O O Si N + SF4 SF3 N + S Visit the C&I Facebook page to join the debate Process technology OH
prove preferable to the batch reactor. An example (Figure 5) of this is
NC NC
CN CN
H2O2
NC NC
O
CN CN
o-xylylenediamine hydrochloride. The product was needed at a kg scale as a building block, but no safe synthetic route could be found to make it in larger quantity in a batch reactor. It could, however, be made on a micro scale in batch, which helped establish the reaction parameters and solubilities, as well as checked the safety of the process. This was important, as one of the reagents used in the process is sodium azide, which is both explosive and highly toxic. When the process was moved over to a continuous flow reactor, the two steps of the reaction were separated. The formation of a diazide and the reduction to a diamine were run in separate flow reactors to develop a safe and effective process to produce an otherwise inaccessible molecule. This process avoided the need to isolate the unstable diazide intermediate, with the crude reaction mixture flowing into the second flow reactor along with the reducing agent triphenylphosphine in toluene. The first reaction, the formation of the diazide, could safely be run at 90°C in water with a residence time in the flow reactor of 10 minutes. The reduction took eight minutes in the second flow reactor and had an overall yield of 60%. It then became possible to make 1kg/day of the diamine compound.
O
R2 N
N
R2 N
N+ R1 R1 Si N + SF4 SF3 N + SiF R2
Cl Cl
NaN3
N3 N3
UNSTABLE PRODUCTS OEt
H2N O PPh3
NH2 NH2
+ R1O
O O S
R3 + –O
O O S
R3
Cl Cl
NaN3 O
‘Flow reactors are a complementary manufacturing toolkit tool for the pharma industry for safer, cost effective production’
R2 N
N
R2 N
N+ R1 OH
If the reaction chemistry works, a 10,000L batch reactor can be replaced by a 1L continuous flow reactor
+ R1O
O O S
R3 + –O
demand is significant, but thanks to its poor thermal stability there is a safe limit of about 3kg/batch, or a 50L reactor scale. This is nowhere near enough to meet commercial demand.
O O S
R3 Si N +
Cl Cl
flow reactor, the required scale-up to meet demand became possible. Using similar chemistry to the batch procedure in a 50ml flow reactor, the flow process gives ethyl diazoacetate as 15wt% solution in toluene, which is suitable for both transport and safe use. The capacity is currently 10kg/day of pure ethyl diazoacetate, and an expansion in capacity is planned to meet demand.
SF4
Simply by moving to a continuous +
SF3 N SiF NaN3
N3 N3
PPh3 H2N O OEt + NaNO2
H2SO4 CH2Cl2
OEt N2 O O
Sometimes it can be the instability of the product itself that renders it inaccessible via large-scale batch reactions. What can be synthesised on a lab or even pilot scale sometimes simply cannot be made at a large enough scale to meet commercial needs. Making many smaller batches allows demand to be met, but this is hardly efficient in terms of cost, time or capacity. Continuous flow reactors can enable products like this to be made in larger amounts by simply leaving the reactor running longer. Ethyl diazoacetate (Figure 6) has many applications as a reagent in organic synthesis and is particularly useful as a carbine precursor in the cyclopropanation of alkenes. The chemical is too unstable for transport and safe use, so it must be kept in a suitable solvent. The market
+ NaNO2
H2SO4 CH2Cl2
R1 O R1 O R2 R2 OEt N2
Continuous flow reactors can be used to produce unstable products in large amounts by running the reactor longer.
O
FASTER AND MORE COST- EFFECTIVE Continuous flow reactors can also offer faster and more cost-effective production, such as in the case of a patented photochromic dye that is used in a new form of colour-changing glass that changes colour much more quickly than coatings containing existing dyes. The problem with the batch process is that a very high temperature is needed – 245°C – and on scale-up the product tends to decompose. While an Indian contract manufacturer had succeeded in producing large quantities of the material, it was with a batch size limit of about 100g of product and 538 batches were required to make sufficient material. This is clearly not ideal, as the customer required 75kg of this intermediate for the fourth step of a nine-step synthesis (Figure 7). In order to move to continuous
R1 O R2
flow, a suitable high-boiling solvent was identified from a group of glycol ethers and the process was carried out in a stainless steel tube reactor. The optimum residence time was 8 minutes with a reaction temperature of 270°C. By running the flow reactor 24/7, sufficient material for three years of the customers’ production was made in two and a half weeks. Manufacturing
Chemistry&Industry • November 2013 23
cost was reduced to 12% of the batch process; the defined and short reaction times enabled cost-efficient production to be achieved.
H2N O + NaNO2
H2SO4 CH2Cl2
R1 O R1 O OEt N2 O
N3 N3
PPh3
O
IN CLOSING There are many areas where continuous flow reactors have proven advantages, but it must be emphasised that there are processes that currently cannot be performed in continuous flow reactors or will not be beneficial, compared with batch reactors. One example is heterogeneous reactions where the small tubes of flow reactors ranging from 10 um to mm have greater potential of becoming clogged. Flow reactors are an additional and complementary manufacturing toolkit for the fine chemical and pharmaceutical industry as they enable safer and more cost-efficient production for many types of reactions. There is no doubt that with the increasing number of chemists using flow reactors and developing continuous processes, we will see many new exciting products which are difficult to make and scale in a batch process.
R2
NH2 NH2
Andreas Weiler is head of strategic marketing; Gregor Wille is senior scientist; Patrick Kaiser is principal scientist and Stefan Gladow is manager, PRD at SAFC
R2
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