Abstract A multikilogram-scale, scalable, and cGMP-compliant synthesis of 4-aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid (TM), a key intermediate for the MTA-cooperative PRMT5 inhibitor GTA182, has been developed to address the limitations of the original medicinal chemistry route. The initial synthesis suffered from poor reproducibility, cumbersome workups, and a high-pressure carbonylation step that introduced equipment constraints and elevated metal residues, creating a supply bottleneck for early clinical development. The redesigned route starts from commercially available 3-fluoro-4-nitrobenzoic acid (SM6), a low-cost commodity chemical, and proceeds through seven steps, including a continuous-flow amination and chromatography-free purifications. This approach improves the overall yield from 7% to 24%, eliminates the need for specialized high-pressure equipment, and ensures metal residues are compliant with ICH guidelines. The process has been successfully demonstrated on a multikilogram scale under cGMP conditions, enabling reliable supply of TM to support ongoing early-stage clinical studies of GTA182.
Abstract Reversible addition–fragmentation chain transfer (RAFT) polymerization is a key tool in modern macromolecular design. Central to its success is the availability of versatile chain transfer agents (CTAs), typically based on thiocarbonylthio compounds. Herein, we report a refined, scalable, and high-yield synthesis of a family of trithiocarbonate RAFT agents based on a propanoic acid leaving group, mimicking the propagating radical of acrylic acid, which permits efficient mediation of the polymerization of a wide range of monomers. We report the synthesis of 2-{[(butylsulfanyl)carbonothioyl]sulfanyl}propanoic acid (BPTC), commonly known as (Propanoic Acid)yl Butyl TrithioCarbonate (PABTC), a highly oil-soluble derivative, 2-{[(dodecylsulfanyl)carbonothioyl]sulfanyl}propanoic acid (DoPAT), and a highly water-soluble derivative, 3-[[[(1-carboxyethyl)thio]carbonothioyl]thio]propanoic acid (CETCP). By optimizing the aqueous-based reaction conditions, we achieved yields of 80% or higher of high-purity products across all three derivatives on a tens of grams scale, without the necessity of intensive organic solvent extraction or multiple recrystallization steps.
Abstract Efficient and scalable methods for the C3 acylation of 2-arylindoles remain limited despite the importance of 3-acyl-2-arylindoles as versatile intermediates in medicinal and synthetic chemistry. Herein, a practical Vilsmeier–Haack acylation protocol employing readily available N,N-dialkylamides and phosphorus oxychloride is described. Systematic reaction optimization identified conditions that provide highly regioselective C3 acylation across a broad range of 2-arylindoles and acylating agents, affording the corresponding products in high isolated yields without chromatographic purification. The operational simplicity of the method, together with its broad functional-group tolerance and gram-scale applicability, makes it a practical alternative to conventional acylation protocols. The synthetic utility of the resulting 3-acyl-2-arylindoles was demonstrated by concise syntheses of representative fused indole heterocycles related to biologically active alkaloids, including fluorescent indoloquinoline, indoloisoquinoline, and carbazole derivatives.
Abstract There is a growing trend in the pharmaceutical industry toward the adoption of continuous processing for the synthesis of active pharmaceutical ingredients (APIs) and intermediates. This enables access to novel synthetic routes by operating at high temperatures and high pressures. Hydrogenation is a key transformation that particularly benefits from continuous processing, offering enhanced volumetric productivity and improved safety profiles. This study presents the development and scale-up of a continuous hydrogenation process, progressing from bench scale to pilot plant operation while addressing challenges associated with material limitations. The scale-up achieved a production rate of 12 kg/day for a pharmaceutical intermediate, with online HPLC employed for real-time process monitoring at both scales. Additionally, this work offers a strategic framework for catalyst selection in continuous hydrogenation and provides a scale-up methodology that can be readily applied when material constraints are present in pharmaceutical manufacturing.
A new cell design for the electrochemical reductive cleavage of l-cystine to l-cysteine has been presented. The so-called alluvial cell exploits the low solubility of l-cystine as a substrate by reducing a cystine suspension at a porous cathode, dissolving only small quantities of the substrate and separating the fully dissolved product by filtration. This setup avoids corrosive, highly concentrated acidic electrolyte systems, which is beneficial for the lifetime of the plant and improves the energy efficiency of the process. Additionally, several alloys were established as novel electrode materials suitable for the electroconversion of cystine. The alluvial cell achieved an almost quantitative yield of l-cysteine upon optimization and was scaled up to a small pilot range, highlighting its technical relevance.
We have previously clearly identified atmospheric nitrogen oxides (NOx) as a key factor in nitrosamine contamination in pharmaceuticals. To implement more appropriate countermeasures, the nitrosation potential of nitrogen monoxide (NO) and nitrogen dioxide (NO2)the primary components of NOxwas evaluated using short-term and long-term gas flow model experiments. The results revealed that NO2 is required for the nitrosation reaction to occur.
Inline Raman spectroscopy-based monitoring enables the development of control systems that allow the implementation of Process Analytical Technology (PAT) principles even in chemical reactions, thereby improving quality, efficiency, and safety. There are only a few articles in the literature that discuss such control systems. This may be due to the numerous challenges involved, including the need for robust measurement setups and the development of chemometric algorithms capable of delivering accurate and stable real-time evaluations. Thus, this study presents the Raman spectroscopic monitoring and chemometric-based feedback control of a highly exothermic and potentially hazardous diazotization reaction, namely, the synthesis of phenyldiazonium chloride from aniline, hydrochloric acid, and sodium nitrite. Raman spectra were analyzed offline using Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) and in real-time using Classical Least Squares (CLS) chemometric methods to monitor and control key reaction components. The developed feedback system successfully controlled concentration levels during both acid-base and diazotization phases. The reduction of the Raman signal-to-noise ratio, induced by the decomposition of the diazonium salt, was also observed. This factor significantly affected the monitoring of the diazotization experiment. Furthermore, a calibration was established to quantify the molar concentrations of key components based on Raman spectra. The calibration experiment successfully demonstrated well-fitted linear molar-spectral relationships for both aniline (R 2 homogeneous = 0.997; R 2 heterogeneous = 0.9947) and aniline hydrochloride (R 2 = 0.9987). For aniline, the molar-spectral relationship exhibited a distinct change in tendency that precisely correlated with its solubility limit in water, marking the transition from homogeneous solution to emulsion.
A robust and enabling synthesis of a sterically encumbered 4-substituted piperidine, a common motif in a novel KRAS G12C inhibitor series, was developed. It was discovered that the critical congested C–C bond could be forged by the regioselective addition of a functionalized Grignard reagent to an N-carbamyl pyridinium species. Kinetic studies demonstrated that the Grignard species was inherently unstable, leading to diminished yields in large-scale batch processes. A semicontinuous reactor train was developed to generate the Grignard continuously using a plug flow reactor, which flowed directly into a stirred reactor containing the preformed pyridinium species. This system was utilized to produce >100 g quantities of the Grignard adduct in a single operation, which could be converted to the desired 4-substituted piperidine in two additional steps. Further studies determined that regioselectivity was governed by the steric environment of the nucleophilic Grignard species.
We developed a headspace gas chromatography method with flame ionization detection (HSGC-FID) for trace nitrite determination in pharmaceutical excipients. The approach reacts nitrite with sodium cyclamate to generate cyclohexene, enabling sensitive detection by flame ionization detector (FID) on a nonpolar G27 column (e.g., Rtx-5). Key method performance characteristics including sensitivity, accuracy, and specificity were established. The limit of quantitation is 0.2 ng/mL, corresponding to 10 ng/g for common excipients with a sample concentration of 20 mg/mL and 2 ng/g for low-nitrite excipients such as microcrystalline cellulose and dibasic calcium phosphate with a sample concentration of 100 mg/mL. Achieving this sensitivity required a novel procedure to minimize nitrite contamination in the blank, a common challenge in nitrite analysis. For excipients with significant matrix effects (e.g., magnesium stearate, sodium lauryl sulfate, and HPMCAS), cyclohexane is used as an internal standard to achieve the desired accuracy. To address the limited selectivity of FID, an orthogonal confirmation method employing a polar G16 column (e.g., DB-Wax) can be used to resolve interferences from residual solvents on a G27 column. The method was validated in accordance with ICH Q2(R2) and applied to more than 20 commonly used excipients. The range is 10 ng/g to 5000 ng/g by successfully meeting acceptance criteria for linearity (R ≥ 0.99), spiked recovery (100 ± 30%), and precision (% RSD ≤ 10%). Given its high sensitivity on common HSGC-FID instrumentation, the method is readily transferable to QC laboratories for routine nitrite testing in pharmaceutical excipients.
Process mass intensity (PMI) and complete E-factor (cEF) are widely accepted metrics for evaluating the sustainability of chemical processes, yet their routine application in peptide synthesis remains limited. This is primarily due to the perceived complexity and time required for mass accounting across repetitive coupling/deprotection cycles and solvent-intensive operations characteristic of both SPPS and LPPS. In this work, we present a simplified and practical approach for the rapid calculation of PMI and cEF specifically tailored to peptide synthesis workflows. The method is implemented through a user-friendly Excel-based tool that converts routinely recorded experimental parameters such as reaction scale, resin loading/tag, reagent, and solvent consumption into quantitative sustainability metrics using built-in formulas. The streamlined workflow allows PMI and cEF to be calculated within minutes without the need for specialized software or extensive additional data collection. By lowering the barrier to quantitative sustainability assessment, this method facilitates the routine inclusion of green metrics in method development, process optimization, and reporting. Importantly, the approach is equally relevant to academic and industrial laboratories, supporting informed decision-making and fostering the broader adoption of sustainability principles in peptide synthesis.
Discovery Process Chemistry (DPC) has emerged as a critical bridge between discovery chemistry and chemical development that allows more seamless progression of drug candidates to the clinic. DPC aims to accelerate projects by integrating SAR-enabling methodologies, scalable route design to inform later campaigns, and early material delivery. Case studies from MSD, Johnson & Johnson, and AstraZeneca highlight how this model can drive innovation and mitigate risks at the interface between medicinal and process chemistry groups. Keywords: discovery process, route scouting, early scale-up, and SAR enabling.
The target compound danuglipron belongs to a family of glucagon-like peptide-1 receptor agonist (GLP-1RA) candidates identified in the Pfizer laboratories for the treatment of type 2 diabetes mellitus and obesity. This article describes a development approach providing a data-centric, holistic methodology toward process design. The approach starts with rapid collection and generation of fundamental data through high-throughput experimentation (HTE), followed by lead evaluation, narrowing process options, and concluding with lead process confirmation. This systematic strategy identifies the most efficient process options, anticipates process sensitivities, removes unconscious bias in decision making, leading to fewer process iterations, and identifies an optimal process. By adopting this approach to danuglipron, a new 5-step process was developed, removing two unnecessary process steps, increasing the yield from 34 to 64%, and reducing PMI from 231 to 73 kg/kgA while being scaled at multiple facilities to generate metric tons of clinical-grade danuglipron.
Amorphous solid dispersion (ASD) manufacturability is constrained by active pharmaceutical ingredient physicochemical properties; high melting point (T m) and high glass transition temperature (T g) limit hot-melt extrusion (HME), and low organic solubility limits spray-drying (SD) throughput. We evaluated lipophilic counterion choice as a solid-state design lever to enable ASD manufacturability by SD or HME. Nine lipophilic salts of atazanavir (ATZ) and mebendazole (MBZ) were prepared with sulfate and sulfonate counterions spanning a range of chain lengths and steric bulk, and characterized by 1H nuclear magnetic resonance spectroscopy, powder X-ray diffraction, differential scanning calorimetry, and polarized light microscopy. Lipophilic salts showed T m and T g reductions relative to their free base, with T g reductions of up to approximately 30 °C. Organic solubility in ethanol, acetone, and tetrahydrofuran improved 2–15× or greater across most salt-solvent combinations. Vacuum compression molding confirmed that a representative lipophilic salt (ATZ-pTSA) enables thermal amorphization at HME-relevant processing temperatures, where the ATZ free base does not fully melt or dissolve into the model polymer. Counterion choice functions as a solid-state design lever for ASD manufacturability through a proposed lattice-packing disruption mechanism that simultaneously reduces T m and T g and improves organic solubility.
The reaction of a carboxylic acid with an amine in the presence of a catalytic carbodithioate affords the corresponding amide under thermal conditions, excluding the requirement for stoichiometric coupling reagents. The high-yield preparation of amides in the presence of sodium azepane-1-carbodithioate, which can be readily prepared, demonstrates that this agent does not behave as a simple nucleophile but rather plays a critical role in acyl activation and transfer. The advantages of the developed simple catalytic method include minimization of reagents, the ability to operate in a solvent-free environment in many cases, minimal solvent requirement, high product yield, and applicability for scale-up in the synthesis of amides. This method allows for the successful use of various aliphatic and/or aromatic substrates as well as some functionalized carboxylic acids. The study also provided mechanistic insights into the amidation process through Fourier transform infrared analysis and density functional theory calculations.
A practical fluoride scavenging strategy was developed to enable the execution of a fluoride-generating SNAr reaction in a glass-lined reactor during the manufacture of NBI-921352. The DABCO-mediated substitution of an activated aryl fluoride with a secondary amine generates hydrogen fluoride, presenting a risk of glass etching during scale-up. Glass coupon studies confirmed measurable mass loss under both the standard and stressed reaction conditions. Screening of calcium salts identified calcium chloride as a soluble and reaction-compatible fluoride scavenger that preserved the reaction performance while preventing reactor damage. After optimization of downstream workup associated with calcium fluoride formation, the process was successfully implemented in a 4000 L glass-lined reactor under cGMP conditions, enabling the production of greater than 60 kg of the NBI-921352 intermediate without detectable glass etching.
Liquid-phase peptide synthesis (LPPS) has emerged as a versatile and efficient method for assembling peptides, offering significant advantages in purity and yield. In this study, we investigate the application of organic solvent nanofiltration (OSN) technology in LPPS for peptide fragment assembly by Nanostar Sieving. We report how a nanostar support decorated with solubilizing polymers can be used to achieve solubility at concentrations of up to 40 mM of a 39-mer peptide. This is assembled from eight peptide fragments on an 8-arm, 20 kDa nanostar support. OSN enables effective removal of reagents, byproducts, and unreacted fragments after each coupling cycle, enhancing synthesis efficiency. A photolabile linker was incorporated into the support before fragment assembly, enabling periodic analysis without full global deprotection. The Rink amide linker facilitated the final cleavage of the synthesized peptide using standard global deprotection protocols. Following synthesis, OSN was employed to isolate the peptide from the support. In contrast to previous OSN-assisted peptide fragment assembly methods, which required chromatographic purification to remove unreacted fragments at the end of synthesis, nanostar sieving enables their removal during synthesis. The potential to eliminate the need for chromatography could lead to more efficient and scalable therapeutic peptide production.
(±)-Citronellal is mainly derived from mint plants and is widely recognized as a key ingredient in many functional products, including (−)-menthol, (±)-isoamyl alcohol, and (±)-citronellol. Asymmetric hydrogenation of citral is the most effective synthetic method to obtain citronellal with high enantioselectivity. This Review provides an overview of the recent advancements in the synthesis of citronellal from citral, with a focus on industrial production processes and key advances in relevant academic literature.
Ramelteon, a melatonin receptor agonist approved by the FDA in 2005 for the treatment of insomnia, serves as the focus of this study. We present a comprehensive investigation into the development of an advanced and efficient synthetic route for ramelteon, enabling batch-scale production of the active pharmaceutical ingredient (API) to meet commercial demands. The four-step synthetic sequence commences with commercially available 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (2), proceeding through: Wittig–Horner reaction, asymmetric hydrogenation of the α,β-unsaturated nitrile double bond, continuous-flow microfluidic hydrogenation for nitrile reduction, and N-propionylation. The synthesized ramelteon exhibited exceptional quality, with a chromatographic purity exceeding 99.9% (by area normalization), enantiomeric excess (ee) >99.9%, and an overall yield of 40%. A key advantage of this approach is its circumvention of the conventional high-pressure batch hydrogenation typically employed in industrial ramelteon synthesis. Furthermore, the developed protocol demonstrates potential applicability for the reduction of other α,β-unsaturated nitrile pharmaceutical intermediates. This scalable and high-efficiency synthetic strategy not only establishes safer production conditions for ramelteon manufacturing but also provides novel insights into the catalytic reduction of α,β-unsaturated nitriles in pharmaceutical synthesis.
HEC96719 is a small-molecule farnesoid X receptor (FXR) agonist with potential for treating nonalcoholic steatohepatitis (NASH). Herein, we report a robust and scalable kilogram-scale synthesis of compound 9, the central and synthetically challenging spirocyclic benzoxepane–pyridine core of HEC96719. This optimized process features: (i) a protecting-group-enabled nucleophilic acylation, (ii) an industrially practical cyclopropanation using NaOH under phase-transfer conditions, (iii) an ortho-phenol-assisted deoxygenation protocol to access a highly strained methylene intermediate, (iv) a copper-mediated intramolecular Ullmann etherification, and (v) a palladium-catalyzed carbonylation employing a safe CO surrogate to avoid high-pressure carbon monoxide. Collectively, this process enhances operator safety, improves overall efficiency and yield, avoids chromatographic purification, and has been successfully demonstrated on a multikilogram scale, underscoring its potential for industrial application.
