title string | abstract string | doi string | has_route int64 |
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Novel Analytical Approach to Quantify Reactive Potentially Mutagenic Sulfonate Ester Impurities in Pharmaceutical Compounds and Its Application in the Development of a Control Strategy for Nonaflate Impurities in Belzutifan Synthesis | Sulfonate esters are encountered frequently as impurities that are potentially mutagenic in different manufacturing processes producing active pharmaceutical ingredients (APIs) due to the widespread use of sulfonyl halide/anhydride or sulfonic acid as reagents in the processes. While a scientific risk assessment, based... | 10.1021/acs.oprd.2c00182 | 0 |
Scalable Synthesis of CVN424, an Inverse Agonist of the GPR6 Receptor | CVN424 is a drug candidate, which is being investigated in clinical trials for the treatment of motor fluctuations associated with Parkinson’s disease. We herein describe the process development of an efficient synthetic route that delivered several kilograms of the drug substance. The synthesis included diacylation of... | 10.1021/acs.oprd.2c00181 | 1 |
Tunable Microwave Flow System for Scalable Synthesis of Alkyl Imidazolium-type Ionic Liquids | A continuous flow auto-frequency tuning single-mode microwave reactor is disclosed as a powerful platform to synthesize alkyl imidazolium salts as ionic liquids/ionic liquid precursors in up to near-quantitative yields, 100–600 g h –1 productivities and record space-time yields. Challenges faced, including viscosity ch... | 10.1021/acs.oprd.2c00180 | 0 |
Biocatalysis: Improving Enzymatic Processes through Protein and Reaction Engineering | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTBiocatalysis: Improving Enzymatic Processes through Protein and Reaction EngineeringCarlos A. Martinez*Carlos A. MartinezBiocatalysis Center of Excellence (BCE) and Chemical R&D, Pharmaceutical Sciences, Small Molecules, Pfizer Inc., Groton Laboratories, Eastern Point Road, Gro... | 10.1021/acs.oprd.2c00179 | 0 |
Axial Chirality in the Sotorasib Drug Substance, Part 1: Development of a Classical Resolution to Prepare an Atropisomerically Pure Sotorasib Intermediate | Described herein is the discovery and development of a process to prepare an atropisomeric intermediate in the synthesis of the KRAS G12C inhibitor sotorasib. Using high-throughput experimentation, (+)-2,3-dibenzoyl- d -tartaric acid [(+)-DBTA] was identified as an inexpensive and readily available resolving agent that... | 10.1021/acs.oprd.2c00176 | 1 |
Transformation of the Manufacturing Process from Discovery to Kilogram Scale for AWZ1066S: A Highly Specific Anti-<i>Wolbachia</i> Drug Candidate for a Short-Course Treatment of Filariasis | Anti- Wolbachia therapy has been clinically proven to be a safe approach for the treatment of onchocerciasis and lymphatic filariasis. AWZ1066S, a first-in-class highly specific anti- Wolbachia drug candidate developed for a short-course treatment of human filariasis, has advanced into clinical development. An improved... | 10.1021/acs.oprd.2c00167 | 1 |
Accelerated Multiphosphorylated Peptide Synthesis | Preparing phosphorylated peptides with multiple adjacent phosphorylations is synthetically difficult, leads to β-elimination, results in low yields, and is extremely slow. We combined synthetic chemical methodologies with computational studies and engineering approaches to develop a strategy that takes advantage of fas... | 10.1021/acs.oprd.2c00164 | 0 |
Synthesis and Applications of Periodate for Fine Chemicals and Important Pharmaceuticals | An emerging interest for the application of periodate in the synthesis of active pharmaceutical ingredients (APIs) and for the valorization of renewable feedstock is eminent. However, periodate exhibits a high molecular mass, is expensive compared to other common bulk-oxidizers and is used only reluctantly in technical... | 10.1021/acs.oprd.2c00161 | 1 |
Process Development and Scale-Up of a Protease Inhibitor for the Treatment of HIV Featuring the Preparation of a Neopentyl Grignard Reagent and Development of a One-Pot Curtius Reaction | Compound 1 is a densely functionalized iminohydantoin that possesses a quaternary stereocenter and is under development as an HIV protease inhibitor. Key challenges that are discussed include the preparation of a neopentyl Grignard reagent via magnesium insertion, development of a one-pot Curtius reaction that generate... | 10.1021/acs.oprd.2c00153 | 1 |
Preparation of Enantiopure 3-Aminopiperidine and 3-Aminoazepane Derivatives from Ornithine and Lysine. Consecutive Syntheses of Pharmacologically Active Analogs, Such as Besifloxacin | null | 10.1021/acs.oprd.2c00152 | 0 |
Development of an Optimized Synthetic Process for an Antiobesity Drug Candidate (S-234462) Featuring Mild Chlorination of Benzoxazolone and In Situ IR Monitoring of a Mitsunobu Reaction | Here, we outline the manufacturing process history of S-234462. For the optimized process, 6-fluorobenzoxazolone, ((1r,4r)-4-aminocyclohexyl)methanol, and ethyl( tert -butylsulfonyl)carbamate were selected as starting materials. The first key to successful process development was the discovery of mild chlorination cond... | 10.1021/acs.oprd.2c00150 | 1 |
An Alternative Route to the Anticancer Agent: 2-Fluorofucose from Readily Available L-(−)Rhamnose and Mechanistic Insights into a Zinc/Ammonium Iodide-Mediated Elimination Reaction | 2-Fluorofucose ( 6 ) is a fucosylation inhibitor administered orally to patients with advanced solid tumors. 6 exhibits antitumor activity, putatively via multiple mechanisms. Herein, we report a robust formal synthetic route for obtaining 6 ( SGD-2083 ) from L-(−)rhamnose as a starting material. This provides an alter... | 10.1021/acs.oprd.2c00146 | 1 |
Synthesis of a Pyridoazepine Scaffold via Rhodium-Catalyzed Ring Expansion and Nitroacetamide Condensation | Pyridoazepines are privileged structures in the search for novel drug candidates. We present the synthesis of a versatile pyridoazepine scaffold employing a precedented rhodium(II)-catalyzed ring expansion and subsequent double-condensation-cyclization with nitroacetamide. The reactions applied several potentially haza... | 10.1021/acs.oprd.2c00145 | 1 |
Suppression of Simultaneous Fmoc-His(Trt)-OH Racemization and <i>N</i><sup>α</sup>-DIC-Endcapping in Solid-Phase Peptide Synthesis through Design of Experiments and Its Implication for an Amino Acid Activation Strategy in Peptide Synthesis | Coupling Fmoc-His(Trt)-OH in solid-phase peptide synthesis is frequently accompanied by significant racemization. Histidine is among the most susceptible amino acid residues inclined to racemize in peptide syntheses. In this study, the His racemized impurity could not be effectively purged by the applied chromatographi... | 10.1021/acs.oprd.2c00144 | 0 |
Route Design and Development of Tetrachlorantraniliprole: Copper-Catalyzed Cyclization and One-Pot Preparation of Pyrazole Acid Chloride | Synthetic strategies for preparing insecticide tetrachlorantraniliprole ( 1 ) were explored. Target compound 1 was synthesized from 2,3,5-trichloropyridine ( 2 ) using a six-step process. The obtained yield of 51.7% was considerably higher than the 4.7% yield of the initial seven-step process. Process highlights includ... | 10.1021/acs.oprd.2c00141 | 1 |
Optimization of Nitrosation Reaction for Synthesis of 4-Aminoantipyrine by Response Surface Methodology and Its Reaction Mechanism | A small-scale process of nitrosation reaction for the preparation of 4-aminoantipyrine (AA) is optimized. Response surface methodology combined with Box–Behnken design is used to build the model and optimize parameters. AT-SO 4 /sodium nitrite molar ratio, antipyrine (AT)/sulfuric acid molar ratio, reaction time, and r... | 10.1021/acs.oprd.2c00132 | 1 |
Development of Dual Practical Manufacturing Routes to Cognate Pyrrolobenzodiazepine-Based Linker-Drugs | The synthetic strategies for two distinct but related linker-toxins 1 and 2 were reconfigured in order to devise an efficient and unified supply chain for both compounds. This involved establishing novel chemical routes to crystalline, monomeric building blocks that could be combined in a unique way for each molecular ... | 10.1021/acs.oprd.2c00129 | 0 |
Development, Validation, and Application of a Custom-Made Mini-Reaction Calorimeter for Thermal Safety Screening | Before scaling up to production, it is of high importance to evaluate the potential of a reaction to lead to an undesired thermal degradation event. The use of a large amount of compounds is usually required for a reliable calorimetry study. In this work, we report the development of a milliliter-scale reaction calorim... | 10.1021/acs.oprd.2c00128 | 0 |
Minimizing Material Consumption in Flow Process Research and Development: A Novel Approach Toward Robust and Controlled Mixing of Reactants | Scarce availability of chemical starting materials is a crucial challenge in the development of flow chemical processes. This is particularly important for organometallic reactions, which typically require high flow rates and hence high material consumption, to generate sufficiently short mixing and residence times. To... | 10.1021/acs.oprd.2c00123 | 1 |
Racemic Synthesis of a Key 1,4-Dihydro-2<i>H</i>-spiro[isoquinoline-3,4′-piperidin]-3′-ol Building Block | The synthesis of a key spiroamine building block for a medicinal chemistry program is described. Key innovations were a regioselective epoxide ring opening and a late-stage Pictet–Spengler reaction that was quickly optimized using Design of Experiments. | 10.1021/acs.oprd.2c00121 | 1 |
Co-immobilized Multienzyme System for the Cofactor-Driven Cascade Synthesis of (<i>R</i>)<i>-</i>2-Amino-3-(2-bromophenyl)propanoic Acid: A Model Reaction | d -Amino acids are important intermediates for the synthesis of β-lactam antibiotics and other vital pharmaceuticals, which can be synthesized by various methods including biocatalysis. In this work, we have demonstrated using immobilized multienzyme cofactor-driven cascade reaction for the synthesis of a model d -amin... | 10.1021/acs.oprd.2c00119 | 0 |
Reactor Design for the Direct Electrosynthesis of Periodate | A reactor design to continuously produce sodium paraperiodate under strongly alkaline conditions is presented. The target compound is generated by direct electrosynthesis. The approach combines the concepts of cyclic flow electrolysis and a continuous stirred tank reactor (e-CSTR), which is operated in a steady-state m... | 10.1021/acs.oprd.2c00116 | 0 |
Development of a New Synthetic Route of the Key Intermediate of Irbesartan | Herein, we describe a new synthetic route to prepare 4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile ( 5 ), an intermediate of irbesartan. Compared with leucine or its derivatives as the starting material to synthesize irbesartan in many previous reports, the intermediate 5 co... | 10.1021/acs.oprd.2c00113 | 1 |
Kilo-Scale Electrochemical Oxidation of a Thioether to a Sulfone: A Workflow for Scaling up Electrosynthesis | Organic electrosynthesis is a rapidly evolving field, providing powerful methods to assemble targets of interest in organic synthesis. Concerns around the scalability of electrochemical methods remain the biggest reason behind their scarce implementation in manufacturing routes for the pharmaceutical industry. To fill ... | 10.1021/acs.oprd.2c00111 | 0 |
Direct Synthesis of Methylchlorosilanes: Catalysts, Mechanisms, Reaction Conditions, and Reactor Designs | Silicone polymers are produced commercially mainly from methylchlorosilanes prepared by direct synthesis. The yield and selectivity of this synthetic process depend not only on chemical reactions but also on transfer phenomena, leading to conflicting results and controversial interpretations within this research field.... | 10.1021/acs.oprd.2c00107 | 0 |
Continuous-Flow Synthesis of <i>syn</i>-2-Amino-1,3-diol via Catalytic Hydrogenation: A Vital Intermediate of (+)-Thiamphenicol and (+)-Florfenicol | In this paper, an expeditious and efficient continuous-flow process is reported for the synthesis of syn -2-amino-1,3-diol. The starting material syn -2-nitro-1,3-diol reacts with hydrogen gas in a micro fixed-bed reactor packed with a Raney Ni catalyst to provide syn -2-amino-1,3-diol in 93% isolated yield. The reacti... | 10.1021/acs.oprd.2c00100 | 1 |
Cost-Efficient, Multigram Scalable Synthesis of Shelf-Stable Electrophilic (Phenylsulfonyl)difluoromethylating Reagents | An easy-to-handle protocol for the synthesis of an efficient electrophilic (phenylsulfonyl)difluoromethylating reagent, namely, the S -([phenylsulfonyl]difluoromethyl)-dibenzothiophenium salt I, is depicted. The latter was synthesized on approximately 40 g scale in a three-step/one-purification sequence from commercial... | 10.1021/acs.oprd.2c00099 | 1 |
Development of a Practical Process for the Large-Scale Preparation of the Chiral Pyridyl-Backbone for the Crabtree/Pfaltz-Type Iridium Complex Used in the Industrial Production of the Novel Fungicide Inpyrfluxam | Herein, we report the development activities leading to an efficient process for the large-scale production of the key intermediate to a crabtree/pfaltz-type iridium complex for industrial application. The process employs a highly efficient Suzuki coupling and a highly enantioselective transfer hydrogenation. | 10.1021/acs.oprd.2c00097 | 1 |
Development of an Ene Reductase-Based Biocatalytic Process for the Production of Flavor Compounds | Ene reductases catalyze the biocatalytic reduction of activated alkenes, offering a powerful biobased alternative to metal-catalyzed and organocatalyzed double-bond reductions. With the aim to utilize the natural catalysts for the development of sustainable industrial processes for the flavor and fragrance (F&F) indust... | 10.1021/acs.oprd.2c00096 | 0 |
Side-Chain Unprotected Fmoc-Arg/His/Tyr-OH Couplings and Their Application in Solid-Phase Peptide Synthesis through a Minimal-Protection/Green Chemistry Strategy | Conventional SPPS (solid-phase peptide synthesis) requires protecting the nucleophilic side-chains of amino acids to prevent undesired modifications. A large volume of TFA (trifluoroacetic acid) is generally needed to remove these protecting groups after the peptide assembly. Such a process significantly lowers the pro... | 10.1021/acs.oprd.2c00083 | 0 |
Fit-for-Purpose Synthesis of an Aza-Cryptophycin Analogue as the Payload for an Antibody–Drug Conjugate | The synthesis of an aza-cryptophycin analogue is described, featuring a highly trans-selective ring-closing metathesis reaction and an asymmetric Corey–Chaykovsky-type reaction to install the epoxide function. This latter reaction is an answer to the long-standing synthetic challenged posed by the efficient formation o... | 10.1021/acs.oprd.2c00080 | 0 |
A Novel and Practical Synthesis of Mavorixafor | A novel and practical synthesis of mavorixafor ( 1 ) is reported. The novelty of this synthetic route is the use of 8-chloro-5,6,7,8-tetrahydroquinoline ( 9 ) and 1,4-diaminobutane as the materials, instead of 8-amino-5,6,7,8-tetrahydroquinoline ( 4 ) and N,N-diprotected aminobutyraldehyde ( 6a or 6b ). The preparation... | 10.1021/acs.oprd.2c00076 | 1 |
Recent Advances in the Solid- and Solution-Phase Synthesis of Peptides and Proteins Using Microflow Technology | Peptides have become increasingly important as drugs and drug candidates. In particular, specialty peptides have garnered considerable attention in recent years because of their improved metabolic stability, higher affinity, and biological target selectivity; some of them have the ability to enable cell membrane permea... | 10.1021/acs.oprd.2c00074 | 1 |
Flow Toolkit for Measuring Reaction Enthalpy and Application to Highly Exothermic Synthesis of Alkylaluminoxanes | We present a flow strategy to characterize reaction enthalpy and showcase the application in synthesis of alkylaluminoxanes from the fast and exothermic alkylaluminum hydrolysis. Our platform mainly encompasses a three-dimensional printed micromixer and a tubular reactor in an adiabatic vacuum box, aided by a thermal i... | 10.1021/acs.oprd.2c00072 | 0 |
Discovery and Process Development of a Scalable Biocatalytic Kinetic Resolution toward Synthesis of a Sterically Hindered Chiral Ketone | Sterically hindered chiral ketones are useful intermediates in the synthesis of active pharmaceutical ingredients. Here, we report a scalable and highly enantioselective synthesis through a kinetic resolution process promoted by a wild-type ketoreductase (KRED) enzyme. The process was investigated thoroughly, including... | 10.1021/acs.oprd.2c00067 | 0 |
Manufacturable Process of a Novel EGFR Inhibitor (Larotinib) for the Treatment of ESCC | The development of an efficient synthetic process for a clinical candidate Larotinib ( 4 ), which is an epidermal growth factor receptor (EGFR) inhibitor for the treatment of esophageal squamous cell carcinoma (ESCC), is reported for scale-up. The process used 3,4-dihydro-7-methoxy-4-oxoquinazolin-6-yl acetate ( 12 ) a... | 10.1021/acs.oprd.2c00059 | 1 |
Development of a Process to a 4-Arylated 2-Methylisoquinolin-1(2<i>H</i>)-one for the Treatment of Solid Tumors: Lessons in Ortho-Bromination, Selective Solubility, Pd Deactivation, and Form Control | We here present an optimized, scalable synthesis of bromodomain and extra-terminal (BET) inhibitor BMS-986378 (CC-90010). The original route and process 1A was 7 steps with 33.8% yield and featured numerous problematic solvents, process safety concerns, difficult to scale unit operations, and challenging to control imp... | 10.1021/acs.oprd.2c00057 | 1 |
Cu-Mediated Ullmann-Type Cross-Coupling and Industrial Applications in Route Design, Process Development, and Scale-up of Pharmaceutical and Agrochemical Processes | Cu-mediated Ullmann-type cross-coupling has experienced significant advances over the last century since the seminal publication by Ullmann in 1901. These advances have significantly expanded the scope of the original classical Ullmann coupling of aryl halides for formation of diaryl compounds to include the formation ... | 10.1021/acs.oprd.2c00050 | 1 |
Multigram Scale Synthesis of Piperarborenines C-E | We report the multigram scale synthesis of heterodimeric β-truxinic imides piperarborenines C-E using a catechol-tethered diastereoselective intramolecular [2 + 2] photocycloaddition. Key innovations lie in the use of catechol as a practical auxiliary for the synthesis of homo- and heterodimeric β-truxinates and the us... | 10.1021/acs.oprd.2c00049 | 1 |
Use of Phosphazene Base BTPP for Phosphorylative Activation in the Scale-Up of BET Inhibitor GSK525762 | In this article, an improved synthesis of a key triazole intermediate in the synthesis of bromo- and extra-terminal domain (BET) inhibitor GSK525762 ( 1 ) is described, which avoids the need for the formation of a thioamide intermediate for the key methyltriazolo[1,4]benzodiazapine formation. Conditions for a phosphory... | 10.1021/acs.oprd.2c00048 | 1 |
Highly Efficient and Selective Hydrogenation of Sugars Catalyzed by Ru-MACHO-BH: Practical Synthesis of Sugar Alcohols | A highly efficient synthesis of sugar alcohols was achieved by selective hydrogenation with a homogeneous catalyst. Ru-MACHO-BH, the PN H P-ruthenium catalyst, promoted the hydrogenation with extremely high reactivity and selectivity. The reaction could be applied to various kinds of mono- and disaccharides and has bee... | 10.1021/acs.oprd.2c00047 | 0 |
Excellence in Industrial Organic Synthesis 2021 | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTExcellence in Industrial Organic Synthesis 2021John A. Ragan*John A. RaganChemical Research & Development, Pfizer Global Research & Development, Eastern Point Road, Groton, Connecticut 06340, United States*Email: [email protected]More by John A. Ragan, Ke ChenKe ChenProcess Res... | 10.1021/acs.oprd.2c00038 | 0 |
Synthesis Optimization, Scale-Up, and Catalyst Screening Efforts toward the MGAT2 Clinical Candidate, BMS-963272 | This paper describes the efficient scale-up synthesis of 1 (BMS-963272) which relies upon a highly selective Mannich-type alkylation strategy to stereospecifically install a quaternary carbon center. An intramolecular cyclization reaction is also used to form the aryl dihydropyridone (ADHP) core. The optimized route ha... | 10.1021/acs.oprd.2c00036 | 1 |
Synthesis of 5-Substituted Tetrazoles: Reaction of Azide Salts with Organonitriles Catalyzed by Trialkylammonium Salts in Non-polar Media | An efficient synthesis of 5-substituted tetrazole derivatives via the addition of azide ions to an organonitrile is presented. This new protocol minimizes the potential generation of hydrazoic acid by employing a catalytic amount of an activating proton source (trialkylammonium chloride) in combination with a phase tra... | 10.1021/acs.oprd.2c00032 | 1 |
Development of an Improved Synthetic Process of Clonazepam by Preventing the Formation of a Trimeric Compound in the Presence of HCl | An improved synthesis process of clonazepam was developed with the key parameters determined. The trimer intermediate ( 9 ) of clonazepam prepared by using the one-pot method was isolated and identified for the first time. It was further confirmed that the depolymerization of 9 at high temperature was the rate-determin... | 10.1021/acs.oprd.2c00023 | 1 |
An Efficient Synthesis of the Bicyclic Darunavir Side Chain Using Chemoenzymatic Catalysis | Herein, we describe a chemoenzymatic synthesis of the bicyclic fragment of Darunavir. A ketoreductase was identified using metagenomic mining to catalyze a highly enantio- and diastereoselective dynamic kinetic resolution of a β-ketolactone. Subsequent lactone reduction with diisobutylaluminum hydride and phase transfe... | 10.1021/acs.oprd.2c00017 | 1 |
Scale-Up of Diazonium Salts and Azides in a Three-Step Continuous Flow Sequence | Rapid synthesis and scale-up of active molecules to support the development process of new drug candidates is key in the pharmaceutical industry. Herein, we describe the development of a scalable continuous flow procedure for three key steps in the synthesis of 2H-indazoles, which were identified as highly potent and s... | 10.1021/acs.oprd.2c00016 | 0 |
Efficient Divergent Synthesis of 2′-<i>O</i>,4′-<i>C</i>-Ethylene-Bridged Nucleic Acid (ENA) Phosphoramidites | 2′- O,4′- C -Ethylene-bridged nucleic acid (ENA) phosphoramidites are highly promising modified nucleic acid monomers discovered by Daiichi Sankyo. To increase the productivity of manufacturing, we have developed a highly efficient synthetic method for ENA phosphoramidites. The basic concept of the new synthetic route ... | 10.1021/acs.oprd.2c00013 | 0 |
Scale-Up of a Heterogeneous Photocatalytic Degradation Using a Photochemical Rotor–Stator Spinning Disk Reactor | High Resolution Image Download MS PowerPoint Slide Many chemical reactions contain heterogeneous reagents, products, byproducts, or catalysts, making their transposition from batch to continuous-flow processing challenging. Herein, we report the use of a photochemical rotor–stator spinning disk reactor (pRS-SDR) that c... | 10.1021/acs.oprd.2c00012 | 0 |
Stereoselective Synthesis of a Tubulysin Core for Antibody–Drug Conjugate Studies | An expeditious synthesis of an advanced tripeptide intermediate en route to a tubulysin antibody–drug conjugate payload is described. The efficient formation of an N -propyl tertiary amide required tailoring the amine component to reduce steric demand. Additionally, double activation of the carboxylate was required via... | 10.1021/acs.oprd.2c00010 | 1 |
Process Safety from Bench to Pilot to Plant | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTProcess Safety from Bench to Pilot to PlantQiang Yang*Qiang YangEli Lilly and Company, Indianapolis, Indiana 46285-0001, United States*E-mail: [email protected]More by Qiang YangView Biographyhttps://orcid.org/0000-0003-3762-5015, S. Camille PeresS. Camille PeresEnvironmental a... | 10.1021/acs.oprd.2c00008 | 0 |
Continuous Processing of Concentrated Organolithiums in Flow Using Static and Dynamic Spinning Disc Reactor Technologies | High Resolution Image Download MS PowerPoint Slide Organometallic reactions involving highly reactive organolithium reagents are widely used in organic synthesis. However, the use of such organometallics in batch mode on a pilot and industrial scale is challenging for safety reasons and frequently requires expensive cr... | 10.1021/acs.oprd.2c00007 | 0 |
Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution | This review describes the practical aspects involved in the implementation of large-scale amidations in process chemistry. Coupling reagent, base, additive, and solvent selections are critically analyzed to highlight their pros and cons. Other important factors to be considered on large scale, such as atom economy, cos... | 10.1021/acs.oprd.2c00005 | 0 |
Mapping Polymorphic Behavior of Process Intermediates, an Often-Overlooked Exercise | Presented are two case studies where polymorphic behavior of a process intermediate was identified and the relationship was investigated for form control. Case study I: 1 is a process intermediate for a novel apoptosis signal-regulating kinase 1 (ASK1) inhibitor that was isolated as an unsolvated hydrochloride salt ( 1... | 10.1021/acs.oprd.2c00003 | 0 |
Identification, Synthesis, and Comprehension of an Imidazole N-3 Regioisomeric Impurity of Olmesartan Medoxomil Key Intermediate | Trityl olmesartan ethyl ester (TOEE), a key intermediate of the launched angiotensin II receptor blocker olmesartan medoxomil, was built using two blocks via an N -alkylation reaction, wherein the imidazole N -1 isomer of this intermediate was the only isomeric product reported previously. Unexpectedly, from a sample o... | 10.1021/acs.oprd.2c00002 | 1 |
High-Yield Synthesis of Enantiopure 1,2-Amino Alcohols from <scp>l</scp>-Phenylalanine via Linear and Divergent Enzymatic Cascades | )-phenylethanolamine was isolated in a 92% yield and >99.9% ee starting from ca. 100 mg of the diol intermediate. In summary, l-phenylalanine was converted into enantiomerically pure 2-phenylglycinol and phenylethanolamine in overall yields of 61% and 69%, respectively. This work exemplifies how linear and divergent en... | 10.1021/acs.oprd.1c00490 | 1 |
Review of Synthetic Approaches toward the Synthesis of Cariprazine, an Antipsychotic Drug | Schizophrenia is a chronic and severe mental disorder affecting 20 million people worldwide. Research has not identified the causes of schizophrenia as one single factor. It is thought that interactions between genes and a range of environmental factors may cause schizophrenia. The majority of schizophrenia cases are c... | 10.1021/acs.oprd.1c00488 | 1 |
Optimization of Metal Affinity Ketoreductase Immobilization for Application in Batch and Flow Processes | Protein isolation from fermentation broth or protein mixtures by using cost-effective, scalable, regenerable resins offers a significant increase in value and productivity; hence, many recombinant proteins contain a fused histidine tag to facilitate immobilized metal affinity chromatography purification. A newly develo... | 10.1021/acs.oprd.1c00483 | 0 |
Development and Process Intensification of an Efficient Flow–Cascade Reaction Sequence in the Synthesis of Afizagabar | Aromatic nitration and catalytic hydrogenation are among the most dangerous reactions in the chemical industry. The traditional, batchwise pilot plant manufacturing process of a key intermediate of our drug candidate afizagabar (S44819) involved these kinds of transformations (besides a Dakin–West-type reaction, a ring... | 10.1021/acs.oprd.1c00481 | 1 |
Development of Enzymatic Variants for the Synthesis of Bioresorbable Polyesters | Enzymatic synthesis of polymeric materials is a powerful approach to make these processes greener, more economical, and safer for scale-up. Herein, we characterized new variants of the hyperthermophilic carboxylesterase from the archaeon Archaeoglobus fulgidus with quantum mechanics/molecular mechanics molecular dynami... | 10.1021/acs.oprd.1c00480 | 0 |
Driving Aspirational Process Mass Intensity Using Simple Structure-Based Prediction | High Resolution Image Download MS PowerPoint Slide An important metric for gauging the impact that a synthetic route has on chemical resources, cost, and sustainability is process mass intensity (PMI). Calculating the overall PMI or step-PMI for a given synthesis from a process description is more and more common acros... | 10.1021/acs.oprd.1c00477 | 1 |
Development and Scale-Up of a Copper-Catalyzed Sulfamidation Coupling Reaction | The plant-scale manufacture of AZD5069 involved the assembly of a pyrimidine sulfonamide (AZD5069 MAPI) via Pd-catalyzed coupling of a chloropyrimidine derivative with an azetidinesulfonamide. This step revealed a number of operational and commercial challenges, in particular the difficulty of removing palladium residu... | 10.1021/acs.oprd.1c00475 | 1 |
Process Development of Enantioselective Imine Reductase-Catalyzed Syntheses of Pharmaceutically Relevant Pyrrolidines | Process development and optimization for an enzymatic reduction of 2-aryl-substituted pyrrolines to enantioselectively access the corresponding pyrrolidines have been carried out. Such chiral pyrrolidines are of high pharmaceutical interest and represent structural subunits in, e.g., larotrectinib and MSC2530818. This ... | 10.1021/acs.oprd.1c00471 | 0 |
Development of a Continuous Photochemical Bromination/Alkylation Sequence En Route to AMG 423 | The development of a photochemical bromination/alkylation sequence as part of a continuous process for the synthesis of an intermediate en route to AMG 423 is discussed. Highlights of this continuous process include a significant reduction in reaction time and the elimination of aqueous waste streams. Also discussed ar... | 10.1021/acs.oprd.1c00469 | 1 |
Development of a Commercial Process for Deucravacitinib, a Deuterated API for TYK2 Inhibition | Deucravacitinib (BMS-986165) is a deuterated small-molecule TYK2 inhibitor developed for the treatment of numerous autoimmune disorders. While the first-generation discovery chemistry route to access deucravacitinib was concise and sufficient to access kilogram quantities of API, impurity control and cost-of-goods conc... | 10.1021/acs.oprd.1c00468 | 1 |
Development of Scalable Processes with Underutilized Biocatalyst Classes | Over the past few decades, biocatalysis has become a significant contributor to the manufacture of complex active pharmaceutical ingredients (APIs), agrochemicals, and commodity chemicals. In the context of API synthesis, the biocatalysis community has long relied on three predominant catalyst classes: lipases, ketored... | 10.1021/acs.oprd.1c00467 | 1 |
A Techno-economic Assessment of a Biocatalytic Chiral Amine Production Process Integrated with <i>In Situ</i> Membrane Extraction | The production of chiral amines through asymmetric synthesis using amine transaminase (ATA) has the potential for high yields in an efficient single-step process. Integrating in situ membrane extraction with this biocatalytic chiral amine production process has been demonstrated to reach higher yields by shifting the e... | 10.1021/acs.oprd.1c00464 | 0 |
Recent Progress and Developments in Chemoenzymatic and Biocatalytic Dynamic Kinetic Resolution | Dynamic kinetic resolution (DKR) is a powerful method to construct complex molecules with one or more stereocenters. In light of their exquisite stereospecificity and stereoselectivity, enzymes are becoming widely used as catalysts in DKR. This review summarizes chemoenzymatic and biocatalytic methodologies for DKR tha... | 10.1021/acs.oprd.1c00463 | 1 |
Application of the Polonovski Reaction: Scale-up of an Efficient and Environmentally Benign Opioid Demethylation | An environmentally benign iron-catalyzed nonclassical Polonovski reaction has been developed and scaled up to accomplish the challenging N -demethylation of MCL-509 Methyl to secondary amine MCL-509 Amine.HCl, key intermediates on the route to potential Parkinson’s treatment, MCL-509. The optimized reaction proceeded v... | 10.1021/acs.oprd.1c00462 | 0 |
Evaluation of the Thermal Hazard of the Oxidation Reaction in the Synthesis of 3,4-Bis(4-nitrofurazan-3-yl)furoxan | Safety evaluation of chemical reactions is very significant before industrial applications are conducted. A lot of thermal hazards are generated in the synthesis of 3,4-bis(4-nitrofurazan-3-yl)furoxan (DNTF) because of the strong exothermicity of the oxidation reaction, unstable hydrogen peroxide, and interactions betw... | 10.1021/acs.oprd.1c00458 | 0 |
Development of a Scalable Route with Efficient Stereoisomer Control to YZJ-1139, an Orexin Receptor Antagonist | An effort toward the synthesis and process development of the orexin receptor antagonist YZJ-1139( 1 ) was described in this article. YZJ-1139( 1 ) contains the azabicyclic nortropane structure with three chiral centers. By the original process, highly pure intermediates or API could be obtained by chromatography with ... | 10.1021/acs.oprd.1c00457 | 1 |
Optimization of the Everolimus Intermediate Preparation Process: Impurity Identification Followed by One-Pot Transformation to the Desired Product | An investigation of the everolimus intermediate PG-EVR preparation process resulted in the identification of three impurities PG-D,E,F constantly formed as byproducts in large amounts. Their structures were reliably established based on two-dimensional (2D) NMR and liquid chromatography–high-resolution tandem mass spec... | 10.1021/acs.oprd.1c00456 | 0 |
Binary Solvent Swap Processing in a Bubble Column in Batch and Continuous Modes | A lab-scale bubble column was investigated as an alternative means to achieve a low-temperature binary solvent swap of solutions containing pharmaceutical materials at atmospheric pressure, for batch and continuous configurations. The rate of solvent evaporation was predicted by first-principles vapor-liquid equilibriu... | 10.1021/acs.oprd.1c00455 | 0 |
Enantioselective Synthesis of the Chiral Pyrrolidine Fragment of Upadacitinib <i>via</i> Chiral Auxiliary Directed Diastereoselective 1,3-Dipolar Cycloaddition | An efficient and elegant enantioselective synthesis of the key chiral pyrrolidine fragment of Upadacitinib (ABT-494) has been described. Oppolzer’s chiral sultam-directed asymmetric 1,3-dipolar cycloaddition was employed as a convenient tool to obtain the desired level of concomitant diastereoselectivity and enantiosel... | 10.1021/acs.oprd.1c00454 | 0 |
Development of a Rapid Scale-Up Synthesis of (<i>S</i>)-<i>N</i>-(8-((2-Amino-2,4-dimethylpentyl)oxy)-5<i>H</i>-chromeno[3,4-<i>c</i>]pyridin-2-yl)acetamide, a Potent Adaptor-Associated Kinase 1 Inhibitor | ( S )- N -(8-((2-Amino-2,4-dimethylpentyl)oxy)-5 H -chromeno[3,4- c ]pyridin-2-yl)acetamide ( 1 ) is a potent adaptor-associated kinase 1 inhibitor, which may have the potential to treat neuropathic pain and other neurological disorders including schizophrenia, Parkinson’s disease, bipolar disorder, and Alzheimer’s dis... | 10.1021/acs.oprd.1c00452 | 1 |
Adsorption of Amine Compounds on the Glass Surface and Their Impact on the Development of Analytical Method and Pharmaceutical Process | A diamine compound (3-{2-[2-(3-aminopropoxy)ethoxy]ethoxy}propan-1-amine) was demonstrated to impact downstream steps in a pharmaceutical synthetic process, and control of this compound to less than 0.015 wt % (or 150 ppm) was necessary. A novel, simple, and sensitive liquid chromatography/mass spectrometry (LC/MS) met... | 10.1021/acs.oprd.1c00451 | 0 |
Process Development and GMP Production of a Conjugate Warhead: Auristatin F-HPA-Ala/TFA (XMT-1864/TFA) | An efficient, large-scale manufacturing process is described for XMT-1864/TFA ( 1-TFA ), an auristatin F derivative, used as a novel, highly potent, cytotoxic warhead in Mersana’s oncology antibody–drug conjugate platforms. The process achieves high diastereomeric purity and controls the impurities with all intermediat... | 10.1021/acs.oprd.1c00449 | 0 |
Leveraging High-Throughput Experimentation to Drive Pharmaceutical Route Invention: A Four-Step Commercial Synthesis of Branebrutinib (BMS-986195) | The invention of a commercial route to the Bruton's tyrosine kinase inhibitor branebrutinib (BMS-986195) in four total chemical steps is described. The execution of high-throughput experimentation (HTE) coupled with a first-principles approach across the proposed synthetic route enabled the identification of a novel in... | 10.1021/acs.oprd.1c00443 | 1 |
Development of an Operationally Simple, Scalable, and HCN-Free Transfer Hydrocyanation Protocol Using an Air-Stable Nickel Precatalyst | Hydrocyanation reactions enable access to synthetically valuable nitriles from readily available alkene precursors. However, hydrocyanation reactions using hydrogen cyanide (HCN) or similarly toxic reagents on laboratory scale can be particularly challenging due to their hazardous nature. In addition, such processes ty... | 10.1021/acs.oprd.1c00442 | 0 |
Continuous-Flow Hofmann Rearrangement Using Trichloroisocyanuric Acid for the Preparation of 2-Benzoxazolinone | A continuous-flow preparation of 2-benzoxazolinone via the Hofmann rearrangement of salicylamide has been implemented employing trichloroisocyanuric acid as the stable and atom-economic chlorinating agent. The system was optimized to avoid solid accumulation and allow the preparation of hundreds of grams of the pure de... | 10.1021/acs.oprd.1c00440 | 0 |
Commercial-Scale Visible Light Trifluoromethylation of 2-Chlorothiophenol Using CF <sub>3</sub> I Gas | Despite the growth of photoredox methods in academia, application of photoredox at scale in the pharmaceutical and fine chemical industries has been slow. In this report, a photoredox trifluoromethylation of a thiophenol was modified from the original literature report, and the mechanism was investigated to define the ... | 10.1021/acs.oprd.1c00436 | 0 |
Unleashing the Potential to Electrify Process Chemistry: From Bench to Plant | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTUnleashing the Potential to Electrify Process Chemistry: From Bench to PlantKevin Lam*Kevin LamDepartment of Pharmaceutical, Chemical and Environmental Sciences, Faculty of Engineering and Science, University of Greenwich, Central Avenue, Chatham Maritime ME4 4TB, United Kingdo... | 10.1021/acs.oprd.1c00434 | 0 |
Scaling up a C–H Borylation: Addressing the Safety Concerns of an Iridium-Catalyzed Process for Multikilo Scale Manufacture | Iridium-catalyzed C–H borylation reactions are a rapid and versatile entry into Suzuki coupling partners, but their inherent safety issues can limit their use in large-scale manufacture. The stoichiometric byproduct from this reaction, HBpin, can liberate hydrogen gas on contact with moisture in air, as well as acting ... | 10.1021/acs.oprd.1c00432 | 1 |
Modified and Scalable Synthesis of <i>N</i> -Tosyl-4-ChlorobenzenesulfonimidoylFluoride (SulfoxFluor):Direct Imidation of Sulfinyl Chlorides with Chloramine-T Trihydrate | Abstract N-Tosyl-4-chlorobenzenesulfonimidoyl fluoride (SulfoxFluor) has emerged as a new fluorination reagent that can be used in the rapid deoxyfluorination of various alcohols. We disclose in this article a general and practical method for the preparation of SulfoxFluor and its adaption to a large scale. Starting fr... | 10.1021/acs.oprd.1c00431 | 1 |
Asymmetric Synthesis of Optically Active 3-Cyclohexene-1-carboxylic Acid Utilizing Lactic Ester as a Chiral Auxiliary in the Diastereoselective Diels–Alder Reaction | The optically active 3-cyclohexene-1-carboxylic acid was synthesized through a TiCl 4 -catalyzed diastereoselective Diels–Alder reaction utilizing lactic acid ester as a chiral auxiliary, which can be removed by washing with H 2 O. The ( S )- and ( R )-isomers were both derived from easily available ethyl l -lactate. | 10.1021/acs.oprd.1c00430 | 1 |
Engineering Enzyme Properties for Improved Biocatalytic Processes in Batch and Continuous Flow | <p>The widespread adoption of biocatalysis by industry to perform highly selective chemical syntheses has been made possible only by the development of highly effective methods in enzyme engineering to overcome the limitations of naturally occurring enzymes. Through these methods we can adapt a broad range of enz... | 10.1021/acs.oprd.1c00424 | 0 |
Multigram Synthesis of Tetrasubstituted Dihydrobenzofuran GSK973 Enabled by High-Throughput Experimentation and a Claisen Rearrangement in Flow | This article describes two routes toward the synthesis of cis or trans C2,3,5,7-tetrasubstituted dihydrobenzofurans as potent and selective bromodomain and extra-terminal BD2 inhibitors, followed by the optimization of the synthesis of the lead molecule GSK973 to support pre-clinical efficacy and safety studies. The us... | 10.1021/acs.oprd.1c00422 | 1 |
Efficient Multigram-Scale Synthesis of 7-Substituted 3-Methyltetral-1-ones and 6-Fluoromenadione | Herein, we report a safe and economical multigram synthesis of 6-fluoromenadione, an intermediate in the synthesis of novel biologically active agents. The key to this six-step sequence process involves the condensation of the readily available starting 4′-fluoropropiophenone and glyoxylic acid, a bromination–eliminati... | 10.1021/acs.oprd.1c00421 | 1 |
“One-Pot” Synthesis of Molnupiravir from Cytidine | High Resolution Image Download MS PowerPoint Slide A one-pot process for preparing molnupiravir from cytidine was developed. The advantages of this synthesis were as follows: (1) The presence of N, N -dimethylformamide dimethyl acetal (DMF-DMA) facilitated the selective protection of 2′,3′-dihydroxyls and amino of cyti... | 10.1021/acs.oprd.1c00419 | 1 |
Process Intensive Synthesis of Propofol Enabled by Continuous Flow Chemistry | A multi-step process using continuous flow chemistry to produce propofol is described. A scale-up of a 5-stage process (two continuous flow chemical steps, two extractions using a semi-batch approach, and one purification) provided propofol in high purity. This process minimizes the number of impurities formed during t... | 10.1021/acs.oprd.1c00416 | 1 |
A Highly Efficient and Sustainable Biocatalytic Oxidation Process toward (<i>R</i>)-Undecavertol | A biotransformation to produce ( R )-Undecavertol has been developed and demonstrated on the pilot scale. The process is a racemic resolution using a highly ( S )-selective alcohol dehydrogenase in the oxidative direction and an NAD(P)H oxidase for cofactor regeneration. Oxygen limitation is prevented by supplying pure... | 10.1021/acs.oprd.1c00415 | 0 |
Initial Route Scouting and Final Process Development for the Multi-Kg Production of 3-Fluoro-6-methoxyquinoline from <i>p</i>-Anisidine and 2-Fluoromalonic Acid | A scalable route to 3-fluoro-6-methoxyquinoline needed to be developed as multi-kg amounts of this heterocycle were required. Initial route development focused on the formation of the key C–F bond via a Balz–Schiemann reaction or electrophilic fluorination using Selectfluor. Both routes were developed on laboratory sca... | 10.1021/acs.oprd.1c00414 | 1 |
Recent Advances in Photobiocatalysis for Selective Organic Synthesis | Photocatalysis has emerged as a powerful tool to generate reactive intermediates under mild reaction conditions. The combination of photocatalysis and biocatalysis, possessing advantages of the reactivity of photocatalysts and the selectivity of enzymes, has received increasing attention for its potential to realize th... | 10.1021/acs.oprd.1c00413 | 1 |
Rapid Continuous-Flow Water-Free Synthesis of Ultrapure Ionic Liquids Assisted by Microwaves | A wide range of imidazole, pyridine including insoluble polymers, and tertiary amine derivatives rapidly reacted with orthoformate using various Brønsted acids or ammonium salts to control the anionic parts. The corresponding ionic liquids were formed in excellent yields under microwave-batch conditions within 10 min. ... | 10.1021/acs.oprd.1c00412 | 0 |
Transaminase Engineering and Process Development for a Whole-Cell Neat Organic Process to Produce (<i>R</i>)-α-Phenylethylamine | The production of ( R )-α-phenylethylamine (( R )-α-PEA) from acetophenone is a classic reaction for the characterization of transaminases. However, developing a commercially viable transaminase process to manufacture ( R )-α-PEA usually suffers from two drawbacks. One is related to the biocatalyst itself, since transa... | 10.1021/acs.oprd.1c00409 | 0 |
Simultaneous Preparation of (<i>S</i>)-2-Aminobutane and <scp>d</scp>-Alanine or <scp>d</scp>-Homoalanine via Biocatalytic Transamination at High Substrate Concentration | ( S )-2-Aminobutane, d -alanine, and d -homoalanine are important intermediates for the production of various active pharmaceutical ingredients and food additives. The preparation of these small chiral amine or amino acids with high water solubility still demands searching for efficient methods. In this work, we identi... | 10.1021/acs.oprd.1c00408 | 0 |
High Yielding Continuous-Flow Synthesis of Norketamine | High Resolution Image Download MS PowerPoint Slide A new continuous-flow process is presented for synthesis of the pharmaceutical intermediate norketamine ( 5 ). Our approach has been to take the well-established and industrially applied batch synthetic route to this promising antidepressant precursor and convert it to... | 10.1021/acs.oprd.1c00407 | 1 |
Tetrahydro-4<i>H</i>-pyran-4-one: From the Laboratory Scale to Pilot Plant Manufacture | This study describes our recent efforts to find an efficient and scalable route to tetrahydro-4 H -pyran-4-one using the commercially available starting materials. The route scouting work and the full development of an efficient access to the target are described. This work culminated in the preparation of above 20 kg ... | 10.1021/acs.oprd.1c00403 | 0 |
Development of a Robust Manufacturing Route for Molnupiravir, an Antiviral for the Treatment of COVID-19 | Herein is described the development of a large-scale manufacturing process for molnupiravir, an orally dosed antiviral that was recently demonstrated to be efficacious for the treatment of patients with COVID-19. The yield, robustness, and efficiency of each of the five steps were improved, ultimately culminating in a ... | 10.1021/acs.oprd.1c00400 | 1 |
Asymmetric Organocatalysis and Continuous Chemistry for an Efficient and Cost-Competitive Process to Pregabalin | High Resolution Image Download MS PowerPoint Slide Herein, we present the scale up development of an innovative synthetic process to pregabalin. The process is underpinned by two enabling technologies critical to its success; continuous chemistry allowed a safe and clean production of nitroalkene, and asymmetric organo... | 10.1021/acs.oprd.1c00394 | 1 |
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