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.

The discovery of new ceramic materials containing Ba-La-Cu oxides in 1986 that exhibited superconducting properties at high temperatures in the range of 35 K or higher, recognized with the Nobel Prize in Physics in 1987, opened a new world of opportunities for nuclear magnetic resonance (NMRs) and magnetic resonance imaging (MRIs) to move away from liquid cryogens. This discovery expands the application of high temperature superconducting (HTS) materials to fields beyond the chemical and medical industries, including electrical power grids, energy, and aerospace. The prototype 400-MHz cryofree HTS NMR spectrometer installed at Amgen's chemistry laboratory has been vital for a variety of applications such as structure analysis, reaction monitoring, and CASE-3D studies with RDCs. The spectrometer has been integrated with Amgen's chemistry and analytical workflows, providing pipeline project support in tandem with other Kinetic Analysis Platform technologies. The 400-MHz cryofree HTS NMR spectrometer, as the name implies, does not require liquid cryogens refills and has smaller footprint that facilitates installation into a chemistry laboratory fume hood, sharing the hood with a process chemistry reactor. Our evaluation of its performance for structural analysis with CASE-3D protocol and for reaction monitoring of Amgen's pipeline chemistry was successful. We envision that the HTS magnets would become part of the standard NMR and MRI spectrometers in the future. We believe that while the technology is being developed, there is room for all magnet options, including HTS, low temperature superconducting (LTS) magnets, and low field benchtop NMRs with permanent magnets, where utilization will be dependent on application type and costs. High temperature superconducting (HTS) ceramic materials provide magnets with liquid cryogen-free working environment, no need of oxygen sensors and exhaust ventilation system, reducing the magnet footprint compared to low temperature superconducting (LTS) magnets, reducing long-term maintenance costs, and enabling installation at smaller facilities. In this mini review, we describe the work successfully done with the prototype 400-MHz HTS cryogen-free spectrometer, installed in the fume hood of a chemistry laboratory, for structure elucidation, reaction monitoring, and computer-assisted 3D structure elucidation (CASE 3D). image

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.

Herein, a novel route to atropisomeric N-arylquinolones with low rotational barriers is demonstrated, leveraginga dual photochemical/organocatalytic approach to the required ringclosure in up to 94% yield and up to >99% ee. The use of a continuousflow system allows for impurity suppression and enables rapid scale-upto a decagram scale.

Monitoring the reaction progress of biphasic reaction mixtures has long presented a significant challenge to modern analytical techniques. While a multitude of widely utilized chemical transformations have been performed under such conditions, in-line separation and analysis of each phase have not been possible, inhibiting detailed kinetic and mechanistic studies of these important processes. Herein, we disclose a novel sampling technology capable of accurately monitoring reaction progress in biphasic mixtures using online high-performance liquid chromatography (HPLC) and multinuclear flow nuclear magnetic reso-nance (NMR) spectroscopy. A biphasic sampling platform was devel-oped to circulate a single phase of a biphasic reaction mixture for anal-ysis using these techniques. The utility of this methodology was demonstrated through analysis of boronic acid distribution and specia-tion under basic conditions as well as for monitoring the reaction prog-ress of a biphasic Suzuki-Miyaura cross-coupling.

Our laboratory has recently reported the highly efficient and chemoselective ipso nitration of aryl boronic acids using fuming nitric acid as the nitrating agent. Herein, we disclose and discuss the hazards associated with this reaction and the safety considerations that must be accounted for when increasing the scale of this process. Reaction Calorimetry was used to accurately determine reaction progress and revealed that careful, substrate-dependent selection of an appropriate reaction and reagent concentration and accurate titration of HNO3 are required to allow for safe and scalable use of this nitration process.

The process to manufacture sotorasib (AMG 510) employs a Suzuki-Miyaura reaction as a key step in the synthetic sequence. Detailed kinetic and mechanistic investigations into this process were utilized to identify the active catalytic species and rate-determining step, rationalizing current procedural requirements and process limitations. This knowledge was applied to demonstrate that simple alteration of the base (from KOAc to K2CO3) provided significant process improvements by shifting the rate-determining step and transmetalation pathways. Kinetic modeling was utilized for parameter optimization and resulted in significant reductions in both the Pd catalyst loading and equivalents of boronic acid as well as removing the requirement for slow reagent dosing. This report highlights the distinct mechanistic pathways that may occur upon alteration of the base in Suzuki- Miyaura coupling reactions.

An organocatalyzed, formal (3+3) cycloaddition reaction is described for the practical synthesis of substituted pyridines. Starting from readily available enamines and enal/ynal/enone substrates, the protocol affords tri- or tetrasubstituted pyridine scaffolds bearing various functional groups. This method was demonstrated on a 50 g scale, enabling the synthesis of 2-isopropyl-4-methylpyridin-3-amine, a raw material used for the manufacture of sotorasib. Mechanistic analysis using two-dimensional nuclear magnetic resonance (NMR) spectrometry revealed the transformation proceeds through the reversible formation of a stable reaction off-cycle species that precedes pyridine formation. In situ reaction progress kinetic analysis and control NMR studies were employed to better understand the role of FeCl3 and pyrrolidine hydrochloride in promoting the reaction.

The development of a photochemical bromination/alkylation sequence as part of a continuous process for the synthesis of an intermediate en route to AMG 423 is discussed. Highlights of this continuous process include a significant reduction in reaction time and the elimination of aqueous waste streams. Also discussed are mechanistic and kinetic studies offering insights into notable features of the photochemical bromination.

The ipso nitration of aryl boronic acid derivatives has been developed using fuming nitric acid as the nitrating agent. This facile procedure provides efficient and chemoselective access to a variety of aromatic nitro compounds. While several activating agents and nitro sources have been reported in the literature for this synthetically useful transformation, this report demonstrates that these processes likely generate a common active reagent, anhydrous HNO3. Kinetic and mechanistic studies have revealed that the reaction order in HNO3 is >2 and indicate that the •NO2 radical is the active species.

The evolution of homochirality via attrition-enhanced deracemization (AED) of enantiomorphic solids is carried out using molecules that differ only in the isotopic composition of a phenyl group positioned remote from the chiral center. Enantioenrichment consistently favors the enantiomorph containing a deuterated phenyl group over the protio or 13C version, and the protio version is consistently favored over the 13C version. While these isotopic compounds exhibit identical crystal structures and solubilities, the trend in deracemization correlates with melting points. Understanding the origin of this isotope bias provides fundamental clues about overcoming stochastic behavior to direct the stereochemical outcome in attrition-enhanced deracemization processes. The energy required for breaking symmetry with chiral bias is compared for this near-equilibrium AED process and the far-from-equilibrium Soai autocatalytic reaction. Implications for the origin of biological homochirality are discussed.

During development of a radical benzylic bromination, observation of polymerized byproducts and variation in isolated yields warranted an in-depth mechanistic investigation to ensure process understanding and robustness. In situ kinetic studies using multinuclear CryoFree NMR spectroscopy revealed molecular bromine to be the active brominating species and variable time normalization analysis allowed accurate determination of the order of each reagent in this process. These kinetic studies allowed for accurate reaction modeling and were used to demonstrate that adoption of a simple procedural change ensured reliability and reproducibility during manufacturing.

A one-pot, four-component Pd-catalyzed coupling has been developed for the synthesis of unsymmetrical 1,2-diketones from aryl halides and alkyl zincs employing tert-butyl isocyanide as a CO source. The intermediate 1,2-diketones have been elaborated to quinoxalines. Mechanistic studies help to rationalize the high selectivity for the bis- vs monoinsertion product.

The first catalytic kinetic resolution by N-sulfonylation is described. 2-Substituted indolines are resolved (s=2.6-19) using an atropisomeric 4-dimethylaminopyridine-N-oxide (4-DMAP-N-oxide) organocatalyst. Use of 2-isopropyl-4-nitrophenylsulfonyl chloride is critical to the stereodiscrimination and enables facile deprotection of the sulfonamide products with thioglycolic acid. A qualitative model that accounts for the stereodiscrimination is proposed.

1-Methylimidazole 3-N-oxide (NMI-O) crystallizes as a monohydrate, C4H6N2O·H2O, in the monoclinic space group P21 with Z′ = 2 (molecules A and B). The imidazole rings display a planar geometry (r.m.s. deviations = 0.0008 and 0.0002 Å) and are linked in the crystal structure into infinite zigzag strands of ...NMI-O(A)...OH2...NMI-O(B)...OH2... units by O—H...O hydrogen bonds. These chains propagate along the b-axis direction of the unit cell.

AbstractThe article describes the preparation of 1‐methylimidazole‐N‐oxide.N‐heterocycles were generally more efficient than theirN‐oxide analogues in the acylation process,N‐oxides were generally more active for the sulfonylation and silylation of alcohol derivatives. In particular, 1‐methylimidazole‐N‐oxide (NMI‐O) was found to be a highly efficient catalyst both for sulfonylation and silylation. NMI‐O was found to be the only amine orN‐oxide Lewis basic organocatalyst capable of promoting the efficient silylation of tertiary alcohol derivatives with low catalyst loading (2.5 mol%) and under mild reaction conditions.

A comparison of the relative catalytic efficiencies of Lewis-basic amines vs. N-oxides for the acylation, sulfonylation and silylation of primary, secondary and tertiary alcohols is reported. Whilst the amines are generally superior to the N-oxides for acylation, the N-oxides are superior for sulfonylation and silylation. In particular, 1-methylimidazole N-oxide (NMI-O) is found to be a highly efficient catalyst for sulfonylation and silylation reactions. To the best of our knowledge, NMI-O is the first amine or N-oxide Lewis basic organocatalyst capable of promoting the efficient silylation of tertalcohols in high yield with low catalyst loading under mild reaction conditions.

Phosphorylation of alcohols by phosphoryl chlorides catalysed by pyridine-N-oxide is reported. The utility of this method is demonstrated through phosphorylation of primary, secondary and a tertiary alcohol as well as phenols under mild reaction conditions and with low catalyst loading (5 mol%).

The chemoselective phosphorylation of hydroxyl containing amino acid derivatives and polyols by phosphoryl chlorides catalyzed by 2-aryl-4-(dimethylamino)pyridine-N-oxides is described.