An Unusual, Methylated Impurity in Diethyl Sulphate: Identification, Structure Elucidation, and Linkage with N‐Methyl Impurity of An Active Pharmaceutical Ingredient

Abstract Diethyl sulphate (DES) is one of the most economical and commonly used reagents for N‐ethylation in bulk manufacturing of active pharmaceutical ingredients (API) and specialty chemicals. In synthesis of an API, involving an N‐ethylation step on a hetero‐aromatic ring, along with the desired N‐ethylated product, formation of an N‐methyl impurity is a commonly encountered challenge. A potential source for methyl group is often linked with the ethylating agents and/or solvents used in the reaction. In case, where DES is used as an ethylating agent, the formation of undesired N‐methyl impurity is generally ascribed to the presence of dimethyl sulphate, a well‐known impurity in DES. In this article, we present a case study wherein another lesser‐known impurity namely, ethyl methyl sulphate (EMS) was revealed to be responsible for the generation of N‐methyl impurity in an API. Systematic evaluation of different batches of DES with varying amounts of this largely unknown impurity was performed using gas chromatography‐mass spectrometry technique and its structure was established as ethyl methyl sulphate. The level of corresponding N‐methyl impurity in various API batches which was found to be in the range 0.02‐0.17% correlated well with that of this mixed alkylated impurity in different DES batches used in the synthesis. An in silico toxicity prediction study suggested the mutagenic and carcinogenic nature of ethyl methyl sulphate further highlighting the importance of its identification and control. It is shown that trace amount of methanol in the bulk ethanol contributes to the formation of ethyl methyl sulphate which ultimately effects the formation of N‐methyl derivative of the API. It is demonstrated that the level of ethyl methyl sulphate in DES could be reduced by a quenching reaction, by treating it with a phenol or an amine as well as by simple normal phase column chromatography.