title string | abstract string | doi string | has_route int64 |
|---|---|---|---|
Case-Based Thermal Safety Evaluation on a Pharmaceutical Process Using Dimethyl Sulfoxide as a Solvent | A rupture disc burst was recorded when conducting a calorimetric test by sensitive detection of exothermic reaction. The tested sample was a reaction mixture from a hydroamination process containing the solvent dimethyl sulfoxide (DMSO). Subsequent investigation indicated that the event was caused by the strong autocat... | 10.1021/acs.oprd.0c00472 | 0 |
Development of a Scalable and Sublimation-Free Route to MTAD | The cyclic azodicarbonyl 4-methyl-1,2,4-triazoline-3,5-dione (MTAD) is a versatile and powerful reagent used mainly in cycloaddition chemistry. Though known for more than 50 years, its unsafe preparation, as well as purification by sublimation, hampered its widespread applicability on a larger scale. Herein we report a... | 10.1021/acs.oprd.0c00470 | 1 |
Development of a Scalable Method for Manufacturing the Central Core of CD73 Inhibitor AB680 | AB680 is a highly potent CD73 small molecule inhibitor discovered and developed by Arcus Biosciences, currently in clinical trials for the treatment of pancreatic cancer. Here, we report the development of a scalable and practical method for the manufacturing of the azaindazole central core. This synthesis features an ... | 10.1021/acs.oprd.0c00469 | 1 |
Heterogeneous Crystallization as a Process Intensification Technology in an Integrated Continuous Manufacturing Process for Pharmaceuticals | Continuous heterogeneous crystallization processes in mixed-suspension mixed-product removal (MSMPR) crystallizers of different configurations (e.g., single-stage cooling, multistage cooling, and multistage evaporative cooling) are developed, in which an active pharmaceutical ingredient (acetaminophen, APAP) is crystal... | 10.1021/acs.oprd.0c00468 | 0 |
Explosive Hazard Identification in Pharmaceutical Process Development: A Novel Screening Method and Workflow for Shipping Potentially Explosive Materials | When a material is identified as potentially capable of explosive propagation by the Yoshida correlation, process safety scientists have few options for semiquantitatively assessing the hazards associated with the use of that material. Oxygen balance calculations, the Rule of 6, and the United Nations (U.N.) explosive ... | 10.1021/acs.oprd.0c00467 | 0 |
Process Development and Protein Engineering Enhanced Nitroreductase-Catalyzed Reduction of 2-Methyl-5-nitro-pyridine | Reduction of aromatic nitro compounds to anilines is of great interest to the chemical industry. Biocatalytic reduction of nitroarenes has made it possible to effectively produce anilines by applying nitroreductase enzymes (NR) in combination with vanadium pentoxide. Herein, the NR-catalyzed reduction of 2-methyl-5-nit... | 10.1021/acs.oprd.0c00464 | 0 |
An Easy, Convenient, and Safe Process for the Synthesis of Lofexidine Hydrochloride | A very efficient, cost-effective, and easily scalable process for the synthesis of lofexidine hydrochloride ( 1 ), an alpha 2-adrenergic receptor agonist used for treating opioid withdrawal is presented. Process development allows the preparation of lofexidine hydrochloride ( 1 ) through a one-pot amidation/imidazoline... | 10.1021/acs.oprd.0c00453 | 1 |
Characterization of Propionyl Phosphate Hydrolysis Kinetics by Data-Rich Experiments and In-Line Process Analytical Technology | In-depth characterization of reaction kinetics often requires a considerable amount of experimental results under various conditions. Recent advances in data-rich experimentation enable the collection of sufficient data to investigate reactions with only a limited number of experiments. In this study, we developed a co... | 10.1021/acs.oprd.0c00451 | 0 |
Development of Scalable Routes to 1-Bicyclo[1.1.1]pentylpyrazoles | The application of bicyclo[1.1.1]pentanes (BCPs) as phenyl bioisosteres has garnered significant attention, as these structural motifs can improve the physiochemical profiles of drug candidates. Despite the potential of using 1-bicyclo[1.1.1]pentylpyrazoles (BCPPs) as 1-phenylpyrazole bioisosteres, this area remains un... | 10.1021/acs.oprd.0c00446 | 0 |
Preparation of Carbamates, Esters, Amides, and Unsymmetrical Ureas via Brønsted Acid-Activated <i>N</i>-Acyl Imidazoliums | We report the application of Brønsted acid–activated N- acyl imidazoliums as versatile intermediates in carbonyl transformations. The efficient and scalable procedure was validated on a diverse set of carbamates, esters, amides, and unsymmetrical ureas (21 examples, up to 91% yield). Additionally, we exemplify this met... | 10.1021/acs.oprd.0c00445 | 0 |
Development of a Scalable Synthesis of <i>trans</i>-4-Fluorocyclohexylamine via Directed Hydrogenation | Herein, a scalable and practical process to prepare trans -4-fluorocyclohexylamine hydrochloride ( 1a ) is described. By exploitation of the embedded gem -difluoride motif in the commercially available 4,4-difluorocyclohexanecarboxylic acid, a derived orthoester-masked acid underwent dehydrofluorination to provide the ... | 10.1021/acs.oprd.0c00444 | 1 |
Implementing Continuous Manufacturing for the Final Methylation Step in the AMG 397 Process to Deliver Key Quality Attributes | In this article, we describe the process development efforts to improve the final methylation step in the AMG 397 drug substance process, culminating in the execution of a Good Manufacturing Practice (GMP) continuous manufacturing process. During the development, batch kinetic studies and detailed NMR analysis of the f... | 10.1021/acs.oprd.0c00440 | 0 |
Synthesis of Rovafovir Etalafenamide (Part II): Dynamic Control for Successful Scale-Up of an Oxygen-Releasing Elimination Reaction Mediated by Oxone | As part of the synthesis of rovafovir etalafenamide, the development and manufacturing-scale demonstration of a dioxirane-mediated oxidative elimination is described. The reaction presented multiple control challenges, including simultaneous addition of two reagent streams, with monitoring and control of temperature an... | 10.1021/acs.oprd.0c00439 | 0 |
Large-Scale Synthesis of Eldecalcitol | Industrial-scale synthesis of eldecalcitol is described. AA highly diastereoselective epoxidation of p -methoxybenzyl (PMB) protected dienol at room temperature provides the key epoxide intermediate with a secondary hydroxyl group, which is alkylated with a triflate to set up all of the subunits at the C-1, C-2, and C-... | 10.1021/acs.oprd.0c00436 | 1 |
Safe and Expeditious Preparation of Ni(cod)<sub>2</sub>for Same-Day High-Throughput Screening | There is an ongoing effort in the catalysis community to replace precious metal catalysts with their base-metal congeners, especially by applied chemists. This is particularly true in the case of nickel and palladium, the latter of which has experienced supply shortages and a concomitant rise in price over the past yea... | 10.1021/acs.oprd.0c00435 | 0 |
Synthesis of Rovafovir Etalafenamide (Part III): Evolution of the Synthetic Process to the Phosphonamidate Fragment | Phosphonamidate 1 is a key fragment in the assembly of rovafovir etalafenamide, a novel nucleotide reverse transcriptase inhibitor under development at Gilead Sciences for the treatment of HIV infection. An early manufacturing route, relying on simulated moving bed (SMB) chromatography for the separation of phosphorus ... | 10.1021/acs.oprd.0c00428 | 1 |
Synthesis of Vixotrigine, a Voltage- and Use-Dependent Sodium Channel Blocker. Part 2: Development of a Late-Stage Process | As vixotrigine ( 1 ) entered a later clinical phase for trigeminal neuralgia ( Zakrzewska, J. M.; et al. Lancet Neurol. 2017, 16, 291−300), the development of a sustainable late-stage process was required to meet the supply needs for formulation optimization, phase 3 clinical trials, and registration stability batches ... | 10.1021/acs.oprd.0c00427 | 1 |
Development and Scale-Up of a Continuous Manufacturing Process for a Hydrazine Condensation Reaction | The development of a continuous manufacturing process for a hydrazine condensation reaction at high temperature is reported. This continuous process represents a safer approach to manufacture 3-phenyl-1 H -pyrazol-5-amine at scale and exhibits better impurity control compared to a traditional batch process. A controlle... | 10.1021/acs.oprd.0c00424 | 0 |
Stereoselective Synthesis of a<i>cis</i>-Cedrane-8,9-diol as a Key Intermediate for an Amber Odorant | The naturally occurring (−)-α-cedrene exhibits a weak woody and cedarlike odor. In contrast, cis -cedrene acetonide, which is a derivative of cedrene, is an extremely powerful semisynthetic aroma molecule. The current process starting from cedrene yields cis -cedrene acetonide in an overall yield of <20%. Herein, we re... | 10.1021/acs.oprd.0c00423 | 0 |
Process Research and Scale-Up Synthesis of 3-(4-Isobutyl-2-methylphenyl)propanal, a Safe and Uniquely Performing Perfumery Ingredient | Ever since the beginning of modern perfumery, muguet (lily-of-the-valley) notes have been sought after and are now found in varying doses in practically every perfume composition, accounting for the warm, soft, and comforting facets of many fragrances. Over the past decades, Lilial and Bourgeonal have evolved to become... | 10.1021/acs.oprd.0c00421 | 1 |
Accelerated Development of a Scalable Ring-Closing Metathesis to Manufacture AMG 176 Using a Combined High-Throughput Experimentation and Computational Modeling Approach | AMG 176 is a drug candidate in our oncology pipeline. Ring-closing metathesis (RCM) is a key reaction in the AMG 176 synthesis that is used to construct the 16-membered macrocycle. Process intensification was executed on a compressed timeline by combining high-throughput experimentation and computational analysis using... | 10.1021/acs.oprd.0c00416 | 0 |
Development of a Scalable Negishi Cross-Coupling Process for the Preparation of 2-Chloro-5-(1-(tetrahydro-2<i>H</i>-pyran-2-yl)-1<i>H</i>-pyrazol-5-yl)aniline | A scalable synthesis of 2-chloro-5-(1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazol-5-yl)aniline ( 1 ), a key intermediate in the synthesis of an immuno-oncology asset, is described. A Negishi cross-coupling between in situ generated heteroaryl zinc reagent 4 and 5-bromo-2-chloroaniline ( 3 ) catalyzed by Pd(Xantphos)Cl 2 ... | 10.1021/acs.oprd.0c00414 | 1 |
Characterization of a Novel Drying Technology for Continuous Processing of Cohesive Materials: An Ibuprofen Case Study | This work addresses the influence of several process parameters on the performance of a novel drying device (patent NL2020740B1). In the new dryer, the processed substance is conveyed through the grooves of a large rotor via an interlocking screw design. A gentle, forced flow is created, preventing agglomeration and at... | 10.1021/acs.oprd.0c00413 | 0 |
Merging Biocatalysis, Flow, and Surfactant Chemistry: Innovative Synthesis of an FXI (Factor XI) Inhibitor | The scalable synthesis of an FXI (Factor XI) inhibitor employing multiple emerging technologies is described. The reduction of ketone to chiral alcohol was established through a biocatalysis approach. The Suzuki–Miyaura cross-coupling reaction was facilitated by surfactant chemistry. A harsh hydrolysis of the nitrile w... | 10.1021/acs.oprd.0c00412 | 1 |
Development of a Continuous Crystallization Process of the Spironolactone Hydrate Form with a Turbidity-Based Level Control Method | In this study, a robust continuous antisolvent crystallization method was developed to produce the hydrate form of spironolactone. Continuous crystallizations were implemented in a one-stage mixed-suspension mixed-product removal crystallizer using a process turbidimeter as a fluid level sensor for the first time. The ... | 10.1021/acs.oprd.0c00409 | 0 |
Precise Preparation of a High-Purity Key Intermediate of Tazobactam | In situ IR was used to precisely prepare high-purity diphenylmethyl 6α-bromopenicillanate 8, a key intermediate of tazobactam. 8 was obtained when 6α-bromopenicillanic acid 2 reacted with diphenyldiazomethane (DDM). 2 is unstable and must therefore react immediately with DDM upon preparation. DDM is also unstable. As D... | 10.1021/acs.oprd.0c00407 | 1 |
Flow Chemistry Enabling Efficient Synthesis | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTFlow Chemistry Enabling Efficient SynthesisJohn R. Naber*John R. NaberMerck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United StatesInstitute of Chemistry, University of Graz, Heinrichstrasse 28, 8010 Graz, AustriaPharma Resource Group Inc., 1005 Ponti... | 10.1021/acs.oprd.0c00406 | 0 |
Developing a Multistep Continuous Manufacturing Process for (1<i>R</i>,2<i>R</i>)-2-Amino-1-methylcyclopentan-1-ol | A multistep continuous manufacturing process to synthesize (1 R,2 R )-2-amino-1-methylcyclopentan-1-ol ( 2 ) was developed. The step 1/2 flow process mitigated the safety hazard associated with high exothermicity during epoxidation, the epoxide-opening reaction, and the low onset of the epoxide intermediate. Process im... | 10.1021/acs.oprd.0c00405 | 1 |
Development of a Novel Chemoenzymatic Process for (<i>S</i>)-1-(Pyridin-4-yl)-1,3-propanediol | We first developed a novel and efficient chemoenzymatic process to prepare ( S )-1-(pyridin-4-yl)-1,3-propanediol, a vital HepDirect prodrug intermediate, from inexpensive and commercially available isonicotinic acid. Through this process, we provide a creative way to obtain the key chiral intermediate, β-hydroxyester,... | 10.1021/acs.oprd.0c00403 | 1 |
Scalable Continuous Synthesis of Organozinc Reagents and Their Immediate Subsequent Coupling Reactions | The continuous synthesis of organozinc reagents and their immediately following subsequent also continuous consumption in catalyzed and noncatalyzed coupling reactions were investigated. In the first step, a bed of Zn turnings at variable liquid throughputs and concentrations of organic halide solutions was used, and t... | 10.1021/acs.oprd.0c00399 | 0 |
Continuous Crystallization Processes in Pharmaceutical Manufacturing: A Review | This scientific paper presents an overview of continuous solution crystallization in the pharmaceutical industry. Since the specific knowledge spectrum of precipitation is very broad, topics covering the following were analyzed and assessed in detail: a comparison between batch and continuous crystallizers, their engin... | 10.1021/acs.oprd.0c00398 | 0 |
Scalable, Telescoped Hydrogenolysis–Enzymatic Decarboxylation Process for the Asymmetric Synthesis of (<i>R</i>)-α-Heteroaryl Propionic Acids | Enantiopure α-aryl propionic acids are useful building blocks for pharmaceutical research and can be accessed enzymatically using arylmalonate decarboxylases (AMDases) from the corresponding malonic acids. However, the intrinsic instability of malonic acids is a major drawback to this approach in which spontaneous deca... | 10.1021/acs.oprd.0c00397 | 1 |
Short Gram-Scale Synthesis of Sulfavant A | Recently, we reported the promising activity of a novel class of sulfoquinovosyl-diacylglycerols named Sulfavants as molecular vaccine adjuvants. Herein, we describe a modified and improved chemical synthesis of the lead product Sulfavant A ( 1 ), with the aim to produce from milligrams to 10 g of the pure compound tha... | 10.1021/acs.oprd.0c00393 | 1 |
High-Throughput Synthesis of (<i>S</i>)-α-Phellandrene through Three-Step Sequential Continuous-Flow Reactions | The combination of continuous-flow processing with heterogeneous catalysts allows for efficient, sustainable, multistep synthesis. Here, we report the continuous-flow synthesis of a valuable terpene product, phellandrene, from a readily available natural feedstock. The protocol consists of selective hydrogenation using... | 10.1021/acs.oprd.0c00391 | 1 |
Design and Commercialization of an End-to-End Continuous Pharmaceutical Production Process: A Pilot Plant Case Study | The pharmaceutical industry faces multiple challenges (e.g., inefficient manufacturing techniques, quality control issues, and supply chain vulnerabilities) because of its current batch-wise approach to manufacturing. Recent regulatory support for continuous manufacturing and advances in continuous process technologies... | 10.1021/acs.oprd.0c00383 | 0 |
Synthesis of Vixotrigine, a Use-Dependent Sodium Channel Blocker. Part 1: Development of Bulk Supply Routes to Enable Proof of Concept | Two syntheses of vixotrigine are reported. Route 1, adapted from the medicinal chemistry route, enabled rapid delivery of drug substance for clinical development. Route 2, which was developed to address many of the limitations of Route 1, was used to manufacture pilot quantities of API. Key features of Routes 1 and 2 a... | 10.1021/acs.oprd.0c00382 | 1 |
Crystallizing Fats? Development of a Scalable, Chromatography-Free Synthesis of Cationic Lipids | Research on the development of scalable routes to pharmaceutical intermediates typically proceeds from explorations of the chemistry to the identification of robust procedures for isolation. Although this order of investigation works well for typical small molecules possessing favorable physical properties and, therefo... | 10.1021/acs.oprd.0c00374 | 0 |
Design of a Kilogram Scale, Plug Flow Photoreactor Enabled by High Power LEDs | A simple and inexpensive photoreactor with a throughput of kilograms of material per day has been developed. This achievement was enabled by using high-power Light Emitting Diodes (LEDs) to provide high light density, leading to minimization of the footprint of the reactor. A study of the impact of tube diameter enable... | 10.1021/acs.oprd.0c00373 | 0 |
Continuous Flow <i>C</i>-Glycosylation via Metal–Halogen Exchange: Process Understanding and Improvements toward Efficient Manufacturing of Remdesivir | High Resolution Image Download MS PowerPoint Slide As remdesivir is the first approved treatment for COVID-19 (SARS-CoV-2), its production is likely to be of vital importance in the near future. Continuous flow processing has been demonstrated as a key technology in the manufacturing of high-volume active pharmaceutica... | 10.1021/acs.oprd.0c00370 | 0 |
Efficient Method for the Synthesis of Amino-1,3-Oxazines from Thioureas | The synthesis of a subtype-selective inhibitor BACE-1 inhibitor is presented. One of the key transformations in this sequence is the conversion of a thiourea to the bicyclic 1,3-aminooxazine. This article outlines the development and application of this method to the target molecule as well as further exploration of it... | 10.1021/acs.oprd.0c00369 | 1 |
Risk-Based Operation of a Continuous Mixed-Suspension-Mixed-Product-Removal Antisolvent Crystallization Process for Polymorphic Control | Innovations in the continuous crystallization field are required for the pharmaceutical industry to go through the paradigm shift from batch to continuous processing. To do so, different risks associated with the continuous crystallization have to be identified and discussed. In this work, a continuous antisolvent crys... | 10.1021/acs.oprd.0c00368 | 0 |
Development of a Nitrene-Type Rearrangement for the Commercial Route of the JAK1 Inhibitor Abrocitinib | The development of a commercial route toward the JAK1 inhibitor abrocitinib is described. The application of a late-stage Lossen rearrangement provided the desired cis -diaminocyclobutane, which was subsequently sulfonylated using a novel water-tolerable triazole sulfonylating reagent to provide the active pharmaceutic... | 10.1021/acs.oprd.0c00366 | 1 |
Toward the Scale-Up of a Bicyclic Homopiperazine via Schmidt Rearrangement and Photochemical Oxaziridine Rearrangement in Continuous-Flow | The scale-up of a chiral bicyclic homopiperazine of pharmaceutical interest was investigated. The outcome and safety profile of a key batch ring-expansion step via Schmidt rearrangement was improved using continuous-flow chemistry. The selectivity of nitrogen insertion for the ring expansion was improved via an alterna... | 10.1021/acs.oprd.0c00361 | 0 |
Process Development of Sotagliflozin, a Dual Inhibitor of Sodium–Glucose Cotransporter-1/2 for the Treatment of Diabetes | The development of an efficient manufacturing process for sotagliflozin (LX4211), a dual inhibitor of sodium–glucose cotransporter-1/2 (SGLT-1/2) for the treatment of diabetes, is described. Sotagliflozin features five contiguous chiral centers on the carbohydrate core flanked by a thioether group and a biaryl moiety. ... | 10.1021/acs.oprd.0c00359 | 1 |
Development of a Scalable Route for a Highly Polar Heterocyclic Aminocyclopropyl Building Block | A robust and scalable route toward key heterocyclic building block 1-(pyrimidin-2-yl)cyclopropan-1-amine hydrochloride from cyclopropanated starting material 1-amino-1-cyclopropanecarbonitrile hydrochloride was successfully developed. The key to success was the construction of a pyrimidine ring via cyclization from an ... | 10.1021/acs.oprd.0c00358 | 1 |
API Continuous Cooling and Antisolvent Crystallization for Kinetic Impurity Rejection in cGMP Manufacturing | Crystallization of 204 kg of final active pharmaceutical ingredient was accomplished continuously using a cascade of mixed suspension mixed product removal crystallizers in cGMP manufacturing. This article describes the journey taken to transform a set of technical to final batch crystallizations into a continuous, com... | 10.1021/acs.oprd.0c00345 | 0 |
A Primer for Pharmaceutical Process Development Chemists and Analysts in Relation to Impurities Perceived to Be Mutagenic or “Genotoxic” | Regulatory guidance on impurities is becoming increasingly comprehensive and complex. The advent of ICH M7(R1) on mutagenic impurities has introduced a significant and sophisticated toxicological component that can easily be underestimated by the unwary. The term “genotoxic impurity” was used in guidelines that predate... | 10.1021/acs.oprd.0c00343 | 0 |
Development of a Quality Risk Based Tool for the Selection of Regulatory Starting Materials for Commercial Drug Substance Manufacturing Processes | The selection of regulatory starting materials (RSMs) is a critical step in determining where the drug substance manufacturing process begins as it relates to the submission and approval of the commercial marketing application and with it the formal expectations for Good Manufacturing Practice (GMP) processing. The det... | 10.1021/acs.oprd.0c00341 | 0 |
Continuous Industrial-Scale Centrifugal Partition Chromatography with Automatic Solvent System Handling: Concept and Instrumentation | Centrifugal partition chromatography (CPC) is an emerging separation technology in pharmaceutical and natural product purifications, reaching recently industrial-scale solutions. Because both the stationary and mobile phases are liquids in CPC, the solvent consumption of such separation processes is considered signific... | 10.1021/acs.oprd.0c00338 | 0 |
Development of Scalable Synthesis of 5-Butyl-4-(4-methoxyphenyl)-6-phenylpyrimidin-2-amine (WQE-134), a Dual Inhibitor of Nitric Oxide and Prostaglandin E<sub>2</sub> Production | We report a scalable efficient synthesis of 5-butyl-4-(4-methoxyphenyl)-6-phenylpyrimidin-2-amine (WQE-134), a dual inhibitor of nitric oxide and prostaglandin E 2 production with potent anti-inflammatory properties. The original five-step synthesis (40% overall yield) was based on two Suzuki–Miyaura reactions and requ... | 10.1021/acs.oprd.0c00324 | 1 |
One-Pot Process for Synthesis of Nalbuphine Hydrochloride and Impurity Control Strategy | An improved kilogram-scale process of synthesis of nalbuphine was developed by investigating the critical parameters. Ten process-related impurities were identified, of which the source and control strategy was elucidated. Moreover, tetramethylammonium triacetoxyborohydride (Me 4 NBH(OAc) 3 ) was developed to reduce th... | 10.1021/acs.oprd.0c00321 | 0 |
Development of a Practical, Biocatalytic Synthesis of <i>tert</i>-Butyl (<i>R</i>)-3-Hydroxyl-5-hexenoate: A Key Intermediate to the Statin Side Chain | The HMG-CoA reductase inhibitors, statins, are one of the most effective and bestselling cholesterol-lowering drugs. The use of statins has greatly extended people’s lives and improved the quality of their life. Development of a more efficient, stereoselective, and sustainable synthesis of statins is continuingly of ut... | 10.1021/acs.oprd.0c00320 | 1 |
Bio- and Chemocatalysis for the Synthesis of Late Stage SAR-Enabling Intermediates for ROMK Inhibitors and MK-7145 for the Treatment of Hypertension and Heart Failure | A synthetic strategy to provide two late-stage intermediates for the synthesis of diverse analogues of ROMK inhibitors for the treatment of hypertension and heart failure is described. Key transformations include carbonylation of a bromoarene, regioselective vinyl ether Heck coupling and bromination, and asymmetric enz... | 10.1021/acs.oprd.0c00314 | 1 |
Development of Manufacturing Processes for the Carboxylic Acid Key Intermediate of Lusutrombopag: One-Pot Reaction Process of Formylation and the Horner–Wadsworth–Emmons Reaction | We describe the development of a one-pot preparation process of ( E )-3,5-dichloro-4-(3-ethoxy-2-methyl-3-oxoprop-1-en-1-yl)benzoic acid ( 3 ), which is a key carboxylic acid intermediate of lusutrombopag. This one-pot reaction process is composed of lithiation of 3,5-dichlorobenzoic acid with lithium diisopropylamide ... | 10.1021/acs.oprd.0c00311 | 0 |
Improvement of the <i>C</i>-glycosylation Step for the Synthesis of Remdesivir | High Resolution Image Download MS PowerPoint Slide The bulk supply of the antiviral C -nucleoside analogue remdesivir is largely hampered by a low-yielding C -glycosylation step in which the base is coupled to the pentose unit. Here, we disclose a significantly improved methodology for this critical transformation. By ... | 10.1021/acs.oprd.0c00310 | 1 |
Chemoenzymatic Process for the Preparation of (<i>S</i>)-7-((<i>tert</i>-Butyldiphenylsilyl)oxy)hept-1-yn-4-ol in a Continuous Packed-Bed Reactor, a Key Intermediate for Eribulin Synthesis | A practical chemoenzymatic process has been developed for the preparation of optically pure ( S )-7-(( tert -butyldiphenylsilyl)oxy)hept-1-yn-4-ol, ( S )- 4 . This was prepared via enantioselective acylation of racemic homopropargylic alcohol (+/−)- 4 catalyzed by Amano lipase from Pseudomonas fluorescens . The acylati... | 10.1021/acs.oprd.0c00308 | 0 |
Development of a Commercial Manufacturing Route to 2-Fluoroadenine, The Key Unnatural Nucleobase of Islatravir | We report the practical synthesis of a key fragment of islatravir (MK-8591), a novel nucleoside reverse transcriptase translocation inhibitor (NRTTI) currently under investigation for treatment and pre-exposure prophylaxis (PrEP) against HIV infection. The fragment, the unnatural nucleobase 2-fluoroadenine, is incorpor... | 10.1021/acs.oprd.0c00304 | 1 |
Simple Synthesis of Amides via Their Acid Chlorides in Aqueous TPGS-750-M | The technology of surfactant chemistry is employed for amide bond construction via the reaction of acyl chlorides with amines in 2 wt % TPGS-750-M aqueous solution. Specifically, this highly efficient method enables a chromatography-free scalable process and recycling of the TPGS-750-M solution. | 10.1021/acs.oprd.0c00303 | 0 |
Synthesis of a Crizotinib Intermediate via Highly Efficient Catalytic Hydrogenation in Continuous Flow | Kilogram-scale highly selective catalytic hydrogenation of the aryl nitro group in the intermediate of crizotinib has been developed, which adopted continuous-flow technology with prepassivated Raney Ni as a catalyst at room temperature. According to the reaction condition optimization, side reactions such as dehalogen... | 10.1021/acs.oprd.0c00302 | 1 |
Practical Synthesis of a Stable Precursor for Positron Emission Tomography Imaging Agent <sup>18</sup>F-GTP1 | 18 F-GTP1 is a deuterated small molecule positron emission tomography (PET) imaging agent used to visualize tau tangles in Alzheimer’s disease patients. The first-generation synthesis of 18 F-GTP1 ’s nonradiolabeled alkyl tosylate precursor was plagued by low-yielding steps, inefficient chromatographic purifications, a... | 10.1021/acs.oprd.0c00301 | 0 |
Facile Preparation of 4-(4-Nitrophenyl)morpholin-3-one via the Acid-Catalyzed Selective Oxidation of 4-(4-Nitrophenyl)morpholine by Sodium Chlorite as the Sole Oxidant | 4-(4-Nitrophenyl)morpholin-3-one and 4-(4-aminophenyl) morpholin-3-one are the key intermediates for rivaroxaban synthesis. A facile and economically efficient process has been developed for the preparation of these intermediates. Excellent yield of 4-(4-nitrophenyl)morpholine is obtained by condensing 4-chloro nitrobe... | 10.1021/acs.oprd.0c00299 | 1 |
Diethanolamine Boronic Esters: Development of a Simple and Standard Process for Boronic Ester Synthesis | Herein, we disclose the unique physical properties of diethanolamine (DEA) boronic esters that have facilitated the development of a simple and standard process for their synthesis and isolation using environmentally sustainable solvents. Moreover, their preparation is facile, robust, and scalable and can be telescoped... | 10.1021/acs.oprd.0c00296 | 0 |
Practical and Scalable Manufacturing Process for Plasma Kallikrein Inhibitor ASP5069 | The plasma kallikrein inhibitor ASP5069 is a promising drug candidate for the treatment of edema and hematoma and for the prevention of bleeding during surgery. Here, we report the development of a practical and scalable process for manufacturing ASP5069 that features a convergent synthetic approach, suppression of imp... | 10.1021/acs.oprd.0c00291 | 1 |
Use of High-Throughput Tools for Telescoped Continuous Flow Synthesis of an Alkynylnaphthyridine Anticancer Agent, HSN608 | Developing continuous syntheses of lead compounds to support in vivo studies and preclinical evaluation remains an underdeveloped area. We report a telescoped continuous flow synthesis of an alkynylnaphthyridine lead compound for the treatment of FLT3 mutations in acute myeloid leukemia. Different strategies were used ... | 10.1021/acs.oprd.0c00289 | 1 |
A General Kilogram Scale Protocol for Suzuki–Miyaura Cross-Coupling in Water with TPGS-750-M Surfactant | The development of a kilogram scale protocol for a Suzuki–Miyaura cross-coupling step toward the synthesis of the drug candidate LSZ102 is described. Particularly, the use of the surfactant TPGS-750-M in water as a medium for the transformation and its impact on the selectivity and quality are reported. Minimization of... | 10.1021/acs.oprd.0c00281 | 0 |
Development of an Efficient Scale-Up Synthesis Method for a β<sub>3</sub>-Adrenergic Receptor Agonist, Ritobegron Ethyl Hydrochloride | An efficient route for the multikilogram synthesis of a selective β 3 -adrenergic receptor agonist, ritobegron ethyl hydrochloride ( 1 ), was developed by changing the coupling method of 4-hydroxynorephedrine ( 2 ) with phenoxyacetate 3 . This new method successfully overcame several obstacles in the first-generation m... | 10.1021/acs.oprd.0c00278 | 1 |
Kinetic Parameter Estimation from Spectroscopic Data for a Multi-Stage Solid–Liquid Pharmaceutical Process | Laboratory and process measurements from spectroscopic instruments are ubiquitous in pharma processes, and directly using the data can pose a number of challenges for kinetic model building. Moreover, scaling up from laboratory to industrial level requires predictive models with accurate parameter values. This means th... | 10.1021/acs.oprd.0c00277 | 0 |
Kinetics, Thermodynamics, and Scale-Up of an Azeotropic Drying Process: Mapping Rapid Phase Conversion with Process Analytical Technology | Distillation processes with several solid-state phases and dynamic multicomponent liquid-phase compositions can be challenging to understand and scale up because of complexity of the thermodynamics combined with process dynamics and kinetics. Often, development scientists will eschew the most efficient process because ... | 10.1021/acs.oprd.0c00275 | 0 |
Drug Development through Modification of Small Molecular Drugs with Monodisperse Poly(ethylene glycol)s | Poly(ethylene glycol)s (PEGs) are the most used polymers in biomedicine, and their so-called “stealth” effects are the “gold standard” for biomaterials. However, the polydispersity in regular PEGs hampers their biomedical application, especially in modification of small molecular drugs (SMDs). To address this issue, ma... | 10.1021/acs.oprd.0c00273 | 1 |
Efficient Processing of Reactions Involving Diazonium Salts: Meerwein Arylation in an Impinging-Jet Reactor | This work reports a novel approach for performing high-throughput synthesis of Meerwein arylation in an impinging-jet reactor. The multistep reaction was performed in a single reactor via in situ diazonium salt generation followed by Meerwein arylation. The work involves many iterations between experiments and simulati... | 10.1021/acs.oprd.0c00271 | 0 |
Electrochemical Cyclobutane Synthesis in Flow: Scale-Up of a Promising Melt-Castable Energetic Intermediate | The design of a scalable, safe, and robust route to a promising energetic material containing a cyclobutane and four nitric ester groups is described. This route includes a streamlined preparation of a linear cyclobutane precursor, the use of safe methods for tetraester reduction and nitration, and the translation of a... | 10.1021/acs.oprd.0c00270 | 1 |
Synthesis of Dipentaerythritol from Pentaerythritol under Acidic Conditions | The direct synthesis of dipentaerythritol (DPE) from pentaerythritol (PE) was studied under acidic conditions. After optimization of the reaction parameters in a batch reactor, DPE was obtained with 50% selectivity when 50% PE was converted. This process, using PE in suspension in sulfolane (PE/sulfolane ratio = 2333 g... | 10.1021/acs.oprd.0c00269 | 0 |
An Improved Process for the Manufacture of 5′-<i>O</i>-(4,4′-Dimethoxytrityl)-<i>N</i><sup>2</sup>-isobutyryl-2′-<i>O</i>-(2-methoxyethyl)guanosine | A revised, optimized process for the manufacture of 5′- O -(4,4′-dimethoxytrityl)- N 2 -isobutyryl-2′- O -(2-methoxyethyl)guanosine (MOE G PNS) that controls critical impurities to less than 0.2% was developed. The 2′- O -alkylation of 2,6-diaminopurine riboside (DAPR) with 1-bromo-2-methoxyethane (MOE-Br) in DMSO was ... | 10.1021/acs.oprd.0c00261 | 0 |
Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264). Part 6: Development of an Improved Commercial Salt Formation Process | The development of a sustainable commercial salt formation process for gefapixant citrate (MK-7264), an investigational new P2X3 antagonist for the treatment of chronic cough, is described. Due to the low solubility of the gefapixant free base, the first-generation process for citrate salt formation was a slurry-to-slu... | 10.1021/acs.oprd.0c00260 | 0 |
Kinetic Investigations To Enable Development of a Robust Radical Benzylic Bromination for Commercial Manufacturing of AMG 423 Dihydrochloride Hydrate | 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 ... | 10.1021/acs.oprd.0c00256 | 1 |
Optimization and Scale-Up of the Continuous Flow Acetylation and Nitration of 4-Fluoro-2-methoxyaniline to Prepare a Key Building Block of Osimertinib | High Resolution Image Download MS PowerPoint Slide The development of a scalable telescoped continuous flow procedure for the acetylation and nitration of 4-fluoro-2-methoxyaniline is described. A subsequent batch deprotection then affords 4-fluoro-2-methoxy-5-nitroaniline, a key building block in the synthesis of osim... | 10.1021/acs.oprd.0c00254 | 0 |
Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 4: Formylation–Cyclization as a Flow–Batch Process Leads to Significant Improvements in Process Mass Intensity (PMI) and CO Generated versus the Batch–Batch Process | Gefapixant citrate (MK-7264) is a P2X3 antagonist for the treatment of chronic cough. The second generation manufacturing route developed for the Step 3A/3B formylation–cyclization reaction to generate the key intermediate diaminopyrimidine ( 1 ) (AF-072) required a significant excess of ethyl formate (EF), potassium t... | 10.1021/acs.oprd.0c00252 | 0 |
Mechanistic Understanding of a Robust and Scalable Synthesis of Per(6-deoxy-6-halo)cyclodextrins, Versatile Intermediates for Cyclodextrin Modification | Cyclodextrin (CD) perfunctionalization reactions are challenging to study because they proceed through a number of regioisomeric intermediates, thus warranting creative approaches to understanding the reaction mechanism. Particularly useful perfunctionalization targets are per(6-deoxy-6-halo)cyclodextrins. Their standa... | 10.1021/acs.oprd.0c00249 | 0 |
Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 1: Introduction and Process Overview | A robust, green, and sustainable manufacturing process has been developed for the synthesis of gefapixant citrate, a P2X3 receptor antagonist that is under investigation for the treatment of refractory and unexplained chronic cough. The newly developed commercial process features low process mass intensity (PMI), short... | 10.1021/acs.oprd.0c00248 | 0 |
Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264). Part 5: Completion of the API Free Base via a Direct Chlorosulfonylation Process | A scalable two-pot sulfonamidation through the process has been developed for the synthesis of gefapixant citrate, a P2X3 receptor antagonist that is under investigation for the treatment of refractory and unexplained chronic cough. Direct conversion of the diaryl ether precursor to a sulfonyl chloride intermediate usi... | 10.1021/acs.oprd.0c00247 | 0 |
Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 3: Development of a One-Pot Formylation–Cyclization Sequence to the Diaminopyrimidine Core | The development of a safe, robust, and efficient manufacturing route for the synthesis of diaminopyrimidine 1, a key intermediate to gefapixant citrate (MK-7264), is described. A full mechanistic understanding of the cyclization step in the presence of guanidine was established by performing isotopic labeling experimen... | 10.1021/acs.oprd.0c00246 | 0 |
Development of a Large-Scale Route to Glecaprevir: Synthesis of the Side Chain and Final Assembly | The preceding article described the development of the large-scale synthetic route to macrocycle 3 of glecaprevir ( 1 ), a potent HCV protease inhibitor. This article describes the development of the synthesis of the difluoromethyl-substituted cyclopropyl amino acid 4, its conversion to the fully elaborated side chain,... | 10.1021/acs.oprd.0c00245 | 1 |
Development of a Large-Scale Route to Glecaprevir: Synthesis of the Macrocycle via Intramolecular Etherification | Glecaprevir was identified as a potent hepatitis C virus (HCV) protease inhibitor, and a large-scale synthesis was required to support the late-stage clinical trials and subsequent commercial launch. The large-scale synthetic route to glecaprevir required the development of completely new synthetic approaches to the tw... | 10.1021/acs.oprd.0c00244 | 1 |
Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 2: Development of a Robust Process for Phenol Synthesis | Various synthetic routes to 2-isopropyl-4-methoxyphenol 3, the phenol core of Gefapixant citrate (MK-7264), are described, which provide better alternatives to the initial four-step supply route. These new routes include a coumarin fragmentation approach in flow, a rhenium-catalyzed isopropylation of mequinol, and a br... | 10.1021/acs.oprd.0c00241 | 0 |
Digital Design of Batch Cooling Crystallization Processes: Computational Fluid Dynamics Methodology for Modeling Free-Surface Hydrodynamics in Agitated Crystallizers | A framework for the digital design of batch cooling crystallization processes is presented comprising three stages, which are based on different levels of process complexity, integrating crystallizer hydrodynamics with crystallization kinetics and consequently with expected crystal size distribution. In the first stage... | 10.1021/acs.oprd.0c00240 | 0 |
Multikilogram per Hour Continuous Photochemical Benzylic Brominations Applying a Smart Dimensioning Scale-up Strategy | High Resolution Image Download MS PowerPoint Slide Although continuous flow technology can facilitate the scale-up of photochemical processes it is not yet routinely implemented on production scale in the fine chemical industries. This can be attributed to additional challenges compared to thermal processes, mostly in ... | 10.1021/acs.oprd.0c00239 | 0 |
Practical and Efficient Synthesis of 2-Thio-imidazole Derivative—<b>ZY12201</b>: A Potent TGR5 Agonist | Early scalable process development for the synthesis of ZY12201, a novel TGR5 receptor agonist, as a potential clinical candidate is described. A practical, efficient, and scalable synthetic route provided ZY12201 in seven steps and 32% overall yield. The key step involves an inexpensive acetic acid-mediated cyclizatio... | 10.1021/acs.oprd.0c00234 | 1 |
Quest for a COVID-19 Cure by Repurposing Small-Molecule Drugs: Mechanism of Action, Clinical Development, Synthesis at Scale, and Outlook for Supply | The outbreak of the COVID-19 pandemic has spurred an intense global effort to repurpose existing approved drugs for its treatment. In this review, we highlight the development of seven small-molecule drugs that are currently being assessed in clinical trials for the treatment of COVID-19. Three sections are presented f... | 10.1021/acs.oprd.0c00233 | 1 |
Development of a Scalable Synthesis of the Small Molecule TGFβR1 Inhibitor <b>BMS-986260</b> | A scalable route to the small molecule TGFβR1 inhibitor BMS-986260 ( 1 ) was developed. This alternative approach circumvented the purification of intermediates by column chromatography and provided access to multikilogram quantities of the key intermediate, 6 . The safety aspects of the synthetic approach to the other... | 10.1021/acs.oprd.0c00232 | 1 |
Development of a Scalable Synthesis of Mevidalen (LY3154207), an Orally Available Positive Allosteric Modulator of the Human Dopamine D1 Receptor | The evolution from early medicinal chemistry to large-scale production of the chemical synthesis of Lilly D1-positive allosteric modulator (PAM) mevidalen (LY3154207) and its hydroxybenzoate co-crystal is outlined. The issues and steps taken to resolve them are outlined across several generations of synthesis, includin... | 10.1021/acs.oprd.0c00229 | 1 |
3D Printed Reactors for Synthesis of Active Pharmaceutical Ingredients in Continuous Flow | Advances in flow chemistry to produce active pharmaceutical ingredients (APIs) require performing reactions in tailor-made equipment as complexity of the planned setups increases. To react quickly and with low costs to these demanding reactions, additive manufacturing, also known as 3D printing, is a preferred way for ... | 10.1021/acs.oprd.0c00228 | 0 |
Process Safety in the Pharmaceutical Industry—Part I: Thermal and Reaction Hazard Evaluation Processes and Techniques | High Resolution Image Download MS PowerPoint Slide Process safety groups in the pharmaceutical industry are important components of active pharmaceutical ingredient (API) development through its life cycle from discovery to commercial scale. The pharmaceutical process safety laboratory staff conduct a series of tests t... | 10.1021/acs.oprd.0c00226 | 0 |
Applications of Quantum Chemistry in Pharmaceutical Process Development: Current State and Opportunities | Application of computational methods to understanding and predicting properties of analogues for drug discovery has enjoyed a long history of success. However, the drug development space (post-candidate selection) is currently experiencing a rapid growth in this arena. Due to the revolution in computing hardware develo... | 10.1021/acs.oprd.0c00222 | 0 |
Toward a Scalable Synthesis and Process for EMA401, Part III: Using an Engineered Phenylalanine Ammonia Lyase Enzyme to Synthesize a Non-natural Phenylalanine Derivative | A process using an engineered phenylalanine ammonia lyase (PAL) enzyme was developed as part of an alternative route to a key intermediate of olodanrigan (EMA401). In the first part of this report, the detailed results from a screening for the optimal reaction conditions are presented, followed by a discussion of sever... | 10.1021/acs.oprd.0c00217 | 0 |
Toward a Scalable Synthesis and Process for EMA401, Part II: Development and Scale-Up of a Pyridine- and Piperidine-Free Knoevenagel–Doebner Condensation | During route scouting for EMA401 ( 1 ), an angiotensin II type 2 antagonist, we identified the synthesis of key amino acid intermediate 2 via its cinnamic acid derivative 3 as a streamlined option. In general, cinnamic acids can be synthesized from the corresponding aldehydes by a Knoevenagel–Doebner condensation in py... | 10.1021/acs.oprd.0c00216 | 0 |
Toward a Scalable Synthesis and Process for EMA401, Part I: Late Stage Process Development, Route Scouting, and ICH M7 Assessment | We present the enantioselective synthesis of sodium (3 S )-5-(benzyloxy)-2-(diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (EMA401, olodanrigan), an angiotensin II type 2 antagonist. The manuscript features the process optimizations of the end game used for late phase clinical supplies, an overv... | 10.1021/acs.oprd.0c00215 | 1 |
Practical and Efficient Approach to the Preparation of Diquafosol Tetrasodium | A scalable and practical route to synthesize the P2Y2 receptor agonist diquafosol tetrasodium has been described. Diquafosol tetrasodium was obtained via a four-step process starting from commercially available 5′-uridylic acid disodium salt. The whole procedure gives the target product in a 45% overall yield with high... | 10.1021/acs.oprd.0c00209 | 1 |
Mini-Monoplant Technology for Pharmaceutical Manufacturing | High Resolution Image Download MS PowerPoint Slide Pharmaceutical production has historically relied on multipurpose batch vessels in order to produce material through scheduled production campaigns. Although this method is flexible, it is becoming less effective in addressing the changing landscape of pharmaceutical p... | 10.1021/acs.oprd.0c00207 | 0 |
Improved Scale-up Synthesis and Purification of Clinical Asthma Candidate MIDD0301 | We report an improved and scalable synthesis of MIDD0301, a positive GABA A receptor modulator that is under development as oral and inhaled treatments for asthma. In contrast to other benzodiazepines in clinical use, MIDD0301 is a chiral compound that has limited brain absorption. The starting material to generate MID... | 10.1021/acs.oprd.0c00200 | 1 |
Multigram Synthesis of BMS-929075, an Allosteric, Palm Site Inhibitor of HCV NS5B Replicase, Involving the Synthesis of a Highly Functionalized Benzofuran through a Telescoped Process | An efficient scale-up synthesis of 4-fluoro-2-(4-fluorophenyl)- N -methyl-5-(2-methyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide ( BMS-929075 ), an allosteric, palm site inhibitor of the HCV NS5B replicase, is described. The highlights of the process involve (a) the copper-mediated, one-p... | 10.1021/acs.oprd.0c00198 | 1 |
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