Process technology
NC NC
CN CN
H2O2 Take the production of
tetracyanoethylene oxide from tetracyanoethylene as an example. When using hydrogen peroxide as the oxidant, the exotherm is difficult to control at a 25g scale, never mind in larger batches. At that 25g scale, the typical yield is 65%. When the scale is increased to 200g, this drops to a variable 0 to 23%. The optimum reaction time is 10 minutes and, in addition to the hazards of the exotherm, the product decomposes on contact with water, generating hydrogen cyanide, (Figure 1). This product was an obvious can-
didate for transferring to flow and the process development proved surprisingly straightforward. No changes were needed to solvent or concentrations and no optimisation was needed. A continuous workup system gave a two-stage continu- ous process, an immediate quench with water providing a constant reaction time. In the flow process, the optimum reac- tion time is three minutes, independent of scale, with a productivity of 100g/h. Without optimisation, a yield of 47% of colourless product is achieved, with simi- lar results in several production runs.
NC NC
CN CN
H2O2
NC NC
O
CN CN
LESS DEVELOPMENT EFFORT Another drawback to batch processing is the amount of development time that can be required to transfer a reaction from the lab scale to a large reactor. While sometimes lab conditions are appropriate and successful at larger scale, this is rarely the case; changes to temperature, pressure, reaction time, concentration and even the reagents used may be necessary. The manufacture of a batch of 500g of high purity retinol is a good example of this, as pure retinol is not an easy molecule to handle – it is unstable at the reaction temperature and sensitive to both air and light. Reproducibility is poor in batch mode, yields are low (typically around 40%) and the batch process takes 16 hours to complete. But perhaps the biggest difficulty in making retinol in highly pure form is that it is not possible to purify the crude product. This poses real problems for process development. The continuous flow process was successful here (Figure 2). A key factor in this success was avoiding precipitation that blocked the reactor tube.
O
R2 N
N
R2 N
N+ R1 + R1O
O O S
R3 + –O
O O S
R3 Si N + SF4 SF3 N O
NC NC
O
CN CN
NC NC
CN CN
Find C&I online at
www.soci.org/chemistryandindustry H2O2
NC NC
O
CN CN
O O
because of the ability to remove excess heat as soon as it is generated, reducing the tendency to form byproducts.
O OH
To do this, the solvent system was changed from methanol and water used in batch mode; two separate reagent streams were fed into the flow reactor, one with 1M retinyl acetate in THF and the second 2M aqueous KOH, both at the reaction temperature of 60°C. The immediate quench flowing out of the flow reactor and into the work-up flow reactor ensured constant reaction time and conditions throughout the process. This process has now been optimised in terms of KOH excess and flow rate; it can produce retinol in 99.99% purity with a productivity of 35g/h. This high purity can cause its own problems by crystallising out spontaneously during the continuous workup.
R2 N
N
R2 N
N+ R1 + R1O
O O S
R3
R2 N
+ –O
O O S
N+ R3 R1 Si N + SF4 SF3 N HIGHER PURITIES O
Purity issues can also be addressed through the use of a continuous flow process. For instance, ionic liquids are increasingly in demand, with applications ranging from solvents to electrolytes. However, it can be challenging to make them in sufficiently pure form for practical use, particularly at a large scale, because of the difficulty of removing impurities and solvents.
Cl Cl
NaN3
N3 N3
H2N O OEt + NaNO2
H2SO4 CH2Cl2
OH R1
In the course of developing a range of high purity ionic liquids at a 5kg scale, there was a real problem with a yellow coloration appearing in the liquid that could not be removed if the reaction temperature rose above 20°C. Avoiding this in batch mode was problematic because the alkylation reaction is strongly exothermic and achieving purity in excess of 96% is difficult (Figure 3). This was overcome by moving to flow;
O R1 O R2 R2 R2 Si N
a productivity of 1.5kg/h is now possible, with purity in excess of 98%. Using a glass vessel was essential to avoid corrosion and the heat removal provided by a 2mm channel glass reactor was sufficient to prevent the coloured impurity from forming. Fast, exothermic reactions like this become manageable in flow
+ 22 Chemistry&Industry • November 2013 Cl NaN3 N3 PPh3 NH2 SiF R1 O R1 O
R2 N
N + R1O
O O S
NC NC
+ R3
CN CN
–O
O O S
R3 Si N + SiF + SF4
IMPROVED SAFETY Perhaps one of the biggest advantages of using a continuous flow reactor over a batch reactor is that it can improve safety when working with hazardous substances. In batch reactors, the large quantities of hazardous reagents can pose real risks to both the operator and the environment. In flow, the quantity of hazardous reagents in the reactor at any one time is much smaller and poses less of a risk. DAST, or (diethylamino) sulfur trifluoride, is a common fluorinating reagent used in the manufacture of many key pharmaceutical intermediates that contain fluorine atoms. However, DAST is difficult to handle in batch mode because of its low heat of decomposition. While it must be purified by distillation, impurities form during the distillation that reduces its thermal stability still further. This poses an additional hazard because it reacts readily with water, forming toxic hydrofluoric acid, (Figure 4). The answer lies in making DAST in situ
OH H2O2
NC NC
O
CN CN
O O SF3 N + SiF PPh3
Cl Cl
One of H2N N2 OEt
OEt O
NaN3
NH2 NH2
R1
the biggest advantages of using a flow reactor over a conventional batch reactor is that it can improve safety
O O
R2 N
N+ R1 +R1
R2 N
N + + NaNO2
in a flow reactor and then introducing it into a second continuous flow reactor where the fluorination itself takes place. Careful design is required since the sulfur tetrafluoride used to make DAST boils at -40°C; a way of using this as a gas in flow had to be developed. To do this, the reaction to make the DAST is carried out without solvent.
OH
N3 N3
PPh3
NH2 NH2
R1O
H2SO4 CH2Cl2
O O S
OEt R3 N2 O Using a continuous flow reactor, a
productivity of 10kg/day was achieved. The stability of the crude product is unchanged, but the small volumes and footprint have significantly enhanced safety, and this method can be used to carry out large-scale continuous fluorinations at a lower cost using crude DAST.
–O
O O S
O R3 R2 + SF4 SF3 N + SiF
Cl Cl
H2N O OEt
EXPANDED CHEMICAL SPACE In certain cases, flow reactors enable access to new chemical entities that were previously not possible with batch techniques. If the production involves overly hazardous chemicals or simply does not work on scale-up, the small quantities in a flow reactor operating under continuous flow conditions also
NaN3
N3 N3
PPh3 + NaNO2
H2SO4 CH2Cl2
N2 O
NH2 NH2
OEt
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