Herein, we report the development of an integrated continuous manufacturing (CM) process for the penultimate step in the synthesis of apremilast, the drug substance (DS) of the commercial product Otezla. This development effort was motivated by the desire to create an alternative manufacturing configuration with a significantly smaller footprint and to impart intensification resulting in a more sustainable process. Three primary aspects of the existing batch process had to be addressed to achieve this goal: (1) long reaction time, (2) low solubility of the starting materials and intermediates in the primary reaction solvent (THF), and (3) extensive postreaction unit operations contributing to significant solvent waste. Key features of the intensified CM process include the following: (1) use of a plug-flow reactor (PFR) to access increased reaction temperatures (130 °C), resulting in a shorter reaction time to reach the target conversion (>18 h in batch to 30 min in flow); (2) replacement of THF with DMSO to solve solubility issues related to starting materials and reaction intermediates, and (3) development of a multistage continuous MSMPR (mixed-suspension, mixed-product removal) crystallization upon addition of water as antisolvent to the end-of-reaction stream containing apremilast. This intensified CM process reduced the number of primary unit operations from nine to three (67% reduction). Moreover, it can be executed at commercial scale using a compact manufacturing skid. Part I of this manuscript series highlights the effort to develop the novel process and the corresponding kg-scale demonstration of the optimized process. Part II describes the process characterization and development of a control strategy in detail to ensure process efficiency and robustness of the small-footprint continuous skid.

A robust and scalable Cu-I-catalyzed diastereoselective vinylation of an aliphatic aldehyde was developed to enable clinical supply of investigational Mcl-1 inhibitors in our oncology pipeline. Through process design and impurity control, a telescoped process consisting of a benzotriazole salt break and diastereoselective vinylation was developed. This process eliminated the need to perform distillation operations, improved reaction performance and efficiency, and was successfully scaled to >100 kg.

This is Part II of a series on the development and characterization of an integrated continuous manufacturing (CM) process developed for the penultimate step in the synthesis of the drug substance Apremilast (Otezla). Part I gives the development history and highlights the achieved process intensification. Here, we describe the process characterization (PC) undertaken. In doing so, we point out aspects of characterization that are unique to an integrated CM process and give our strategy for navigating PC in this scenario. Moreover, we provide data that support a robust control strategy which relies on parametric control only (i.e., no in-process controls) followed by batch release of the produced Apremilast drug substance intermediate. Such a control strategy is advantageous as it minimizes divert-to-waste loss and operational costs.

In this article, we describe the process development efforts to improve the final methylation step in the AMG 397 drug substance process, culminating in the execution of a Good Manufacturing Practice (GMP) continuous manufacturing process. During the development, batch kinetic studies and detailed NMR analysis of the final step identified that rapid base addition and the presence of stoichiometric water were critical to ensure consistent levels of reaction conversion and to obtain the desired active pharmaceutical ingredient (API) in high purity. As a result, a continuous process was developed to facilitate the rapid base addition and short deprotonation residence time, ensuring reliable process performance on a multi-kilogram scale. The AMG 397 GMP manufacture, comprised of the continuous reaction process and semi-batch isolation, delivered the final API in high purity (>99%) and yield (76%), exceeding the API specifications. The lessons learned from the manufacturing campaign, which include equipment clogging and loss of tubing integrity, are discussed and drove the development of a second-generation continuous process to improve reaction processing for future deliveries. The second-generation process has not encountered the challenges of the GMP campaign due tothe implementation of important equipment modifications, and the improved processhas been successfully demonstrated on a 100 g scale.

Epoxyketone 4 is an isolated intermediate in the manufacturing route to the commercial proteasome inhibitor carfilzomib (Kyprolis). Commercial process development and optimization efforts toward the preparation of epoxyketone 4 highlighted several opportunities for process improvement. In this article, three case studies are presented that demonstrate how a detailed understanding of the reaction mechanism led to improvements that increased the overall robustness of the process. In the first case study, the mechanism of racemization of an alpha-chiral enone was investigated, resulting in the development of an improved aqueous workup procedure. Next, the stability of a bleach/pyridine mixture used for the step 3 epoxidation reaction was studied, leading to the identification of pyridine as a key raw material and improved reaction conditions and control strategy to meet the conversion target. Finally, oxidized butylated hydroxytoluene (oBHT) was identified as an impurity arising from the use of BHT-stabilized tetrahydrofuran in steps preceding the oxidation. The process understanding obtained from these investigations led to the implementation of process improvements that improved the robustness of the process. The development of a second-generation route to 4 is the subject of part 2 in this series (DOI: 10.1021/acs.oprd.0c00052).

The last two decades have provided a large weight of preclinical data implicating the neurokinin-1 receptor (NK1) and its cognate ligand substance P (SP) in a broad range of both central and peripheral disease conditions. However, to date, only the NK1 receptor antagonist aprepitant has been approved as a therapeutic and this is to prevent chemotherapy-induced nausea & vomiting (CINV). The belief remained that the full therapeutic potential of NK1 receptor antagonists had yet to be realized; therefore clinical evidence that NK1 receptor antagonists may be effective in major depression disorder, resulted in a significant further investment in discovering novel CNS penetrant druggable NK1 receptor antagonists to address this condition. At GlaxoSmithKline after the discovery of casopitant, that went on to demonstrate efficacy as a novel antidepressant in the clinic, additional novel analogues of this NK1 receptor antagonist were designed to further enhance its drug developability characteristics. Herein, we therefore describe the discovery process and the vivo pharmacological and pharmacokinetic profile of the new NK1 receptor antagonist 3a (also called orvepitant), selected as clinical candidate and further progressed into clinical studies for major depressive disorder. Moreover, molecular modeling studies enabled us to improve the pharmacophore model of the NK1 receptor antagonists with the identification of a region able to accommodate a variety of heterocycle moieties.

The hypothalamic peptides orexin-A and orexin-B are potent agonists of two G-protein coupled receptors, namely the OX1 and the OX2 receptor. These receptors are widely distributed, though differentially, in the rat brain. In particular, the OX1 receptor is highly expressed throughout the hypothalamus, whilst the OX2 receptor is mainly located in the ventral posterior nucleus. A large body of compelling evidence, both pre-clinical and clinical, suggests that the orexin system is profoundly implicated in sleep disorders. In particular, modulation of the orexin receptors activation by appropriate antagonists was proven to be an efficacious strategy for the treatment of insomnia in man. A novel, drug-like bis-amido piperidine derivative was identified as potent dual OX1 and OX2 receptor antagonists, highly effective in a pre-clinical model of sleep.

Acylation of N-Boc-N-methylhydrazones followed by TFA treatment affords regioselective access to substituted pyrazoles. Both regioisomers of 1-methyl-3,5-disubstituted-1H-pyrazoles can be selectively obtained. This procedure can also be employed for the regioselective preparation of fully substituted 1H-pyrazoles.

An interesting and surprising rearrangement was observed during the reaction of 4-N-benzyl piperazinone derivatives with Lawesson’s reagent as a thionating agent. Investigation into the possible mechanism responsible for these results is reported herein.

Treatment of 2-alkyl pyridine N-oxides with acylating reagents represents an established procedure for the introduction of oxygen functionality into alkyl group at the ortho position of N heteroaromatic rings. We have reported the first example of asymmetric Boekelheide rearrangement applied to a set of 2-alkyl-pyridine N-oxide derivatives using (R) Mosher’s acyl chloride as activator of the rearrangement to give, after hydrolysis, enantiomerically enriched 1-(2-pyridinyl)alkyl alcohol. Diastereoselectivity of the process was studied at low temperatures in different solvents, and was supported by a preliminary in silico modeling.

A pharmacophore model for triple reuptake inhibitors and the new class of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes were recently reported. Further investigation in this area led to the identification of a new series of potent and selective triple reuptake inhibitors endowed with good developability characteristics. Excellent bioavailability and brain penetration are associated with this series of 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanes together with high in vitro potency and selectivity at SERT, NET, and DAT. In vivo microdialysis experiments in different animal models and receptor occupancy studies in rat confirmed that derivative 17 showed an appropriate profile to guarantee further progression of the compound.

An efficient scalable route to synthesize the enantiomerically pure tert-butyl-(1R,4S,6R)-4-(hydrox)methyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate is described. Compared to the original routes, significant improvements were made by using an innovative approach starting from commercially available chiral lactone. In this approach, one of the key steps described is an elegant epimerization/hydrolysis of the undesired diastereoisomer avoiding tedious purification. The chemistry has been scaled up to produce kilogram amounts of tert-butyl-(1R,4S,6R)-4-(hydroxymethyl)-3azabicyclo[4.1.0]heptane-3-carboxylate in 43% yield over nine chemical transformations.

A series of AMPA receptor positive allosteric modulators has been optimized from poorly penetrant leads to identify molecules with excellent preclinical pharmacokinetics and CNS penetration. These discoveries led to 17i, a potent, efficacious CNS penetrant molecule with an excellent pharmacokinetic profile across preclinical species, which is well tolerated and is also orally bioavailable in humans.

Stereochemical and synthetic aspects encountered during the preparation of the four possible isomers of 1 are reported. The 5-aryl 2-azabicyclo [3.2.1] octane derivatives represent a novel class of compounds which can be deemed as an example of aryl-piperidine conformationally constrained of potential interest for medicinal chemistry exploration. In particular isomers of 1 are characterised by a potent in vitro serotonine, dopamine and noradrenaline re-uptake inhibitor (TRUI) activity superior/comparable to standard compounds such as DOV 21,947 and DOV 102,677.