ReactIR Provides Insight into Optimizing the Synthesis of the Ester
Allsop, G. L., Carey, J. S., Joshi, S., Leong, P., & Mirata, M. A. (2021). Process Development toward a Pro-Drug of R-Baclofen. Organic Process Research & Development, 25(1), 136–147
In the development of complex molecules, chemists search for ways to simplify multi-step syntheses. The use of enzymes either as catalysts and in the resolution of racemic compounds is well-established. In-situ analytical techniques are complementary and highly useful for aiding in the optimization of chemical and biochemical transformations in the individual synthesis steps.
In this work, the researchers were involved in developing a multi-kilogram synthesis for the drug arbaclofen placarbil, used for alcohol abuse disorders. One step involved the synthesis of a key succinate ester intermediate compound and subsequent resolution of the ester to a single (S)-enantiomer. To obtain this single enantiomer in sufficient quantities, they explored two different approaches, preparative chiral chromatography and enzymatic resolution. The latter approach was deemed advantageous, and they found that C. antartica A lipase immobilized on polymethacrylate (IMMCALA-T2-150 lipase) provided the viable route to the resolved ester succinate intermediate.
To initially synthesize the succinate ester, they found that the analogous thiocarbonate compound reacted with sulfuryl chloride, to yield the desired ester. In order to optimize the yield of the ester, and minimize a by-product, ReactIR was employed. In-situ FTIR showed that when the thiocarbonate compound and sulfuryl chloride reacted, an intermediate chloroformate compound formed that had limited thermal stability. Once this intermediate formed and prior to decomposition, N-hydroxysuccinimide was added, followed by the addition of triethylamine. The addition of triethylamine was highly exothermic and led to the chloroformate intermediate transforming into the desired succinate ester.