Continuous Process for Phase Transfer-Catalyzed Bis-Alkylation of Cyclopentadiene for the Synthesis of Spiro[2.4]hepta-4,6-diene
The transfer of a highly exothermic phase transfer-catalyzed bis-alkylation of cyclopentadiene with 1,2-dichloroethane from batch to continuous mode is presented, using standard and widely available laboratory equipment. Besides the optimization of the reaction temperature and residence time, the efficient mixing of the organic phase (cyclopentadiene, 1,2-dichloroethane, MeBu3NCl) and the aqueous phase (30% NaOH) was studied in detail and optimized by using of a simple, home-made 'PTFE Raschig ring static mixer' consisting of a PTFE tube filled with small pieces cut from the same PFTE tube. A flow set-up with two 'PTFE Raschig ring static mixers' and three residence time units with a three-staged temperature profile allowed for the synthesis of highly energetic spiro[2.4]hepta-4,6-diene in a yield of 95% with a productivity of 15 g/h under safe conditions.
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.
Results and discussion
Initial Tests
- 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
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%
Conclusion and outlook
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.
This work is published in Organic Process Research & Development 2016, 20, 432−439.