Context of the project
Spiro[2.4]hepta-4,6-diene is a key intermediate for the synthesis of an Active Pharmaceutical Ingredient at Actelion Pharamceuticals Ltd. It can be prepared by semi-batch mode by phase transfer-catalyzed (PTC) alkylation of cyclopentadiene with 1,2-dichloroethane using conc. NaOH as base at 50-60 °C (Figure 1). A detailed thermal risk assessment of this reaction points out the challenges of this synthesis - it requires a careful process control of the semi-batch reaction. This and the circumstance it's a biphasic reaction mixture, motivated us to develop a flow process for this synthesis.
Figure 1 : PTC Synthesis of Spiro[2.4]hepta-4,6-diene
Results and discussion
•First tests with one mixer and one residence time units gave yield of maximum 55% (Figure 2)
•Several mixer types were tested (simple T-mixer, MX from Little Things Factory, LH2 from Ehrfeld) – the best results were obtained with the MX-mixer from Little Things Factory (Table 1)
•Using less concentrated NaOH solution (30% vs. 50%) circumvented blocking of the flow system
Figure 2 : Yield in function of residence time for a one-mixer set-up
Optimization of “Multi-Mixer" Set-up
•Multi-Mixer step was used for re-mixing of the biphasic reaction mixture to avoid coalescence (Figure 3)
•A staggered temperature profile (25 °C, 40 °C, 60 °C) was ideal to cope with evaporation of cyclopentadiene and decomposition reactions
•A home-made PTFE Rasching ring static mixer (RRSM, Figure 4) allowed very efficient mixing, which boosted the yield to 95%
Figure 3 : Scheme of the flow set-up and picture of the home-made RRSM
The PTC synthesis of spiro[2.4]hepta-4,6-diene was successfully transferred into a high yielding continuous process. Key feature is the specifically designed mixer to secure optimal mixing within the flow system. A well-adapted temperature profile and optimization of the reagents (NaOH, PTC-catalyst, 1,2-dichloroethane) allowed a practical residence time of 25 minutes for complete conversion. The flow system could be easily operated several hours with a productivity of 15 g/h.