title string | abstract string | doi string | has_route int64 |
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Continuous Processing in the Manufacture of Active Pharmaceutical Ingredients and Finished Dosage Forms: An Industry Perspective | Continuous manufacturing as a way of producing fine chemicals, active pharmaceutical ingredients, and finished dosage forms is gaining widespread attention. Although potential benefits over traditional batch-wise production have been discussed at many occasions and appear evident, continuous processes are only slowly b... | 10.1021/op300159y | 0 |
A Practical Kilogram-Scale Process to a Milnacipran Analogue, <i>N</i>,<i>N</i>-Diallyl (1<i>R</i>, 2<i>R</i>)-2-(Aminomethyl)-1-(2-thienyl)cyclopropanecarboxamide | A robust chemical process to produce N, N -diallyl (1 R,2 R )-2-(aminomethyl)-1-(2-thienyl)cyclopropanecarboxamide ( 2 ) has been developed and optimized. This unique process, employing the MsCl/NaN 3 and Zn/NH 4 Cl system, overcomes many pitfalls of the literature reported processes, which mostly use chromatographic p... | 10.1021/op3001542 | 1 |
Development of a Practical and Scalable Synthesis of a Potent CRTH2 Antagonist | This contribution describes the process research and development of a practical and scalable synthetic method towards compound 1, which has a potent CRTH2 antagonistic activity. The medicinal chemistry synthetic route and second generation synthetic route had several issues in scale-up synthesis. In contrast, the synth... | 10.1021/op3001492 | 1 |
Benign and High-Yielding, Large-Scale Synthesis of Diphenylphosphinodithioic Acid and Related Compounds | Diphenylphosphinodithioic acid ( 6b ) and its triethyl ammonium salt ( 6a ) were prepared by two new synthetic pathways, each employing cheap and readily available starting materials. These facile one-pot reactions were conducted on a kilogram scale and produced the desired products in high yield and quality, thereby s... | 10.1021/op300147f | 1 |
The Eight Criteria Defining a Good Chemical Manufacturing Process | As pharmaceutical API projects advance from Development to Chemical Production, the primary objective of the Process Research and Development (R&D) chemists is a smooth transfer of a well-developed, safe, scalable, robust, and economical chemical process to their customers in Chemical Production. Since the definition o... | 10.1021/op300144g | 0 |
Crystallization Engineering in Aza-Steroid: Application in the Development of Finasteride | High Resolution Image Download MS PowerPoint Slide Novel and robust crystallization approach based on solid solution formation was developed for the purification of finasteride. This is an unprecedented approach that describes the use of pure finasteride 1 to purify different lots of finasteride 1 (impure) contaminated... | 10.1021/op300142a | 0 |
Inclusion of Environmental Impact Parameters in Radial Pentagon Material Efficiency Metrics Analysis: Using Benign Indices as a Step Towards a Complete Assessment of “Greenness” for Chemical Reactions and Synthesis Plans | A new benign index (BI) parameter is developed and applied to assess the overall “greenness” of chemical reactions and synthesis plans. Previously described radial pentagon green metrics based solely on material efficiency are extended to include BI which takes into account the following potentials for environmental ha... | 10.1021/op3001405 | 0 |
An Asymmetric Synthesis of a Chiral Sulfone Acid with Concomitant Hydrolysis and Oxidation to Enable the Preparation of a Glucokinase Activator | This contribution describes the demonstration of an asymmetric synthesis of a glucokinase activator via protonation of the enolate generated from an alkylaryl ketene and ( R )-pantolactone. Additionally, a one-pot hydrolysis/oxidation protocol with lithium hydroperoxide was developed to afford a chiral sulfone acid wit... | 10.1021/op300139g | 1 |
Development of a Practical and Scalable Synthesis of (<i>R</i>)- and (<i>S</i>)-3-Amino-2-[(benzyloxy)methyl]propan-1-ol Monohydrochloride: A Useful C-4 Chiral Building Block | The development of a practical and scalable synthesis of a C-4 chiral amine building block ( R ) - 1·HCl and ( S ) - 1·HCl is described. This important chiral intermediate ( R ) - 1·HCl is efficiently synthesized from the commercially available, inexpensive, and simple 2-(hydroxymethyl)-1,3-propanediol ( 31 ) using lip... | 10.1021/op3001383 | 1 |
An Efficient Synthesis of 3-Substituted <i>N</i>-Glycoside Indoles Useful as Sodium-Dependent Glucose Transporter Inhibitors | A practical synthesis of two N -glycoside indoles 1 and 2, identified as highly potent sodium-dependent glucose transporter (SGLT) inhibitors is described. Highlights of the synthetic process include a selective and quantitative Vilsmeier acylation and a high-yielding Grignard coupling reaction. The chemistry developed... | 10.1021/op3001355 | 1 |
Development of a Practical and Convergent Process for the Preparation of Sulopenem | Previous synthetic processes for the preparation of sulopenem involved multistep linear sequences in which the chiral sulfoxide side chain was introduced early in the process. This contribution summarizes the development of a practical and convergent process for the large-scale preparation of 1 . The key step in the sy... | 10.1021/op300131e | 1 |
Development of a Second-Generation Process to Antibacterial Candidate Sulopenem | The research, development, and scale-up of the broad-spectrum antibacterial candidate sulopenem are presented. An enabled medicinal chemistry synthesis of this active pharmaceutical ingredient was utilized for Phase 1 and early Phase 2 manufacture but was not conducive to larger scale. The limitations associated with t... | 10.1021/op300130p | 1 |
Route Development and Multikilogram GMP Delivery of a Somatostatin Receptor Antagonist | Route development and demonstration on multikilogram scale for the first GMP delivery of MK-4256 are described. Key aspects of the convergent route include a regioselective green iodination, one-pot oxadiazole synthesis, and an efficient ketone Pictet–Spengler reaction with diastereomeric upgrade via crystallization to... | 10.1021/op300128c | 1 |
A Continuous Kilogram-Scale Process for the Manufacture of <i>o</i>-Difluorobenzene | An expeditious and multikilogram-scale process for the Balz–Schiemann synthesis of o -difluorobenzene from o -fluoroaniline via two separate continuous flow reactors in 90.0% yield has been set up. The main steps involved the generation of stable diazonium fluoborate intermediate in situ via continuous diazotization re... | 10.1021/op300127x | 0 |
Application of the Quality by Design Principles for the Development of the Crystallization Process for a Piperazinyl-Quinoline and Definition of the Control Strategy for Form 1 | The studies carried out to develop a robust crystallization method for the substituted piperazinyl-quinoline ( 1 ) a compound potentially active in the treatment of depression, are described in this contribution. These studies include the control of a solvate that could have potentially formed in the crystallization pr... | 10.1021/op300126e | 1 |
Response to the Comments by Rautenstrauch et al. on our Article, “Convergent Kilo-Scale Synthesis of a Potent Renin Inhibitor for the Treatment of Hypertension” | ADVERTISEMENT RETURN TO ISSUEPREVLetter to the EditorNEXTResponse to the Comments by Rautenstrauch et al. on our Article, "Convergent Kilo-Scale Synthesis of a Potent Renin Inhibitor for the Treatment of Hypertension" Louis-Charles Campeau* and Erin N. GuidryView Author Information Global Process Chemistry Merck, P.O. ... | 10.1021/op3001228 | 0 |
Development of an Efficient, Scalable Route for the Preparation of a Novel Insulin-Like Growth Factor-1 Receptor Modulator | A chromatography-free and efficient synthesis of insulin-like growth factor-1 receptor (IGF-1R) modulator is reported. Herein we describe an improved synthesis for the target compound, which features facile introduction of a novel pyrrolidinyl-pyrimidyl isoxazole 8, via in situ sulfone displacement by fluorine. The ove... | 10.1021/op300120r | 1 |
A New Solvent System (Cyclopentyl Methyl Ether–Water) in Process Development of Darifenacin HBr | Darifenacin is a potent and competitive M 3 selective receptor antagonist (M 3 SRA), and its hydrobromide salt ( 1 ) is the active ingredient of pharmaceutical formulations for oral treatment of urinary incontinence. The present work demonstrates an efficient, commercial manufacturing process for darifenacin hydrobromi... | 10.1021/op300119s | 1 |
Nitration Under Continuous Flow Conditions: Convenient Synthesis of 2-Isopropoxy-5-nitrobenzaldehyde, an Important Building Block in the Preparation of Nitro-Substituted Hoveyda–Grubbs Metathesis Catalyst | Herein, we describe the use of continuous flow chemistry for selective, efficient and reproducible nitration of 2-isopropoxybenzaldehyde to produce the desired 2-isopropoxy-5-nitrobenzaldehyde, an important building block in the preparation of a ligand of nitro-substituted Hoveyda–Grubbs metathesis catalyst. Nitration ... | 10.1021/op300116j | 1 |
Science of Synthesis Workbench Edition: Stereoselective Synthesis | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewScience of Synthesis Workbench Edition: Stereoselective SynthesisTrevor LairdCite this: Org. Process Res. Dev. 2012, 16, 6, 1242Publication Date (Web):May 17, 2012Publication History Published online17 May 2012Published inissue 15 June 2012https://pubs.acs.org/doi/10.1021/op3... | 10.1021/op300112z | 0 |
Pharmaceutical Process Development: Current Chemical and Engineering Challenges | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewPharmaceutical Process Development: Current Chemical and Engineering ChallengesWill WatsonView Author Information Scientific Update, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, United Kingdom, E-mail: [email protected]Cite this: Org. Process Res. Dev. 2012, 1... | 10.1021/op300105m | 0 |
Safety Assessment for the Scale-up of an Oxime Reduction with Melted Sodium in Standard Pilot-Plant Equipment | A pilot-plant process is described for the reduction of 2-allyl cyclohexanone oxime with melted sodium in xylenes, toluene, and 4-methyl-2-pentanol. The trans / cis ratio was 3–4:1. Safety data are presented from a range of thermokinetic experiments (heat flow calorimetry, differential scanning calorimetry, and acceler... | 10.1021/op300101d | 0 |
Sulphuric Acid as Neutralization Agent for the Removal of Caesium in the Production Process of a Commodity Polyether-Polyol | The aim of this work was the optimization of the neutralization process to remove the catalyst from a polyether polyol. Some parameters were studied: water content, dehydration curve conditions, the acid concentration of the neutralization solution, and temperature. The final cesium content was kept under the specified... | 10.1021/op3000948 | 0 |
Synthesis of an H<sub>3</sub> Antagonist via Sequential One-Pot Additions of a Magnesium Ate Complex and an Amine to a 1,4-Ketoester followed by Carbonyl-Directed Fluoride Addition | We describe the development of an efficient and scalable process for the preparation of fluorocyclobutane-containing H 3 antagonist, 1 . The synthesis was accomplished by the chemoselective addition of a magnesium ate complex and an amine to a 1,4-ketoester in a one-pot sequence, followed by a diastereoselective carbon... | 10.1021/op300093j | 0 |
Process Development and Optimization for Production of a Potassium Ion Channel Blocker, ICA-17043 | A scalable process for the manufacture of a potassium ion channel blocker was developed and optimized. Key features of the process include an optimized Grignard reaction, a direct cyanation of the intermediate trityl alcohol derivative, and an improved nitrile hydrolysis protocol, relative to the original acidic hydrol... | 10.1021/op3000916 | 1 |
OPRD’s First Large Scale Review | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTOPRD's First Large Scale ReviewJaan PestiCite this: Org. Process Res. Dev. 2012, 16, 6, 1155Publication Date (Web):April 9, 2012Publication History Published online9 April 2012Published inissue 15 June 2012https://pubs.acs.org/doi/10.1021/op3000866https://doi.org/10.1021/op3000... | 10.1021/op3000866 | 0 |
A Flow-Based Synthesis of 2-Aminoadamantane-2-carboxylic Acid | The development of a new, high-yielding, scalable and safe process for the preparation of 2-aminoadamantane-2-carboxylic acid ( 1 ) is described. This geminal, functionalized achiral amino acid has been reported to possess interesting biological activity as a transport mediator due to its unique physiochemical properti... | 10.1021/op300084z | 1 |
Continuous Processes: Go with the Flow! | ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTContinuous Processes: Go with the Flow!Jaan PestiCite this: Org. Process Res. Dev. 2012, 16, 5, 843Publication Date (Web):April 4, 2012Publication History Published online4 April 2012Published inissue 18 May 2012https://pubs.acs.org/doi/10.1021/op300081qhttps://doi.org/10.1... | 10.1021/op300081q | 0 |
Identification, Synthesis, and Strategy For Minimization of Potential Impurities Observed In Raltegravir Potassium Drug Substance | Multiple sources of anticipated degradation and process impurities of raltegravir potassium drug substance observed during the laboratory optimization and later during its bulk synthesis are described in this article. The impurities were monitored by UPLC, and their structures are tentatively assigned on the basis of f... | 10.1021/op300077m | 1 |
Enantioselective, Chromatography-Free Synthesis of β<sup>3</sup>-Amino Acids with Natural and Unnatural Side Chains | β 3 -Amino acids are key components of some pharmaceuticals, excellent surrogates for metabolically labile α-amino acids, and building blocks for chiral heterocycles. Unfortunately they are not easily accessible in enantiomerically pure form, especially when possessing unnatural side chains. A flexible, chromatography-... | 10.1021/op300069n | 1 |
Process Development of a Novel Azetidinyl Ketolide Antibiotic | Process development and the multikilogram synthesis of a novel azetidinyl ketolide antibiotic is described. Starting with clarithromycin, the eight-step synthesis features several telescoped operations and direct isolations, which results in a significant improvement in throughput and a major reduction in solvent usage... | 10.1021/op300064b | 0 |
Process Development and Pilot-Plant Synthesis of (<i>S</i>)-<i>tert</i>-Butyl 1-Oxo-1-(1-(pyridin-2-yl)cyclopropylamino)propan-2-ylcarbamate: Studies on the Scale-Up of Kulinkovich–Szymoniak Cyclopropanation | A practical and scalable synthesis of ( S )- tert -butyl 1-oxo-1-(1-(pyridin-2-yl)cyclopropylamino)propan-2-ylcarbamate, an intermediate in the manufacture of a lymphocyte function-associated antigen 1 inhibitor, is described. The titled compound is prepared via an efficient one-pot, two-step telescoped sequence starti... | 10.1021/op300059b | 1 |
An Efficient Synthesis of 1-(2-Methoxyphenoxy)-2,3-epoxypropane: Key Intermediate of β-Adrenoblockers | An efficient process for the preparation of 1-(2-methoxyphenoxy)-2,3-epoxypropane, a key intermediate for the synthesis of ranolazine is described. | 10.1021/op300056k | 1 |
Rapid Crystallization Process Development Strategy from Lab to Industrial Scale with PAT Tools in Skid Configuration | Batch cooling crystallization is a commonly used separation and purification step in the pharmaceutical industry. Various properties of the crystalline product from a batch crystallizer can have a strong impact on the efficiency of downstream processes such as filtration and drying, on the formulation process and on th... | 10.1021/op300055g | 0 |
The Development of an Asymmetric Hydrogenation Process for the Preparation of Solifenacin | The successful development of a catalytic imine asymmetric hydrogenation process for the reduction of the hydrochloride salt of 1-phenyl-3,4-dihydroisoquinoline to 1-( S )-phenyl-1,2,3,4-tetrahydroisoquinoline is described. This represents a novel approach to the key intermediate in preparing the urinary antispasmodic ... | 10.1021/op3000543 | 1 |
Development of an Enantioselective Hydrogenation Based Synthesis of a Glucokinase Activator | This article describes the development and optimization of chemical reactions and subsequent multikilogram preparation of the glucokinase activator ( R )- 1 to fund clinical evaluation as a potential therapeutic for type II diabetes. The major process developments presented here are a Wittig olefination isomerization b... | 10.1021/op300053a | 1 |
Synthesis of Phenylboronic Acids in Continuous Flow by Means of a Multijet Oscillating Disc Reactor System Operating at Cryogenic Temperatures | A multijet oscillating disk (MJOD) millireactor system suitable for operating at cryogenic temperatures has been developed, assembled, and investigated. This new reactor system (cryoMJOD) was realized with the purpose to prepare various phenylboronic acids in a continuous two (three)-step telescoped synthetic process a... | 10.1021/op3000493 | 0 |
Kinetic and Safety Characterization of the Nitration Process of Methyl Benzoate in Mixed Acid | The nitration of methyl benzoate is studied from a chemical and a kinetic point of view. The reaction network through which the system could evolve following the loss of thermal control or the uncorrect feed of the reagents is completely characterized. The data collected during the present investigation indicate that r... | 10.1021/op300043x | 0 |
Process Development of Citalopram/Escitalopram Oxalate: Isolation and Synthesis of Novel Impurities | During process optimization of Escitalopram oxalate novel impurities, 6 and 7 were observed, which were isolated and characterized, and the proposed structure was confirmed by chemical synthesis. Investigation of the cause of impurities formation improved the yield and purity of the drug product during the bulk API syn... | 10.1021/op300039c | 1 |
Innovation in Generic API Synthesis and Manufacture | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTInnovation in Generic API Synthesis and ManufactureTrevor LairdCite this: Org. Process Res. Dev. 2012, 16, 3, 365Publication Date (Web):March 7, 2012Publication History Published online7 March 2012Published inissue 16 March 2012https://pubs.acs.org/doi/10.1021/op300038xhttps://... | 10.1021/op300038x | 0 |
Streamlined Process for the Conversion of Artemisinin to Artemether | We report an improvement to the previously published manufacturing process for artemether, a key antimalarial drug, utilizing readily available reagents, easily controlled manufacturing conditions, and a greatly simplified workup and isolation. New analytical methods and in-process controls allow for optimization of yi... | 10.1021/op300037e | 0 |
Heat Transfer Based Scale-Down of Chemical Reactions | Mathematical models of dose controlled reactions based on heat flow data (1, 2) are quite common and well developed; however, such predictions for nondose controlled reactions from heat flow data are difficult, requiring extensive study of the kinetics of multiple chemical transformations as well as physical phenomena ... | 10.1021/op300036p | 0 |
Corey–Itsuno Reduction of Ketones: A Development of Safe and Inexpensive Process for Synthesis of Some API Intermediates | A safe and inexpensive procedure for asymmetric reduction of ketones using in situ prepared N, N -diethylaniline borane (DEANB) and oxazaborolidine catalyst from sodium borohydride, N, N -diethylaniline hydrochloride and ( S )-α,α-diphenylprolinol is described. This protocol is demonstrated successfully to manufacture ... | 10.1021/op300034u | 1 |
Convergent, Kilogram Scale Synthesis of an Akt Kinase Inhibitor | The development of a convergent, chromatography-free synthesis of an allosteric Akt kinase inhibitor is described. The route comprised 17 total steps and was used to produce kilogram quantities of the target molecule. A key early transformation, for which both batch and flow protocols were developed, was formylation of... | 10.1021/op300031r | 1 |
An Efficient and Telescopic Process for Valsartan, an Angiotensin II Receptor Blocker | An efficient, telescopic, and scalable process for an antihypertensive drug substance, valsartan with an overall yield of 58%, and ∼99.9% purity is described. A simple, and safe process is developed for the recovery of tributyltin chloride from the tributyltin hydroxide, byproduct formed in the tetrazole ring construct... | 10.1021/op3000306 | 1 |
Improved Process for Ranolazine: An Antianginal Agent | An improved process has been developed for the active pharmaceutical ingredient, ranolazine with 99.9% purity and 47% overall yield (including three chemical reactions and one recrystallization). Formation and control of all the possible impurities is described. All the solvents used in the process were recovered and r... | 10.1021/op300026r | 1 |
Flexible and Scalable Route to HDAc Inhibitors Containing an Unusual Trisubstituted Pyridine Core | A scalable route to histone deacetylase inhibitors containing an unusual 2-aryl-3-cyano-5-aminomethylpyridine core has been developed which has the flexibility to deliver a range of compounds on at least a multigram scale. The key step involves a novel Mannich reaction using 3-dimethylaminoacrolein, formaldehyde, and a... | 10.1021/op300021m | 1 |
An Improved Scalable Route to Pure Dronedarone Hydrochloride | An efficient scalable synthesis for dronedarone hydrochloride ( 2 ) via Friedel–Craft acylation of 2-(-2-butyl-1-benzofuran-5-yl)-1 H -isoindole-1,3(2 H )dione ( 12 ) with 4-(3-chloropropoxy) benzoic acid ( 13 ) in good yield and high purity has been developed by using Eaton’s reagent instead of hazardous and toxic met... | 10.1021/op300017v | 1 |
Safety Concerns in a Pharmaceutical Manufacturing Process Using Dimethyl Sulfoxide (DMSO) as a Solvent | During the process safety analysis of a fluoride displacement reaction, a highly exothermic event was observed when the reaction mixture was heated, which appears to be due to the decomposition of DMSO catalyzed by the HF byproduct from the displacement reaction. Although the T D24 for the decomposition is 42 °C above ... | 10.1021/op300016m | 0 |
Process Research for Multikilogram Production of Etamicastat: A Novel Dopamine β-Hydroxylase Inhibitor | In order to develop a manufacturing route to etamicastat, three synthetic approaches to the pivotal chiral 3-aminochroman intermediate have been studied as well as four methods for the construction of the 2-aminoethyl imidazolethione fragment. The evolution of the synthetic strategy based on the early discovery route w... | 10.1021/op300012d | 1 |
New Manufacturing Procedure of Cetirizine | A new procedure for the manufacture of cetirizine dihydrochloride via the new intermediate 2-(2-{4-[(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethoxy)- N, N -dimethylacetamide dihydrochloride, synthesized by O-alkylation of 2-{4-[(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethanol with 2-chloro- N, N -dimethylacet... | 10.1021/op300009y | 1 |
Initial Process Development and Scale-Up of the Synthesis of a Triple Reuptake Inhibitor ALB 109780 | Early process development toward a triple reuptake inhibitor is described. Three different routes were evaluated; one of them was optimized and scaled up to generate 470 g of API as this route minimized the formation of undesired side products. The selected route featured Eaton’s reagent-mediated cyclization of a pheny... | 10.1021/op3000064 | 1 |
Kilogram-Scale Production of Corannulene | An efficient entry process for the synthesis of corannulene has been demonstrated on kilogram scale. Compared to the discovery and gram-scale syntheses, the amounts of solvents and reagents per gram of product were greatly reduced. Priority was given to implement the least toxic agents possible. Improvements in the pur... | 10.1021/op200387s | 1 |
Preparation of Spherical Particles of 1,1-Diamino-2,2-dinitroethene (FOX-7) Using a Micellar Nanoreactor | The need and preparation of spherical 1,1-diamino-2,2-dinitroethene (FOX-7) particles to meet certain special applications in high explosives and propellant formulation have been illustrated. Preparation of spherical FOX-7 particles by using a microemulsion technique has not been reported in the literature. In the pres... | 10.1021/op200386u | 0 |
A Safe and Scalable Procedure for Preparation of α-Picoline–Borane from Sodium Mono-acyloxyborohydrides and α-Picoline | Sodium monobenzoxyborohydride, which is easily prepared from sodium borohydride and benzoic acid in THF in situ, is treated with α-picoline in THF under mild conditions to give α-picoline–borane in an excellent yield. This method can be a practical preparation for α-picoline–borane. | 10.1021/op2003858 | 0 |
Continuous Dehydration and Hydrogenolysis of Glycerol over Non-Chromium Copper Catalyst: Laboratory-Scale Process Studies | A non-chromium Cu:Al catalyst was developed for glycerol dehydration under N 2 atmosphere to acetol and hydrogenolysis to 1,2-propanediol (1,2-PDO). Among the various copper-based catalysts screened in this work, Cu:Al-1 catalyst showed the highest activity and acetol selectivity in water medium, whereas transfer hydro... | 10.1021/op200383r | 0 |
Large-Scale Carbonyl Reductions in the Pharmaceutical Industry | Herein we present a review on methods for carbonyl reductions on large scale (≥100 mmol) applied to the synthesis of drug candidates in the pharmaceutical industry. We discuss the most common and reliable methods for the reduction of aldehydes, ketones, carboxylic acids, esters, amides, imides, and acid chlorides. Repr... | 10.1021/op2003826 | 0 |
Asymmetric and Diastereoselective Conjugate Addition Reactions: C–C Bond Formation at Large Scale | Asymmetric and diastereoselective conjugate addition reactions are discussed from an industrial perspective including examples of (1) Lewis acid/Brønsted base catalysis, (2) phase transfer catalysis, (3) organocatalysis, and (4) transition metal/ligand catalysis with organometallic reagents. | 10.1021/op200381w | 1 |
Development of a Practical and Scalable Synthesis of a Potent Selective Dual Antagonist for 5-HT2B and 5-HT7 Receptors | Process research and development of a practical and scalable synthetic route toward compound ( S ) - 1 and compound ( R ) - 1, which are potent selective dual antagonists for 5-HT2B and 5-HT7 receptors, respectively, is described. The medicinal chemistry route and second generation route were also unattractive for larg... | 10.1021/op200380z | 1 |
Scale-Up of an Enantioselective Overman Rearrangement for an Asymmetric Synthesis of a Glycine Transporter 1 Inhibitor | An enantioselective Overman 3,3-sigmatropic rearrangement on a quinuclidine skeleton was developed for the pilot-plant synthesis of a glycine transporter 1 inhibitor. The first stereocenter was produced by a Ru-catalyzed asymmetric transfer hydrogenation process followed by chirality transfer using the Overman rearrang... | 10.1021/op200378r | 1 |
Why Publish in <i>Organic Process Research & Development</i>??? | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTWhy Publish in Organic Process Research & Development???Jaan PestiCite this: Org. Process Res. Dev. 2012, 16, 2, 173Publication Date (Web):January 30, 2012Publication History Published online30 January 2012Published inissue 17 February 2012https://pubs.acs.org/doi/10.1021/op200... | 10.1021/op200374v | 0 |
A Brief Review on Industrial Alternatives for the Manufacturing of Glycerol Carbonate, a Green Chemical | Glycerol carbonate is one the glycerol derivatives which attracts attention for industrial applications. This review compares strategies for its synthesis, and their analyses lead to the conclusion that (indirect) procedures starting from glycerol- and/or CO 2 -derivatives are the most attractive. These are described a... | 10.1021/op200369v | 1 |
Development of an Efficient and Practical Route for the Multikilogram Manufacture of Ethyl 5-Cyano-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate and Ethyl 6-Chloro-5-cyano-2-methylnicotinate, Key Intermediates in the Preparation of P2Y12 Antagonists | Elucidation of the mechanism of formation of two major impurities in the synthetic route towards key intermediate ethyl 5-cyano-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate 1, led directly to the development of a route with significant process improvements in terms of yield, purity, and operability. The overall pro... | 10.1021/op200368m | 1 |
Green Chemistry is Good Process Chemistry | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTGreen Chemistry is Good Process ChemistryTrevor LairdCite this: Org. Process Res. Dev. 2012, 16, 1, 1–2Publication Date (Web):January 5, 2012Publication History Published online5 January 2012Published inissue 20 January 2012https://pubs.acs.org/doi/10.1021/op200366yhttps://doi.... | 10.1021/op200366y | 0 |
Route Selection and Process Development of a Multikilogram Route to the Inhaled A<sub>2a</sub> Agonist UK-432,097 | This article describes the selection, process development, and scale-up of a synthetic route to a complex nucleoside analogue, the A 2a agonist UK-432,097 ( 1 ), that culminated in the manufacture of over 25 kg of the API. The key steps in the process were (1) a stereoselective glycosidation reaction; (2) a scalable bl... | 10.1021/op200365n | 1 |
Development of Two Complementary Syntheses for a Privileged CGRP Receptor Antagonist Substructure | 1-(Piperidin-4-yl)-1 H -imidazo[4,5- b ]pyridin-2(3 H )-one ( 1 ) is a privileged substructure found in >1000 unique CGRP receptor antagonists. Two practical and efficient syntheses of 1 are described from complementary starting materials. One route features a chemoselective reductive amination, while the second route ... | 10.1021/op2003634 | 1 |
Development and Scale-Up of a Continuous, High-Pressure, Asymmetric Hydrogenation Reaction, Workup, and Isolation | A fully continuous process including an asymmetric hydrogenation reaction operating at 70 bar hydrogen, aqueous extraction, and crystallization was designed, developed, and demonstrated at pilot scale. This paper highlights safety, quality, and throughput advantages of the continuous reaction and separations unit opera... | 10.1021/op200362h | 1 |
Development of a Large-Scale Synthetic Route to Manufacture (−)-Huperzine A | A safe, practical and scalable process for manufacture of (−)-huperzine A has been developed and scaled up to manufacture several hundred grams of (−)-huperzine A with chemical and optical purity of >99%. The process consists of 11 chemical stages starting from commercially available materials with only nine isolation ... | 10.1021/op200360b | 1 |
First- and Second-Generation Practical Syntheses of Chroman-4-one Derivative: A Key Intermediate for the Preparation of SERT/5-HT<sub>1A</sub> Dual Inhibitors | Two approaches to large-scale synthesis of the key intermediate 9, a precursor of novel dual inhibitors of SERT/5-HT 1A receptor, are described. These two approaches each feature a mild and efficient method for construction of the chroman-4-one scaffold, which can be used with substrates containing base-sensitive funct... | 10.1021/op200357h | 1 |
Preparation of (<i>S</i>)-1-Cyclopropyl-2-methoxyethanamine by a Chemoenzymatic Route Using Leucine Dehydrogenase | ( S )-1-Cyclopropyl-2-methoxyethanamine is a key chiral intermediate for the synthesis of a corticotropin-releasing factor-1(CRF-1) receptor antagonist. Resolution of the racemic amine by transaminase from Vibrio fluvalis gave a 38% yield of the S -amine with 53% ee. Resolution by lipase-catalyzed acylation provided th... | 10.1021/op2003562 | 1 |
Practical Asymmetric Synthesis of (+)-erythro Mefloquine Hydrochloride | A highly enantioselective and cost efficient process for the synthesis of (+)-erythro mefloquine has been developed. The key step is an enantioselective reduction of pyridyl ketone KI using transfer hydrogenation with formic acid as the hydrogen source. The ratio of formic acid to NEt 3 was found to be very important t... | 10.1021/op200354f | 1 |
Multikilogram Synthesis of 4-<scp>d</scp>-Erythronolactone via Batch and Continuous Processing | The conversion of a batch process to continuous (flow) operation has been investigated. The manufacture of 4, d -erythronolactone at kilogram scale was used as an example. Fully continuous processing was found to be impracticable with the available plant because of the difficulty in carrying out a multiphase isolation ... | 10.1021/op200352k | 0 |
Rapid Development and Scale-Up of a 1<i>H</i>-4-Substituted Imidazole Intermediate Enabled by Chemistry in Continuous Plug Flow Reactors | The development of reactions in a continuous fashion in plug flow tube reactors (PFR) offers unique advantages to the drug development and scale-up process and can also enable chemistry that would be difficult to perform via batch processing. Herein, we report the development of two different continuous flow approaches... | 10.1021/op200351g | 1 |
Mixing and Dispersion in Small-Scale Flow Systems | Continuous flow chemistry is being used increasingly; however, without detailed knowledge of reaction engineering, it can be difficult to judge whether dispersion and mixing are important factors on reaction outcome. Understanding these effects can result in improved choices of reactor dimensions and give insight for r... | 10.1021/op200349f | 0 |
Managing Solids in Microreactors for the Upstream Continuous Processing of Fine Chemicals | The management of solid compounds is a major challenge facing the upstream, continuous processing of pharmaceuticals and fine chemicals. Many reactions relevant to fine chemical production either react with or form insoluble materials, which become problematic in continuous flow microreactors. The deposition, growth, o... | 10.1021/op200348t | 0 |
Using Continuous Processes to Increase Production | Continuous operations have become popular in both academia and the pharmaceutical industry. Continuous operations may be developed to make high-quality material safely, or because continuous operations are the only effective and economical way to make larger quantities of material. This review surveys the area of conti... | 10.1021/op200347k | 0 |
Development of an Improved Process for Doxercalciferol via a Continuous Photochemical Reaction | Doxercalciferol (1α-hydroxyvitamin D2) is a commercially approved vitamin D derivative used to treat chronic kidney disease (CKD) patients whose kidneys cannot metabolically introduce a hydroxyl group at C1. A new process for the production of doxercalciferol from ergocalciferol was developed using a continuous photois... | 10.1021/op200346g | 1 |
Manufacture of a β-Hydroxyester via a Continuous Reformatsky Process | The use of continuous processing in a Reformatsky reaction has been investigated as a means to control the large heat of reaction and reduce the inventory of hazardous materials. A laboratory-scale continuous miniplant for manufacture of an aromatic β-hydroxyester has been designed and built for a production rate of ab... | 10.1021/op2003453 | 0 |
Development of a Continuous Schotten–Baumann Route to an Acyl Sulfonamide | The development and scale-up of a synthetic route to tasisulam sodium (5-bromo-thiophene-2-sulfonic acid 2,4-dichlorobenzoylamide sodium salt, hereafter referred to as tasisulam) utilizing continuous Schotten–Baumann reaction conditions is disclosed. A new synthetic route for the cytotoxic API amenable to continuous pr... | 10.1021/op200344a | 1 |
Process Development and Scale-Up of AZD7545, a PDK Inhibitor | A brief comparison of the early manufacturing routes to AZD7545 is given. Process development of the preferred long-term manufacturing route is reported in detail, and changes from the initial kilogram-scale route are discussed. Scale-up experience from the pilot-plant manufacture is included in the discussion of each ... | 10.1021/op2003419 | 1 |
Development of a Continuous Flow Scale-Up Approach of Reflux Inhibitor AZD6906 | Early scale-up work of a promising reflux inhibitor AZD6906 is described. Two steps of an earlier route were adapted to be performed in continuous flow to avoid issues related to batch procedures, resulting in a robust method with reduced cost of goods and improved product quality. Toxic and reactive reagents and start... | 10.1021/op200340c | 1 |
Process Development and Large-Scale Synthesis of MK-6186, a Non-Nucleoside Reverse Transcriptase Inhibitor for the Treatment of HIV | A new synthetic route has been developed to drug candidate 1, a second-generation NNRTI being developed as a potential treatment of HIV. Regiocontrol in a key alkylation step was achieved by selective N -alkylation of hydrazone 13 . After a deprotection and cyclisation sequence, 1 was isolated in six steps in 35% overa... | 10.1021/op200334x | 1 |
Kilogram-Lab-Scale Oxindole Synthesis via Palladium-Catalyzed C–H Functionalization | A scalable method for the preparation of oxindole 8, a key intermediate en route to a serine palmitoyl transferase inhibitor, compound 1, is presented. A three-step, chromatography-free route has been designed that takes advantage of Buchwald’s palladium-catalyzed C–H functionalization to cyclize an α-chloroacetanilide... | 10.1021/op200332p | 1 |
Selective Continuous Flow Processes Using Fluorine Gas | The use of continuous gas–liquid flow reactors for processes involving fluorine gas is reviewed. Falling film, microbubble, and laminar flow reactors that have been adapted to carry out direct fluorination reactions are described, and a range of selective fluorination reactions involving direct fluorination of a variet... | 10.1021/op200331s | 1 |
Development of a Robust Procedure for the Copper-catalyzed Ring-Opening of Epoxides with Grignard Reagents | A general procedure for the copper-catalyzed regioselective ring-opening of epoxides with Grignard reagents is described. The procedure developed provides robust reaction conditions which limit the formation of impurities and has been applied successfully using a series of epoxides and Grignard reagents to provide the ... | 10.1021/op200329x | 0 |
Practical and Scalable Synthesis of S1P<sub>1</sub> Receptor Agonist ACT-209905 | A practical and scalable route for the fast delivery of 12 kg of S1P 1 agonist (ACT-209905) has been developed. ACT-209905 is composed of an amino pyridine group, an oxadiazole spacer, a 2-ethyl-5-methylphenol moiety and a chiral 1-amino-2-propanol side chain. The convergent synthesis consists of 16 steps with 9 isolat... | 10.1021/op200326s | 1 |
Process Improvements of Prasugrel Hydrochloride: An Adenosine Diphosphate Receptor Antagonist | An improved process for the synthesis of prasugrel hydrochloride with an overall yield of 58%, 99.9% purity, and meeting all other quality requirements is described. | 10.1021/op200325u | 1 |
Understanding and Control of Dimethyl Sulfate in a Manufacturing Process: Kinetic Modeling of a Fischer Esterification Catalyzed by H<sub>2</sub>SO<sub>4</sub> | The formation and fate of monomethyl sulfate (MMS) and dimethyl sulfate (DMS) were studied by proton NMR for a sulfuric acid catalyzed esterification reaction in methanol. The kinetic rate constants for DMS and MMS were determined at 65 °C by fitting time-dependent experimental data to a model using DynoChem . In reflu... | 10.1021/op200323j | 0 |
Development of a Safe and Efficient Two-Step Synthesis for Preparing 1-Bromoacetyl-3,3-dinitroazetidine, a Novel Clinical Anticancer Candidate | An efficient process for synthesizing and isolating a new investigative anticancer agent, 1-bromoacetyl-3,3-dinitroazetidine, is described. The reaction entails a sequence of oxidative nitration followed by acylative dealkylation. The methods reported give 50–60-g batches of high-purity product without a designated pur... | 10.1021/op2003216 | 0 |
An Efficient, Direct Bis-ortho-chlorination of 4-(Difluoromethoxy)aniline and Its Application to the Synthesis of BMS-665053, a Potent and Selective Pyrazinone-Containing Corticotropin-Releasing Factor-1 Receptor Antagonist | An efficient scale-up synthesis of ( S )-5-chloro-1-(1-cyclopropylethyl)-3-(2,6-dichloro-4-(difluoromethoxy)phenylamino)-pyrazin-2(1 H )-one, 1 ( BMS-665053 ), is described. This new process features a one-step direct bis-ortho-chlorination of 4-(difluoromethoxy)aniline with HCl and H 2 O 2, and a palladium-catalyzed c... | 10.1021/op2003198 | 1 |
Selection and Development of a Route for Cholesterol Absorption Inhibitor AZD4121 | The development of a synthetic route to the cholesterol absorption inhibitor AZD4121 is presented. Key steps are a highly enantioselective CBS reduction, a stereospecific Staudinger reaction, an amine/lithium chloride mediated ester hydrolysis, and a resolution of a 50:50 diastereomeric mixture by recrystallization. Th... | 10.1021/op200314z | 1 |
Development and Scale-Up of an Optimized Route to the ALK Inhibitor CEP-28122 | Evolution of the process strategies to prepare CEP-28122, an anaplastic lymphoma kinase (ALK) inhibitor, is presented. The initial medicinal chemistry route, used for the preparation of key supplies for biological screening, is reviewed. In addition, the process research and development of the final optimized process f... | 10.1021/op200313v | 1 |
A New Efficient Synthetic Route for the Synthesis of the Antiallergic Drug, Olopatadine Hydrochloride, via Stereospecific Palladium-Catalyzed Reaction | A new practical and efficient synthetic route for the synthesis of olopatadine hydrochloride via the intramolecular stereospecific seven-membered ring cyclization from an alkyne intermediate using palladium catalyst and hydride source was established. Furthermore, the optimization of that key stereospecific reaction wa... | 10.1021/op200312m | 1 |
The Use of Glycidyl Ethers Involving Aziridinium Intermediates and Other Methodology for the Preparation of Enantiomerically Pure Drug Candidates | An enantiospecific 1,2-amine migration process through an aziridinium intermediate involving ring-opening with potassium phthalimide derivatives to produce precursors to drug candidates was developed. The precursor amine derivatives were readily available by epoxide opening of simple glycidyl ether derivatives. The reg... | 10.1021/op200310y | 1 |
New Synthetic Route to a Dipeptidyl Peptidase-4 Inhibitor | A new synthetic route to a dipeptidyl peptidase-4 (DPP4) inhibitor was developed and demonstrated on a multigram scale. This approach takes advantage of the cheap and readily available Boc- trans -4-hydroxy- l -proline methyl ester as starting material which was derivatized through an S N 2 reaction. Several leaving gr... | 10.1021/op200309z | 1 |
A Practical Stereoselective Synthesis and Novel Cocrystallizations of an Amphiphatic SGLT-2 Inhibitor | A practical synthesis of the SGLT-2 inhibitor β- C -aryl- d -glucoside ( 1 ) has been developed. The route employed 2,3,4,6-tetra- O -trimethlysilyl- d -glucano-1,5-lactone as the key chiral building block, prepared efficiently from the commercially available, inexpensive raw materials, d -gluconolactone and trimethyls... | 10.1021/op200306q | 1 |
Design and Scale-Up of a Practical Enantioselective Route to 5-Phenylbicyclo[2.2.2]oct-5-en-2-one | A practical enantioselective route to chiral 5-phenylbicyclo[2.2.2]oct-5-en-2-one 1 has been designed and developed. The target compound has been obtained as colorless crystals in 22% yield from 2-cyclohexenone, with an enantiomeric ratio higher than 99.5:0.5 and notably high chemical purity (> 99%). Three intermediate... | 10.1021/op200305y | 1 |
Practical Synthesis of A Benzophenone-Based NNRT Inhibitor of HIV-1 | A convergent synthesis of NNRTI 1 is described. The key step involves a direct coupling of acid chloride 4 with Grignard reagent 11 in the presence of bis[2-( N, N -dimethylamino)ethyl] ether that moderates the reactivity of the Grignard reagent to give benzophenone 7 . An efficient 2-step process for the preparation o... | 10.1021/op200301h | 1 |
Convergent, Fit-For-Purpose, Kilogram-Scale Synthesis of a 5-Lipoxygenase Inhibitor | Process research and development of a synthetic route towards a novel 5-lipoxygenase inhibitor is described. The synthetic route provided 1 in 27% yield in nine steps (seven steps in the longest linear sequence) and was performed on kilogram scale. The synthesis began with the preparation of the coumarin core via an ef... | 10.1021/op200299p | 1 |
Development and Application of a User-Friendly Automated HPLC Dilution Macro for API Route Optimization | Concentration determination by HPLC analysis is often utilized in pharmaceutical development activities. Traditionally, manual dilutions employing volumetric glassware have to be performed to obtain accurate concentration results. To circumvent this, an automated dilution method for the Agilent 1100 HPLC system has bee... | 10.1021/op200289r | 0 |
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