FLOW CHEMISTRY
|
Vapoutec E-series |
|
Vapoutec E-series |
|
1 in DMF |
90 ° C
0.5 ml / min
|
3
Batch: 8 hours Flow: 20 mins
|
-40 ° C 0.5 ml / min |
10 1 O '
Batch:-78 ° C; 70 % yield( dr 1: 1) Flow:-40 ° C; 82 % yield( dr 2:1)
|
|
.,..... F
Ar
2 in DMF
|
|
RMgCI
9 in THF
|
OEt + oEt OEt 5
Pyridine CH 2 Cl 2
Vapoutec E-series
25 ° C 0.2 ml / min
Figure 3 – Examples of scale-up in Vapourtec E-series photo-flow reactor
interdisciplinary communication between chemists, chemical engineers and other engineers who understand how scale can dramatically affect processes.
Piramal Pharma Solutions has proven its ability to scale up flow chemistry. A team runs small-scale experiments to generate proof-ofconcept for reactions and generate the key flow parameters, while the development team familiarises itself with this lab-scale flow chemistry, accommodates and develops parameters, and adapts the isolation process prior to scale-up.
Value of integrated capabilities
Integrated capabilities equip Piramal to advance projects efficiently from the discovery stage to the production of kilograms of material using flow chemistry. The company can use its technology with the discovery team to find a development candidate and then move the chemistry to development for scale-up, thereby bridging discovery-scale synthesis and development together in an efficient manner.
The model has been shown to work. One client had an advanced chemical
0 OEt F, Jl� F � "-./ ' OEt
F
6
Vapoutec E-series
25 ° C 0.2 ml / min
intermediate that needed to be made using the flow technique. Piramal generated the key flow parameters in its discovery laboratory. Members of the development team further studied the chemistry and process before transferring it to their larger-scale flow equipment.
Early experiments showed that flow chemistry was suitable for the process. One of the substrates was volatile and the reaction required pressure. Using a batch process, the whole system would need to be exposed to pressure of 10 bar and the volatility of the substrate would create safety concerns, particularly at large scales. Flow reactors can tolerate up to 100 bars of pressure, providing flexibility.
Extensive interactions between the Discovery and Development teams enabled the combined, customer and Piramal, team to stay informed about the current status of the project and contribute to the efficient scale-up of the process via efficient weekly updates. Close collaboration helped Piramal to navigate challenges, such as the formation of an impurity, and deliver around 0.5 kg of the material to the client on reduced time, despite a tight schedule requirement.
7
Batch: 7 4 % yield Flow: 89 % yield
Conclusion
The above discussion demonstrates that a flow process is the preferred mode for certain reactions. The project validated the power of applying integrated discovery and process development capabilities to flow chemistry.
By harnessing expertise and capabilities across the discovery and development stages of R & D, Piramal accelerated the scaleup and production of a chemical to help its client get the drug to patients with unmet medical needs. Deploying similar approaches for other molecules will empower Piramal and its clients to speed up the development of life-changing therapies using green chemistry techniques, thereby displaying patient-centricity. ●
J j
Jean-François Carniaux
VICE PRESIDENT & GLOBAL API TECHNICAL LEAD
PIRAMAL PHARMA SOLUTIONS jean-francois. carniaux @ piramal. com www. piramal. com
48 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981