Computation-driven synthesis of pentothal sodium

摘要

Different reaction conditions or reaction sequences are critical problems to be solved in synthetic chemistry research. Calculating possible reaction paths with quantum chemistry methods could effectively drive the development of chemical synthesis. Here, we take the synthesis of thiopental (or pentothal sodium), an ultra-short-acting general anesthetic that induces hypnosis and anesthesia, as an example. Different synthetic routes for this compound have been reported in the literature, but detailed information such as the alkylation sequence is illusive. In this work, we revisited the thiopental synthesis path with combined computational prediction and experimental validation. We explored the reaction mechanism of each putative elementary step with density functional theory (DFT) calculations. Our computations show that two different alkylation paths (with either 2-bromopentane or bromoethane) are both possible. However, the reaction order has a significant impact on the amount of by-products in the synthesis product. The subsequent experiments validated the predicted alkylation sequence from DFT calculations. We further showed that EtONa/EtOH is much better than NaH/EtOH to produce thiopental through thiourea's reaction with 2-ethyl-2-(1-methylbutyl) diethyl malonate with a higher yield of the target product. The proposed synthetic path gives a total yield of 66%, higher than the literature reported. Therefore, the computation-driven synthesis of drug molecules provides new insight into the synthetic route's appropriate design and optimization of reaction conditions.