|Credit: Grongsaard et al., Org. Process. Res. Dev.|
For the bulk production, this formylation step was ﬁrst run in 2 × 5 kg batches in a 100 L vessel at −60 °C. During the second batch, the reaction solution turned into a thick gel at the dianion (14) stage, a phenomenon which had not been observed in gram scale experiments. The batch temperature had to be raised to −45 °C and the agitator manually manipulated until the mixture was suﬃciently mobile to allow stirring to continue automatically. Fortuitously, these additional operations did not impact the reaction yield, as each 5 kg batch gave a 76% assay yield of aldehyde 5. However, from a practical perspective, the gelling problem encountered with the longer hold times needed for temperature control in these kilogram scale runs presented a concern for further scale-up in ﬁxed vessel equipment. This spurred a preliminary evaluation of the feasibility of performing the formylation under ﬂow conditions, which have been applied to a number of other organolithium processes, since the more eﬃcient mixing and heat transfer in a continuous operation could result in shorter hold times...
The reactor was constructed of 0.25-in. internal diameter stainless steel tubing and immersed in a dry ice/acetone bath to maintain a low temperature. Reagent streams were fed by peristaltic pumps with pressure gauges (PI) through polytetraﬂuoroethylene (PTFE) tubing.
[snip] To demonstrate proof-of-principle for this process, a preparative scale run was perfomed using the setup shown at the bottom of Figure 1. The anion 13 derived from 1 kg of bromide 11 was processed through the ﬂow reactor in 1 h, at a ﬂow rate of 114 mL/min. Eﬃcient cooling of the system in the rudimentary cold bath was maintained even at this high ﬂow rate (the temperatures recorded at steady-state were −70, −65, and −55 °C at T1, T2, and T3, respectively). The solution assay yield of aldehyde 5 at the end of the run (85%) was higher than on the 5 kg scale in batch mode (76%), and the level of debrominated side-product was lower (4% vs 7−8%). Furthermore, even with a slightly higher concentration of dianion 14 in ﬂow mode (in 7 volumes of solvent compared to 10 in batch mode), no gelling or plugging of the reactor was observed.(I think the high-tech flow reactor cooling vessel is a big plastic box, if I'm not mistaken.) A pretty neat experiment -- and a challenge to all of us to try flow chemistry.
1. Grongsaard, P. et al. "Convergent, Kilogram Scale Synthesis of an Akt Kinase Inhibitor." Org. Process. Res. Dev. ASAP, dx.doi.org/10.1021/op300031r