Investigation on the Formation and Hydrolysis of N,N-Dimethylcarbamoyl Chloride (DMCC) in Vilsmeier Reactions Using GC/MS as the Analytical Detection Method

Abstract

The formation of N,N-dimethylcarbamoyl chloride (DMCC) in Vilsmeier reactions (VRs) and the hydrolysis of DMCC during aqueous workup were investigated. The amount of DMCC formed was dependent on the chlorination reagent. The activity order was found to be: thionyl chloride > oxalyl chloride > phosphorus oxychloride. The concentrations of DMCC found in the tested reactions were normally at a level of 0-20 ppm. In the presence of a base the level was higher. DMCC hydrolyzed quickly under aqueous workup conditions. No more than 3 ppm of DMCC could be detected in the product after aqueous workup of the tested VR. Our results clearly indicate that by following the described procedure for VR it is perfectly safe from the health risk point of view to operate this chemistry when preparing compounds for pharmaceutical use. A very useful analytical procedure for detection and quantification of trace amounts of DMCC formed in the VR was developed. The method was based on derivatization of DMCC with ethanol to form ethyl N,N-dimethylcarbamate and analysis by GC coupled to a mass spectrometer in selected ion monitoring mode. The analytical method was selective and showed very good linearity. The limit of detection (LOD) and limit of quantification (LOQ) of DMCC using standard addition analysis with real Vilsmeier reaction matrices were determined to be LOD ) 0.2 ppm and LOQ ) 0.7 ppm.

Identification and Elimination of an Unexpected Catalyst Poison in Suzuki Coupling

“…However, SOCl 2 is known to decompose to SO 2 Cl 2 and SCl 2 , and the latter can react with DMF to generate dimethyl carbamoyl chloride (DMCC), along with sulfur as the stoichiometric byproduct (Scheme ). , SCl 2 might also be a process impurity in SOCl 2 , since it is commonly used in the commercial production of SOCl 2…”

Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals

“…However, one disadvantage of thionyl chloride is the potential formation of dimethylcarbamoyl chloride, a known carcinogen in animal models, when used in combination with DMF as catalyst . The mechanisms for the formation of this side product are shown in Scheme …”

Potential Safety Hazards Associated with Using N,N-Dimethylformamide in Chemical Reactions

“…An analogous incident involving SOCl 2 /DMF was reported by Joshi in 1986, in which a sudden exotherm and pressure rise caused by spontaneous decomposition occurred in a 400 L reactor during vacuum distillation of a SOCl 2 /DMF mixture to remove SO 2 . In addition to SO 2 , sulfur (S), HCl, and N , N -dimethylcarbamoyl chloride (DMCC), a potent carcinogen that is heavily regulated in many countries with strict site volume limits, were also identified among the decomposition products. Thermal stability studies using an adiabatic calorimeter indicated that a runaway reaction occurred after 8 h at 60 °C, but after only 20 min when the mixture was maintained at 85 °C.…”