Quantum Calculations for Feasibility of Routes of Synthesis

Background:
Our approach to optimizing chemical synthesis pathways involves using in-silico quantum calculations to predict the feasibility and efficiency of different routes. By simulating the energy profile of a reaction, we can identify the most promising synthetic pathways before any lab work begins. This approach saves significant time and resources by allowing us to prioritize routes that are kinetically and thermodynamically favorable. We then validate these computational findings with experimental studies.

Case Study: Synthesis of an API Impurity

This case study demonstrates our use of quantum calculations to determine the most feasible route for synthesizing an API impurity. The goal was to compare two proposed routes, RoS-1 and RoS-2, to find the most efficient one.

The Challenge:

When synthesizing a molecule, especially an impurity that may be present in a drug substance, it is critical to find the most efficient and reliable method. Traditional trial-and-error lab work can be time-consuming and expensive. We needed a way to predict which of the two proposed routes would be more successful.

Our Solution: Quantum Feasibility Analysis

We performed detailed quantum calculations on both synthetic routes to model their energy profiles.

Analysis of RoS-1:

• The analysis of RoS-1, as shown in the energy diagram, revealed a clear and favorable reaction pathway (Pathway 1).
• The transition state (TS) and intermediates along this path are energetically accessible, indicating a viable reaction. The most significant energy barrier is relatively low.
• This suggests that the reaction is likely to proceed smoothly without requiring extreme conditions.

Analysis of RoS-2:

• In contrast, the quantum calculations for RoS-2 predicted a high-energy barrier for a key step in Pathway 1, as shown in the table. The positive ΔG value for the species I1+H2O+H2SO4 suggests that this step is not thermodynamically favorable, meaning it is unlikely to proceed spontaneously.
• The large positive ΔH (enthalpy change) and ΔG (Gibbs free energy change) values indicate that this reaction is likely to be very difficult or impossible under standard conditions.

Outcome:

Based on our in-silico calculations, we concluded that RoS-1 is synthetically more feasible than RoS-2. The calculated energy barriers for RoS-1 are significantly lower, indicating a more favorable reaction pathway. We then validated this finding with an experimental study, which confirmed our computational predictions. This case study demonstrates how quantum calculations can be a powerful tool for predicting reaction feasibility, enabling us to make informed decisions about which synthetic routes to pursue, thus saving considerable time and resources in the lab.