Photoredox Fluorodecarboxylation: Rapid and Reliable Kilogram-scale Access to Drug-like Motifs

Introduction to Photoredox Catalysis

Visible-light photoredox catalysis is extremely powerful and has enabled development of new transformations within organic synthesis [1]. While in the past photochemistry has been considered unfavourable in process chemistry, for example through perceived high costs, safety concerns and difficulties with reproducibility, in recent years there have been significant advances with the use of LED technology and development of modular ‘plug and play’ photochemical appliances. In particular, flow chemistry has proven extremely useful, allowing uniform sample irradiation, excellent temperature control, and the opportunity for reaction automation, facilitating rapid scale-up and library generation [2].

The use of ruthenium and iridium-polypyridyl complexes within photocatalysis is well-established [1] but these metals are scarce and comparatively expensive, therefore their use during scale-up is neither economical nor environmentally sustainable. However, researchers in Process Chemistry at Pharmaron have developed the use of an organic photocatalyst in flow for rapid installation of fluorine into drug-like molecules, at scale, through fluorodecarboxylation [3]. The advantages of organic photocatalysts are that they are environmentally friendly and inexpensive, with a high molar absorption coefficient in the UVA−visible region (380−495 nm) and useful oxidation potential (E_1/2 = +1.50 V vs SCE).

Installation of a fluorine atom to tune a drug candidate’s physicochemical and biological properties has been used by medicinal chemists for decades, with addition of fluorine shown to adjust lipophilic efficiency values, block sites of metabolism, enhance potency and improve pK_a [4]. Installation can be achieved through nucleophilic (e.g. DAST) or electrophilic fluorinating agents (e.g. Selectfluor™), with enantioselective installation also possible [4a]. The use of photoredox catalysis using radical-based fluorodecarboxylation of aliphatic carboxylic acids is a burgeoning research area, with redox-active photocatalysts such as Ir- and Ru-complexes [5], organic dyes [6] and polymeric carbon nitride [7] and all reported. However, the adaption of photoredox fluorodecarboxylation to kilogram scale using an organocatalyst had not been developed up to this point.

Rapid scale-up: Using photo-HTE, DoE and flow chemistry to facilitate expediate pilot production

The team at Pharmaron developed a four-step workflow: photo-HTE, DoE-guided optimization in batch, lab-scale flow assessment and finally, pilot production using a kilogram-scale plug flow photoreactor (PFP). Initial experiments used a 96-well block that allowed rapid screening of 24 photocatalysts, 13 bases (organic and inorganic), and four fluorinating agents. From this, hit conditions were validated on 100 mg scale in a batch photoreactor. Riboflavin was identified as an excellent photocatalyst that was cost-effective and sustainable, and DoE studies were used to fine-tune base loading and fluorinating agent. Optimised conditions were identified, and further control experiments confirmed that the wavelength of the LEDs, base, photocatalyst and Selectfluor™ were all necessary.  A range of commercially available aliphatic carboxylic acids were tested, affording the corresponding alkyl fluorides in good yields (59 – 93%), Figure 1.

Once suitable batch conditions had been identified, conversion of the protocol to make it suitable for flow was undertaken. It was expected that the use of flow would circumvent the drawbacks associated with photochemical transformations under batch conditions and enable significant scale-up of the transformation. However, there were concerns about the potential for reactor fouling as the riboflavin solution was not homogenous. In the event, the use of riboflavin tetrabutyrate (RFTB), a commercially available derivative of riboflavin, gave a fully homogenous solution and was equally effective, maintaining excellent yields.  

Finally, flow chemistry is uniquely suited to address the undesirable background reaction between 2,6-lutidine and Selectfluor™. A two-feed approach, wherein the reagents were prepared in separate vessels before mixing and irradiation in the kilogram-scale PFP setup was successfully implemented. Flow assessment of 1-benzoylpiperidine-4-carboxylic acid (2 g) was successful, and scale-up to 25 g and then 100g was undertaken without incident. At a 100 g scale, a flow-rate of 100 mL/minute gave 99% conversion and 93% yield of the fluorinated material. The final scale-up to 1.5 kg with a ~5 minutes residence time demonstrated excellent conversion (>99%) and yield (92%, 1.23 kg), equating to 6.56 kg per day of throughput, Figure 2.