Development of Industrial Process for the Production of (S)-Metolachlor

Hui-Fang Nie

Department of Medicinal Chemistry, School of Pharmacy,

Fourth Military Medical University

Metolachlor is the active ingredient of Dual^® (one of the most-important grass herbicides using in maize and a number of other crops. It has two chiral elements: a chiral axis and an asymmetric carbon center, leading to four possible stereoisomers. Dual^® was introduced to the market in1976 containing a mixture of all four metolachlor stereoisomers, soon after it was found that about 95% of the herbicidal activity of metolachlor relies on the two (S)-diastereomers. After years of intensive research, Dual Magnum^® with content of approximately 90% two active (S)-diastereomers was introduced in UAS, and then achieved great success.

The key step of the industrial production of (S)-Metolachlor (active ingredient of Dual Magnum^®) is the asymmetric hydrogenation of an imine intermediate. Using optimized conditions, the isolated high purity imine intermediate could be hydrogenated at a hydrogen pressure of 80 bars and 50°C with a substrate-to-catalyst ratio of > 1,000,000. This amazing chiral conversion requires an extremely efficient catalyst system, which was made possible by an iridium ferrocenyl diphosphine (Xyliphos) complex. Our research began with the synthesis and large-scale production of this ferrocenyl diphosphine.