Organic Process Research & Development最新文献

The development of a concise synthesis of crisaborole (1), a phosphodiesterase 4 (PDE4) inhibitor, is described. There are several challenges with the initial commercial synthesis that were drivers for process redesign and simplification, most notably the need for protection/deprotection steps. Key bond disconnections and reordering of steps were evaluated to streamline the process focusing on greener options for manufacture and eliminating protecting groups. The resulting alternate synthesis features a similar Miyaura borylation to install the key boron atom but provides a more direct route to crisaborole through an important crystalline intermediate for impurity purge. Other challenges addressed by the alternate route include avoiding environmentally undesirable reagents DMF and boric acid (both included on the REACH list of substances of very high concern), reducing palladium usage, and eliminating the use of a palladium scavenging treatment. Successful demonstration of the alternate route for crisaborole has been achieved at pilot plant scale and ultimately has been validated at commercial scale consistent with ICH Q11 principles. The route was approved for commercial use to supply crisaborole in 2023 and to date has produced approximately 750 kg of the crisaborole drug substance.

Over functionalization of sugars under condition-dependent constraints without disrupting their native architecture remains a significant challenge in vaccine development. Here, we report an AI-guided, automated flow platform with variable reaction conditions that enables azide incorporation at the C2 and C2–C4 positions of l-rhamnose and l-fucose derivatives, achieving yields of up to 90–97%. This approach delivers a safe handling of NaN₃, minimum human intervention, and approximately 3000-fold enhancement in space–time yield compared to conventional batch synthesis. Subsequent in-flow Cu-catalyzed azide–alkyne cycloaddition (CuAAC) affords mono- and ditriazoles, offering a scalable route to glycoconjugates for both medicinal and material applications.

This study details the development of manufacturing processes for TAFIa (activated thrombin-activatable fibrinolysis inhibitor) inhibitor 1 and its prodrug 2. To establish an industrial-scale production process for 1, a comprehensive screening of chiral catalysts for an asymmetric hydrogenation of intermediate 12 was conducted. This effort revealed that Ru/BINAP catalyst system in fluorous alcohol solvents (2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)) significantly improves both reactivity and selectivity. As a result, a practical and efficient process was successfully constructed, achieving 85% overall yield from intermediate 12 over 5 steps. This represents a notable increase compared to the early stage process (40% overall yield in 5 steps from intermediate 12). In parallel, a manufacturing process was developed for prodrug 2. A novel optically active prodrug fragment, (R)-32–utilizing HFIP as a leaving group–was designed to avoid a troublesome chromatographic process, and its synthetic route was established. Enzyme screening identified Chirazyme L-2, C4 as an effective choice, producing (R)-32 in 37% yield with an optical purity of 99.8%ee. A racemization method utilizing catalytic amount of Ac₂O was combined with the crystallization of the desired isomer 2 utilizing diastereomer mixture of 2c ((R,R)- and (R,S)-forms). Crystallization-induced asymmetric transformation (CIAT) from (R,R)-form to the desired (R,S)-form was achieved, resulting in 97% yield with 94.8%de. Building on these methods, a manufacturing process was established for prodrug 2, attaining an overall yield of 74% from intermediate 12 through 6 steps.

Wet milling offers efficient production of a consistent, high-quality particle size distribution (PSD) in active pharmaceutical ingredients (APIs). However, scaling from the laboratory to plant is a challenge. Scale-up methods that depend on a single parameter can result in inaccurate predictions and longer processing time and produce off-target PSD at the plant scale. This study introduces a model-aided workflow for scaling wet milling processes from the laboratory to the plant using multiparameter population balance modeling (PBM) in gFormulate. The PBM model was developed at the laboratory scale (80–125 g), adjusted by a single parameter at the kiloscale (1.5 kg), and applied to the plant scale (50 kg) without any additional changes. The model achieved right-first-time results for the predicted conditions (e.g., 26 h processing time): 55 ± 2 μm, 95% yield at the plant scale. This framework provides a reliable, adaptable solution for efficient scale-up of wet milling across different APIs and equipment, improving reliability and efficiency in pharmaceutical production.

This article describes the development of a liquid-phase peptide synthesis (LPPS) process for LUNA18 (paluratide), an N-alkyl-rich cyclic undecapeptide with KRAS inhibitory activity. Departing from conventional solid-phase peptide synthesis, we developed a high-yielding LPPS process by addressing key challenges: (1) low reactivity caused by steric hindrance of the N-alkylated amino acids, (2) incomplete hydrolysis of excess active esters during workup, (3) instability of N-alkyl-rich peptide backbone under acidic conditions, and (4) diketopiperazine formation in N-deprotected intermediates. Through a convergent synthetic route consisting of 24 telescoped chemical transformation steps followed by a final crystallization step, LUNA18 was synthesized with >98.5% purity (HPLC-UV) and >30% overall yield. This process enabled rapid supply of high-purity active pharmaceutical ingredients at the kilogram scale under Good Manufacturing Practice conditions, demonstrating the utility and scalability of our approach for N-alkyl-rich cyclic peptides.

In this study, we performed a hazard assessment of actual and potential impurities involved in the synthesis of a newly developed LpxC inhibitor T-1228 in accordance with the ICH M7(R2) guideline. We identified eight mutagenic/carcinogenic impurities in need of control: benzyl chloride, 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride, O-(tetrahydro-2H-pyran-2-yl)hydroxylamine, 2-(4-iodophenyl)-2-oxoethyl acetate, (S)-1-(4-ethynylphenyl)ethane-1,2-diol, isopropyl methanesulfonate, hydroxylamine, and (S)-4-((4-(1,2-dihydroxyethyl)phenyl)ethynyl)-N-hydroxybenzamide. We then conducted risk assessments of the first six impurities using purge factors, and determined that Option 4 control of ICH M7(R2) guideline was the optimal approach for controlling these impurities. Furthermore, as (S)-1-(4-ethynylphenyl)ethane-1,2-diol and isopropyl methanesulfonate are impurities introduced during the later stages of active pharmaceutical ingredient (API) synthesis, we obtained additional experimental data (verification of reactivity, solubility, spike experiments, and analytical experiments) to verify the validity of the purge-based risk assessment. Regarding the final two impurities, hydroxylamine may be produced as a byproduct in the final intermediate and final processes; therefore, we determined that Option 1 control of ICH M7(R2) guideline was the optimal control strategy and set appropriate API criteria. Although (S)-4-((4-(1,2-dihydroxyethyl)phenyl)ethynyl)-N-hydroxybenzamide is a degradation product of API, in vivo mutagenicity assay conducted according to the ICH M7(R2) guideline showed negative results. Therefore, we determined that (S)-4-((4-(1,2-dihydroxyethyl)phenyl)ethynyl)-N-hydroxybenzamide can be managed as a nonmutagenic impurity according to the ICH Q3A(R2) guideline. The risk assessment of mutagenic impurities related to the T-1228 API manufacturing method, performed in accordance with ICH M7(R2) guideline, can guarantee the quality of this manufacturing method for initial clinical trials.

In recent years, the detection of nitrosamine impurities in pharmaceuticals has emerged as a significant safety concern, primarily due to their potential carcinogenic and mutagenic effects on patients. These impurities may be introduced as byproducts from synthetic steps or formed in the presence of specific precursors. Although pharmaceutical manufacturers have methodologies for source identification, risk assessment, and mitigation strategies at their disposal, implementing rigorous analytical testing is paramount for quantifying nitrosamine levels and ensuring compliance with regulatory standards. This Review provides a comprehensive overview of integrating robust analytical testing within risk assessment frameworks, focusing on methods to detect nitrosamines in both drug products and substances. Sample preparation is highlighted as a pivotal step in ensuring robust nitrosamine quantitation, as it directly impacts analytical sensitivity and specificity by isolating trace-level impurities from complex pharmaceutical matrices while minimizing matrix effects, analyte instability, and artifactual formation. Despite its critical importance, no prior reviews have comprehensively addressed the challenges and strategies associated with sample preparation for nitrosamine analysis. This review fills this gap by emphasizing the role of optimized sample preparation techniques, discussing key challenges such as matrix interference and contamination risks, and presents a compilation of solutions published in the literature. Additionally, a phase-appropriate method validation strategy is proposed, tailored to drug development stages, ensuring that methods are fit for purpose while meeting regulatory expectations. By presenting a comprehensive framework for optimizing sample preparation and validation approaches, this Review aims to support accurate nitrosamine quantitation and ensure pharmaceutical product safety.

As part of pharmaceutical research, development, and manufacturing, it is critical to assess and select appropriate materials of construction (MOC) for processing equipment to ensure that the chemicals in the process do not degrade the equipment. The earlier any potential MOC compatibility issues are identified, the less likely they are to cause problems in preparing a process for drug manufacturing. In this paper, we discuss the strategy of Merck & Co., Inc., Rahway, NJ, USA (hereinafter “MSD”) for evaluating MOC compatibility, including a testing approach for metals, glass, and plastics, with associated acceptance criteria for general and localized incompatibility. We also summarize our phase-appropriate approach for risk evaluation, which helps ensure that the process transitions smoothly from research through piloting and into commercial manufacture.

The novel LpxC inhibitor T-1228 is a candidate drug molecule for multidrug-resistant Gram-negative bacterial infection. We developed a process chemistry route to T-1228. The final step of T-1228 drug substance synthesis consists of a deprotection reaction under acidic conditions and a crystallization process incorporating polymorph control. The process parameters of the deprotection reaction were optimized through a Design of Experiments (DoE) study to limit the formation of a critical impurity. The production method established for the crystallization process was developed by means of process analytical technology (PAT): it controls the quality and particle size of the drug substance and selectively yields only the desired crystal polymorph. By applying the newly developed process chemistry route, we have successfully manufactured T-1228 at 24% total yield from commercially available 1,3-diethyl 2-bromo-2-methylpropanedioate.

We required rapid access to hundreds of grams of a key building block to support early scale-up campaigns during one of our Oncology programs. Accordingly, we report herein the exploration of two synthetic approaches to this compound by our Discovery Process team. This work culminated in the development and optimization of a phase-appropriate synthetic route that was successfully utilized by one of our contract development and manufacturing organizations (CDMOs) to quickly deliver 300 g of intermediate 1•TsOH.