Wednesday, April 11, 2012

Process Wednesday: organolithiums and flow chemistry

Credit: Grongsaard et al., Org. Process. Res. Dev.
One of the concerns that I have about implementing flow chemistry in the lab is plugging or other issues of moving slurries through narrow tubes. But this work from Merck [1] tends to indicate that might be less of an issue than I thought -- and that it may serve to help with those issues:
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

3 comments:

  1. Interesting example. If the dianion "gel" behaves like a Bingham plastic fluid (solidifies until shear stress is high enough to induce flow) then pushing the suspension through a narrow tube can prevent low shear zones. In low shear stress zones crystals aggregate and the suspension appears solid.

    In a reactor the high shear stress zone is near the agitator (mixing cavern with fast moving fluid). The resulting low viscosity at the impeller causes poor power draw and gives a "reactor candle" effect (agitator shaft = wick).

    Bingham plastic fluids are fascinating. The effect limits scale-up in in some crystallizations where it is sometimes caused by edge-to-face aggregation of plate crystals.

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    1. You're clearly more knowledgeable than I -- thanks for your input!

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