title string | abstract string | doi string | has_route int64 |
|---|---|---|---|
Convenient Continuous Flow Synthesis of <i>N</i>-Methyl Secondary Amines from Alkyl Mesylates and Epoxides | The first continuous flow process was developed to synthesize N -methyl secondary amines from alkyl mesylates and epoxides via a nucleophilic substitution using aqueous methylamine. A variety of N -methyl secondary amines were produced in good to excellent yields, including a number of bioactive compounds or their prec... | 10.1021/acs.oprd.0c00193 | 0 |
Short and Easily Scalable Synthesis of the Sex Pheromone of the Horse-Chestnut Leaf Miner (<i>Cameraria ohridella</i>) Relying on a Key Ligand- and Additive-Free Iron-Catalyzed Cross-Coupling | We describe in this work a short six-step convergent high-scale synthesis of the sex pheromone of the horse-chestnut leaf miner ((8 E,10 Z )-tetradeca-8,10-dienal). This procedure relies on a key stereoselective iron-catalyzed Kumada cross-coupling, which affords the coupling product in high yield in the absence of add... | 10.1021/acs.oprd.0c00191 | 1 |
A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 3: Manganese-Catalyzed Asymmetric Epoxidation, Crystallization, and Filtration | This article describes the process characterization and development of models to inform a process control strategy to prepare ( R, R )-epoxy ketone 2, an intermediate in the manufacture of carfilzomib. Model calibration for relevant unit operations and the development of a dynamic integrated flowsheet-level model in gP... | 10.1021/acs.oprd.0c00189 | 0 |
A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 2: Enone Synthesis via a Barbier-Type Grignard Process | This article details efforts to characterize and develop a process control strategy for the manufacture of enone 2, a carfilzomib drug substance intermediate obtained through a Barbier-type Grignard reaction of morpholine amide 1 . This includes the development of a novel mechanistic model for the heterogeneous Barbier... | 10.1021/acs.oprd.0c00188 | 1 |
A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 1: CDI-Promoted Amide Bond Formation | This article details process characterization efforts and the development of corresponding process models to inform a process control strategy to produce a carfilzomib drug substance intermediate, morpholine amide 3 . Model calibration for relevant unit operations and development of a dynamic integrated flowsheet-level... | 10.1021/acs.oprd.0c00187 | 1 |
Development and Execution of a Production-Scale Continuous [2 + 2] Photocycloaddition | This article details the approach to large-scale production of cyclobutane 2 by the continuous-flow [2 + 2] photocycloaddition of maleic anhydride and ethylene, including (1) focused reaction optimization and development of a robust isolation protocol, (2) the approach to equipment design and process safety, and (3) th... | 10.1021/acs.oprd.0c00185 | 0 |
Optimized Synthesis of 7-Azaindazole by a Diels–Alder Cascade and Associated Process Safety | Although pyrimidines are not among the most reactive partners in intramolecular inverse-electron-demand [4π s + 2π s ] reactions with alkynes, they can be activated under mild and practical conditions, leading to fused nitrogen-containing heterocycles. We report an optimized synthesis of a 5-iodo-7-azaindazole by a one... | 10.1021/acs.oprd.0c00184 | 1 |
Evaluation and Screening of Spherical Pd/C for Use as a Catalyst in Pharmaceutical-Scale Continuous Hydrogenations | Over the past several years GSK has been developing the capability to perform continuous hydrogenations within trickle bed reactors. Motivation to develop this technology stems from the ability of trickle bed reactors to perform hydrogenations at high pressures (up to 100 bar within GSK), which is considerably greater ... | 10.1021/acs.oprd.0c00183 | 0 |
Practical and Scalable Synthesis of a Glucokinase Activator via One-Pot Difluorination and Julia Olefination | We describe the process research and development of a practical synthesis of glucokinase activator 1 as a potential drug for treating type 2 diabetes mellitus. The key structure, a 3,4- cis -difluorinated cyclopentane moiety, was constructed via diastereoselective epoxidation, followed by one-pot difluorination with Et... | 10.1021/acs.oprd.0c00180 | 1 |
Cost-Effective Flow Peptide Synthesis: Metamorphosis of HPLC | We present the further development and fine-tuning of an efficient, economic (≤3 equivalents of activated amino acid ), and environmentally friendly (6 mL organic waste/cycle) procedure for peptide synthesis using a fast amino acid coupling reaction (1.7 min). The designed setup can assist the synthesis of highly pure ... | 10.1021/acs.oprd.0c00178 | 0 |
Development of a Large-Scale Cyanation Process Using Continuous Flow Chemistry En Route to the Synthesis of Remdesivir | The implementation of cyanation chemistry at manufacturing scales using batch equipment can be challenging because of the hazardous nature of the reagents employed and the tight control of reaction parameters, including cryogenic temperatures, that help to afford acceptable selectivity and conversion for the desired re... | 10.1021/acs.oprd.0c00172 | 1 |
Development of a Zinc-Mediated Approach to a 2,3-<i>cis</i>-Pyrrolidine Arginase Inhibitor | This manuscript outlines the development activities toward a robust synthesis of cis -2,3-pyrrolidine via tandem zinc-enolate cyclization/Negishi coupling that proceeds with high diastereoselectivity. The methodology facilitated a gram-scale delivery of the target API and eliminated the need for costly chiral resolutio... | 10.1021/acs.oprd.0c00171 | 1 |
Supporting-Electrolyte-Free and Scalable Flow Process for the Electrochemical Synthesis of 3,3′,5,5′-Tetramethyl-2,2′-biphenol | The most efficient electrochemical synthesis of 3,3′,5,5′-tetramethyl-2,2′-biphenol by dehydrogenative coupling is reported. The electrolysis is performed supporting-electrolyte-free in 1,1,1,3,3,3-hexafluoroisopropanol and at carbon electrodes, whereby glassy carbon electrodes turned out to be superior. To provide suf... | 10.1021/acs.oprd.0c00170 | 0 |
Investigation of On-Resin Disulfide Formation for Large-Scale Manufacturing of Cyclic Peptides: A Case Study | Peptide molecules bearing disulfide moieties constitute an important category of therapeutics. The establishment of the disulfide structure plays a pivotal role in the production of those peptides. In-solution cyclization is generally adopted in industrial peptide production as a synthetic strategy to build disulfide f... | 10.1021/acs.oprd.0c00168 | 0 |
Preparation of Mono- and Diisocyanates in Flow from Renewable Carboxylic Acids | Diisocyanates used in polyurethanes are commonly prepared by phosgenation of petroleum-sourced diamines. This involves highly toxic phosgene and produces corrosive HCl, limiting synthetic applications. In our search for a renewable source for diisocyanates, we have developed a practical methodology for the production o... | 10.1021/acs.oprd.0c00167 | 1 |
A Structured Approach To Cope with Impurities during Industrial Crystallization Development | The perfect separation with optimal productivity, yield, and purity is very difficult to achieve. Despite its high selectivity, in crystallization unwanted impurities routinely contaminate a crystallization product. Awareness of the mechanism by which the impurity incorporates is key to understanding how to achieve cry... | 10.1021/acs.oprd.0c00166 | 0 |
Scalable Synthesis of Esp and Rhodium(II) Carboxylates from Acetylacetone and RhCl<sub>3</sub>·<i>x</i>H<sub>2</sub>O | Rhodium(II) carboxylates are privileged catalysts for the most challenging carbene-, nitrene-, and oxo-transfer reactions. In this work, we address the strategic challenges of current organic and inorganic synthesis methods to access these rhodium(II) complexes through an oxidative rearrangement strategy and a reductiv... | 10.1021/acs.oprd.0c00164 | 0 |
Chemical Reaction of Carbon Dioxide with Bisepoxides for Synthesis of Organic Cyclic Dicarbonates at Ambient Pressure for Polyhydroxy Urethane Synthesis | The synthesis of multifunctional cyclic carbonates starting from different epoxides will most likely be an important step to open an alternative way for an isocyanate-free formation of linear and cross-linked polyhydroxy urethanes. Within this contribution, we demonstrate the advantages of a cyclic-performed chemical f... | 10.1021/acs.oprd.0c00163 | 0 |
Development of a Versatile Modular Flow Chemistry Benchtop System | Flow chemistry devices have seen an increase as research tools in recent years. We present a modular system for benchtop continuous flow that allows user flexibility and reliability in the pursuit of challenging chemistry. An oscillating baffle reactor mold-formed in perfluoroalkoxy alkane enables handling reactions fo... | 10.1021/acs.oprd.0c00160 | 0 |
Seeking for Selectivity and Efficiency: New Approaches in the Synthesis of Raltegravir | The present work describes the development of an improved synthesis of active pharmaceutical ingredient raltegravir. The isolation of a new process intermediate and the newly developed conditions solve the issue of selectivity typical of this production process, with no need for the use of protecting groups, making the... | 10.1021/acs.oprd.0c00155 | 1 |
Two-Phase Flow in a Coiled Flow Inverter: Process Development from Batch to Continuous Flow | The transfer of batch processes to continuous flow is a major driver for the application of microreactors. Here, we present a methodology for the transfer of (bio)chemical reactions in batch mode to two-phase continuous flow. For our purposes, the coiled flow inverter (CFI) is a promising reactor design providing enhan... | 10.1021/acs.oprd.0c00152 | 0 |
Seeding Techniques and Optimization of Solution Crystallization Processes | Over the past few decades, seeding strategies for solution crystallization processes have been developed for various applications, and significant improvements in crystal quality and process robustness have been achieved. Here a systematic review of seeding techniques from the preparation and characteristics of seed cr... | 10.1021/acs.oprd.0c00151 | 0 |
Design and Characterization of a Scaled-up Ultrasonic Flow Reactor | Ultrasonic microreactors are increasingly applied to particle synthesis, crystallization processes, or organic synthesis involving solids because of the clogging prevention offered by ultrasound irradiation. However, the further application of this technology is limited by the scalability of ultrasonic flow reactors. I... | 10.1021/acs.oprd.0c00148 | 0 |
A Continuous Flow Sulfuryl Chloride-Based Reaction—Synthesis of a Key Intermediate in a New Route toward Emtricitabine and Lamivudine | We demonstrate a continuous two-step sequence in which sulfenyl chloride is formed, trapped by vinyl acetate, and chlorinated further via a Pummerer rearrangement. These reactions produce a key intermediate in our new approach to the oxathiolane core used to prepare the antiretroviral medicines emtricitabine and lamivu... | 10.1021/acs.oprd.0c00146 | 1 |
Synthesis of an Oxathiolane Drug Substance Intermediate Guided by Constraint-Driven Innovation | A new route was developed for construction of the oxathiolane intermediate used in the synthesis of lamivudine (3TC) and emtricitabine (FTC). We developed the presented route by constraining ourselves to low-cost, widely available starting materials-we refer to this as supply-centered synthesis. Sulfenyl chloride chemi... | 10.1021/acs.oprd.0c00145 | 1 |
Fully Automated Chemical Synthesis: Toward the Universal Synthesizer | Automated peptide and oligonucleotide synthesizers enabled a revolution in molecular biology and helped pave the way to modern synthetic biology. Similarly, fully automated synthetic chemistry could herald a new wave of innovation in biology and materials sciences by greatly facilitating access to known and novel molec... | 10.1021/acs.oprd.0c00143 | 0 |
Development and Production of an Enantioselective Tetrahydroisoquinoline Synthesis Enabled by Continuous Cryogenic Lithium–Halogen Exchange | Route invention, process development, and production of 185 kg of a key tetrahydroisoquinoline intermediate for the dopamine D1 receptor positive allosteric modulator mevidalen are reported. The synthesis leveraged widely commercially available chiral starting materials to build a challenging 1,3- trans -tetrahydroisoq... | 10.1021/acs.oprd.0c00141 | 1 |
Cross-Pharma Collaboration on the Development and Evaluation of a New Mid-Scale Preparative Supercritical Fluid Chromatography Instrument | Precompetitive collaborations on the development of new enabling technologies for conducting pharmaceutical research and development are becoming increasingly popular, as pharmaceutical companies recognize the economic and practical benefits of cross-industry collaborations. We report here one of the first new technolo... | 10.1021/acs.oprd.0c00136 | 0 |
Development and Execution of an Ni(II)-Catalyzed Reductive Cross-Coupling of Substituted 2-Chloropyridine and Ethyl 3-Chloropropanoate | We describe the development and scale-up of a nickel-catalyzed reductive cross-electrophile coupling reaction between a substituted 2-chloropyridine and ethyl 3-chloropropanoate using manganese dust as the terminal reductant. Several additives were screened for the activation of the manganese reductant in situ, and chl... | 10.1021/acs.oprd.0c00134 | 0 |
Semicontinuous Process for GMP Manufacture of a Carbapenem Intermediate via Carbene Insertion Using an Immobilized Rhodium Catalyst | A two-stage flow process for cGMP manufacture of a commercially important carbapenem intermediate was developed. Stage 1 featured an intramolecular N–H insertion reaction catalyzed by an immobilized rhodium catalyst. In stage 2, phosphorylation of the resulting keto ester intermediate afforded the target, which was iso... | 10.1021/acs.oprd.0c00133 | 0 |
Process Intensification for Obtaining a Cannabidiol Intermediate by Photo-oxygenation of Limonene under Continuous-Flow Conditions | We have investigated the synthesis of p -mentha-2,8-dien-1-ol ( 1 ) as a cannabidiol precursor by photochemical oxidation of ( R )-limonene ( 2 ) with singlet oxygen ( 1 O 2 ) using meso -tetraphenylporphyrin (TPP) as a photosensitizer. Different home-made engineered set-ups were used for reaction intensification. Unde... | 10.1021/acs.oprd.0c00131 | 0 |
Development of a Scalable and Practical Synthesis of AB928, a Dual A<sub>2a</sub>/A<sub>2b</sub> Receptor Antagonist | AB928 is a potent and selective dual antagonist of the A 2a and A 2b receptors, which is currently in clinical trials. Here, we report the development of two scalable and practical syntheses of AB928. The first-generation synthesis was used to successfully obtain AB928 in excellent yield and purity to support our precl... | 10.1021/acs.oprd.0c00124 | 1 |
Ketone Reductase Biocatalysis in the Synthesis of Chiral Intermediates Toward Generic Active Pharmaceutical Ingredients | A range of generic active pharmaceutical ingredients were examined for potential chiral alcohol motifs and derivatives within their structures that could be employed as key synthetic intermediates. For seven generic active pharmaceutical ingredients (APIs), eight precursor ketones were acquired and then subjected to re... | 10.1021/acs.oprd.0c00120 | 0 |
Enzymatic Preparation of the Chiral (<i>S</i>)-Sulfoxide Drug Esomeprazole at Pilot-Scale Levels | Esomeprazole is the most popular proton pump inhibitor (PPI) for treating gastroesophageal reflux disease. Enzymatic asymmetric sulfoxidation is a green approach to produce chiral sulfoxides. In this report, we focused on optimizing asymmetric sulfoxidation catalyzed by prazole sulfide monooxygenase ( Ac PSMO). The cos... | 10.1021/acs.oprd.0c00115 | 0 |
Practical Considerations and Examples in Adapting Amidations to Continuous Flow Processing in Early Development | Amidation is among the most frequently executed reactions in pharmaceutical research and development. We have explored the feasibility of adapting amidations to plug flow reactor (PFR) process conditions for the preparation of early development compounds. Among coupling reagents possessing good thermal stability, carbo... | 10.1021/acs.oprd.0c00112 | 0 |
Scalable Synthesis of <i>S</i>-Fluoromethyl Benzenesulfonothioate | A general and practical method for the preparation of S -fluoromethyl benzenesulfonothioate on a 500 g scale in two steps from readily available CH 2 FCl, sulfur, and sodium benzenesulfinate is reported. The reaction was found to be rather sensitive to water and temperature. Furthermore, the main side product of the re... | 10.1021/acs.oprd.0c00101 | 0 |
Design of a Continuous Solvent Recovery System for End-to-End Integrated Continuous Manufacturing of Pharmaceuticals | Disadvantages of the traditional batch process have encouraged the pharmaceutical industry to explore continuous manufacturing, including end-to-end approaches, such as integrated continuous manufacturing (ICM). As the pharmaceutical industry is relatively solvent-intensive, solvent recovery is necessary to achieve the... | 10.1021/acs.oprd.0c00092 | 0 |
Continuous Process for Preparing the Difluoromethylating Reagent [(DMPU)<sub>2</sub>Zn(CF<sub>2</sub>H)<sub>2</sub>] and Improved Synthesis of the ICHF<sub>2</sub> Precursor | Complex [(DMPU) 2 Zn(CF 2 H) 2 ] 1 is a crystalline organometallic reagent with utility in various catalytic difluoromethylation reactions under mild conditions. Unfortunately, this reagent is not commercially available and the procedure for the preparation of this air- and moisture-sensitive zinc complex has only been... | 10.1021/acs.oprd.0c00089 | 0 |
Efficient Asymmetric Synthesis of Ethyl (<i>S</i>)-4-Chloro-3-hydroxybutyrate Using Alcohol Dehydrogenase <i>Sm</i>ADH31 with High Tolerance of Substrate and Product in a Monophasic Aqueous System | Bioreductions catalyzed by alcohol dehydrogenases (ADHs) play an important role in the synthesis of chiral alcohols. However, the synthesis of ethyl ( S )-4-chloro-3-hydroxybutyrate [( S )-CHBE], an important drug intermediate, has significant challenges concerning high substrate or product inhibition toward ADHs, whic... | 10.1021/acs.oprd.0c00088 | 0 |
Process Development and Large-Scale Synthesis of BTK Inhibitor BIIB068 | Chemical process development efforts leading to multikilogram production of BIIB068 hemiadipate are discussed. Process optimization resulted in (1) removal of transition metal from the process, (2) a streamlined process with significantly improved overall yield, and (3) appropriate impurity control (including potential... | 10.1021/acs.oprd.0c00087 | 1 |
Continuous-Flow Synthesis of Cationic Lipid SST-01 via Safe and Scalable Aerobic Oxidation and Reductive Amination | The synthesis of the cationic lipid SST-01, a key component of Kyowa Kirin’s siRNA–lipid nanoparticles, through a two-step homogeneous continuous-flow process is described. Safe and scalable aerobic oxidation with a catalytic Cu I /TEMPO system and diluted oxygen (5% O 2 in N 2 ) was utilized in the first step to provi... | 10.1021/acs.oprd.0c00084 | 1 |
An Economical Route to Lamivudine Featuring a Novel Strategy for Stereospecific Assembly | An economical synthesis of lamivudine was developed by employing a new method to establish the stereochemistry about the heterocyclic oxathiolane ring. Toward this end, an inexpensive and readily accessible lactic acid derivative served the dual purpose of activating the carbohydrate's anomeric center for N-glycosylati... | 10.1021/acs.oprd.0c00083 | 1 |
Large-Scale Practical Synthesis of Boc-Protected 4-Fluoro-<scp>l</scp>-Proline | A large-scale synthesis process of N -Boc-4-fluoro- l -proline ( 1 ) from N -Boc-4-hydroxy- l -proline methyl ester ( 2 ) using nosyl fluoride ( 13 ) as a deoxyfluorinating agent has been developed. An eco-friendly and large-scale feasible process using a single solvent was developed to afford moderate yields of produc... | 10.1021/acs.oprd.0c00080 | 1 |
Scale-up and Optimization of a Continuous Flow Synthesis of an α-Thio-β-chloroacrylamide | Use of continuous flow processing to undertake a multistep chlorination cascade has been achieved with effective inline workup and end-of-line crystallization in batch, leading to isolation of α-thio-β-chloroacrylamide Z -3 in pure form from a complex reaction mixture, exploiting the advantage of efficient heat transfe... | 10.1021/acs.oprd.0c00079 | 0 |
An Efficient Synthesis of Tenofovir (PMPA): A Key Intermediate Leading to Tenofovir-Based HIV Medicines | Herein, we report further improvements to the synthesis of tenofovir 1, the precursor to tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF). Starting from acyclic precursor diaminomalononitrile 12, a four-step protocol to tenofovir 1 will allow for vertical integration for more manufacturers. ... | 10.1021/acs.oprd.0c00078 | 1 |
Synthesis Development of the Selective Estrogen Receptor Degrader (SERD) LSZ102 from a Suzuki Coupling to a C–H Activation Strategy | The development of the synthetic process to the selective estrogen receptor degrader (SERD) drug candidate LSZ102 from the medicinal chemistry synthesis to the streamlined large-scale manufacturing route is described. The synthesis of LSZ102 could be significantly improved in regard to overall yield, removal of all chr... | 10.1021/acs.oprd.0c00076 | 1 |
5-Hydroxymethylfurfural Synthesis in Nonaqueous Two-Phase Systems (NTPS)–PC-SAFT Predictions and Validation | The condensation reaction of fructose to 5-hydroxymethylfurfural (HMF) is acid-catalyzed, and it suffers from thermodynamic limitation of the conversion, poor kinetics, and consecutive reactions such as formation of humins from HMF. Different approaches exist to overcome these limitations. In this work, the combination... | 10.1021/acs.oprd.0c00072 | 0 |
Scale-Up Synthesis of IID572: A New β-Lactamase Inhibitor | The new potentially best-in-class β-lactamase inhibitor IID572 was discovered by a late-stage functionalization approach. An alternative synthesis was developed to satisfy the short-term material need for toxicological studies in animals. The new synthetic strategy was built on two key features, an intramolecular azome... | 10.1021/acs.oprd.0c00069 | 0 |
A Safer Synthesis of the Explosive Precursors 4-Aminofurazan-3-Carboxylic Acid and its Ethyl Ester Derivative | A safe and efficient one-pot synthesis of 4-aminofurazan-3-carboxylic acid and its hydrogen chloride gas-free conversion to the ethyl ester derivative are described. Previous syntheses of these intermediates were plagued with mischaracterization issues, low yields, and/or dangerous exothermic profiles. The safe scale-u... | 10.1021/acs.oprd.0c00068 | 1 |
Development of a Scalable and Safer Synthesis of Diazeniumdiolates | Although diazeniumdiolates (DAZDs) and the synthetic methods to access DAZDs were discovered over 50 years ago, the current methodology is not safe, has a limited substrate scope, and is not amenable to large-scale production. For example, a recent investigation utilizing the standard methodology to prepare DAZDs resul... | 10.1021/acs.oprd.0c00067 | 1 |
Photo-oxidation of Cyclopentadiene Using Continuous Processing: Application to the Synthesis of (1<i>R</i>,4<i>S</i>)-4-Hydroxycyclopent-2-en-1-yl Acetate | (1 R,4 S )-4-Hydroxycyclopent-2-en-1-yl acetate is a chiral small building block that was requested to advance several Pfizer programs into the clinic. Pfizer and Syncom partnered to develop a photo-oxidation process of cyclopentadiene using a flow approach followed by subsequent bis-acetylation of the meso diol and fi... | 10.1021/acs.oprd.0c00066 | 1 |
Nontraditional Application of the Photo-Fenton Process: A Novel Strategy for Molecular Construction Using Formamide and Flow Chemistry | Instead of destroying organic compounds, for the first time the photo-Fenton reaction was employed to construct them. Oxindole and spiro-oxindole scaffolds, which are frequently found in natural products, were selected as molecular targets. The development of a photochemical flow reactor employing the photo-Fenton reac... | 10.1021/acs.oprd.0c00057 | 0 |
<i>N</i>-Acyl-5,5-Dimethylhydantoins: Mild Acyl-Transfer Reagents for the Synthesis of Ketones Using Pd–PEPPSI or Pd/Phosphine Catalysts | N -Acyl-hydantoins have emerged as novel acyl-transfer reagents for the synthesis of ketones via selective N–C(O) cleavage. Herein, we report two new protocols for the cross-coupling of N -acyl-5,5-dimethylhydantoins using versatile and readily accessible Pd–PEPPSI or Pd/phosphine catalysts. The acyl Suzuki reactions a... | 10.1021/acs.oprd.0c00054 | 0 |
Continuous Process Improvement in the Manufacture of Carfilzomib, Part 2: An Improved Process for Synthesis of the Epoxyketone Warhead | The development and kilogram-scale demonstration of an improved process for the synthesis of the epoxyketone warhead of carfilzomib is described. Critical to the success of this process was: (1) development of a scalable asymmetric epoxidation protocol; (2) identification of a crystalline intermediate with improved phy... | 10.1021/acs.oprd.0c00052 | 0 |
Continuous Process Improvement in the Manufacture of Carfilzomib, Part 1: Process Understanding and Improvements in the Commercial Route to Prepare the Epoxyketone Warhead | Epoxyketone 4 is an isolated intermediate in the manufacturing route to the commercial proteasome inhibitor carfilzomib (Kyprolis). Commercial process development and optimization efforts toward the preparation of epoxyketone 4 highlighted several opportunities for process improvement. In this article, three case studi... | 10.1021/acs.oprd.0c00051 | 1 |
Continuous Safety Improvements to Avoid Runaway Reactions: The Case of a Chloro-Thiadiazole Intermediate Synthesis toward Timolol | Detailed process safety investigation of an old process revealed hidden, previously unnoticed danger. The synthesis of morpholine-adduct 2 was performed under reaction conditions very close to triggering a potentially dangerous runaway reaction. Process modifications such as dilution with an inert solvent allowed gaini... | 10.1021/acs.oprd.0c00048 | 0 |
Understanding API Static Drying with Hot Gas Flow: Design and Test of a Drying Rig Prototype and Drying Modeling Development | Developing a continuous isolation process to produce a pure, dry, free-flowing active pharmaceutical ingredient (API) is the final barrier to the implementation of continuous end-to-end pharmaceutical manufacturing. Recent work has led to the development of continuous filtration and washing prototypes for pharmaceutica... | 10.1021/acs.oprd.0c00035 | 0 |
Where Does the Fluorine Come From? A Review on the Challenges Associated with the Synthesis of Organofluorine Compounds | Fluorinated organic molecules are increasingly being prepared for a variety of applications, including pharmaceutical products. However, the supply chain to access the necessary raw materials, which originate primarily from calcium fluoride, is often not considered, may be difficult to access at commercial scale, and h... | 10.1021/acs.oprd.0c00030 | 1 |
Development of the Convergent, Kilogram-Scale Synthesis of an Antibacterial Clinical Candidate Using Enantioselective Hydrogenation | Early chemical development studies into the best way of assembling AZD9742, an antibacterial drug candidate, have involved swapping the order of two reductive aminations. The orthogonally functionalized aminopiperidine partner for these couplings is now enantioselectively synthesized using ruthenium-catalyzed asymmetri... | 10.1021/acs.oprd.0c00029 | 1 |
Development of an Efficient Synthetic Process for Broflanilide | This article describes the development of an efficient and scalable synthetic route to the novel insecticide broflanilide ( 1 ). This redesigned synthetic sequence starts from 2-fluoro-3-nitrobenzoic acid and 4-(perfluoropropan-2-yl)-2-(trifluoromethyl) aniline and provides the target product in a high overall yield th... | 10.1021/acs.oprd.0c00028 | 1 |
<scp>d</scp>-Serine as a Key Building Block: Enzymatic Process Development and Smart Applications within the Cascade Enzymatic Concept | An efficient enzymatic method catalyzed by an enzyme from the d -threonine aldolase (DTA) family was developed for d -serine production at industrial scale. This process was used for the synthesis of two valuable ketoses, l -erythrulose and d -fructose, within the cascade enzymatic concept involving two other enzymes. ... | 10.1021/acs.oprd.0c00024 | 0 |
What Elements Contribute to a High-Quality Continuous Processing Submission for <i>OPR&D</i>? | This editorial seeks to provide guidance to prospective OPR&D authors with respect to submissions involving continuous processing. Industrially relevant flow drivers are emphasized, along with increased attention to detail and holistic process awareness. Guidelines are provided for topics such as continuous process sca... | 10.1021/acs.oprd.0c00020 | 0 |
A Practical Synthesis of the TGFβRI Inhibitor <i>N</i>-(4-(3-(6-(Difluoromethyl)pyridin-2-yl)-1<i>H</i>-pyrrolo[3,2-<i>b</i>]pyridin-2-yl)pyridin-2-yl)acetamide via One-Pot Sequential Sonogashira and Cacchi Reactions Catalyzed by Pd(OAc)<sub>2</sub>/BINAP | N -(4-(3-(6-(Difluoromethyl)pyridin-2-yl)-1 H -pyrrolo[3,2- b ]pyridin-2-yl)pyridin-2-yl)acetamide ( 5 ) is a potent inhibitor of TGFβRI kinase that provides durable antitumor activity when combined with an anti-PD-1 antibody. In order to conduct a full range of preclinical studies, over 150 g of high-quality material ... | 10.1021/acs.oprd.0c00015 | 1 |
Process Development Overcomes a Challenging Pd-Catalyzed C–N Coupling for the Synthesis of RORc Inhibitor <b>GDC-0022</b> | Process development for a multi-kilogram-scale synthesis of GDC-0022, an inhibitor of retinoic acid receptor-related orphan receptor γ (RORc), is described. Delivery of the active pharmaceutical ingredient (API) relied on diastereoselective preparation of a six-membered sultam building block, as well as execution of it... | 10.1021/acs.oprd.0c00012 | 1 |
One-Pot Enzymatic Synthesis of Enantiopure 1,3-Oxathiolanes Using <i>Trichosporon laibachii</i> Lipase and the Kinetic Model | The dynamic covalent kinetic resolution protocol was efficiently used for the synthesis of the enantiopure (( R )-5-acetoxy-1,3-oxathiolan-2-yl)ethyl benzoate (P R ) from substrates 2-(phenylmethoxy)acetaldehyde (A), 1,4-dithiane-2,5-diol (B), and phenyl acetate (D) by a one-pot process with 99.6% conversion, 97.3% yie... | 10.1021/acs.oprd.0c00010 | 1 |
Total Synthesis of (+)-Oxo-tomaymycin | (+)-Oxo-tomaymycin, a naturally occurring substance of the pyrrolo-1,4-benzodiazepine family, was synthesized using a short and efficient route. The key construction of the seven-membered ring by amide bond formation was realized via a chemoselective Ar-NO 2 reduction using TiCl 3 under acidic conditions, followed by a... | 10.1021/acs.oprd.0c00009 | 1 |
Review of Synthetic Routes and Crystalline Forms of the Antiandrogen Oncology Drugs Enzalutamide, Apalutamide, and Darolutamide | This article reviews the synthetic routes and final crystalline forms of the recently approved antiandrogen drugs enzalutamide, apalutamide, and darolutamide, used for the treatment of prostate cancer. The patent literature was the primary source of information. | 10.1021/acs.oprd.0c00005 | 1 |
Reiterative Chiral Resolution/Racemization/Recycle (RRR Synthesis) for an Effective and Scalable Process for the Enantioselective Synthesis of a Dual IDO1/TDO2 Inhibitor Imidazoisoindole Derivative | Herein, we report an effective and scalable highly enantioselective synthesis of an 5H-imidazo[5,1- a ]isoindole derivative via an RRR-synthesis approach (resolution–racemization–recycle). Chiral resolution performed with the aid of 2,3-dibenzoyl- d -tartaric acid allowed the obtaining of the desired enantiomer in high... | 10.1021/acs.oprd.0c00004 | 1 |
New synthetic route to 2,2,6,6-tetraethylpiperidin-4-one: A key-intermediate towards tetraethyl nitroxides | null | 10.1016/j.tetlet.2019.151207 | 1 |
An improved route for the synthesis of Rolloamide B | null | 10.1016/j.tetlet.2016.07.044 | 1 |
Development of a Practical Synthesis of 4-[6-(Morpholinomethyl)-pyridin-3-yl]naphthalen-1-amine, a Key Intermediate for the Synthesis of BIRB 1017, a Potent p38 MAP Kinase Inhibitor | The development of synthetic routes to 4-[6-(morpholinomethyl)pyridin-3-yl]naphthalen-1-amine, the key intermediate of p38 MAP kinase inhibitor BIRB 1017, via (1) trialkylmagnesium ate complex mediated metalation and borylation followed by Suzuki coupling reactions and (2) pyridine-ring formation from a vinamidinium sa... | 10.1055/s-0032-1317790 | 1 |
Evolution of the Process for the Preparation of a Selective ErbB VEGF Receptor Inhibitor | An efficient synthetic route to the potent and selective ErbB VEGF receptor inhibitor, BMS-690514 ( 1 ) is described. Strategic modifications in both approach and procedure addressed several issues, which led to a safe, efficient, and economical process for the preparation of multi-kilogram quantities of 1 . The conver... | 10.1055/s-0032-1317540 | 1 |
A scalable and eco-friendly total synthesis of poly(ADP-ribose) polymerase inhibitor Olaparib | A scalable and eco-friendly total synthesis of PARP inhibitor. | 10.1039/d3gc02617e | 1 |
Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement | A convergent and robust synthesis of a developmental CCR1 antagonist is described using continuous flow technology. | 10.1039/c6gc03123d | 1 |
Practical and scalable one-pot synthesis of arbekacin | An efficient and scalable one-pot production process was developed to prepare arbekacin from dibekacin. | 10.1039/d3re00598d | 1 |
Rapid route design of AZD7594 | Multidisciplinary collaboration enables the rapid and efficient design and selection of an improved manufacturing route to a new potential medicine for the treatment of asthma. | 10.1039/c9re00118b | 1 |
A Convergent Synthesis of CGS23305, A Thromboxane Synthase Inhibitor | All articles of this category A convergent synthesis of CGS23305 was discovered. The route to the pyridine aldehyde intermediate 5 was reduced from four to two steps. The pyridine aldehyde was converted to the key pyridine aldehyde ester intermediate 7 via Miachel Addition of the N , N -diethylenamine 6 to ethyl acryla... | 10.1055/s-1999-3458 | 1 |
A New and Practical Synthesis of Vortioxetine Hydrobromide | A new and improved synthetic route to vortioxetine hydrobromide is established on a hectogram scale through three simple steps in 63% yield and with 99% purity (HPLC). The key step is the cyclization of the piperazine ring in the final step. Purification methods for the intermediates involved in the route are given. | 10.1055/s-0034-1380505 | 1 |
Efficient Route to Canagliflozin via Anhydroketopyranose | The development of an efficient route for the synthesis of Canagliflozin is reported. The anhydroketopyranose intermediate was isolated as a novel intermediate, which was used to prepare Canagliflozin API in high purity. | 10.1021/acs.orglett.2c00980 | 1 |
Total Synthesis of (+)-Aureol | A total synthesis of the marine sponge meroterpenoid (+)-aureol has been achieved in 12 steps (6% overall yield) from (+)-sclareolide. Key steps of the synthesis include a biosynthetically inspired sequence of 1,2-hydride and methyl shifts, and a biomimetic cycloetherification reaction. | 10.1021/ol301715u | 1 |
Total synthesis of diazonamide A | A total synthesis of the marine natural product diazonamide A (1) has been accomplished. This work features a highly stereoselective synthesis of the C(10) quaternary center and the central furanoindoline core enabled by an iminium-catalyzed alkylation-cyclization cascade. Additionally, a magnesium-mediated intramolecu... | 10.1039/c0sc00577k | 1 |
A synthesis of strychnine by a longest linear sequence of six steps | Strychnine is synthesized via a longest linear sequence of six steps from commercially available starting materials. Key steps include a base-mediated intramolecular Diels–Alder reaction of a tryptamine-derived Zincke aldehyde, a Ru-catalyzed trans-hydrosilylation of 1,4-butynediol, and a tandem Brook rearrangement/int... | 10.1039/c1sc00009h | 1 |
The First Total Synthesis of Racemic Chebulic Acid | Abstract The first total synthesis of racemic chebulic acid is reported, which is the aglycon of several antioxidant ingredients of the fruit of the Terminalia chebula tree. The route started with the straightforward preparation of an indanone‐based β‐oxoester from a benzaldehyde derivative (84 % over the first five st... | 10.1002/ejoc.202101508 | 1 |
Total Synthesis of Indolizidine (+)‐223A | Abstract We described the diastereoselective total synthesis of indolizidine (+)‐223A in 10 % overall yield over 14 steps starting from 6‐chlorohex‐2‐ynoate. Our strategy involved chain elongation through aldolization, the formation of the indolizidine skeleton by cyclization, and stereocontrolled hydrogenation. | 10.1002/ejoc.201101530 | 1 |
Second Generation Total Synthesis of (–)‐Preussochromone D | An improved enantioselective synthesis of the natural product (–)‐preussochromone D ( 3 ) and first insights into a possible route to the trans ‐preussochromones E and F are described. Starting from commercially available 5‐hydroxy‐4 H ‐chromen‐4‐one, two stereocenters are established via auxiliary controlled Michael a... | 10.1002/ejoc.202000465 | 1 |
Asymmetric Total Synthesis of Pinnaic Acid | Pinned together: Asymmetric total synthesis of pinnaic acid was accomplished through a stereospecific route that features as key steps a Pd-catalyzed trimethylenemethane (TMM) [3+2] cyclization, a four-step tandem hydrogenation–cyclization, and cross-olefin-metathesis reactions (see scheme). | 10.1002/anie.200701581 | 1 |
Scalable Enantioselective Total Synthesis of (−)‐Goniomitine | A scalable enantioselective total synthesis of (-)-goniomitine has been developed by using an iridium-catalyzed asymmetric hydrogenation of an exocyclic enone ester to control the configuration of the molecule. The synthesis begins from commercially available starting materials, and proceeds through an integrated asymm... | 10.1002/anie.201812822 | 1 |
Development of a Convergent Large-Scale Synthesis for Venetoclax, a First-in-Class BCL-2 Selective Inhibitor | The process development of a new synthetic route leading to an efficient and robust synthetic process for venetoclax (1: the active pharmaceutical ingredient (API) in Venclexta) is described. The redesigned synthesis features a Buchwald-Hartwig amination to construct the core ester 23c in a convergent fashion by connec... | 10.1021/acs.joc.8b02750 | 1 |
A Practical Synthesis of 5-Lipoxygenase Inhibitor MK-0633 | Practical, chromatography-free syntheses of 5-lipoxygenase inhibitor MK-0633 p-toluenesulfonate (1) are described. The first route used an asymmetric zincate addition to ethyl 2,2,2-trifluoropyruvate followed by 1,3,4-oxadiazole formation and reductive amination as key steps. An improved second route features an inexpe... | 10.1021/jo100561u | 1 |
Total Synthesis of the Sphingolipid Biosynthesis Inhibitor Fumonisin B<sub>1</sub> | The first total synthesis of the sphingolipid biosynthesis inhibitor fumonisin B(1) has been achieved. This convergent synthesis utilizes oxonia Cope rearrangements to prepare two key homoallylic alcohols, which are then functionalized to the primary components A and B for cross-coupling. Other highlights of our approa... | 10.1021/ja9009265 | 1 |
Twelve-Step Asymmetric Synthesis of (−)-Nodulisporic Acid C | A short, enantioselective synthesis of (-)-nodulisporic acid C is described. The route features two highly diastereoselective polycyclizations en route to the terpenoid core and the indenopyran fragment and a highly convergent assembly of a challenging indole moiety. Application of this chemistry allows for a 12-step s... | 10.1021/jacs.8b09965 | 1 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.