title string | abstract string | doi string | has_route int64 |
|---|---|---|---|
Scale-Up of Polymerization Process: A Practical Example | The scale-up/-down of polymerization reactors has to deal with large viscosity changes during the process, addressing mass- and heat-transfer issues. A practical example on scale-up of styrene and methyl methacrylate free radical bulk and solution polymerization is presented. The main critical parameters are mixing at ... | 10.1021/op025605p | 0 |
Process Development on the Enantioselective Enzymatic Hydrolysis of <i>S</i>-Ethyl 2-Ethoxy-3-(4-hydroxyphenyl)propanoate | A novel biocatalytic approach for the large-scale production of S -2-ethoxy-3-(4-hydroxyphenyl)propanoic acid S -1 from its racemic ethylester rac -2 by enantioselective hydrolysis has been developed. S -1 is an important building block in the synthesis of PPARα and -γ agonists such as Ragaglitazar [NNC 61-0029 ((−)DRF... | 10.1021/op0256035 | 1 |
Process for Purification of 3-Alkenylcephem Carboxylic Acid | The present report describes a novel and efficient method for enrichment of 7-amino-3-[( Z )-propen-1-yl]-3-cephem-4-carboxylic acid ( 1 ) in a mixture of ( Z / E ) 7-amino-3[( Z / E )-propen-1-yl]-3-cephem-4-carboxylic acid via formation of 7-β-isopropylideneammonium salt in acidic conditions. This method provides hig... | 10.1021/op025602c | 0 |
SPECIAL FEATURE SECTION: SAFETY OF CHEMICAL PROCESSES | ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTSPECIAL FEATURE SECTION: SAFETY OF CHEMICAL PROCESSESTrevor LairdView Author Information EditorCite this: Org. Proc. Res. Dev. 2002, 6, 6, 876Publication Date (Web):October 30, 2002Publication History Published online30 October 2002Published inissue 1 November 2002https://p... | 10.1021/op025601k | 0 |
Development of a Scaleable Route for the Production of<i>cis</i>-<i>N</i>-Benzyl-3-methylamino-4-methylpiperidine | The synthesis of cis - N -benzyl-3-methylamino-4-methylpiperidine ( 5 ) via hydroboration of tetrahydropyridine 3 followed by oxidation and reductive amination was optimized and scaled up to produce 10-kg quantities of product. Three routes to 3 were identified, and the reduction of pyridinium salt 7 was selected as th... | 10.1021/op025599x | 1 |
In Situ Recycling of Chiral Ligand and Surplus Nucleophile for a Noncatalytic Reaction: Amplification of Process Throughput in the Asymmetric Addition Step of Efavirenz (DMP 266) | The synthesis of efavirenz (DMP 266) involves a highly enantioselective asymmetric reaction of ketone 2a with lithium cyclopropylacetylide 3a in the presence of (1 R,2 S )-pyrrolidinylnorephedrine (PNE) 4b as the chiral mediator to produce 6b, a key advance intermediate bearing a tetrasubstituted chiral carbon. The maj... | 10.1021/op025595s | 0 |
Pilot-Scale Lipase-Catalyzed Regioselective Acylation of Ribavirin in Anhydrous Media in the Synthesis of a Novel Prodrug Intermediate | The ester 4 was synthesized via Candida antarctica lipase-catalyzed acylation of ribavirin ( 3 ) with the oxime ester of l -Cbz-Ala ( 2 ) in anhydrous THF. The reaction was highly regioselective, resulting in the exclusive acylation of the 5‘-hydroxyl. The process practiced on pilot-plant scale produced 82 kg of 4 in t... | 10.1021/op0255938 | 0 |
Rapid Development of an Enantioselective Synthesis of (<i>R</i>)-1-Hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic Acid | A two-stage, three-step synthesis of ( R )-1-hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid from 7-methoxy tetralone is described which employed an optimised Wittig olefination of 7-methoxytetralone and Sharpless asymmetric dihydroxylation followed by platinum-catalysed oxidation. | 10.1021/op025590v | 1 |
Synthesis of <i>p</i>-Aminophenol by Catalytic Hydrogenation of <i>p</i>-Nitrophenol | The catalytic hydrogenation of p -nitrophenol to p -aminophenol was investigated in a laboratory-scale batch-slurry reactor. Pt/C catalyst (1%) was chosen for optimization of reaction conditions and kinetic studies because of its higher catalytic activity compared to that of other heterogeneous transition metal catalys... | 10.1021/op025589w | 0 |
Identification of the Decomposition Products in an Industrial Nitration Process under Thermal Runaway Conditions | Directive 96/82/EC on the control of major-accident hazards involving dangerous substances, so-called Seveso II Directive, requires inventorying of dangerous substances which are believed might be generated during loss of control of an industrial chemical process. In the present work a nitration process that has underl... | 10.1021/op0255884 | 0 |
A Practical Synthesis of <scp>l</scp>-Valyl-pyrrolidine-(2<i>R</i>)-boronic Acid: Efficient Recycling of the Costly Chiral Auxiliary (+)-Pinanediol | A practical synthesis of l -valyl-pyrrolidine-(2 R )-boronic acid ( 1 ) is detailed. A previously disclosed synthesis of 1 (Snow, R.; Kelly, T. R.; Adams, J.; Coutts, S.; Perry, C. (Boehringer Ingelheim Pharmaceuticals, Inc.). WO 93/10127, 1993) was significantly improved by developing an efficient process for recyclin... | 10.1021/op025587b | 1 |
3,4,5-Tri-Dodecyloxybenzoic Acid: Combining Reaction Engineering and Chemistry in the Development of an Attractive Tool To Assist Scaling Up Solid−Liquid Reactions | The synthesis of tris- O -dodecyl-gallic acid (3,4,5-tri-dodecyloxybenzoic acid) was selected as a model system in our program to define design tools and a methodology for fine-chemical scale-up. The just-suspended conditions of potassium carbonate in MIBK have been studied to find a scale-up rule for this system from ... | 10.1021/op020007w | 0 |
A “Bottom-Up” Approach to Process Development: Application of Physicochemical Properties of Reaction Products toward the Development of Direct-Drop Processes | The “bottom-up” approach to development of direct-drop processes is a powerful, yet simple, strategy that every process chemist should consider for the development of efficient, cost-effective, and environmentally friendly processes. This approach is aided by a “parallel crystallization” technique, which allows for rap... | 10.1021/op0102114 | 0 |
<i>SPECIAL FEATURE SECTION: <u>PROCESS INTENSIFICATION/CONTINUOUS PROCESSING IN THE FINE CHEMICALS ARENA</u></i> | ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTSPECIAL FEATURE SECTION: PROCESS INTENSIFICATION/CONTINUOUS PROCESSING IN THE FINE CHEMICALS ARENATrevor LairdView Author Information EditorCite this: Org. Proc. Res. Dev. 2001, 5, 6, 612Publication Date (Web):October 18, 2001Publication History Published online18 October 2... | 10.1021/op010083j | 0 |
Urea as an Efficient Reagent for the Synthesis of 3-Ethyl-3-(hydroxymethyl)oxetane: A Novel Component in Cationic Ring-Opening Polymerisation | Urea is a very attractive chemical raw material for large-scale production as it combines low cost with virtually unlimited supply and essentially no toxic effects. Here, we present a study on its use in the dehydration of trimethylolpropane with formation of 3-ethyl-3-(hydroxymethyl)oxetane. The reaction consists of c... | 10.1021/op010037j | 0 |
A Concise Asymmetric Synthesis of A β-Lactam-Based Cholesterol Absorption Inhibitor | A concise, four-step, asymmetric synthesis of a β-lactam-based\ncholesterol absorption inhibitor, Sch 57939, was developed. The\ndiscovery of a one-step enantio- and diastereoselective synthesis\nof a <i>trans</i>-β-lactam provided easy access to the desired three\nchiral centers. A novel zinc phenoxide-pro... | 10.1021/op000079s | 0 |
3,4,5-Tri-dodecyloxybenzoic Acid: Optimisation and Scale-Up of the Synthesis | The synthesis of tris- O -dodecyl-gallic acid (3,4,5-tri-dodecyloxybenzoic acid) a versatile building block for organic liquid crystalline materials has been selected for fine chemical scale-up. A large-scale procedure of the alkylation of methyl gallate was optimised with experimental design techniques. Apart from the... | 10.1021/op000066e | 1 |
<i>N</i>(π)-2-Naphthylmethoxymethyl-Protected Histidines: Scalable, Racemization-Free Building Blocks for Peptide Synthesis | Histidine (His) racemizes with relative ease during peptide synthesis. One strategy to suppress this racemization is to protect the nitrogen atom of the imidazole moiety in His with a suitable protecting group. Among the numerous protecting groups that have already been tested, the p -methoxybenzyloxymethyl (PMBOM) gro... | 10.1021/acs.oprd.9b00538 | 1 |
A Concise and Efficient Synthesis of Dapagliflozin | A concise and efficient synthesis of the SGLT-2 inhibitor dapagliflozin ( 1 ) has been developed. This route involves ethyl C -aryl glycoside 9 as the key intermediate, which is easily crystallized and purified as the crystalline n -propanol solvate with high purity (>98.5%). The tetra-O-unprotected compound 9 could be... | 10.1021/acs.oprd.9b00141 | 1 |
<i>N</i>-Acyl-5,5-dimethylhydantoin, a New Mild Acyl-Transfer Reagent in Pd Catalysis: Highly Efficient Synthesis of Functionalized Ketones | The palladium-catalyzed Suzuki–Miyaura cross-coupling of N -acyl-5,5-dimethylhydantoins with arylboronic acids has been developed via selective amides C–N bond cleavage. The new reagent is commercially available and air-/moisture-stable, and it offers a variety of ketones in good yields through Suzuki coupling under mi... | 10.1021/acs.oprd.8b00182 | 0 |
<i>N</i>-Butylpyrrolidinone as Alternative Solvent for Solid-Phase Peptide Synthesis | High Resolution Image Download MS PowerPoint Slide By means of a systematic approach, several green solvent candidates were tested for their feasibility to replace the reprotoxic dimethylformamide (DMF) as a solvent used in solid-phase peptide synthesis (SPPS). According to the results presented in this paper, it is cl... | 10.1021/acs.oprd.7b00389 | 0 |
<i>In Situ</i> Generated Palladium on Aluminum Phosphate as Catalytic System for the Preparation of β,β-Diarylated Olefins by Matsuda–Heck Reaction | In situ generated palladium on aluminum phosphate provides a novel and active catalytic system for the preparation of β,β-diarylated olefins using the Matsuda–Heck reaction. The reaction conditions of this catalytic protocol were optimized by a Response-Surface model. | 10.1021/acs.oprd.7b00279 | 0 |
A Combined High-Throughput Screening and Reaction Profiling Approach toward Development of a Tandem Catalytic Hydrogenation for the Synthesis of Salbutamol | A combined high-throughput screening and reaction profiling approach to the telescoping of two reductions in the synthesis of Salbutamol is described. Optimization studies revealed the beneficial effect of mildly acidic conditions, and the use of water as a cosolvent. Persistent formation of deoxygenated impurities usi... | 10.1021/acs.oprd.7b00261 | 1 |
A Comparison between Continuous and Batch Processes to Capture Aldehydes and Ketones by Using a Scavenger Resin | A low-cost isoniazid-based scavenger resin was previously prepared and successfully used to capture aldehydes and ketones in solution by using a batch approach. The present work compares batch and continuous processes in relation to the preparation of the scavenger resin and the effectiveness of cyclohexanone scavengin... | 10.1021/acs.oprd.7b00256 | 0 |
Use of Catalytic Static Mixers for Continuous Flow Gas–Liquid and Transfer Hydrogenations in Organic Synthesis | Catalytic static mixers were used for the continuous flow hydrogenation of alkenes, alkynes, carbonyls, nitro- and diazo-compounds, nitriles, imines, and halides. This technique relies on tubular reactors fitted with 3D printed static mixers which are coated with a catalytic metal layer, either Pd or Ni. Additive manuf... | 10.1021/acs.oprd.7b00180 | 0 |
(Chloromethyl)dimethylchlorosilane–KF: A Two-Step Solution to the Selectivity Problem in the Methylation of a Pyrimidone Intermediate en Route to Raltegravir | The present work describes a two-step process, namely, silylation with (chloromethyl)dimethylchlorosilane and desilylation, to address the selectivity problem in the N -methylation of a pyrimidone intermediate toward the synthesis of the raltegravir active pharmaceutical ingredient. The said methodology delivers the de... | 10.1021/acs.oprd.7b00171 | 1 |
A Chemoenzymatic Route to Chiral Intermediates Used in the Multikilogram Synthesis of a Gamma Secretase Inhibitor | A chemoenzymatic route for the production of an intermediate to a gamma secretase inhibitor is described. The route is robust and was run at multikilogram scale. The process employs both a transaminase catalyzed reductive amination of a substituted tetralone and an alcohol dehydrogenase catalyzed reduction of an α-keto... | 10.1021/acs.oprd.7b00096 | 1 |
A Chlorine Gas-Free Synthesis of Dichloroglyoxime | A new procedure for the synthesis and isolation of dichloroglyoxime is discussed. This material has historically been synthesized from glyoxime and elemental chlorine gas. Chlorine gas is difficult to handle and control in the laboratory and has a high toxicity profile. Our method for making dichloroglyoxime in high pu... | 10.1021/acs.oprd.6b00252 | 1 |
Kinetic Research of <i>O</i>,<i>O</i>′-Dibenzoyltartaric Anhydride Synthesis: Tartaric Acid and Its <i>O-</i>Acyl Derivatives. Part 12 | A kinetic study of dibenzoyl- l -tartaric anhydride synthesis was described. The kinetic equation and the dependence of the reaction rate constant on the temperature were determined. It was shown that the reaction is of the pseudo first order. The kinetic data enable the design of a continuous reactor. | 10.1021/acs.oprd.6b00147 | 1 |
Development of an Enantioselective Novozym 435 Mediated Acetylation for the Preparation of (1<i>S</i>,3<i>R</i>)-3-Acetamidocyclohexane-1-carboxylic Acid | Starting from a cheap and readily available starting material, a short and enantioselective route to (1 S,3 R )-3-acetamidocyclohexane-1-carboxylic acid was developed. The key steps were a rhodium catalyzed hydrogenation of 3-aminobenzoic acid and an enantioselective Novozym 435 mediated acetylation of racemic isopropy... | 10.1021/acs.oprd.6b00146 | 1 |
A Scalable Synthesis of 2-(1,2,4-Oxadiazol-3-yl)propan-2-amine Hydrobromide Using a Process Safety-Driven Protecting Group Strategy | A safe and scalable synthesis of 2-(1,2,4-oxadiazol-3-yl)propan-2-amine hydrobromide is described. A process safety-driven synthetic strategy was employed for the selection of thermally stable compounds en route to the target 1,2,4-oxadiazole. Application of process safety principles and tools for predicting the stabil... | 10.1021/acs.oprd.6b00145 | 1 |
Enabling the Scale-Up of a Key Asymmetric Hydrogenation Step in the Synthesis of an API Using Continuous Flow Solid-Supported Catalysis | High Resolution Image Download MS PowerPoint Slide The development of a continuous flow process for asymmetric hydrogenation with a heterogenized molecular catalyst in a real industrial context is reported. The key asymmetric step in the synthesis of an API (active pharmaceutical ingredient) has been developed on a kil... | 10.1021/acs.oprd.6b00143 | 1 |
Concise Cu (I) Catalyzed Synthesis of Substituted Benzofurans via a Tandem SNAr/C–O Coupling Process | A novel and convergent approach to tetrasubstituted benzofurans was developed from ortho -bromo aryl fluorides and keto-amides via one-pot SNAr displacement and subsequent Cu(I) catalyzed C–O coupling on the ortho -bromide. The scope of this methodology was demonstrated on several similar substrates. | 10.1021/acs.oprd.6b00141 | 1 |
Organic Solvent Nanofiltration (OSN): A New Technology Platform for Liquid-Phase Oligonucleotide Synthesis (LPOS) | Organic solvent nanofiltration (OSN) technology is a membrane process for molecular separation in harsh organic media. However, despite having well-documented potential applications, development hurdles have hindered the widespread uptake of OSN technology. One of the most promising areas of application is as an iterat... | 10.1021/acs.oprd.6b00139 | 0 |
Two Approaches to the Chemical Development and Large-Scale Preparation of a Pyrimidyl Tetrazole Intermediate | Two new routes to a pyrimidyl tetrazole intermediate are described. The first-generation route featured an iron-catalyzed cross-coupling between 4-butenylmagnesium bromide and a 4-chloropyrimidine derivative to afford an alkene-bearing pyrimidine intermediate. A subsequent intramolecular Heck cyclization afforded the d... | 10.1021/acs.oprd.6b00136 | 1 |
Flow Grignard and Lithiation: Screening Tools and Development of Continuous Processes for a Benzyl Alcohol Starting Material | Efficient continuous Grignard and lithiation processes were developed to produce one of the key regulatory starting materials for the production of edivoxetine hydrochoride. For the Grignard process, organometallic reagent formation, Bouveault formylation, reduction, and workup steps were run in continuous stirred tank... | 10.1021/acs.oprd.6b00131 | 0 |
Evaluation of PAT Methods for Potential Application in Small-Scale, Multipurpose Pharmaceutical Manufacturing Platforms | Small-scale (refrigerator-sized, 1.0 (width) × 0.7 (length) × 1.8 m (height)), multipurpose pharmaceutical manufacturing platforms (PMP) necessitate unique high demands on process analytical technologies (PAT), for instance, in in situ, real-time monitoring of liquid formulations (solution and suspension) to determine ... | 10.1021/acs.oprd.6b00129 | 0 |
A Biocatalytic Route to the Novel Antiepileptic Drug Brivaracetam | An asymmetric synthesis of the novel antiepileptic drug Brivaracetam 1 is described. The stereochemistry of the 4- n -propyl substituent is introduced by a biocatalytic resolution of ( rac )-methyl 2-propylsuccinate 4- tert -butyl ester 4 . The selection of the resolution substrate and the screening of enzymes were car... | 10.1021/acs.oprd.6b00094 | 1 |
Up-Scale Pseudotelescopic Photoinduced Arndt-Eistert α-Amino Acid Homologation in a Flow Reactor Cascade | We present an efficient, pseudotelescopic synthesis of β-amino acids via the Arndt-Eistert homologation of α-amino acids using a flow reactor cascade. Our system utilizes flow generation of diazomethane, diazoketone preparation, and subsequent photoflow Wolff rearrangement without intermediate isolation. This innovativ... | 10.1021/acs.oprd.5c00061 | 0 |
Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products | High Resolution Image Download MS PowerPoint Slide Recently, application of the flow technologies for the preparation of fine chemicals, such as natural products or Active Pharmaceutical Ingredients (APIs), has become very popular, especially in academia. Although pharma industry still relies on multipurpose batch or s... | 10.1021/acs.oprd.5b00325 | 0 |
<i>OPR&D</i>: An Exceptional Legacy and Exciting Opportunities for the Future of Process Chemistry | null | 10.1021/acs.oprd.4c00537 | 0 |
A Concise Flow Synthesis of the IKZF2 Glue Degrader DKY709 | DKY709, a protein degrader targeting Helios (IKZF2), was efficiently synthesized via flow chemistry. The synthetic sequence comprised a visible-light-induced benzyl bromination, an amination–cyclization cascade, a photoinduced C(sp 2 )–C(sp 3 ) coupling, and a high-temperature, high-pressure de-Boc/alkylation. Each rea... | 10.1021/acs.oprd.4c00476 | 1 |
1,2,3-Triazole Synthesis: Development of Safe and Effective Batch and Continuous Manufacturing Processes | In this paper, we present the development of a safe water-based synthesis of 1,2,3-triazole using cheap raw materials. Starting from glyoxal and hydrazine, a safe and efficient three-step end-to-end continuous process was developed. This protocol transforms heterogeneous batch reactions into a homogeneous streamlined c... | 10.1021/acs.oprd.4c00020 | 1 |
2,5-Dihydro-1<i>H</i>-pyrrol-3-yl Boronic Derivatives: Multigram Synthesis and Coupling Reactions | A protocol for the multigram synthesis of 3-substituted 2,5-dihydro-1 H -pyrrole boronic derivatives is reported. The method relied on the triflation of N -Boc-3-oxopyrrolidine and subsequent palladium-catalyzed borylation. Optimization studies demonstrated the high efficiency of t -BuOK as a base for the triflation st... | 10.1021/acs.oprd.3c00454 | 0 |
Use of a Dynamic Flow Platform To Translate a Batch Immobilized Transaminase Process to a Packed Bed Reactor for the Synthesis of an Intermediate of Nemtabrutinib | Herein we describe the translation of an immobilized transaminase process in batch to a packed bed reactor for the synthesis of cyrene amine, an intermediate of Nemtabrutinib. This change in reactor design provided significant benefits in both robustness of the immobilized enzyme preparation and minimization of the amo... | 10.1021/acs.oprd.3c00374 | 0 |
Opportunities and Challenges in Mechanochemical Cocrystallization toward Scaled-Up Pharmaceutical Manufacturing | Recently, pharmaceutical cocrystals have gained immense interest because of their potential to tune mechanical, pharmacokinetic, and physicochemical properties of active pharmaceutical ingredients (APIs) while keeping their therapeutic action intact. In this review, cocrystallization is raised as a viable strategy towa... | 10.1021/acs.oprd.2c00314 | 0 |
Modified Greener Procedure for the Synthesis of Cucurbit[6]uril | A modified procedure for the synthesis of cucurbit[6]uril on the kilogram scale was elaborated. The procedure includes reaction of glycoluril with paraformaldehyde in the minimal amount of concentrated sulfuric acid, filtration of the product directly from the reaction mixture, and workup by dissolution and reprecipita... | 10.1021/acs.oprd.2c00308 | 0 |
Scale-Up Synthesis of 1-Methyladamantane and Its Functionalization as a Key Point for Promising Antiviral Agents | Methyladamantane and its derivatives are rare chemotypes for industrial and even wide research use. The proposed scalable and inexpensive approach to such compounds opens the door to further extensive study of biologically active derivatives based on this uncommon core. Optimized synthesis of the key precursor, the chi... | 10.1021/acs.oprd.2c00305 | 1 |
Development of Commercial Manufacturing Processes for Acalabrutinib | The development of processes to produce the Bruton tyrosine kinase inhibitor, acalabrutinib 1, has resulted in improvements to the yield, cycle time, and operability, to realize a robust commercial manufacturing process. A highly accelerated clinical program meant that numerous key process challenges had to be resolved... | 10.1021/acs.oprd.2c00304 | 1 |
Large-Scale Amide Coupling in Aqueous Media: Process for the Production of Diazabicyclooctane β-Lactamase Inhibitors | Herein, the amide coupling of six primary amines with the sodium salt of diazabicyclooctane acid in an aqueous medium without an additional base/surfactant or organic solvent is described. The product was efficiently isolated from the reaction through simple filtration and recrystallized using hot water treatment as a ... | 10.1021/acs.oprd.2c00299 | 0 |
Early Process Development and Scale-Up of Orally Active Apomorphine Drug Candidates | The manufacturing route to a novel apomorphine Parkinson’s drug candidate (MCL-509) has been developed from a mg laboratory scale to that suitable for use on a 20–50 L scale. While the synthetic sequence could not be bettered, all six reaction steps required significant improvement for scale-up. Hazardous and toxic rea... | 10.1021/acs.oprd.2c00297 | 1 |
Toward the Development of a Manufacturing Process for the Insecticide Tyclopyrazoflor. Part I. Evaluation of Strategies using Ullmann Coupling of Pyrazole Derivatives | Synthetic strategies based on Ullmann coupling of functionalized pyrazoles and 3-halopyridine to access the insecticide tyclopyrazoflor ( 1 ) were evaluated. A five-step route featuring a middle-stage Ullmann coupling approach was selected as the lead route for optimization and was scaled up in a pilot plant at more th... | 10.1021/acs.oprd.2c00296 | 1 |
A Review of Tangential Flow Filtration: Process Development and Applications in the Pharmaceutical Industry | Tangential flow filtration is an efficient membrane separation technology utilized across a wide range of industries for separation and purification applications. The requirement of telescoped manufacturing to produce high-volume drugs in the pharmaceutical industry has led to increased adoption of membrane separation ... | 10.1021/acs.oprd.2c00291 | 0 |
Continuous Process to Safely Manufacture an Aryldiazoacetate and Its Direct Use in a Dirhodium-Catalyzed Enantioselective Cyclopropanation | We report the development and demonstration of a continuous-flow process for the safe formation, extraction, and drying of aryldiazoacetate 2, which enables direct use in a fed-batch dirhodium-catalyzed enantioselective cyclopropanation reaction to provide cyclopropane 4 . Designing this process with safety as a primar... | 10.1021/acs.oprd.2c00288 | 0 |
Process Research for ZG1077, a KRAS G12C Inhibitor | A novel, efficient, and robust synthetic route to ZG1077 with an atropisomer structure for KRAS G12C inhibitors was designed. The critical process parameters were optimized and established to reduce or avoid process-related impurities. The formation mechanism, purge pathways, and control strategy for these impurities a... | 10.1021/acs.oprd.2c00284 | 1 |
Process Development of a Triphasic Continuous Flow Suzuki–Miyaura Coupling Reaction in a Plug Flow Reactor | We have successfully adapted a Suzuki–Miyaura coupling reaction to a continuous flow process. The reaction was a triphasic mixture involved with two liquid phases that are only partially miscible in addition to the presence of an insoluble catalyst as a solid phase. The reaction required very rapid reaction heat up and... | 10.1021/acs.oprd.2c00278 | 0 |
Targeting Particle Size Specification in Pharmaceutical Crystallization: A Review on Recent Process Design and Development Strategies and Particle Size Measurements | Obtaining a particle size within the specifications for a pharmaceutical compound in an industrial crystallization can be a challenging task. The events affecting the final particle size of the product include nucleation, growth, breakage, and agglomeration, which are often convoluted. Secondary nucleation may signific... | 10.1021/acs.oprd.2c00277 | 0 |
Commercially Viable Synthesis of Medetomidine Using a Classical Approach to the Imidazole Ring Formation | A commercially viable and efficient method for the synthesis of medetomidine hydrochloride ( 1 ) was developed combining two reliable synthetic approaches: the modern method for C–C bond formation through the sp 2 –sp 3 Kumada cross-coupling and the classical method for the imidazole ring formation based on the Weidenh... | 10.1021/acs.oprd.2c00273 | 1 |
Pd-Catalyzed Cyanation of a Bromoaryl Carboxylate En Route to Etrumadenant: Robust Process with Low Catalyst Loading Enabled by Preactivation | Palladium-catalyzed cyanation of aryl bromides is a powerful approach to install a functional group commonly found in active pharmaceutical ingredients starting from readily available precursors. The development of a robust cyanation of a bromo benzoic acid to generate an intermediate en route to etrumadenant is descri... | 10.1021/acs.oprd.2c00272 | 1 |
Scale-Up of a Rh-Catalyzed Asymmetric sp<sup>3</sup>–sp<sup>2</sup> Suzuki–Miyaura-Type Reaction | High Resolution Image Download MS PowerPoint Slide Csp 2 –Csp 2 Suzuki–Miyaura couplings (SMCs) are ubiquitous in the synthesis of small molecules, but analogous Csp 2 –Csp 3 bond-forming SMCs are rare, especially asymmetric variants. Recently, we developed a series of Rh-catalyzed couplings between racemic sp 3 -hybri... | 10.1021/acs.oprd.2c00268 | 0 |
“On-Water” Reaction of (Thio)isocyanate: A Sustainable Process for the Synthesis of Unsymmetrical (Thio)ureas | We describe a facile, sustainable, and chemoselective process for the synthesis of unsymmetrical (thio)ureas through the “on-water” reaction of (thio)isocyanates with amines. Detailed mechanistic studies revealed that the physical nature and solubility of reagents in water are responsible for the observed reaction rate... | 10.1021/acs.oprd.2c00266 | 0 |
Enantioselective Synthesis of <i>trans</i>-Disubstituted Cyclopropyltrifluoroborate Building Blocks through Ru-Catalyzed Cyclopropanation | Enantioselective synthesis of trans -1,2-disubstituted cyclopropanes containing Lewis basic nitrogen functionalities remains a challenge to metal-catalyzed cyclopropanation reactions. Herein, we reported an alternative strategy to access similar products by a sequence of enantioselective cyclopropanation of potassium v... | 10.1021/acs.oprd.2c00265 | 1 |
Cost and Energy Saving Process for the Laboratory-Scale Production of Chloroform-<i>d</i> | Deuterochloroform (CDCl 3 ), a commonly deuterated solvent in research and undergraduate laboratories and widely employed for nuclear magnetic resonance analyses, could be prepared using a more sustainable and efficient catalytic process. The synthesis includes a one-pot reaction of hexachloroacetone with deuterium oxi... | 10.1021/acs.oprd.2c00260 | 0 |
Large-Scale Synthesis of Chiral Tetrahydropyran via Asymmetric Allylation Catalyzed by (<i>S</i>)-3,3′-Cl<sub>2</sub>-BINOL | Asymmetric synthesis of chiral tetrahydropyran 3, a key intermediate of PDE2 inhibitor 1, has been achieved in five linear steps with a 49% overall yield and >99:1 er on a large scale. The whole chemical process was realized without silica gel chromatography purification, starting from tert -butyl 2-chloro-5-(2-chloroa... | 10.1021/acs.oprd.2c00258 | 1 |
Understanding Chemical Processes with Entropic Sampling | High Resolution Image Download MS PowerPoint Slide Kinetic models are widely used in simulating the relationship between the input space and the outcome space of a chemical process. Ignoring the computational cost, complete profiling, i.e., performing simulations at all grid points in the input space, would be the best... | 10.1021/acs.oprd.2c00254 | 0 |
Continuous-Flow Supercritical CO<sub>2</sub> Platform for In-Situ Synthesis and Purification of Small Molecules for Drug Discovery | The use of supercritical CO 2 (scCO 2 ) as an enabling technology paves the way for an efficient in-line integration of the synthesis and purification of organic molecules. The scCO 2 platform presented here provides a streamlined process to produce a diverse family of triazoles, common drug precursors, by 1,3-dipolar ... | 10.1021/acs.oprd.2c00253 | 0 |
Safer and Convenient Synthesis of 3,4-Bis(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,5-oxadiazole-2-oxide (BNFF/DNTF) | A safer, convenient, and scalable synthesis for 3,4-bis(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,5-oxadiazole-2-oxide (BNFF or DNTF) is described. The obtained products were fully characterized and further confirmed by single-crystal X-ray diffraction. The reaction process of tandem nitration–cyclization was optimized, and th... | 10.1021/acs.oprd.2c00250 | 1 |
Development of a Commercial Manufacturing Process for Sotorasib, a First-in-Class KRAS<sup>G12C</sup> Inhibitor | A commercial process to manufacture sotorasib (AMG 510), a first-in-class KRAS G12C inhibitor, is described. Development efforts focused on rendering a fit-for-purpose early-phase route into a viable long-term commercial process through the reduction of side reactions to improve yield and product quality, as well as re... | 10.1021/acs.oprd.2c00249 | 1 |
Unique Superbase TBD (1,5,7-Triazabicyclo[4.4.0]dec-5-ene): From Catalytic Activity and One-Pot Synthesis to Broader Application in Industrial Chemistry | TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) is an organic superbase with unique catalytic effects due to its bifunctionality. It is already successfully used as a versatile catalyst, e.g., for transesterification, amidation, Michael addition, and aldol reactions, in technical silicone chemistry and even for enantioselect... | 10.1021/acs.oprd.2c00248 | 0 |
Development of an Efficient Process to Prepare Methyl 4,5,6-Trichloropicolinate Using Highly Selective C–H Borylation/Chlorodeborylation Reactions | This report details the development of an efficient process to prepare methyl 4,5,6-trichloropicolinate using Ir-catalyzed C–H borylation followed by CuCl 2 -mediated chlorodeborylation under optimized conditions. The process featured extremely low loadings (as low as 0.0005 equiv) of an [Ir(OMe)cod] 2 precatalyst with... | 10.1021/acs.oprd.2c00247 | 1 |
Development of a Telescoped Alkylation/Reduction Reaction Sequence and an Asymmetric Hydrogenation to Enable the Kilogram Synthesis of ABBV-3748 | Challenges in the synthesis of the cystic fibrosis transmembrane receptor corrector ABBV-3748 were addressed to enable a multikilogram-scale GMP sequence. Implementation of an early-stage telescoped titanium-mediated alkylation and palladium-catalyzed hydrogenation limited the formation of a dimerization impurity and p... | 10.1021/acs.oprd.2c00245 | 1 |
Improved Synthesis of the Selected Serine Protease uPA Inhibitor UAMC-00050, a Lead Compound for the Treatment of Dry Eye Disease | The α-aminophosphonate UAMC-00050, a newly developed trypsin-like serine protease inhibitor, is a lead compound for the treatment of dry eye syndrome and ocular inflammation. The medicinal chemistry route developed at the University of Antwerp possessed several problems hampering the scale-up such as poor yields for so... | 10.1021/acs.oprd.2c00244 | 1 |
Practical Process for synthesizing<i>R</i>-Tetrahydropapaverine─A Key Intermediate of Cisatracurium Besylate (Nimbex) | In this paper, a practical process to synthesize the key intermediate R -tetrahydropapaverine of cisatracurium besylate was proposed. First, tetrahydropapaverine hydrochloride ( 1 .HCl) was prepared from inexpensive and commercially available 2-(3,4-dimethoxyphenyl)ethanamine ( 2 ) and 3,4-dimethoxybenzeneacetic acid (... | 10.1021/acs.oprd.2c00243 | 1 |
Development of a Robust and Scalable Synthetic Route for a Potent and Selective Isoindolinone PI3Kγ Inhibitor | We recently described the structure-guided optimization of a series of pyrazolopyrimidine isoindolinone PI3Kγ inhibitors, which resulted in the identification of an advanced lead compound ( 1 ) with favorable potency, selectivity, and drug-like properties. To support preclinical characterization of 1, a robust and scal... | 10.1021/acs.oprd.2c00240 | 1 |
Efficient Process for Obeticholic Acid: Synthesis, Structural Assignment, and Control Strategy for Diastereoisomeric Impurities | An efficient process for the preparation of chirally pure obeticholic acid [ 1, (6α, 7α), OCA] with an overall yield of 30.78% from compound 5 (CDCA) is presented in this article. During the process development, there is a requirement for characterization of physical samples of all the possible diastereomers of 1 such ... | 10.1021/acs.oprd.2c00237 | 1 |
Development of an Efficient New Route to PPARδ Agonist Fonadelpar: Formation of the C–C Bond by Claisen Condensation | An efficient new synthesis of a peroxisome proliferator-activated receptor delta agonist fonadelpar was developed. The new process features a more practical approach to construct the ethylene linker of fonadelpar by coupling an advanced aldehyde and a ketone via Claisen–Schmidt condensation, which is followed by hydrog... | 10.1021/acs.oprd.2c00235 | 1 |
Process Development and Optimization of Linagliptin Aided by the Design of Experiments (DoE) | A design of experiments (DoE) approach was applied to the development and optimization of the manufacturing process to prepare linagliptin. DoE techniques such as a central composite face-centered design and a fractional factorial design were applied to obtain the critical process parameters and establish the optimal r... | 10.1021/acs.oprd.2c00230 | 1 |
Direct Construction of Chiral Ether via Highly Efficient Heck Reaction and N-Directed Asymmetric Hydrogenation for Large-Scale Synthesis of MALT1 Inhibitor RGT-068A | Chemical process development efforts leading to the large-scale production of RGT-068A are discussed. Process optimization resulted in (1) successful replacement of the Stille coupling reaction involving toxic stannane reagent via highly efficient Heck reaction of methyl vinyl ether, (2) construction of the chiral ethe... | 10.1021/acs.oprd.2c00229 | 1 |
Safety Considerations and Proposed Workflow for Laboratory-Scale Chemical Synthesis by Ball Milling | High Resolution Image Download MS PowerPoint Slide Chemical reactions that take place in a ball mill and in the absence of a bulk reaction solvent present different safety profiles to stirred solution reactions. Herein, we present and describe steps that a researcher may take to better ensure that they have considered ... | 10.1021/acs.oprd.2c00226 | 0 |
Optimized Synthesis of a Key Intermediate of Nirmatrelvir | In this study, the development of a concise alternative process for synthesis of a key nirmatrelvir intermediate cyclic glutamine analog is described. The process proceedes via α-cyanomethylation of dimethyl N -BocGlu in the presence of NdCl 3, followed by one-pot Raney nickel-catalyzed hydrogenation of the cyano group... | 10.1021/acs.oprd.2c00225 | 1 |
Scalable Process of Spiro(cyclopropane)oxazepane Pyridine Carboxylic Acid through Kulinkovich, Mitsunobu, and Pd-Catalyzed Intramolecular C–N Coupling | The oxazepane pyridine intermediate, an important fragment of active pharmaceutical ingredients, is of great interest in the pharmaceutical industry. In this manuscript, a scalable and economical process for the synthesis of a fused 2′,3′-dihydro-5’ H -spiro[cyclopropane-1,4′-pyrido[3,2-b][1,4]oxazepine]-8′-carboxylic ... | 10.1021/acs.oprd.2c00221 | 1 |
<i>tert</i>-Butylethylcarbodiimide as an Efficient Substitute for Diisopropylcarbodiimide in Solid-Phase Peptide Synthesis: Understanding the Side Reaction of Carbodiimides with OxymaPure | The undesired reaction between carbodiimides (peptide coupling reagent) and OxymaPure (peptide coupling additive), which takes place in very low extension during peptide bond formation, is dependent on the steric hindrance around the carbodiimide backbone. Carbodiimides containing tertiary substituents on N such as di-... | 10.1021/acs.oprd.2c00220 | 0 |
Efficient and Improved Solution-Phase Synthesis of Modified RNA Dinucleotides: Versatile Synthons in Cap 1 mRNA Therapeutics | An efficient and improved chemical method for the gram-scale synthesis of RNA dinucleotides such as pA m pA, pA m pG, and pA m pU is described that utilizes phosphoramidite chemistry using a solution-phase strategy. The first step involves the coupling between 5′- O -MMT protected nucleoside-3′- O -phosphoramidite and ... | 10.1021/acs.oprd.2c00218 | 0 |
Antibody–Drug Conjugate Synthesis Using Continuous Flow Microreactor Technology | Continuous flow reactors enable chemical reactions to occur within shielded pipes and tubes. This synthetic process is considered to overcome some limitations of commonly used batch reactors. Many successful examples of the synthesis of small molecules by continuous flow processes have been reported; however, their app... | 10.1021/acs.oprd.2c00217 | 0 |
Computer Vision for Kinetic Analysis of Lab- and Process-Scale Mixing Phenomena | A software platform for the computer vision-enabled analysis of mixing phenomena of relevance to process scale-up is described. By bringing new and known time-resolved mixing metrics under one platform, hitherto unavailable comparisons of pixel-derived mixing metrics are exemplified across non-chemical and chemical pro... | 10.1021/acs.oprd.2c00216 | 0 |
Synthesis of Thiomorpholine via a Telescoped Photochemical Thiol–Ene/Cyclization Sequence in Continuous Flow | A procedure for the continuous flow generation of thiomorpholine in a two-step telescoped format was developed. The key step was the photochemical thiol-ene reaction of cysteamine hydrochloride and vinyl chloride as low-cost starting materials. This reaction could be conducted under highly concentrated (4 M) conditions... | 10.1021/acs.oprd.2c00214 | 0 |
Novel, Practical, and Efficient Process for the Preparation of 4,5-Dichloroindole | A novel, practical, and efficient three-step process for the preparation of 4,5-dichloroindole 5, an important starting material for a wide range of fine chemicals and pharmaceuticals has been developed. The process comprises nitration of commercially available 2,3-dichlorobenzaldehyde 1, a telescopic process for the H... | 10.1021/acs.oprd.2c00212 | 1 |
Streamlined Synthesis of Aminoacridinium Photocatalysts with Improved Photostability | The efficient synthesis of photocatalysts with improved photostability from readily available resources is a requirement for more sustainable and scalable photocatalysis. Herein, we describe a strategy utilizing a high-yielding threefold C–N cross-coupling selective for three out of six arylbromide sites to avoid alkyl... | 10.1021/acs.oprd.2c00209 | 1 |
Mathematical Modeling and Optimization to Inform Impurity Control in an Industrial Active Pharmaceutical Ingredient Manufacturing Process | Mathematical modeling of pharmaceutical manufacturing processes can provide insights and understanding regarding the key factors impacting product quality. In this study, we describe the development of a dynamic model for a stage in an active pharmaceutical ingredient (API) manufacturing process, its calibration and va... | 10.1021/acs.oprd.2c00208 | 0 |
Development of a Robust and Scalable Process for the Large-Scale Preparation of Vilazodone | A robust and scalable synthesis for vilazodone was developed to avoid the formation of impurities derived from N-detosylation reactions under alcoholic conditions. During our research, these impurities, potentially genotoxic alkyl tosylate and out-of-specification indole N-alkylated vilazodones, were identified as proc... | 10.1021/acs.oprd.2c00206 | 1 |
Refractive Index to Monitor Solid-Phase Oligonucleotide Synthesis | Automated solid-phase oligonucleotide synthesis (SPOS) is a highly developed and efficient process, which has been used in academia and industry since decades. Still, some chemical transformations as well as all washing steps are run in a black box modus as only a few process analytical technology tools are available, ... | 10.1021/acs.oprd.2c00203 | 1 |
Practical Asymmetric Synthesis of a Bicyclic Pyrrolidinol | The “butterfly-shaped” bicyclic pyrrolidinol ((2 R,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)-methanol ( 1 ) is a key building block for drug candidates, and its practical chemical synthesis remains elusive. As such, an asymmetric synthesis for ((2 R,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)-me... | 10.1021/acs.oprd.2c00200 | 1 |
Advancing Scalable Chemistry toward Novel CELMoDs: Process Development for the Synthesis of CC-90009 | CC-90009 ( 1 ) is a cereblon E3 ligase modulating drug (CELMoD) in clinical trials for the treatment of acute myeloid leukemia (AML). An efficient synthesis of 1 was required to support drug substance supply for clinical trials. The structure features an isoindolinone core, an α,α-difluorophenylacetamide, and a chemica... | 10.1021/acs.oprd.2c00199 | 1 |
Multigram Synthesis of Pure HMF and BHMF | 5-Hydroxymethylfurfural (HMF) is a bio-based platform chemical that can be used as a building block to produce several compounds with diverse applications. Even though HMF synthesis holds promise for a greener future, the current state of technology and the high production cost limit its competitiveness on an industria... | 10.1021/acs.oprd.2c00196 | 0 |
Synthesis of MDM2-p53 Inhibitor BI-0282 via a Dipolar Cycloaddition and Late-Stage Davis–Beirut Reaction | Herein, we report the structure and synthesis of the potent MDM2-p53 inhibitor BI-0282. The complex spirooxindole scaffold bearing four stereocenters embedded in a rigid polycyclic ring-system was effectively prepared on a multi-gram scale in only five synthesis steps employing a three-component 1,3-dipolar cycloadditi... | 10.1021/acs.oprd.2c00192 | 1 |
Manufacturing Process Development for Uprifosbuvir (MK-3682): A Green and Sustainable Process for Preparing Penultimate 2′-Deoxy-α-2′-Chloro-β-2′-Methyluridine | A simple and efficient process to prepare Uprifosbuvir intermediate, 2′-deoxy-α-2′-chloro-β-2′-methyluridine ( 1 ), from bis-pivaloyl tertiary alcohol 5a is described. The key discoveries are a novel BSA-promoted anhydrouridine formation catalyzed by HCl as an additive and a milder safe Me 2 SiCl 2 -promoted chlorinati... | 10.1021/acs.oprd.2c00191 | 1 |
Addition Reaction of Alcohol to Isocyanate Catalyzed by Copper Present in Tap Water: Robust Manufacturing Process of Naldemedine Tosylate | We discovered that copper present in laboratory tap water could catalyze an addition reaction of the hydroxyl group of acetylnaltrexone to isocyanate. The first pilot manufacturing of naldemedine tosylate encountered an unexpected problem in which the addition reaction was seriously delayed. Detailed investigations sho... | 10.1021/acs.oprd.2c00187 | 1 |
Scalable Process of Methimazole | Base hydrolysis of imidazole carboxylate was observed to be an efficient route for the scalable synthesis of the antithyroid drug methimazole. Ethyl 3-methyl-2-thioxo-2,3-dihydro-1H-imidazole-1-carboxylate ( 12 ) was produced as a key intermediate in the reaction of 1-methyl-1H-imidazole ( 4 ) with ethyl chloroformate ... | 10.1021/acs.oprd.2c00185 | 1 |
Development of a Continuous Flow Synthesis of Lorazepam | Lorazepam, a widely used sedative that appears on the World Health Organization list of essential medicines, experiences periodic shortages. Using a workflow involving route scouting, high-throughput experimentation, and impurity profiling to develop an optimal sequence, we report a novel 5-step route for synthesis of ... | 10.1021/acs.oprd.2c00184 | 1 |
Efficient Synthesis of a Key Intermediate for Moxifloxacin Via Intramolecular Double Stereodifferentiation | An intramolecular double stereodifferentiation methodology was developed during the synthetic process development of ( S, S )-2,8-diazobicylo[4.3.0] nonane ( 1 ), the key intermediate of the fourth-generation fluoroquinolone Moxifloxacin. The dual chiral-auxiliary strategy employed in this process guaranteed high stere... | 10.1021/acs.oprd.2c00183 | 1 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.