly, DMS was found to form about 10 000 times more slowly than it could be consumed by water in the reaction mixture (k 2 = 4.9 × 10 −9 L/mol•s versus k −2 = 1.3 × 10 −4 L/mol•s). At steady state, assuming completely anhydrous reaction conditions, the model predicted a maximum of 4 ppm of DMS could form within the process solution.…”

“…First, kinetic experiments were performed on the small scale, in the absence of the drug substance, to examine the rates of esterification of sulfuric acid in methanol under the esterification conditions employed in the manufacturing plant. Using a carefully designed series of 1 H NMR experiments, all of the rate constants for the formation and degradation of monomethyl sulfate (MMS) and DMS were determined . Interestingly, DMS was found to form about 10 000 times more slowly than it could be consumed by water in the reaction mixture ( k 2 = 4.9 × 10 –9 L/mol·s versus k –2 = 1.3 × 10 –4 L/mol·s).…”