The History of Flow Chemistry at Eli Lilly and Company.

Flow chemistry was initially used for speed to early phase material delivery in the development laboratories, scaling up chemical transformations that we would not or could not scale up batch for safety reasons. Some early examples included a Newman Kwart Rearrangement, Claisen rearrangement, hydroformylation, and thermal imidazole cyclization. Next, flow chemistry was used to enable safe scale up of hazardous chemistries to manufacturing plants. Examples included high pressure hydrogenation, aerobic oxidation, and Grignard formation reactions. More recently, flow chemistry was used in Small Volume Continuous (SVC) processes, where highly potent oncolytic molecules were produced by fully continuous processes at about 10 kg/day including reaction, extraction, distillation, and crystallization, using disposable equipment contained in fume hoods.

Process Development for a 1H-Indazole Synthesis Using an Intramolecular Ullmann-Type Reaction.

Within the scope of developing a new route to an active pharmaceutical ingredient intermediate, we had need of a fluorinated indazole. Although an established route was in place, it was undesirable due to safety and selectivity concerns. A concise and improved route was developed to form the desired indazole, which takes advantage of an electronically directed metalation/formylation sequence followed by condensation with methyl hydrazine to form a hydrazone and culminates in a copper-catalyzed intramolecular Ullmann cyclization. The Ullmann reaction was plagued with difficulties ranging from poor reactivity to thermal hazard concerns, but use of high-throughput screening, statistical modeling, and an unusual isolation method for fine chemicals, safe and optimal conditions were found that produce high-purity isolated material in excellent yields at a laboratory scale.

Visible Light Mediated Aryl Migration by Homolytic C-N Cleavage of Aryl Amines.

The photocatalytic preparation of aminoalkylated heteroarenes from haloalkylamides via a 1,4-aryl migration from nitrogen to carbon, conceptually analogous to a radical Smiles rearrangement, is reported. This method enables the substitution of amino groups in heteroaromatic compounds with aminoalkyl motifs under mild, iridium(III)-mediated photoredox conditions. It provides rapid access to thienoazepinone, a pharmacophore present in multiple drug candidates for potential treatment of different conditions, including inflammation and psychotic disorders.

Continuous flow technology vs. the batch-by-batch approach to produce pharmaceutical compounds.

INTRODUCTION: For the manufacture of small molecule drugs, many pharmaceutical innovator companies have recently invested in continuous processing, which can offer significant technical and economic advantages over traditional batch methodology. This Expert Review will describe the reasons for this interest as well as many considerations and challenges that exist today concerning continuous manufacturing. Areas covered: Continuous processing is defined and many reasons for its adoption are described. The current state of continuous drug substance manufacturing within the pharmaceutical industry is summarized. Current key challenges to implementation of continuous manufacturing are highlighted, and an outlook provided regarding the prospects for continuous within the industry. Expert commentary: Continuous processing at Lilly has been a journey that started with the need for increased safety and capability. Over twelve years the original small, dedicated group has grown to more than 100 Lilly employees in discovery, development, quality, manufacturing, and regulatory designing in continuous drug substance processing. Recently we have focused on linked continuous unit operations for the purpose of all-at-once pharmaceutical manufacturing, but the technical and business drivers that existed in the very beginning for stand-alone continuous unit operations in hybrid processes have persisted, which merits investment in both approaches.

Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions.

Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.

Reagent-free continuous thermal tert-butyl ester deprotection.

Continuous processing enables the use of non-standard reaction conditions such as high temperatures and pressures while in the liquid phase. This expands the chemist's toolbox and can enable previously unthinkable chemistry to proceed with ease. For a series of amphoteric amino acid derivatives, we have demonstrated the ability to hydrolyze the tert-butyl ester functionality in protic solvent systems. Using a continuous plug flow reactor at 120-240°C and 15-40min reaction times, no pH modification or additional reagents are needed to achieve the desired transformation. The method was then expanded to encompass a variety of more challenging substrates to test selectivity and racemization potential. The acid products were generally isolated as crystalline solids by simple solvent exchange after the deprotection reaction in good to high yield and purity.

Photochemical Perfluoroalkylation with Pyridine N-Oxides: Mechanistic Insights and Performance on a Kilogram Scale.

The direct trifluoromethylation of (hetero)arenes is a process of high importance to the pharmaceutical industry. Many reagents exist for this purpose and have found widespread use in discovery efforts; however, the step-intensive preparation of these reagents and their corresponding cost have resulted in minimal use of these methods in large-scale applications. For the ready transition of direct trifluoromethylation methodologies to large-scale application, the further development of processes utilizing inexpensive CF3 sources available on a metric ton scale is highly desirable. We report the use of pyridine N-oxide derivatives in concert with trifluoroacetic anhydride to promote a high-yielding and scalable trifluoromethylation reaction. Key mechanistic insights include the observation of electron donor-acceptor complexes in solution as well as a high dependence on photon flux. These observations have culminated in the application of this chemistry on a kilogram scale, demonstrating the utility of this reagent combination for preparative applications.

A Visible-Light-Mediated Radical Smiles Rearrangement and its Application to the Synthesis of a Difluoro-Substituted Spirocyclic ORL-1 Antagonist.

A visible-light-mediated radical Smiles rearrangement has been developed to address the challenging synthesis of the gem-difluoro group present in an opioid receptor-like 1 (ORL-1) antagonist that is currently in development for the treatment of depression and/or obesity. This method enables the direct and efficient introduction of the difluoroethanol motif into a range of aryl and heteroaryl systems, representing a new disconnection for the synthesis of this versatile moiety. When applied to the target compound, the photochemical step could be conducted on 15 g scale using industrially relevant [Ru(bpy)3Cl2] catalyst loadings of 0.01 mol %. This transformation is part of an overall five-step route to the antagonist that compares favorably to the current synthetic sequence and demonstrates, in this specific case, a clear strategic benefit of photocatalysis.

A scalable and operationally simple radical trifluoromethylation.

The large number of reagents that have been developed for the synthesis of trifluoromethylated compounds is a testament to the importance of the CF3 group as well as the associated synthetic challenge. Current state-of-the-art reagents for appending the CF3 functionality directly are highly effective; however, their use on preparative scale has minimal precedent because they require multistep synthesis for their preparation, and/or are prohibitively expensive for large-scale application. For a scalable trifluoromethylation methodology, trifluoroacetic acid and its anhydride represent an attractive solution in terms of cost and availability; however, because of the exceedingly high oxidation potential of trifluoroacetate, previous endeavours to use this material as a CF3 source have required the use of highly forcing conditions. Here we report a strategy for the use of trifluoroacetic anhydride for a scalable and operationally simple trifluoromethylation reaction using pyridine N-oxide and photoredox catalysis to affect a facile decarboxylation to the CF3 radical.

Ligand functionalization as a deactivation pathway in a fac-Ir(ppy)3-mediated radical addition.

Knowledge of the kinetic behavior of catalysts under synthetically relevant conditions is vital for the efficient use of compounds that mediate important transformations regardless of their composition or driving force. In particular, these data are of great importance to add perspective to the growing number of applications of photoactive transition metal complexes. Here we present kinetic, synthetic, and spectroscopic evidence of the mechanistic behavior of fac-Ir(ppy)3 in a visible light-mediated radical addition to 3-methylindole, demonstrating the instability of fac-Ir(ppy)3 under these conditions. During the reaction, rapid in situ functionalization of the photocatalyst occurs, eventually leading to deactivation. These findings demonstrate a conceivable deactivation process for catalytic single electron reactions in the presence of radicophilic ligands. Attempts to inhibit photocatalyst deactivation through structural modification provide further insight into catalyst selection for a given system of interest.

Photoredox catalysis in a complex pharmaceutical setting: toward the preparation of JAK2 inhibitor LY2784544.

We report a detailed investigation into the application of visible light-mediated photocatalysis to a challenging bond construction in a complex pharmaceutical target. The optimized reaction allowed the direct coupling of N-methylmorpholine with an unfunctionalized pyridazine in good yield and selectivity, and with high purity of the product isolated via crystallization. The reaction also facilitated the expedient synthesis of a range of analogues via the use of other commercially available N-methyl substituted tertiary amines, and therefore it represents an attractive tool for medicinal chemistry. Furthermore, a number of other interesting photoredox reactions were discovered during the course of this investigation, such as a formal methylation reaction via C-N bond cleavage, functionalization of C-H bonds alpha to amides, and a visible light-mediated iminium ion reduction.

Total synthesis of (±)-phomactin A. Lessons learned from respecting a challenging structural topology.

Our struggles and ultimate success in achieving a total synthesis of phomactin A are described. Our strategy features an intramolecular oxa-[3 + 3] annulation to construct its unique ABD-tricyclic manifold. Although the synthesis would constitute a distinctly new approach with the 12-membered D-ring of phomactin A being assembled simultaneously with the 1-oxadecalin at an early stage, the ABD-tricycle represents a unique structural topology that would pose a number of unprecedented challenges. One challenge concerned elaborating this tricycle to have oxygenation at the proper carbon atoms. To overcome this, we would utilize a Kornblum-DeLaMare ring-opening of a peroxide bridge as well as a challenging late-stage 1,3-allylic alcohol transposition. Further, the structural intricacies of the ABD-tricycle were uncovered by a conformational analysis that would be critical for the C5a-homologation.

Constructing the Architecturally Distinctive ABD-Tricycle of Phomactin A through an Intramolecular Oxa-[3 + 3] Annulation Strategy.

Our efforts in constructing the ABD-ring of phomactin A through an intramolecular oxa-[3 + 3] annulation strategy is described. This struggle entailed finding a practical and efficient preparation of annulation precursor, and a realization of the unexpected competing regioisomeric pathway. The success entailed accessing the A-ring through Diels-Alder cycloaddition of Rawal's diene. Furthermore, the discovery that the regioisomers from the annulation existed as atropisomers with respect to the D-ring olefin and that they could be equilibrated to the desired ABD-tricycle, allowing large quantities of tricycle to be accessed.

Total synthesis of phomactin A.

A total synthesis of (+/-)-phomactin A is described to highlight the final completion of a complex natural product target that had commenced with an intramolecular oxa-[3 + 3] annulation strategy in the construction of the ABD-tricycle. These efforts reveal structural intricacies of this ABD-tricycle with an illustrative example being the conformational analysis that was ultimately critical for the C5a-homolgation.

Chemical Synthesis of the GHIJKLMNO Ring System of Maitotoxin.

As the largest secondary metabolite to be discovered as of yet, the polyether marine neurotoxin maitotoxin constitutes a major structural and synthetic challenge. After its originally proposed structure ( 1) had been questioned on the basis of biosynthetic considerations, we provided computational and experimental support for structure 1. In an effort to provide stronger experimental evidence of the molecular architecture of maitotoxin, its GHIJKLMNO ring system 3 was synthesized. The (13)C NMR chemical shifts of synthetic 3 matched closely those corresponding to the same domain of the natural product providing strong evidence for the correctness of the originally proposed structure of maitotoxin ( 1).

An Enantioselective Synthesis of the ABD Tricycle for (-)-Phomactin A Featuring Rawal's Asymmetric Diels-Alder Cycloaddition.

An enantioselective synthesis of the ABD-ring of (-)-phomactin A is described here. The sequence features Rawal's asymmetric Diels-Alder cycloaddition. The overall length is significantly reduced from our previous attempt.

An Enantioselective Synthesis of the ABD Tricycle for (-)-Phomactin A Featuring Rawal's Asymmetric Diels-Alder Cycloaddition.

An enantioselective synthesis of the ABD-ring of (-)-phomactin A is described here. The sequence features Rawal's asymmetric Diels-Alder cycloaddition. The overall length is significantly reduced from our previous attempt.

Total synthesis of marinomycins A-C and of their monomeric counterparts monomarinomycin A and iso-monomarinomycin A.

Marinomycins A-C (1-3), and their monomeric analogues monomarinomycin A (m-1) and iso-monomarinomycin A (m-2), were synthesized by a convergent strategy from key building blocks ketophosphonate 5, aldehyde 6, and dienyl bromide carboxylic acid 7. The first attempt to construct marinomycin A [1, convertible to marinomycins B (2) and C (3) by light] by direct Suzuki-type dimerization/cyclization of boronic acid dienyl bromide 4 led to premature ring closure to afford, after global desilylation, monomarinomycin A (m-1) and iso-monomarinomycin A (m-2) in good yield and only small amounts (< or =2%) of the desired product. A subsequent stepwise approach based on Suzuki-type couplings improved considerably the overall yield of marinomycin A (1), and hence of marinomycins B (2) and C (3). Alternative direct dimerization approaches based on the Stille and Heck coupling reactions also led to monomarinomycins A (m-1 and m-2), but failed to deliver useful amounts of marinomycin A (1).