化合物3制备化合物4The predicted set of conditions were tested in the lab and achieved full conversion in 24 h, allowing a reduction in the amount of methylamine required by 42.5% and 40% reduction in solvent usage with respect to the initial proof of concept conditions
化合物5制备化合物6The model predicted that maintaining the reaction at 50 °C while continuously adjusting pH to 7 using a 10% wt. NaOH solution would result in a cyclization yield of 99% within 1 hSubsequent experimental validation at the laboratory scale confirmed the model predictions, with 98.8% area by liquid chromatography of 6 achieved within 1 h. The implementation of the new model-guided conditions facilitated a 24-fold reduction in reaction time (from 24 to 1 h), providing enhanced control over the end point of the reaction
API的制备Overall, development of an optimized process for formation of balcinrenone 1 enabled a 98% reduction in reaction time, 39% reduction in overall process time, 58% reduction in acetonitrile usage in the process, and removed the requirement for heating and distilling the reaction mixture 小结The model-guided telescoped batch process was used to manufacture 256 kg of intermediate 4, streamlining manufacturing and reducing the cycle time to generate 4 by 50%.This enabled savings of 28% cost reduction, 36% solvent use reduction, and 59% methylamine reduction in the total synthesis of balcinrenone. 参考文献https://doi.org/10.1021/acs.oprd.4c00387
