title string | abstract string | doi string | has_route int64 |
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Industrial-Scale Continuous Vacuum Drying of Active Pharmaceutical Ingredient Paste: Determination of the Process Window | Many efforts have been made in recent years to adopt and implement continuous processing into the pharmaceutical production chain, driven by the desire to optimize the process efficacy and cost as well as the product quality. In the current challenging times, the need for fast adaptable processes to enlarge and facilit... | 10.1021/acs.oprd.1c00393 | 0 |
Development of a Practical and Scalable Synthetic Route for the Adenosine Monophosphate-Activated Protein Kinase Activator, ASP4132 | This paper describes the research and development of a practical and efficient process for making the adenosine monophosphate-activated protein kinase (AMPK) activator, ASP4132 ( 1 ). The newly developed process includes an efficient telescoping process consisting of Suzuki–Miyaura coupling and hydrogenation, effective... | 10.1021/acs.oprd.1c00392 | 1 |
Quantum Mechanical Methods for Thermal Hazard Risk Assessment in Early Phase Pharmaceutical Development | Quantum mechanical (QM) applications to predict heat of reaction (Δ H r ) and thermal stability of strained aminocarbocylic salts, diazo compounds, and nitroalkanes for early phase thermal hazard risk assessment is presented. We provide examples on the use of explicit solvation to predict accurate Δ H r . Based on the ... | 10.1021/acs.oprd.1c00391 | 0 |
Development of a Practical and Greener Process for the Dual Leucine Zipper Kinase Inhibitor GDC-0134 Comprising Two S<sub>N</sub>Ar Reactions, Oxidation and Suzuki Coupling | A sustainable second-generation process for GDC-0134 was developed with a particular focus on safety and greenness, while complying with strong specifications to supply pivotal clinical studies. Through these efforts, we discovered solvents to replace the solvents classified as substances of very high concern by the RE... | 10.1021/acs.oprd.1c00389 | 1 |
Scale-Up and Development of Synthesis 2-Ethylhexyl Nitrate in Microreactor Using the Box–Behnken Design | In this study, kilogram-scale synthesis of 2-ethylhexyl nitrate in a microreactor was reported. Using Box–Behnken experimental design, the effects of process parameters such as temperature, molar ratio, total flow rate, and mass fraction of sulfuric acid on the yield of the target product were systematically investigat... | 10.1021/acs.oprd.1c00388 | 0 |
Convenient, Large-Scale Synthesis of (<i>S</i>)-TRIP Using Suzuki Cross-Coupling Conditions | A three-step synthesis of ( S )-TRIP enabled by efficient Suzuki cross-coupling conditions using commercial starting materials was developed and demonstrated on a kilogram scale. These novel Suzuki reaction conditions feature Pd 2 (dba) 3 /CataCXium A in the presence of TBAB and KOH and provide conversions up to 90% wh... | 10.1021/acs.oprd.1c00386 | 0 |
Concise Process for Pyriftalid Synthesis by Introducing the Mercapto Group Directly from a Nitro Group | A concise and efficient process for the synthesis of pyriftalid is described herein. The improved process features the direct introduction of the mercapto group by one-step substitution of a nitro group using sodium sulfide and elemental sulfur. A systematic study of the key step is also carried out in this article. Co... | 10.1021/acs.oprd.1c00384 | 1 |
Kilogram-Scale Preparation of the Easily Available, Low-Cost Electrophilic Trifluomethylating Reagent YlideFluor | A kilogram-scale process for the preparation of a potentially broadly applicable electrophilic trifluoromethylating reagent, (trifluoromethyl)(4-nitrophenyl)bis(carbomethoxy)methylide (YlideFluor), was reported. The reagent was prepared in three steps from a cheap, commercially available starting material, and the pric... | 10.1021/acs.oprd.1c00381 | 0 |
Engineering a Transaminase for the Efficient Synthesis of a Key Intermediate for Rimegepant | Transaminases have been increasingly utilized as efficient biocatalysts in the synthesis of pharmaceutical intermediates, but a major drawback is their poor substrate acceptance, especially the limitation for the synthesis of sterically hindered chiral amines. Herein we report the engineering of a transaminase that can... | 10.1021/acs.oprd.1c00376 | 0 |
Development of an Improved Route to a Human Immunodeficiency Virus Maturation Inhibitor by Chromium-Free Allylic Oxidation and an Efficient Asymmetric Henry Reaction | Development of an improved route to a human immunodeficiency virus maturation inhibitor is described. Key features of the chemistry that was developed include avoidance of chromium reagents by use of a novel allylic oxidation with NBS/water and an aldehyde oxidation using either bleach/TEMPO under flow conditions or di... | 10.1021/acs.oprd.1c00374 | 1 |
An Optimized Safe Process from Bench to Pilot cGMP Production of API Eptifibatide Using a Multigram-Scale Microwave-Assisted Solid-Phase Peptide Synthesizer | High Resolution Image Download MS PowerPoint Slide A growing industrial interest toward the peptide drug market fueled the need for the development of effective and cGMP compliant manufacturing methods for these complex molecules. Solid-phase strategies are considered methods of election for medium-length peptide synth... | 10.1021/acs.oprd.1c00368 | 1 |
Stereoselective Nickel(II)-Catalyzed Addition of Aryl Grignards to Diphenylacetylene in the Synthesis of Zuclomiphene | Stereoselective synthesis of zuclomiphene was developed using nickel-catalyzed addition of 4-fluorophenylmagnesium bromide to 1,2-diphenylacetylene, followed by quenching with a chlorinating reagent. Since the aryl fluoride addition and chlorination reactions occur consecutively in one pot, the cis orientation of the t... | 10.1021/acs.oprd.1c00366 | 1 |
Scalable Synthesis of <i>N</i>,<i>N</i>′-Di(2,3-dihydroxy-propyl)-1,4-naphthalenedipropanamide and Its 1,4-Endoperoxide as a Singlet Oxygen-Releasing Molecule | We report a greatly improved, operationally simple, and scalable three-step synthesis of the nonionic and water-soluble singlet oxygen ( 1 O 2 ) carrier molecule N, N ′-bis(2,3-dihydroxypropyl)-1,4-naphthalenedipropanamide-1,4-endoperoxide (DHPNO 2 ). Starting from 1,4-dibromonaphthalene, the developed sequence involve... | 10.1021/acs.oprd.1c00364 | 1 |
Synthesis of 5-Nitrotetrazolate via the Aqueous Oxidation of 5-Aminotetrazole | The preparation of the important energetic precursor sodium nitrotetrazolate has long been plagued by safety and purity problems. The prevailing synthesis methods utilizing the Sandmeyer reaction proceed via sensitive, explosive intermediates and would be classified as a high-hazard process. In this work, we directly o... | 10.1021/acs.oprd.1c00361 | 0 |
MSD’s Process Safety Scale-Up Methodology for Pilot Plant Scale and Beyond | Process safety testing is critical for small molecule active pharmaceutical ingredient (API) scale-up and manufacturing by proactively identifying any process safety hazards, including environmental and industrial hygiene issues. The intent of this contribution is to describe how Merck & Co., Inc. Kenilworth, NJ (known... | 10.1021/acs.oprd.1c00360 | 0 |
Impact of Phosphine Featurization Methods in Process Development | Modern high-throughput experimentation (HTE) has enabled the rapid exploration of large expanses of chemical reaction space to accelerate the development of key synthetic steps in pharmaceutical processes. However, the dimensionality of reaction parameters, the desire to use minimal starting material, and the need to t... | 10.1021/acs.oprd.1c00357 | 0 |
Development of a Scalable Route to a Pyrrolidone Compound via a Hydroxyfuranone | Herein, we describe the preparation of pyrrolidone compound 1 as a potential antiepileptic drug. The key steps of this synthetic route are based on the preparation of a heterocyclic amine and its condensation with a hydroxyfuranone in a three-step one-pot process. The development of the synthesis led to decreased route... | 10.1021/acs.oprd.1c00350 | 1 |
Comparison of One-Dimensional and Two-Dimensional Population Balance Models for Optimization of a Crystallization Process for a Needle-Shaped Active Pharmaceutical Ingredient | The two-dimensional population balance model (2D PBM) introduces the enhanced capability of modeling two different sets of growth kinetics, which can offer advantages to modeling crystallization processes that generate needle-like particles, a commonly encountered active pharmaceutical ingredient (API) morphology. Alth... | 10.1021/acs.oprd.1c00344 | 0 |
Automated High-Throughput Partition Coefficient Determination with Image Analysis for Rapid Reaction Workup Process Development and Modeling | With this work, we explore the application of a novel image analysis algorithm in combination with a high-throughput automated workflow to extract partition coefficient measurements and full mass balance from small-scale samples. An image analysis algorithm was developed in MATLAB R2018b to determine the volume of the ... | 10.1021/acs.oprd.1c00343 | 0 |
Asymmetric Synthesis of the Cyclohexyl Fragment in RORγt Inhibitor (BMS-986251) Enabled by a Dynamic Kinetic Resolution of Hageman’s Ester | The cyclohexyl fragment 1 in BMS-986251 was synthesized starting from Hagemann’s ester 2 in 7 steps and 5 isolations. The route is highlighted by a dynamic kinetic resolution (DKR), a telescoped enol nonaflation followed by a palladium-catalyzed carbonylation, and a rhodium-catalyzed directed diastereoselective olefin ... | 10.1021/acs.oprd.1c00339 | 1 |
Continuous Flow Synthesis of a Blocked Polyisocyanate: Process Intensification, Reaction Monitoring Via In-Line FTIR Analysis, and Comparative Life Cycle Assessment | The traditional batch production of blocked polyisocyanates, key components in the preparation of self-cross-linking resins, has significant drawbacks associated with the exothermic character of the reaction and the high viscosity of some of the materials involved. We have developed a continuous flow strategy for the g... | 10.1021/acs.oprd.1c00329 | 0 |
Design, Development, and Analysis of an Automated Sampling Loop for Online Monitoring of Chiral Crystallization | of both the liquid and the solid. This work demonstrates a proof of concept of both the experimental and theoretical aspects of the new system. | 10.1021/acs.oprd.1c00320 | 0 |
Development of the Enabling Route for a Novel HCV NS3/4A Inhibitor, Furaprevir | Furaprevir demonstrated adequate safety and effectiveness in clinical phases I and II, which was identified as a potent Hepatitis C virus (HCV) NS3/4A protease inhibitor. Research on the synthesis process of Furaprevir is insufficient, so a reliable manufacturing procedure is required to support subsequent clinical tri... | 10.1021/acs.oprd.1c00315 | 1 |
Sulfone Displacement Approach for Large-Scale Synthesis of 4-Chloro-<i>N</i>-(1-methyl-1<i>H</i>-pyrazol-4-yl)pyrimidin-2-amine | Route evaluation, process development, and large-scale manufacturing of 4-chloro- N -(1-methyl-1 H -pyrazol-4-yl)pyrimidin-2-amine ( 1 ) are described. The improved route consists of two linear chemical steps: oxidation of 4-chloro-2-(methylthio)pyrimidine ( 11 ) to 4-chloro-2-(methylsulfonyl)pyrimidine ( 7 ) and displ... | 10.1021/acs.oprd.1c00314 | 1 |
High-Throughput Experimentation Enabling Rapid Process Optimization of an RSV Drug Candidate | The process optimization for the synthesis of an RSV antiviral agent is described. Key to the identification of these optimal conditions was the use of high-throughput experimentation to greatly reduce the development time and realize significant process improvements in key steps such as the telescoped pyrazolopyrimidi... | 10.1021/acs.oprd.1c00313 | 1 |
Scalable Synthesis of (<i>R</i>,<i>R</i>)-<i>N</i>,<i>N</i>-Dibenzyl-2-fluorocyclohexan-1-amine with CsF under Hydrogen Bonding Phase-Transfer Catalysis | Hydrogen bonding phase-transfer catalysis offers a convenient solution to activate safe and economical metal alkali fluorides for enantioselective nucleophilic fluorination. Herein, we demonstrate the scalability of this protocol with the fluorination of 200 g of racemic trans - N, N -dibenzyl-2-bromocyclohexan-1-amine... | 10.1021/acs.oprd.1c00312 | 0 |
Deracemization via Periodic and Non-periodic Temperature Cycles: Rationalization and Experimental Validation of a Simplified Process Design Approach | Solid-state deracemization via temperature cycles is a promising technique that combines crystallization and racemization in the same batch process to attain enantiomer purification. This method is particularly attractive because the target enantiomer can be isolated with a 100% yield, and a large number of operating p... | 10.1021/acs.oprd.1c00310 | 0 |
Multidecagram Scale Synthesis of an Endoperoxide, Precursor of Anti-malarial and Anti-leishmanial Agents, <i>via</i> Free-Radical [2 + 2 + 2] Annulation with Molecular Oxygen | From screening experimental parameters to scaling up, a safe approach is reported for the multidecagram scale preparation of methyl ester of 6,6-dibutyl-3-hydroxy-3-methyl-1,2-dioxane-4-carboxylic acid ( 7 ), a flexible common intermediate for the synthesis of a variety of anti-malarial and/or anti-leishmanial compound... | 10.1021/acs.oprd.1c00309 | 0 |
Development of a Kilogram-Scale Route for Clinical Sample Production of the Intravenous Anesthetic Cipepofol | Propofol has been widely used as a clinical anesthetic for a few decades. Its derivative with a three-membered ring, Cipepofol, was found to be equally effective and with less side effects. Here, we report a process for the scale-up total synthesis of Cipepofol . It could be obtained in five steps from the commercially... | 10.1021/acs.oprd.1c00306 | 1 |
Stirring Peptide Synthesis to a New Level of Efficiency | Accelerating solid-phase synthesis is crucial for accessing a large number of peptides in a short time. Since standard peptide synthesis is usually done under poor diffusion conditions with slow or no mixing of the solid support, acceleration of the process is achieved by applying a large excess of reagents. In this wo... | 10.1021/acs.oprd.1c00304 | 0 |
Efficient, Protecting Group Free Kilogram-Scale Synthesis of the JAK1 Inhibitor GDC-4379 | The development of an improved kilogram-scale synthesis of the JAK1 inhibitor GDC-4379 for the treatment of asthma is described. The new process is highlighted by a step-economical construction of a 3-substituted-4-aminopyrazole employing a telescoped oximation and hydrazine condensation of a 1,3-dielectrophile to gene... | 10.1021/acs.oprd.1c00302 | 1 |
PAT Implementation on a Mobile Continuous Pharmaceutical Manufacturing System: Real-Time Process Monitoring with In-Line FTIR and Raman Spectroscopy | The strategies and experimental methods for implementation of process analytical technology (PAT) on the mobile pharmaceutical manufacturing system, Pharmacy on Demand (PoD), are discussed. With multiple processes to be monitored on the PoD end-to-end continuous manufacturing process, PAT and its real-time process moni... | 10.1021/acs.oprd.1c00299 | 0 |
Synthesis of the C1–C13 Fragment of Eribulin on a Kilogram Scale | An improved kilogram-scale synthesis of the C1–C13 fragment of eribulin is disclosed. Rh-mediated 6- endo - tet cyclization of a vinyl epoxide provides a crystalline tetrahydropyran intermediate, which was transformed to a lactol intermediate having the bicyclic motif of the C3–C12 fragment. This intermediate was furth... | 10.1021/acs.oprd.1c00295 | 0 |
Process Intensification Enabling Continuous Manufacturing Processes Using Modular Continuous Vacuum Screw Filter | A novel apparatus concept for integrated, small-scale continuous filtration, washing, and drying is presented. The continuous vacuum screw filter (CVSF) allows obtaining dried and free-flowing product particles from the continuously fed suspension. While the first study presented the CVSF concept in detail and focused ... | 10.1021/acs.oprd.1c00294 | 0 |
Study on the Safety Design of 3-Amino-6-Bromo-1,2,4-Triazine Drying Process Based on Thermal Analysis Technology | The thermal decomposition behavior of 3-amino-6-bromo-1,2,4-triazine (ABTA) with different moisture contents was studied with a differential scanning calorimeter (DSC). It was found that the thermal stability of the original wet ABTA was worse than that of the qualified dry ABTA. As the drying process proceeded and wat... | 10.1021/acs.oprd.1c00293 | 0 |
Large-Scale Enantioselective Reduction of 2,3-Disubstituted Indenopyridine Enables a Practical Manufacturing Process for an 11β-HSD-1 Inhibitor | An economical and practical manufacturing process for an 11β-HSD-1 inhibitor is reported. The key feature of the synthesis is the identification of a unique and effective MeO-BoQPhos ligand for the Ir-catalyzed asymmetric hydrogenation of a fused tricyclic indenopyridinium salt. It is the first highly reactive chiral P... | 10.1021/acs.oprd.1c00290 | 1 |
Synthesis of 1-Chloronaloxone and 2-Chloronaloxone | This paper describes the unambiguous synthesis of authentic samples of 1-chloronaloxone and 2-chloronaloxone to support the unequivocal assignment of impurities observed in a drug product containing a combination of buprenorphine hydrochloride and naloxone hydrochloride. The key step in the synthesis of 1-chloronaloxon... | 10.1021/acs.oprd.1c00288 | 0 |
Development of a Scalable Enantioselective Synthesis of JAK Inhibitor Upadacitinib | Process development of a six-stage synthesis of upadacitinib, a JAK1 inhibitor, is described. It is highlighted by an enantioselective and diastereoselective hydrogenation of a tetrasubstituted olefin to set the two pyrrolidine stereocenters. Preparation of the main fragments and strategies to link them together, optim... | 10.1021/acs.oprd.1c00287 | 1 |
Scalable Synthesis of β-Lactamase Inhibitor QPX7728 by Sequential Nickel-Catalyzed Boron Insertion into a Benzofuran Substrate and Enantioselective Cyclopropanation of the Resulting Vinylboronate | We report the scalable, high-yielding, and highly selective synthesis of the β-lactamase inhibitor QPX7728 featuring two key synthetic steps: nickel-catalyzed boron insertion of benzofuran 1 followed by enantioselective cyclopropanation of the resulting cyclic vinylboronate 2 . The identification of the key reagents (c... | 10.1021/acs.oprd.1c00285 | 1 |
Process Development, Manufacture, and Understanding of the Atropisomerism and Polymorphism of Verinurad | The manufacturing route toward verinurad, an amphoteric, class II atropisomer that readily forms solvates, has proven to be highly complex. This previously required the isolation of intermediates with challenging physical properties and the application of cryogenic processes. New processes were designed and optimized, ... | 10.1021/acs.oprd.1c00284 | 1 |
Expedited Kilolab Development of AZD7624 Using Kulinkovich-de Meijere Cyclopropanation | AZD7624 is a small molecule compound developed for the treatment of chronic obstructive pulmonary disease. This study describes the lab development and kilolab manufacture of the drug substance. A small number of route options were evaluated using lab proof-of-concept and predictive studies, before a Kulinkovich-de Mei... | 10.1021/acs.oprd.1c00283 | 1 |
Review of Synthetic Routes and Crystalline Forms of the Oncology Drugs Capmatinib, Selpercatinib, and Pralsetinib | This article reviews the synthetic routes and final crystalline forms of the recently approved oncology drugs capmatinib, selpercatinib, and pralsetinib. The patent literature served as the primary source of information. | 10.1021/acs.oprd.1c00282 | 1 |
A Scalable Synthesis of Roxadustat (FG-4592) | A scalable five-step protocol for synthesis of roxadustat, an orally administered hypoxia-inducible factor-propyl hydroxylase inhibitor (HIF-PHI), was developed with an emphasis placed on aspects of medicinal chemistry. The isoquinoline core of the molecule was prepared using a purposefully designed cyclocondensation i... | 10.1021/acs.oprd.1c00281 | 1 |
Using Oxygen as the Primary Oxidant in a Continuous Process: Application to the Development of an Efficient Route to AZD4635 | An aerobic oxidation operated in continuous flow is described as the key step in an efficient three-step route to AZD4635. By implementing this technique for the oxidation step, safety concerns in batch mode were addressed and an improved yield and quality of the product were obtained. Moreover, a PAT method (Fourier t... | 10.1021/acs.oprd.1c00279 | 1 |
An Efficient Second-Generation Manufacturing Process for the pan-RAF Inhibitor Belvarafenib | Herein, the development of a streamlined manufacturing process for the pan-RAF inhibitor belvarafenib (GDC-5573) is reported. The process to belvarafenib features a number of efficient key reactions, including a robust and scalable Pd-catalyzed carbonylation reaction to generate thienopyrimidine 2 and a highly chemosel... | 10.1021/acs.oprd.1c00277 | 1 |
Hybrid Flow-Batch Model for the Efficient Synthesis of 2-(Dimethylamino)-6-methylpyridin-4-ol | A practical and scalable method for the synthesis of 2-(dimethylamino)-6-methylpyridin-4-ol is described. Despite its structural simplicity, the synthesis and isolation of this molecule in useful yields has proven to be challenging. A hybrid-flow (flow–batch–flow) mode approach was designed to circumvent issues associa... | 10.1021/acs.oprd.1c00264 | 1 |
Efficient Manufacturing Process for the Selective Estrogen Receptor Degrader GDC-9545 (Giredestrant) via a Crystallization-Driven Diastereoselective Pictet–Spengler Condensation | GDC-9545 is a selective estrogen receptor degrader that is being developed as a treatment for ER+/HER2– breast cancer. A robust, convergent manufacturing process for GDC-9545 was developed. The process features a Wenker aziridine synthesis to produce the key starting material tryptamine 11, a highly efficient C–N coupl... | 10.1021/acs.oprd.1c00263 | 1 |
First-Generation Asymmetric Synthesis of the Selective Estrogen Receptor Degrader GDC-9545 (Giredestrant) Featuring a Highly Efficient Pictet–Spengler Reaction and a C–N Coupling Reaction | An asymmetric synthesis of the selective estrogen receptor degrader GDC-9545 ( 1 ) is described. The synthesis features a Friedel–Crafts indole functionalization and a strain-release aminoazetidine formation to construct the two key starting materials 2 and 4, respectively, a diastereoselective Pictet–Spengler reaction... | 10.1021/acs.oprd.1c00262 | 1 |
Development of an Intrinsically Safer Methanolysis/Aromatic Nitro Group Reduction for Step 1 and 2 of Talazoparib Tosylate | A change in facility for the synthesis of the step 2 intermediate for talazoparib tosylate ( 1 · TsOH ) required the development of an alternative, intrinsically safer process. Rapid route scouting and considerations of process safety enabled the development of a telescoped two-step process that was demonstrated on a m... | 10.1021/acs.oprd.1c00259 | 1 |
Catalytic Static Mixer-Enabled Hydrogenation of a Key Fenebrutinib Intermediate: Real-Time Analysis for a Stable and Scalable Process | Catalytic static mixer (CSM) technology is presented as an industrially viable solution for aromatic nitro group reduction in the synthesis of fenebrutinib. Factors affecting catalyst inhibition could be rapidly understood and mitigated by the use of real-time analytics (FT-IR and UHPLC). This facilitated the developme... | 10.1021/acs.oprd.1c00258 | 0 |
Safety Assessments Supporting Scale-up of Chemistry Involving Hydrogen | Asymmetric transfer hydrogenation (ATH) is a commonly used transformation in the pharmaceutical industry for the reduction of ketones to establish key stereocenters. Yet, the potential for hydrogen gas generation during reaction, workup, and waste handling processes could be overlooked, resulting in serious safety issu... | 10.1021/acs.oprd.1c00256 | 1 |
Application of Biocatalytic Reductive Amination for the Synthesis of a Key Intermediate to a CDK 2/4/6 Inhibitor | Biocatalytic reductive amination catalyzed by engineered imine reductase (RedAms) is a new and powerful tool for the synthesis of substituted chiral amines. Herein, we describe a streamlined synthesis of compound 3, a key intermediate to a CDK 2/4/6 inhibitor 1, relying on the enzymatic reductive amination of a hydroxy... | 10.1021/acs.oprd.1c00255 | 1 |
A Study on the Reaction Mechanisms and Process Safety of Pyrisoxazole Synthesis | Understanding the kinetics and thermodynamic parameters of main reactions is critical for identifying the optimal operating conditions for chemical processes. The reaction mechanism and process safety for the synthesis of pyrisoxazole from 3-acetylpyridine, p -chloroprene, and n -methylhydroxylamine sulfate with sodium... | 10.1021/acs.oprd.1c00254 | 0 |
Fully Continuous Flow Synthesis of 5-(Aminomethyl)-2-methylpyrimidin-4-amine: A Key Intermediate of Vitamin B<sub>1</sub> | Herein, we demonstrate an expeditiously fully continuous flow synthesis of 5-(aminomethyl)-2-methylpyrimidin-4-amine, a key intermediate for vitamin B 1 . The process is accomplished via three chemical transformations in six sequential continuous flow devices from an economical starting material, 2-cyanoacetamide. Firs... | 10.1021/acs.oprd.1c00253 | 1 |
Enzyme Optimization and Process Development for a Scalable Synthesis of (<i>R</i>)-2-Methoxymandelic Acid | The rational protein engineering of wild type BCJ2315 nitrilase and its use in the development of a one-pot, enantioselective, dynamic kinetic resolution for ( R )-2-methoxymandelic acid is reported. Through a combination of molecular docking and B -factor analyses, a focused library of mutants was identified and scree... | 10.1021/acs.oprd.1c00250 | 1 |
Continuous Multiphase Flow Nitration and Cryogenic Flow Formylation: Enabling Process Development and Manufacturing of Pharmaceutical Intermediates | Manufacturing API and pharmaceutical intermediates requires the development of scalable, safe, and environmentally friendly processes. Reactions with high exothermicity or otherwise hazardous in nature, as well as reactions involving the formation of unstable intermediates, can benefit from continuous processing. This ... | 10.1021/acs.oprd.1c00249 | 0 |
Synthesis of Fingolimod Employing Regioselective Aziridine Ring-Opening Reaction as a Key Step | An efficient and scalable synthesis of the immunomodulating drug fingolimod hydrochloride has been developed with the aziridine regioselective ring-opening reaction as a key step. This manuscript describes design, detailed synthetic route scouting, and optimization study of the aziridine ring-opening reaction. As a sta... | 10.1021/acs.oprd.1c00248 | 1 |
Development and Scale-Up of a Novel Photochemical C–N Oxidative Coupling | A visible light promoted C–N-coupling of a functionalized pyridazinone with veratrole was developed to forge the central C–N bond of an agrochemical intermediate. Dosing aqueous NaOCl and 4% O 2 in N 2 under blue light irradiation (460 nm) was key to promote the desired transformation while generating benign wastes. Me... | 10.1021/acs.oprd.1c00244 | 1 |
Manufacturing Process Development for Belzutifan, Part 5: A Streamlined Fluorination–Dynamic Kinetic Resolution Process | Here we report the fluorination–dynamic kinetic resolution (DKR) process for the commercial supply of belzutifan (MK-6482). Key process safety and robustness issues in the Selectfluor fluorination reaction were identified and addressed on the basis of increased mechanistic understanding. Aggressive process optimization... | 10.1021/acs.oprd.1c00242 | 0 |
Manufacturing Process Development for Belzutifan, Part 2: A Continuous Flow Visible-Light-Induced Benzylic Bromination | We report the development and scale-up of a continuous flow photochemical benzylic bromination en route to belzutifan (MK-6482), a small molecule for the treatment of renal cell carcinoma associated with Von Hippel–Lindau syndrome. Compared with the clinical supply route, the photochemical approach circumvents the need... | 10.1021/acs.oprd.1c00240 | 0 |
Manufacturing Process Development for Belzutifan, Part 6: Ensuring Scalability for a Deoxyfluorination Reaction | The development of a regio- and stereoselective deoxyfluorination process for the manufacture of belzutifan (MK-6482) was challenging because of a combination of particular reaction and engineering sensitivities. These aspects were addressed through a series of mechanistic, range-finding, and mixing studies that enable... | 10.1021/acs.oprd.1c00239 | 0 |
Development of a Commercial Process for Odalasvir | Odalasvir is a selective inhibitor of hepatitis C virus NS5A protein, a key target for combination therapies. This paper describes the chemical process development for the synthesis of this active pharmaceutical ingredient and the improvements that were achieved over the medicinal chemistry route. Optimization of all o... | 10.1021/acs.oprd.1c00237 | 1 |
Manufacturing Process Development for Belzutifan, Part 1: A Concise Synthesis of the Indanone Starting Material | A four-step synthesis of the indanone core of belzutifan (MK-6482) is described. This route starts from the commodity raw material dihydrocoumarin and was successfully demonstrated on a large scale to produce indanone 11 in the synthesis of belzutifan, an FDA-approved first-in-class therapy for the treatment of patient... | 10.1021/acs.oprd.1c00236 | 0 |
Manufacturing Process Development for Belzutifan, Part 3: Completing a Streamlined Through-Process with a Safe and Scalable Oxidation | We report the development of a modified Kornblum oxidation mediated by 2-picoline N -oxide for the synthesis of belzutifan that circumvented safety and stench problems associated with the original clinical supply route conditions. A robust quench for the crude bromination stream with 1,3-dimethoxybenzene and 2,6-lutidi... | 10.1021/acs.oprd.1c00232 | 0 |
Manufacturing Process Development for Belzutifan, Part 4: Nitrogen Flow Criticality for Transfer Hydrogenation Control | A scalable and efficient synthesis of hydroxyindanone 3, a key intermediate for belzutifan (MK-6482), is described. Mechanistic studies revealed the sensitivity of the reduction reaction toward the CO 2 byproduct. Special effort was required to design a scale-insensitive process for the removal of CO 2 with active nitr... | 10.1021/acs.oprd.1c00231 | 1 |
Preparative Synthesis of an <i>R</i><sub>P</sub>-Guanosine-3′,5′-Cyclic Phosphorothioate Analogue, a Drug Candidate for the Treatment of Retinal Degenerations | High Resolution Image Download MS PowerPoint Slide Cyclic guanosine monophosphorothioate analogue 1a is currently showing potential as a drug for the treatment of inherited retinal neurodegenerations. To support ongoing preclinical and clinical work, we have developed a diastereoselective synthesis via cyclization and ... | 10.1021/acs.oprd.1c00230 | 1 |
Scalable Process for Making 5,7-Dichlorotetrahydroisoquinoline-6-carboxylic Acid Using Methylene as the Protecting Group | The development of an industrially scalable synthetic route for 5,7-dichlorotetrahydroisoquinoline-6-carboxylic acid ( 1 ), a key starting material for lifitegrast, is described. This route includes the following features: (1) tetrahydroisoquinoline 19 was prepared in three steps from readily commercially available 3,5... | 10.1021/acs.oprd.1c00229 | 1 |
Scale-Up of a Continuous Manufacturing Process of Edaravone | Edaravone belongs to a class of brain-protective agents, which can scavenge free radicals. To reduce impurities and improve the yield, a continuous flow production process of edaravone was developed. The synthesis is continuously carried out in two steps. The throughput can reach 11.328 kg/day and the purity of the fin... | 10.1021/acs.oprd.1c00228 | 0 |
Homocoupling of a Grignard Reagent toward the Synthesis of 2,2′-Bis(trifluoromethyl)-4,4′-diaminobiphenyl | A new process for the synthesis of 2,2′-bis(trifluoromethyl)-4,4′-diaminobiphenyl (TFMB) comprising three steps has been industrially developed. The first step is the homocoupling of the Grignard reagent derived from 1-chloro-2-(trifluoromethyl)benzene with iron chloride(III) in the presence of an oxidizing agent to af... | 10.1021/acs.oprd.1c00227 | 0 |
Finkelstein Reaction in Non-polar Organic Solvents: A Streamlined Synthesis of Organic Iodides | The Finkelstein reaction of organic halides was found to proceed smoothly in non-polar organic solvents other than acetone when operated in the presence of a catalytic amount of tetra- n -butylammonium bromide and water. The new protocol was successfully applied to a preparation of ethyl 5-iodopentanoate from the corre... | 10.1021/acs.oprd.1c00226 | 0 |
Crystallization-Based Synthetic Route to Antimalarial Agent BRD5018: Diazocene Ring Formation via a Staudinger-aza-Wittig Reaction on an Azetidine-Ribose Template | The development of an entirely crystallization-based synthetic route to the antimalarial BRD5018 is described, which assembles a structurally complex bicyclic azetidine scaffold adorned with five stereogenic centers without the need for any chromatographic separations. A diastereoselective glycine ester Claisen rearran... | 10.1021/acs.oprd.1c00225 | 1 |
Synthesis of BACE1 Inhibitors <b>E2609</b>/<b>E2071</b> via Oxime–Olefin Cycloaddition Following a Process Risk Mitigation Strategy | Process development of E2609 from the preclinical stage to the clinical stage following a process risk mitigation strategy is described here. Key features include a turbo Grignard reaction monitored by in-situ IR, [3 + 2] cycloaddition in water, chemoselective amide coupling via in-situ protection, and a Reformatsky/de... | 10.1021/acs.oprd.1c00223 | 1 |
Toward a Practical, Nonenzymatic Process for Investigational COVID-19 Antiviral Molnupiravir from Cytidine: Supply-Centered Synthesis | A scalable four-step synthesis of molnupiravir from cytidine is described herein. The attractiveness of this approach is its fully chemical nature involving inexpensive reagents and more environmentally friendly solvents such as water, isopropanol, acetonitrile, and acetone. Isolation and purification procedures are im... | 10.1021/acs.oprd.1c00219 | 1 |
Efficient Synthesis of (<i>S</i>)-1-Boc-3-aminopiperidine in a Continuous Flow System Using ω-Transaminase-Immobilized Amino-Ethylenediamine-Modified Epoxide Supports | We developed a continuous flow system using ω-transaminase covalently immobilized on an epoxy resin modified with ethylenediamine (EDA) to synthesize ( S )-1-Boc-3-aminopiperidine, which is a key intermediate for several novel inhibitors. A second functional group (−NH 3 + ) was introduced to rapidly adsorb ω-transamin... | 10.1021/acs.oprd.1c00217 | 0 |
Development of a High-Throughput Kinetics Protocol and Application to an Aza-Michael Reaction | High-throughput experimentation (HTE) has become integral to the pharmaceutical industry with most major pharmaceutical companies investing in automation and high-throughput screening technologies. Testing hundreds of reactions in parallel has distinct advantages; however, one clear disadvantage is that performing a re... | 10.1021/acs.oprd.1c00213 | 0 |
Practical Kilogram Synthesis of (<i>S</i>)-1-Benzyl-4-Bromo-3-Methyl-1,2,3,6-Tetrahydropyridine | Despite chiral piperidines being a commonly found motif in approved drugs and drug candidates, the synthesis of these compounds occasionally suffers from challenges of scalability and stereochemical control. As part of a medicinal chemistry program, we sought access to a series of stereochemically pure 3,4-disubstitute... | 10.1021/acs.oprd.1c00212 | 0 |
Unconventional Synthetic Process of Fasudil Hydrochloride: Costly Homopiperazine Was Avoided | An efficient, robust, and cost-effective synthetic process of fasudil hydrochloride 1 was developed. Starting from readily available ethylenediamine and 5-isoquinoline sulfonyl chloride, the target product 1 was prepared through a six-step reaction, including sulfonamidation, protection, nucleophilic substitution, depr... | 10.1021/acs.oprd.1c00211 | 1 |
Advancing Base-Metal Catalysis: Development of a Screening Method for Nickel-Catalyzed Suzuki–Miyaura Reactions of Pharmaceutically Relevant Heterocycles | Interest in replacing palladium catalysts with base metals resulted in the development of a 24-reaction screening platform for identifying nickel-catalyzed Suzuki–Miyaura reaction conditions. This method was designed to be directly applicable to process scale-up by employing homogeneous reaction conditions alongside st... | 10.1021/acs.oprd.1c00210 | 0 |
Synthesis of Enantiopure Unnatural Amino Acids by Metallaphotoredox Catalysis | We describe herein a two-step process for the conversion of serine to a wide array of optically pure unnatural amino acids. This method utilizes a photocatalytic cross-electrophile coupling between a bromoalkyl intermediate and a diverse set of aryl halides to produce artificial analogues of phenylalanine, tryptophan, ... | 10.1021/acs.oprd.1c00208 | 0 |
Practical Gas Cylinder-Free Preparations of Important Transition Metal-Based Precatalysts Requiring Gaseous Reagents | A simple and safe setup for the synthesis of a selection of important transition metal-based precatalysts is reported, all requiring low-molecular weight gaseous reagents for their preparation. Hydrogen, carbon monoxide, ethylene, and acetylene are each liberated in a controlled manner from a corresponding easy-to-hand... | 10.1021/acs.oprd.1c00205 | 0 |
Accelerated Development of a Scalable Synthesis of CY6463, a CNS-Penetrant sGC Stimulator for the Treatment of Neurodegenerative Diseases | High Resolution Image Download MS PowerPoint Slide Soluble guanylate cyclase (sGC) stimulators are small molecules that increase nitric oxide (NO) signaling by binding to sGC, leading to an increase in cyclic guanosine monophosphate production. Such compounds have previously been studied clinically for noncentral nervo... | 10.1021/acs.oprd.1c00204 | 1 |
Hydrogen Evolution from Telescoped Miyaura Borylation and Suzuki Couplings Utilizing Diboron Reagents: Process Safety and Hazard Considerations | The hazard assessment of a telescoped Miyaura borylation and Suzuki coupling reaction employing bis(pinacolato)diboron (BisPin), used in the developmental synthesis of an intermediate for abemaciclib, led to the observation of hydrogen being generated. Quantitative headspace GC and solution 11 B NMR were used to show t... | 10.1021/acs.oprd.1c00198 | 0 |
Practical Synthesis of (+)-Biotin Key Intermediate by Calcium Borohydride Reduction and Temperature-Dependent Purity Upgrade during Crystallization | An expedient synthesis of a key intermediate for (+)-biotin has been accomplished through high-yielding reduction of chiral imide with calcium borohydride and efficient isolation of the desired isomer by crystallization at a specific temperature where only undesired isomer was converted to soluble anhydrate while the d... | 10.1021/acs.oprd.1c00196 | 1 |
Investigating the Activation Kinetics of Phosphoramidites for Oligonucleotide Synthesis | Solid-phase synthesis of oligonucleotides relies on a repeating cycle of rapid and well-defined synthetic steps to generate the target sequence. It is recognized that the underlying skeleton of the nucleotide influences the rates of the coupling reactions when the phosphoramidite coupling method is used. Using both in-... | 10.1021/acs.oprd.1c00195 | 0 |
Early Development and Kilogram Scale-Up of a Non-steroidal FXR Agonist for the Treatment of Non-alcoholic Steatohepatitis (NASH) | Non-alcoholic steatohepatitis (NASH) is a serious chronic liver disease characterized by progressive fibrosis that can lead to cirrhosis, liver failure, and death. Compound 1 is a farnesoid X receptor (FXR) agonist that was investigated for use as a treatment for NASH. This paper describes process development efforts e... | 10.1021/acs.oprd.1c00193 | 1 |
Development of a Scalable Lanthanide Halide/Quaternary Ammonium Salt System for the Nucleophilic Addition of Grignard Reagents to Carbonyl Groups and Application to the Synthesis of a Remdesivir Intermediate | This manuscript describes the development and implementation of a scalable additive system, consisting of a lanthanide salt and a solubilizing quaternary ammonium salt, to improve the yield and robustness of the addition of an organomagnesium reagent to a ribonolactone en route to remdesivir. This system was found to b... | 10.1021/acs.oprd.1c00191 | 0 |
Efficient Biocatalytic Synthesis of (<i>R</i>)-2-Chloro-1-(3,4-difluorophenyl)ethanol by the Short-Chain Dehydrogenase <i>Pp</i>KR8 from <i>Paraburkholderia phymatum</i> STM815 | Bioreductions catalyzed by ketoreductases play an important role in the synthesis of chiral alcohols. However, the synthesis of ( R )-2-chloro-1-(3,4-difluorophenyl)ethanol (24b), an important chiral intermediate for the synthesis of the anticoagulant ticagrelor, poses significant challenges in terms of high substrate ... | 10.1021/acs.oprd.1c00189 | 0 |
Daisy-Chaining Photo- and Thermal Chemistry: Multistep Continuous Flow Synthesis of Visible-Light-Mediated Photochemistry with a High-Temperature Cascade Reaction | A highly efficient visible-light-mediated photochemical [2 + 2] cycloaddition is coupled with an atom economic thermal cascade reaction in a continuous flow process. By moving the photochemistry from ultraviolet (UV) to visible, it is made more energy-efficient and can be conducted with readily available equipment. The... | 10.1021/acs.oprd.1c00187 | 0 |
Discovery and Development of an Unusual Organocatalyst for the Conversion of Thymidine to Furanoid Glycal | Our work required a reliable efficient preparation of 2-trimethylsilyloxymethyl((2 R,3 S )-3-(trimethylsilyloxy)-2,3-dihydrofuran (glycal 1 ). The best literature protocol for the preparation of this dihydrofuran glycal is the treatment of thymidine with 20 mol % (NH 4 ) 2 SO 4 in (TMS) 2 NH (HMDS) at reflux. Unfortuna... | 10.1021/acs.oprd.1c00186 | 0 |
A Holistic Strategy for Cyanide Control and Safety for Pharmaceutical Manufacturing | The manufacturing route toward gefapixant citrate generates a trace amount of cyanide as a byproduct of a reaction employing the reagent chloroacetonitrile. In the development of a cyanide control strategy, conventional process and analytical approaches fell short because of challenges and incompatibilities with the ma... | 10.1021/acs.oprd.1c00185 | 1 |
Facile and Cost-Effective Route for the Synthesis of Simmerafil | An improved synthesis of simmerafil, a potent PDE5 inhibitor as a clinical candidate, is described with a 38.1% overall yield and 99.7% purity. Starting from the safe and inexpensive salicylamide ( 15 ), the key intermediate 2-propoxybenzimidamide ( 21 ), which is also a potential precursor for the preparation of pyrim... | 10.1021/acs.oprd.1c00184 | 1 |
Kilogram-Scale Synthesis of 2′-<i>C</i>-Methyl-<i>arabino</i>-Uridine from Uridine via Dynamic Selective Dipivaloylation | We report a practical 3′,5′-diprotection strategy suitable for the kilogram-scale preparation of 2′- C -methyl- arabino -uridine, a key intermediate in the synthesis of the HCV NS5B inhibitor uprifosbuvir. Starting from uridine, dipivaloylation afforded an ∼2:1 mixture of 3′,5′- and 2′,5′-dipivaloyluridine. Subjecting ... | 10.1021/acs.oprd.1c00175 | 1 |
Experiment and Simulations for the Thermal Safety of the Nitration Reaction Liquid of the Final State in the Synthesis Process of <i>N</i>-Nitrodihydroxyethyl Dinitrate (DINA) | In the synthesis process of N -nitrodihydroxyethyl dinitrate (DINA) with the HNO 3 –Mg(NO 3 ) 2 method, the thermal stability of the nitration reaction liquid of the final state is poor, which leads to the thermal runaway of the entire reaction system easily. The research on the thermal runaway reaction under actual re... | 10.1021/acs.oprd.1c00172 | 0 |
Large-Scale Cyclopropanation of Butyl Acrylate with Difluorocarbene and Classical Resolution of a Key Fluorinated Building Block | To address challenges in the preparation of a key building block containing a difluorocyclopropane moiety, we have developed a new protocol for difluorocarbene generation that relies on a Krapcho-type dealkylation of ethyl bromodifluoroacetate (EBDFA), an inexpensive and readily available fluorinated feedstock. Applica... | 10.1021/acs.oprd.1c00171 | 0 |
Nitrosamine Reactivity: A Survey of Reactions and Purge Processes | Drug recalls have led to increased regulatory scrutiny into the formation and presence of nitrosamine ( N -nitrosoamine) impurities in medicines. This review aims to assist the development of risk mitigation strategies by summarizing known reactions of nitrosamines, with a focus on reactions useful within the context o... | 10.1021/acs.oprd.1c00162 | 0 |
From Screening to Scale-Up: The DoE-Based Optimization of Electrochemical Reduction of <scp>l</scp>-Cystine at Metal Cathodes | Design of experiment (DoE) is a powerful statistical tool in establishing improved chemical processes. An optimization and scale-up of the electrochemical reduction of l -cystine to l -cysteine is presented. Subsequent to an electrode screening of 17 metals and alloys in divided batch-type cells, the lead electrode was... | 10.1021/acs.oprd.1c00153 | 0 |
DMF-Assisted Iodination Side Reaction during the Preparation of Disulfide Peptides, Its Substrate/Solvent/pH Dependence, and Implications on Disulfide-Peptide Production | Severe iodination of a disulfide peptide molecule (peptide D) was detected from the on-resin disulfide cyclization process. LC/MS/MS results indicated that iodination occurred on the Thi (thienylalanine) residue. Systematic investigation revealed that the iodination reaction occurred predominantly in the I 2 /DMF-media... | 10.1021/acs.oprd.1c00151 | 0 |
Optimization and Development of a Scalable Palladium-Catalyzed C–H Activation Process for the Geometry-Selective Preparation of Kilograms of YLF466D, a Potent AMP-Activated Protein Kinase Activator | Adenosine 5′-monophosphate-activated protein kinase (AMPK) activator YLF466D is a promising preclinical drug candidate to treat metabolic diseases and myocardial ischemia-reperfusion injury (MIRI). Herein, we report our efforts on optimization and development of a practical and scalable process for the preparation of Y... | 10.1021/acs.oprd.1c00150 | 0 |
Development of a Practical Manufacturing Process to Relebactam via Thorough Understanding of the Origin and Control of Oligomeric Impurities | The development of a robust manufacturing process to relebactam, a potent β-lactamase inhibitor, is described. The origin and control strategy of oligomer impurities formed during hydrogenolysis of benzyl urea intermediate 9 and deprotection of Boc-sulfate intermediate 11 have been thoroughly studied and developed. The... | 10.1021/acs.oprd.1c00149 | 1 |
Application of a Statistical Approach to Process Development of Futibatinib by Employing Quality-by-Design Principles. Part 3: Development of Design Space for Control of Particle Size Distribution | This study constructs a control strategy with a design space of the particle size distribution for futibatinib using a design of experiment and statistical approach without an additional milling process to save resources for validating consistency and equivalence. First, an L 12 orthogonal experiment of the Plackett–Bu... | 10.1021/acs.oprd.1c00147 | 0 |
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