In order to test the robustness of this process, the reaction was extended for an additional 20 h. While the cyclization was complete within 2 h, the level of 18 increased almost linearly with reaction time, reaching 50% after 22 h at the expense of product 11, indicating that 18 was mainly generated from 11 (Figure 1a) [CJ's note: Left-hand graph above.] Thus, it became critical that the reaction be stopped at the right time point to minimize degradation, a challenge at plant scale. As the de-ethylation is likely acid catalyzed, base additives were considered to slow this process. The addition of 2,6-lutidine (2 equiv) was found to significantly retard the rate of the formation of 18 without a negative impact on the cyclization rate (Figure 1b) [center graph]
Subsequently, an improved cyclization procedure was developed, using 1 equiv of p-toluenesulfonic acid (p-TSA) buffered with 3 equiv of pyridine as the catalyst and a Dean−Stark trap to remove water generated during the reaction. The cyclization of 10 was complete within 3 h, and 11 precipitated out from the reaction mixture as the p-TSA salt.
More importantly, once the reaction was complete, no further decomposition of 11 to 18 was detected (Figure 2) [graph to right]; the levels of 11 and 18 remained essentially constant at 94% and 4%, respectively, even after heating the mixture to reflux for an additional 21 h. After cooling to room temperature, 11-TSA was isolated in 97% yield and 95.8% purity (containing 2.6% of 18). Material of this quality can be directly used in the next step. Interestingly, pyridine and p-TSA were found to be the ideal combination. Reactions catalyzed by p-TSA alone or with 2,6-lutidine in place of pyridine were observed to be slower and generated higher levels (4.8−8.8%) of 18.I can't agree more about the difficulty of stopping a reaction at the right time. I think it's just very difficult to get that sort of thing to take place in a busy chemical manufacturing plant; it's much better to build that robustness in from the start.
1. Shu, L.; Gu, C.; Dong, Y.; Brinkman, R. "Efficient Large-Scale Synthesis of a 2,4,5-Triarylimidazoline MDM2 Antagonist." Org. Process Res. Dev. ASAP. DOI: dx.doi.org/10.1021/op300294g