Die Entwicklung eines neuen, umweltgerechten Produktionsprozesses für Terbinafin

An efficient process for the production of terbinafine is described. Starting from (E)-I,3-dichloropropene, neohexene, and N-methyl-( I-naphthylmethyl)amine and using a palladium-catalyzed coupling methodology, terbinafine is produced exclusively as (E)-isomer in a convergent manner. The new process avoids the very toxic and nasty starting materials acrolein and phosphorus pentachloride used in the old process

Match-Making Reactors to Chemistry: A Continuous Manufacturing-Enabled Sequence to a Key Benzoxazole Pharmaceutical Intermediate

The focus of this study was to develop a chemical reaction sequence toward a key benzoxazole building block, required for clinical manufacturing of a lead candidate in the respiratory disease area. The chemistry consisted of initial low-temperature reactions with an organometallic reagent to generate the benzoxazole core, and was followed by noncryogenic transformations toward a sulfonamide substituent. With particular interest in continuous-flow manufacturing we attempted to integrate the entire sequence on lab scale. Subsequent in-depth process research, supported by PAT and calorimetry studies, revealed the critical parameters of each step, leading to a more rational attribution of mode of operation: flow, batch, or semibatch. Two bench-scale cascades of continuously stirred tank reactors (CSTRs) were constructed to meet the challenge of high exothermicity and solids formation and were key to smoothly upscaling the chemistry to deliver 17 kg of benzoxazole in superior yield, quality, and robustness

Multistage, multi-zones antisolvent-cooling crystallisation of a proprietary API : experimental comparison of effect of geometry and hydrodynamics in four batch crystallisers

Early decision making of batch vs continuous and which type of crystalliser to select is a key decision point. Four different lab-scale (100’s ml) crystallisers were investigated and compared for multistage, multi--zone, antisolvent-cooling crystallisation of a proprietary anticancer active pharmaceutical ingredient (API). The seeding load (1&5%), antisolvent addition rate and residence times were fixed across all four platforms based on fixed process conditions. This work aims to enable decision making earlier in the development cycle by understanding how batch reactors compare to their continuous counterparts. Investigate how to run small scale "batch" experiments to replicate continuous performance. Develop a comparative basis to select an ideal crystalliser for early stage development with less material than is currently possible

Continuous Flow as an Enabling Technology: A Fast and Versatile Entry to Functionalized Glyoxal Derivatives

Organometallic chemistry is a remarkable opportunity for continuous processing and has been applied to demonstrated effect in the industrial landscape. We herein report two complementary strategies employing organolithium chemistry for the synthesis of glyoxal derivatives. Micro-mixer technology allows for the generation of unstable organometallic intermediates and their instantaneous in-line quench with esters as electrophiles. Selective mono-addition was observed via putative stabilized tetrahedral intermediates. Advantages offered by flow chemistry technologies facilitate a direct and efficient access to masked 1,2-dicarbonyl compounds while mitigating undesired by-product formation. These two approaches enable the production of advanced and valuable synthetic building blocks for heterocyclic chemistry with throughputs of grams per minute

Dichloromethyl lithium: A valuable reagent in organic synthesis handled in continuous flow mode

A simple and robust procedure for the synthesis and usage of thermally unstable dichloromethyl lithium in continuous flow mode is described. By utilizing residence times in the range of milliseconds for the generation and electrophilic quench of dichloromethyl lithium, the straightforward synthesis of dichloro carbinols and benzylic pinacol esters was realized at reaction temperatures of −30°C whereas typical temperature in traditional batch mode are below −78°C. The excellent purity profile obtained from the flow process allows to directly telescope the exiting flow stream into semi-batch quenches for further modifications. All transformations gave the desired product in remarkable purity and yield on multigram scale without the necessity for any chromatography

Selective Acylation of Aryl- and Heteroarylmagnesium Reagents with Esters in Continuous Flow

A selective acylation of readily accessible organomagnesium reagents with commercially available esters proceeds at convenient temperatures (-5 to 25 °C) and short residence times (2-10 min) in continuous flow producing various functionalized ketones. The use of flow conditions allows to prevent premature collapse of the hemiacetal intermediates despite non-cryogenic conditions, thus furnishing ketones in good yields. Several ester electrophiles, including ethyl trifluoroacetate, diethyl oxalate and N-heterocyclic esters were suitable substrates for this acylation procedure. Throughout, the coordinating ability of the ester and/or Grignard was found to be a determinant factor in the reaction outcome. This was leveraged by the obtention of several bis-aryl ketones using 2-hydroxy ester derivatives as substrate

Minimizing Material Consumption in Flow Process Research and Development: A Novel Approach Toward Robust and Controlled Mixing of Reactants

Scarce availability of chemical starting materials is a crucial challenge in the development of flow chemical processes. This is particularly important for organometallic reactions, which typically require high flow rates and hence high material consumption, to generate sufficiently short mixing and residence times. To address this issue, micromixers that mix efficiently even at small Re numbers and that have a low tendency of clogging are necessary. Here, we propose the usage of microannular gear pumps as active mixers, which allow the reduction of material consumption by >10-fold while achieving fast mixing times for common organometallic reactions. This novel approach is benchmarked against several commercially available mixers with respect to the mixing time at low flow rates, showing that the gear pumps can achieve fast mixing (< 50 ms) even at <1 mL/min. To assess the crucially important factor of time to blockage in a consistent manner, a novel protocol is developed based on the controlled precipitation of lithium salts during the mixing process. This shows that the gear pump is significantly more robust than common mixers as operation can be maintained for over 2 h. Lastly, we highlight that the microannular gear pump approach allows the manipulation of mixing time at equal residence time, by tuning the rotation speed, thus allowing for characterization of the mixing sensitivity of reactions. Taken together, our multiparametric analysis of common mixing approaches highlights that the usage of microannular gear pumps for active mixing of fast organometallic reactions presents a powerful alternative able to address current limitations of organic process development

Reaction Calorimetry in continuous flow mode. A new approach for the thermal characterization of high energetic and fast reactions

A new method for the calorimetric characterization of high-energetic, fast reactions in flow mode has been developed. The use of an engineered flow reactor in combination with a process modelling software allowed the deconvolution of the reaction enthalpy from space-resolved temperature profiles. The new procedure was verified in a comparison with a conventional batch calorimeter and subsequently implemented for the thermal characterization of an organolithium flow process. The information collected for this reaction successfully supported a scale-up to the pilot plant. Overall, the new approach resulted to be superior when compared with established procedures, enabling the generation of precise calorimetric data in an accurate scale-down flow device

Continuous manufacturing as an enabling tool with green credentials in early-phase pharmaceutical chemistry

The paper outlines the application of continuous manufacturing to hazardous chemistries, with particular application to early-phase pharmaceutical chemistry. Three case studies are shared with a view to highlighting the factors which render continuous flow setups a suitable tool for minimizing risk within exothermic and unstable chemistries. In each case the evolution of the chemical process from gram scale in discovery chemistry to kilogram scale in process development is detailed, with emphasis on thermal safety and general health and safety considerations. Process intensification, risk reduction and improved yield are highlighted, supporting continuous manufacturing as an enabling tool in line with green principles