title string | abstract string | doi string | has_route int64 |
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Process Development and Scale-up for (±)-Reboxetine Mesylate | Redevelopment of the commercial process for the synthesis of (±)-reboxetine methanesulfonate is described. An optimized and efficient process for the synthesis of (±)-reboxetine starting from cinnamyl alcohol was developed. The redeveloped process minimizes impurity formation and utilizes simplified processing to subst... | 10.1021/op7000063 | 1 |
Fundamentals of Early Clinical Drug Development: From Synthesis Design to Formulation Edited by A. F. Abdel-Magid and S. Caron. Wiley: New Jersey. 2006. 323 pp. £58.95. ISBN 0-471-69278-6. | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTFundamentals of Early Clinical Drug Development: From Synthesis Design to Formulation Edited by A. F. Abdel-Magid and S. Caron. Wiley: New Jersey. 2006. 323 pp. £58.95. ISBN 0-471-69278-6.Cite this: Org. Process Res. Dev. 2007, 11, 3, 649–650Publication Date (Web):Februar... | 10.1021/op7000035 | 0 |
Development of a Practical and Reliable Synthesis of Laquinimod | Laquinimod (5-chloro-1,2-dihydro- N -ethyl-4-hydroxy-1-methyl-2-oxo- N -phenyl-3-quinoline carboxamide) is a drug candidate for treatment of Multiple Sclerosis. A short and industrially feasible process for the preparation of laquinimod starting from 2-amino-6-chlorobenzoic acid, in essentially four steps, is dis-cusse... | 10.1021/op700001c | 1 |
Development of a Practical Synthesis of STA-5312, a Novel Indolizine Oxalylamide Microtubule Inhibitor | An efficient synthesis of the novel microtubule inhibitor STA-5312 (3-[(4-cyanophenyl)methyl]- N -(3-methyl-5-isothiazolyl)-α-oxo-1-indolizineacetamide) was developed. A novel DMF/Me 2 SO 4 directed regioselective synthesis of the 3-(4-cyanobenzoyl)-indolizine ( 4 ) was a critical transformation within the four-step pr... | 10.1021/op6002852 | 1 |
Development of an Effective Palladium Removal Process for VEGF Oncology Candidate AG13736 and a Simple, Efficient Screening Technique for Scavenger Reagent Identification | AG13736 (Axitinib), an inhibitor of vascular endothelial growth factor (VEGF) under investigation as an oncology drug, is currently manufactured via a three-step process that utilizes two palladium-mediated cross-couplings. Historically, removal of residual heavy metals from the active pharmaceutical ingredient has bee... | 10.1021/op600280g | 1 |
Synthesis of Acetylenes, Allenes and Cumulenes: Methods and Techniques, 1st ed by Lambert Brandsma. Elsevier Academic Press: Boston, Amsterdam. 2004. xxxii + 469 pp. $249. ISBN 0-1212-5751-7. | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTSynthesis of Acetylenes, Allenes and Cumulenes: Methods and Techniques, 1st ed by Lambert Brandsma. Elsevier Academic Press: Boston, Amsterdam. 2004. xxxii + 469 pp. $249. ISBN 0-1212-5751-7.Roderick BatesView Author Information Chemistry and Biological Chemistry, Nanyang... | 10.1021/op600279b | 0 |
Enantioselective Synthesis of Hydrobenzofuranones Using an Asymmetric Desymmetrizing Intramolecular Stetter Reaction of Cyclohexadienones | A series of cyclohexadienones were synthesized by dearomatization of phenols followed by Dess-Martin oxidation. Asymmetric intramolecular Stetter reactions of these substrates provide hydrobenzofuranones in good to excellent yields and excellent stereoselectivities. Up to three stereocenters as well as quaternary stere... | 10.1021/op600278f | 0 |
Development of a Scalable Process for the Synthesis of <i>trans</i>-2-Methylcyclopropanecarboxylic Acid | A scalable process has been developed for the synthesis of trans -2-methylcyclopropanecarboxylic acid via the stereoselective cyclopropanation of ethyl crotonate with dimethylsulfoxonium methylide (Corey’s ylide). This well-known reaction is generally low yielding and very challenging to scale up as it involves highly ... | 10.1021/op600275g | 0 |
An Improved Process for the Preparation of 4,4-Dimethyloxazolidine-2-thione | An improved process for the preparation of 4,4-dimethyloxazolidine-2-thione ( 1 ), an auxiliary used in the synthesis of (3 S,4 S )-[( R )-1‘-(( tert -butyldimethylsilyl)oxy)ethyl]-4-[( R )-1-carboxyethyl]-2-azetidinone ( 2 ), a key intermediate for carbapenem synthesis is reported. | 10.1021/op6002677 | 0 |
A Systematic Approach for the Development of Liquid Chromatographic Methods | Developing chromatographic methods can be laborious, time-consuming, and expensive. The definition of a strategy to find rapid separation conditions has therefore become of prime importance since the analytical development has to follow the rhythm of the generation of new compounds. To meet this demand, chemists clearl... | 10.1021/op6002665 | 0 |
Development of the Commercial Route for the Manufacture of a 5-Lipoxygenase Inhibitor PF-04191834 | A de novo three-step-one-pot process for the formation of PF-04191834 was developed. This methodology employed inexpensive, odorless, and readily available commodity chemical iso-octyl-3-mercaptopropionate as a sulfur source, which could be a general alternative to the popular TIPS-SH in the formation of diarylthioethe... | 10.1021/op500412a | 1 |
Synthesis of Formic Acid from Monosaccharides Using Calcined Mg-Al Hydrotalcite as Reusable Catalyst in the Presence of Aqueous Hydrogen Peroxide | Formic acid (FA) can be synthesized from monosaccharides such as glucose, galactose, xylose, arabinose and lyxose by using both calcined Mg-Al hydrotalcite as a solid catalyst and aqueous H 2 O 2 as an oxidant in ethanol solvent at 343 K for 5 h. For the glucose oxidation, the FA yield and H 2 O 2 utilization efficienc... | 10.1021/op5004083 | 0 |
An Improved and Practical Synthesis of Tranexamic Acid | Tranexamic acid 1, a synthetic antifibrinolytic drug with the treatment being considered highly cost-effective in many countries, has been included in the WHO list of essential medicines. In this paper, we designed the synthesis of 1 via a novel seven-step route from the readily available starting material dimethyl ter... | 10.1021/op500395b | 1 |
A DMAP-Catalyzed Approach to the Industrial-Scale Preparation of <i>N</i>-6-Demethylated 9,10-Dihydrolysergic Acid Methyl Ester: A Key Cabergoline and Pergolide Precursor | A scalable new approach for the preparation of N -6-demethylated 9,10-dihydrolysergic acid methyl ester using 2,2,2-trichloroethyl chloroformate was developed. A key discovery that enabled the efficient and industrial-scalable process is linked to the rigorous extrusion of water in the reaction system and application o... | 10.1021/op500394f | 1 |
Process Development of an N-Benzylated Chloropurine at the Kilogram Scale | A two-step pharmaceutical manufacturing process was developed for the large-scale preparation of 6-chloro-9-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-9 H -purin-2-amine methanesulfonic acid salt ( 4 ) from commercially available starting materials. In the first step, the benzylpurine free base ( 3 ) was prepared by ... | 10.1021/op5003903 | 1 |
A Novel and Practical Synthesis of Ramelteon | An efficient and practical process for the synthesis of ramelteon 1, a sedative-hypnotic, is described. Highlights in this synthesis are the usage of acetonitrile as nucleophilic reagent to add to 4,5-dibromo-1,2,6,7-tetrahydro-8 H -indeno[5,4- b ]furan-8-one 2 and the subsequent hydrogenation which successfully implem... | 10.1021/op500386g | 1 |
Scalable Synthesis of a Nucleoside Phosphoramidate Prodrug Inhibitor of HCV NS5B RdRp: Challenges in the Production of a Diastereomeric Mixture | A scalable process is described for the synthesis of 2′- C -methylguanosine-5′-[2-[(3-hydroxy-2,2-dimethyl-1-oxopropyl)thio]ethyl- N -benzylphosphoramidate], a nucleotide prodrug inhibitor of hepatitis C virus NS5B polymerase. The route features the use of phenylboronic acid to transiently protect the 2′,3′-hydroxyls o... | 10.1021/op5003837 | 1 |
Leveraging an Industrial–Academic Partnership To Optimize Small Molecule Process Development within the Pharmaceutical Industry | There is a growing trend in Ireland toward greater collaboration between academia and the pharmaceutical industry. This is an activity encouraged at a national policy level as a means of providing researchers from academic institutions the opportunity to gain important first-hand experience in a commercial research env... | 10.1021/op5003825 | 0 |
The History of the Development of the <i>Organic Process Research</i> & <i>Development</i> (OPR&D) Journal—A Personal Perspective | ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTThe History of the Development of the Organic Process Research & Development (OPR&D) Journal—A Personal PerspectiveTrevor LairdCite this: Org. Process Res. Dev. 2015, 19, 1, 249Publication Date (Web):January 2, 2015Publication History Published online2 January 2015Published... | 10.1021/op5003819 | 0 |
Process Development of a GCS Inhibitor Including Demonstration of Lossen Rearrangement on Kilogram Scale | A small molecule was under investigation as an inhibitor of glucosylceramide synthase (GCS) for potential use in Fabry disease. To support preclinical activities, a four-step synthesis was developed and used to prepared kilogram quantities of the drug substance. The new route features a scalable CDI-mediated Lossen rea... | 10.1021/op500379a | 1 |
Effect of Reaction Parameters on the Synthesis of 5-Arylidene Barbituric Acid Derivatives in Ball Mills | The influence of crucial reaction parameters on Knoevenagel condensation in planetary ball mills was investigated. Rotation frequency ( ν rot ), milling ball diameter ( d MB ), milling ball filling degree ( Φ MB ), and beaker size had obvious influences on yield. It was found that higher ν rot, lower d MB, milling beak... | 10.1021/op5003787 | 0 |
Development of a Synthesis of a 2,3-Disubstituted 4,7-Diazaindole Including Large-Scale Application of CH<sub>3</sub>Li/TiCl<sub>4</sub>-Mediated Methylation of an Enolizable Ketone | The chemical development of a 2,3-disubstituted 4,7-diazaindole is described. The requisite tertiary carbinol substrate was prepared employing in situ -generated CH 3 TiCl 3 as a chemoselective and preferred reagent compared to CH 3 MgX for methyl addition to an enolizable ketone. The 4,7-diazaindole ring system was ef... | 10.1021/op5003769 | 1 |
Multi-Kilo Delivery of AMG 925 Featuring a Buchwald–Hartwig Amination and Processing with Insoluble Synthetic Intermediates | The development of a synthetic route to manufacture the drug candidate AMG 925 on kilogram scale is reported herein. The hydrochloride salt of AMG 925 was prepared in 23% overall yield over eight steps from commercially available raw materials, and more than 8 kg of the target molecule were delivered. The synthetic rou... | 10.1021/op500367p | 1 |
A Practical, Protecting-Group-Free Synthesis of a PI3K/mTOR Inhibitor | We report a practical and protecting-group-free synthesis amenable to produce multikilogram amounts of PI3K/mTOR inhibitor GDC-0980 . The route employed metalation/formylation and reductive amination followed by a metal catalyzed Suzuki–Miyaura cross-coupling. The metalation was performed via triarylmagnesiate intermed... | 10.1021/op500366s | 1 |
Commercial Synthesis of Azilsartan Kamedoxomil: An Angiotensin II Receptor Blocker | A commercially viable process for the preparation of azilsartan kamedoxomil, an angiotensin II receptor blocker, has been developed. The present work describes the novel synthesis of azilsartan medoxomil from amidoxime methyl ester. The present work also describes the improved synthesis of amidoxime methyl ester and az... | 10.1021/op500357r | 1 |
Synthesis of Condensed Heterocycles by the Gould–Jacobs Reaction in a Novel Three-Mode Pyrolysis Reactor | In the present paper we report the synthesis of condensed pyrimidone heterocycles (including novel ones) prepared by the Gould–Jacobs reaction using an in-house-built vacuum-to-high pressure multipurpose “three-mode” pyrolysis reactor. Four of the ring systems have not been described in the literature to date. The pyro... | 10.1021/op500354z | 0 |
Synthesis of BACE Inhibitor LY2886721. Part I. An Asymmetric Nitrone Cycloaddition Strategy | A scalable, asymmetric synthesis of (3 aS,6 aS )-6 a -(5-bromo-2-fluorophenyl)-1-(( R )-1-phenylpropyl)tetrahydro-1 H,3 H -furo[3,4- c ]isoxazole, a key intermediate in the synthesis of LY2886721, is reported. Highlights of the synthesis include the development of an asymmetric [3 + 2] intramolecular cycloaddition faci... | 10.1021/op500351q | 1 |
Large-Scale Continuous Flow Transformation of Oximes into Fused-Bicyclic Isoxazolidines: An Example of Process Intensification | Here, we report a continuous flow protocol for the [3 + 2] cycloaddition of nitrones, in situ generated from oximes, into bicyclic isoxazolidines. This thermal process required very high temperatures to be efficient that were not easily reached in conventional reactors. A couple of examples are presented and in both th... | 10.1021/op500350y | 0 |
Investigation of a Kumada Cross Coupling Reaction for Large-Scale Production of (2<i>S</i>, 7<i>R</i>, <i>E</i>)-2-Isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-<i>N</i>,<i>N</i>,8-trimethylnon-4-enamide | An investigation into the Kumada cross coupling reaction was conducted by developing a reliable, efficient procedure for the Grignard reagent and its subsequent cross coupling reaction. Safe Mg metal activation as well as a moisture-free system was created by using MeMgCl reagent and improved the efficiency of the Grig... | 10.1021/op500343d | 0 |
Development of a Scalable Synthesis of a Serotonin Receptor Antagonist | An efficient process was developed for the manufacture of MSA100, a serotonin receptor antagonist, via a five-step synthetic route furnishing a high quality of active pharmaceutical ingredient. Highlights of this synthesis include: (1) replacing carcinogenic methyl iodide with methyl p -toluenesulfonate as the methylat... | 10.1021/op5003402 | 1 |
Scalable Ruthenium-Catalyzed Asymmetric Synthesis of a Key Intermediate for the β2-Adrenergic Receptor Agonist | An enantioselective and robust synthetic process to obtain a useful intermediate for the β2-adrenergic receptor agonist is described. Asymmetric transfer hydrogenation of ketone 1c by ( S, S )- 3b (Ms-DENEB) afforded chiral alcohol 2c in 71% isolated yield and 99% ee. The deprotection completed the synthesis of ( R )- ... | 10.1021/op500338d | 0 |
Scalable Synthesis of 8-Amino-3-hydroxy-6<i>H</i>-benzo[<i>c</i>]chromen-6-one: Key Intermediate for SEGRA via the Hurtley Reaction | A practical and scalable process for the preparation of 8-amino-3-hydroxy-6 H -benzo[ c ]chromen-6-one in multihundred kilogram amounts has been developed. The key features of this synthesis are the application of the Hurtley reaction with a copper and base combination and the development of a purification process. The... | 10.1021/op500334b | 1 |
Robust Ruthenium(II)-Catalyzed C–H Arylations: Carboxylate Assistance for the Efficient Synthesis of Angiotensin-II-Receptor Blockers | Ruthenium(II) complexes have emerged as effective catalysts for C–H arylations of tetrazolyl-substituted arenes by chelation assistance. Particularly, bifunctional additives, such as carboxylates or phosphates, set the stage for versatile C–H functionalizations with organic halides, which allowed for the step-economica... | 10.1021/op500330g | 0 |
Synthesis of BACE Inhibitor LY2886721. Part II. Isoxazolidines as Precursors to Chiral Aminothiazines, Selective Peptide Coupling, and a Controlled Reactive Crystallization | An efficient synthesis of LY2886721 ( 1 ) in five steps and 46% overall yield from the chiral nitrone cycloadduct 2 is presented. Minimizing formation of a des-fluoro impurity during hydrogenolysis to cleave the isoxazolidine ring and remove the benzyl chiral auxiliary was a key challenge. Installation of the aminothia... | 10.1021/op500327t | 1 |
Special Feature Issue: Continuous Processing | ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTSpecial Feature Issue: Continuous ProcessingJaan A. PestiCite this: Org. Process Res. Dev. 2014, 18, 11, 1284–1285Publication Date (Web):November 21, 2014Publication History Published online21 November 2014Published inissue 21 November 2014https://pubs.acs.org/doi/10.1021/o... | 10.1021/op500323a | 0 |
Development of an Immobilized Ketoreductase for Enzymatic (<i>R</i>)-1-(3,5-Bis(trifluoromethyl)phenyl)ethanol Production | The development of an immobilized ketoreductase via covalent binding on resin EC-HFA has demonstrated that it is highly active and stable in organic solvents and can be recycled and reused many times in both batch mode and flow reactor mode. ( R )-1-(3,5-Bis(trifluoromethyl)phenyl)ethanol, a key chiral intermediate in ... | 10.1021/op5003215 | 0 |
Development of Pilot-Scale Continuous Production of an LY2886721 Starting Material by Packed-Bed Hydrogenolysis | The design, development, and implementation of a pilot-scale continuous hydrogenolysis in a catalytic packed bed to generate a starting material is described. Control of a critical defluorination impurity under the reaction conditions has been achieved by reducing residence time inside the catalyst bed to 15–30 min. A ... | 10.1021/op5003177 | 0 |
Utilization of ReactIR in Fit for Purpose Process Enablement | An efficient four-step synthesis of 1 is described in which utilization of ReactIR was key to efficient processing and reaction monitoring. Key chemical steps included (i) nucleophilic aromatic substitution, iron reduction of aromatic nitro group to aniline, (ii) decarboxylation, and (iii) ester formation. | 10.1021/op5003165 | 1 |
Route Optimization and Synthesis of Taxadienone | Early process development toward the scalable production of taxadienone on a decagram scale is described. A continuous flow reactor was employed to safely run a potentially hazardous cyclopropane ring opening. The route featured two copper-mediated additions, a Diels–Alder reaction and a palladium-catalyzed Negishi cou... | 10.1021/op500314c | 1 |
Rapid Synthesis of Pharmaceutical Oxidation Products Using Electrochemistry: A Systematic Study of N-Dealkylation Reactions of Fesoterodine Using a Commercially Available Synthesis Cell | A new method for the fast and convenient synthesis of pharmaceutical oxidation products is described. Two oxidation products of fesoterodine were electrochemically synthesized, isolated, and characterized. The influence of synthetic operating parameters such as pH, percentage of organic solvent in diluent, initial elec... | 10.1021/op500312e | 0 |
Process Development for Biocatalytic Oxidations Applying Alcohol Dehydrogenases | Alcohol dehydrogenases are able to catalyze the conversion of alcohols to aldehydes or ketones, simultaneously reducing the cofactor NAD + or NADP + to NAD(P)H. Because of the high costs of these pyridine cofactors, in situ cofactor regeneration is required for preparative applications in order to reach turnover number... | 10.1021/op500307e | 0 |
Synthesis of an α-Amylase Inhibitor: Highly Stereoselective Glycosidation and Regioselective Manipulations of Hydroxyl Groups in Carbohydrate Derivatives | Here, we describe the efficient synthesis of α-amylase inhibitor 1 . To introduce the most expensive C ring unit at a late stage in the synthesis, we developed 1,2- cis - O -glycosidation of AB and C ring intermediates. Taking advantage of the effect of non-neighboring protecting groups, reaction solvents, and temperat... | 10.1021/op500306p | 0 |
Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals | This review showcases various coupling reagents which have been implemented specifically for large-scale amide synthesis via the condensation of an acid and amine, while highlighting the benefits and drawbacks of each reagent on an industrial scale. | 10.1021/op500305s | 0 |
Development of a Practical Process for the Opening of Macrocyclic Cyclosporin A and Amino Acid Deletion | A practical and robust process for the derivatization of Cyclosporin A was demonstrated. The processes rely on the opening of Cyclosporin A and removal of amino acid fragments via Edman degradation, with the isolation of crystalline tetrafluoroboric salts of the corresponding acyclic polypeptides. | 10.1021/op5003038 | 0 |
Development of a Scalable Synthesis of Oligomeric Piperidine-<i>N</i>-<i>O</i>-alkyl Ethers | An efficient two-step manufacturing process for a novel polypiperidine- N - O -alkyl ether was developed. Starting from an oligomeric 2,2,6,6-tetramethylpiperidine derivative, oxidation by hydrogen peroxide yielded a polynitroxide radical. Subsequently, the intermediate was reacted with alkyl radicals to provide the co... | 10.1021/op500301r | 0 |
Quality by Design in Action 2: Controlling Critical Material Attributes during the Synthesis of an Active Pharmaceutical Ingredient | Quality by Design (QbD) is of paramount importance not only for patient safety but also for the timely and uninterrupted supply of products at affordable prices into the market. Both of these objectives can be achieved only through a robust process, and one of the major obstacles for developing a robust process is the ... | 10.1021/op500297g | 0 |
Applications of Gage Reproducibility & Repeatability (GRR): Understanding and Quantifying the Effect of Variations from Different Sources on a Robust Process Development | During process development, it is always a debatable issue whether the variation in analytical results is due to the measurement system (MS) or due to the process. The best approach is to quantify total variation coming from the MS prior to any process improvement activity. This quantification is done by “Gage Reproduc... | 10.1021/op5002935 | 0 |
Development of a Grignard-Type Reaction for Manufacturing in a Continuous-Flow Reactor | This paper describes the scale-up of a highly exothermic and fast reaction from a microreactor with an internal volume of less than 1 mL to a mesoreactor with an internal volume of 13.5 mL. The development of a continuous process for manufacturing a ketone from an ester using a Grignard reagent is described. The differ... | 10.1021/op500290x | 0 |
Development of a Practical and Scalable Synthetic Route to YM758 Monophosphate, A Novel I<sub>f</sub> Channel Inhibitor | A novel, practical, and efficient synthesis of (−)- N -{2-[( R )-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide monophosphate (YM758 monophosphate, ( R )-1·H 3 PO 4 (Figure 1 ) is described. The target molecule ( R )-1 has a potent I f current channel inhibitor. Medicinal... | 10.1021/op5002885 | 1 |
Specifications of Drug Substances and Products: Development and Validation of Analytical Methods | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewSpecifications of Drug Substances and Products: Development and Validation of Analytical MethodsJohn KnightView Author Information Scientific Update LLP, Maycroft Place, Stone Cross, Mayfield TN20 6EW, U.K.Cite this: Org. Process Res. Dev. 2014, 18, 9, 1154Publication Date (W... | 10.1021/op5002879 | 0 |
Using PAT To Understand, Control, and Rapidly Scale Up the Production of a Hydrogenation Reaction and Isolation of Pharmaceutical Intermediate | The development of a hydrogenation process and subsequent isolation for an intermediate in the manufacture of an active pharmaceutical ingredient is described. In-line process analytical technology (PAT) approaches were applied to gain process understanding and control. First, a calibration-free, qualitative, scale-ind... | 10.1021/op500285x | 0 |
Process Safety Evaluation and Scale-up of a Lactam Reduction with NaBH<sub>4</sub> and TFA | The development of a practical and scalable method for the synthesis of morpholine derivative 2 via reduction of lactam 1 using NaBH 4 and trifluoroacetic acid (TFA) is described. Through the mechanistic studies using 11 B NMR spectroscopy, we observed that active species were generated during TFA addition, which avoid... | 10.1021/op500284e | 0 |
Organometallic Carbanions in Practical Organic Synthesis: Grignards, Organolithiums, and More | ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTOrganometallic Carbanions in Practical Organic Synthesis: Grignards, Organolithiums, and MoreAman A. Desai and Victor SnieckusView Author Information Aether Industries Limited, Surat 394230, Gujarat, India. E-mail: [email protected] Department of Chemistry, Queen’s Universi... | 10.1021/op500283p | 0 |
Short Synthesis of a Proline Amide Orexin Receptor Antagonist on the Pilot Plant Scale | A three-step fully telescoped synthesis of an N -sulfonyl proline amide, a nonpeptide antagonist of human orexin receptors, is described. The process development from the medicinal chemistry route up to the 240 kg production of 1 is discussed with a focus on an economical and efficient amide bond formation and identifi... | 10.1021/op500277s | 1 |
Survey of Solvent Usage in Papers Published in<i>Organic Process Research</i>&<i>Development</i>1997–2012 | A survey of solvent usage for papers published in Organic Process Research & Development has been carried out for the years 1997–2012. Three solvent categories were studied: (i) solvents of concern, (ii) dipolar aprotic solvents, and (iii) neoteric solvents. In the analysis of dipolar aprotic solvent use it was found t... | 10.1021/op500276u | 0 |
Kinetic and Scale-up Investigations of a Michael Addition in Microreactors | Microreactors are an efficient tool for process development and intensification. However, the scale-up from lab studies to small-scale commercial production is challenging, since a change in the channel dimensions requires good knowledge of heat and mass transfer phenomena. In this work, complete process development fo... | 10.1021/op5002758 | 0 |
An Improved and Efficient Process for the Preparation of Tofacitinib Citrate | The present invention is related to a simple and efficient process for the preparation of tofacitinib citrate 1, a Pfizer molecule approved for the treatment of rheumatoid arthritis. The process relies upon an improved process for the preparation of a key intermediate (3 R,4 R )-(1-benzyl-4-methylpiperidin-3-yl)methyla... | 10.1021/op500274j | 1 |
Synthesis of Akt Inhibitor Ipatasertib. Part 1. Route Scouting and Early Process Development of a Challenging Cyclopentylpyrimidine Intermediate | Herein, the route scouting and early process development of a key cyclopentylpyrimidine ketone intermediate toward the synthesis of Akt inhibitor Ipatasertib are described. Initial supplies of the intermediate were prepared through a method that commenced with the natural product ( R )-(+)-pulegone and relied on the ea... | 10.1021/op500271w | 1 |
Synthesis of Akt Inhibitor Ipatasertib. Part 2. Total Synthesis and First Kilogram Scale-up | Herein, the first-generation process to manufacture Akt inhibitor Ipatasertib through a late-stage convergent coupling of two challenging chiral components on multikilogram scale is described. The first of the two key components is a trans -substituted cyclopentylpyrimidine compound that contains both a methyl stereoce... | 10.1021/op500270z | 1 |
Lab-Scale Preparation of a Novel Cyclopenta[b]furan Chemokine Receptor Antagonist | The preparation of a chemokine receptor type 2 (CCR-2) antagonist bearing a cyclopenta[b]furan core is described on a 600 g scale. Compared to our previously reported synthesis of the all-carbon core CCR-2 antagonist with a similar peripheral 3-methoxypyran appendage, our work required a redesign of the original Discov... | 10.1021/op500266w | 1 |
Lab-Scale Preparation of a Novel Carbocyclic Chemokine Receptor Antagonist | The preparation of a novel chemokine receptor type 2 (CCR-2) antagonist is described on a 135 g scale. The synthesis of an all-carbon bicyclic core was accomplished using a radical cyclization strategy using chiral precursors, wherein elaboration led to N -Boc carboxylic acid in good yield. After amidation using a trad... | 10.1021/op500265z | 1 |
Concise Preparation of a Stable Cyclic Sulfamidate Intermediate in the Synthesis of a Enantiopure Chiral Active Diamine Derivative | A classical resolution was studied and developed from 2-benzoyl-pyridine in order to prepare SSR504734, a novel antipsychotic derivative. The key step of this route is the substitution of a sulfamidate derivative by a benzamide anion with complete inversion of configuration. The sulfamidate is prepared in a two-step pr... | 10.1021/op500264v | 1 |
Development of Multikilogram Continuous Flow Cyclopropanation of <i>N</i>-Benzylmaleimide through Kinetic Analysis | A convenient and high-yielding method for the synthesis of trans -(dioxo)-azabicyclo-[3.1.0]-hexane carboxylate, a key intermediate of complex molecules, is presented using a flow cyclopropanation process. From a detailed kinetic study, it is demonstrated that the reaction concentration, addition time of reagents, and ... | 10.1021/op500263m | 1 |
A Process for the Formation of Nanocrystals of Active Pharmaceutical Ingredients with Poor Aqueous Solubility in a Nanoporous Substrate | A potential process for the formation of nanocrystals of the poorly soluble drug, ibuprofen, within a nanoporous material is demonstrated. Nanocrystalline ibuprofen (IBP) is prepared at ≤106 nm by adding a solution containing IBP to particles of controlled pore glass (CPG) within a column so that the pores contain IBP ... | 10.1021/op500262q | 0 |
Assessment of Recent Process Analytical Technology (PAT) Trends: A Multiauthor Review | This multiauthor review article aims to bring readers up to date with some of the current trends in the field of process analytical technology (PAT) by summarizing each aspect of the subject (sensor development, PAT based process monitoring and control methods) and presenting applications both in industrial laboratorie... | 10.1021/op500261y | 0 |
Safe Scale-Up of Pharmaceutical Manufacturing Processes with Dimethyl Sulfoxide as the Solvent and a Reactant or a Byproduct | Thermal hazard analyses of two reactions, one with DMSO as the solvent and a reactant and one with DMSO as the solvent and a byproduct, identified low-probability but severe consequence process risks associated with violent decomposition of DMSO during heating control failure or external heating. Although DMSO cannot b... | 10.1021/op500260n | 0 |
Chemical Process Technology, Second Edition | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTChemical Process Technology, Second EditionTrevor LairdCite this: Org. Process Res. Dev. 2014, 18, 9, 1153Publication Date (Web):August 15, 2014Publication History Published online15 August 2014Published inissue 19 September 2014https://pubs.acs.org/doi/10.1021/op500256yh... | 10.1021/op500256y | 0 |
Practical Asymmetric Hydrogenation-Based Synthesis of a Class-Selective Histone Deacetylase Inhibitor | Two syntheses of the class-selective histone deacetylase inhibitor 1 are reported. In the first, eight-step entailing synthesis, the key transformations were a highly efficient [3 + 2] dipolar cycloaddition affording trans - rac - 5 and its resolution. In the second, asymmetric approach, the key steps were a highly sel... | 10.1021/op500250b | 1 |
Practical Large-Scale Synthesis of 6-Bromo-2-naphthylmethanesulfonamide Using Semmler–Wolff Reaction | A practical, scalable synthetic process for a sulfonamide was developed featuring a Semmler–Wolff aromatization as the key step. The optimized reaction conditions using HCl in HOAc give directly the desired naphthylamine in high yield as opposed to a naphthylacetamide commonly formed in the Semmler–Wolff reactions. One... | 10.1021/op500247h | 1 |
Batch-to-Batch Variation: A Key Component for Modeling Chemical Manufacturing Processes | For chemical manufacturing processes, the chemical kinetics literature contains virtually no mention of quantitative models that involve batch-to-batch variation. Models for chemical process manufacturing quality improvement are being more carefully considered, particularly by the pharmaceutical industry and its regula... | 10.1021/op500244f | 0 |
How to Convert a Walk-in Hood into a Manufacturing Facility: Demonstration of a Continuous, High-Temperature Cyclization to Process Solids in Flow | An intramolecular thermal cyclization protocol was developed in a flow reactor to take advantage of the high pressures and temperatures that are easily obtained in small scale autoclave reactors that have been modified to handle slurries. This reactor was equipped with a fill/empty pumping system to enable easy and nea... | 10.1021/op500239f | 0 |
Microwave Heated Flow Synthesis of Spiro-oxindole Dihydroquinazolinone Based IRAP Inhibitors | A fast and convenient synthetic route towards spiro-oxindole dihydroquinazolinones as novel and drug-like insulin-regulated aminopeptidase (IRAP) inhibitors is reported. The synthesis is performed using a MW heated continuous flow system employing 200 mm × 3 mm Ø i MW absorbing silicon carbide (SiC) or MW transparent b... | 10.1021/op500237k | 0 |
Aryldiazonium Tetrafluoroborate Salts as Green and Efficient Coupling Partners for the Suzuki–Miyaura Reaction: From Optimisation to Mole Scale | The use of aryldiazonium tetrafluoroborate salts as coupling partners in the Suzuki–Miyaura reaction was investigated from a process chemistry perspective including safety evaluation, solvent and catalyst screening and multivariate factor optimisation. Optimised conditions were applied to a range of substrates to evalu... | 10.1021/op5002353 | 1 |
Investigation on Main Reaction and Side Reaction Mechanism in the Synthetic Process of 1-(5-Bromothiophen-2-yl)-3-(4-nitrophenyl)prop-2-en-1-one Using Raman Spectroscopy | High Resolution Image Download MS PowerPoint Slide 1-(5-Bromothiophen-2-yl)-3-(4-nitrophenyl) prop-2-en-1-one (BTNP) has unique and highly attractive properties, which make them a new kind of nonlinear optical (NLO) organic material for wide applications in the fields of optical communication and flat panel display. In... | 10.1021/op500234a | 0 |
Kiloscale Buchwald–Hartwig Amination: Optimized Coupling of Base-Sensitive 6-Bromoisoquinoline-1-carbonitrile with (<i>S</i>)-3-Amino-2-methylpropan-1-ol | This work describes the optimization and scale-up of a Buchwald–Hartwig amination reaction for the preparation of a pharmaceutical intermediate. This C–N bond formation is challenged by the use of a chiral primary amine, which both adds cost and favors formation of biaryl byproducts. In order to develop a scalable proc... | 10.1021/op5002319 | 0 |
Preparative Synthesis of Highly Substituted Tetrahydropyridines via a Rh(I)-Catalyzed C–H Functionalization Sequence | High Resolution Image Download MS PowerPoint Slide We report a Rh(I)-catalyzed C–H activation/alkenylation/electrocyclization cascade and subsequent reduction for the synthesis of highly substituted tetrahydropyridines. These products can be accessed on a gram scale with low catalyst loadings and at high reaction conce... | 10.1021/op500225c | 0 |
Convergent Synthesis of Diverse Tetrahydropyridines via Rh(I)-Catalyzed C–H Functionalization Sequences | High Resolution Image Download MS PowerPoint Slide A Rh-catalyzed C–H bond activation/alkenylation/electrocyclization cascade reaction provides diverse 1,2-dihydropyridines from simple and readily available precursors. The reaction can be carried out at low (<1%) Rh-catalyst loadings, and the use of the robust, air-sta... | 10.1021/op500224x | 0 |
Process Development and Scale-up of T3-Sulfate, A New Prodrug Alternative to the Conventional Hormone Therapy of Hypothyroidism | An efficient and scalable preparation of the thyroid hormone analogue O -[3-iodo-4-(sulfooxy)phenyl]-3,5-diiodo- l -tyrosine sodium salt (T3-sulfate, 1 ) is reported. The synthesis involved monoiodination of O -(4-hydroxyphenyl)-3,5-diiodo- l -tyrosine to give liothyronine ( 2 ) which was sulfated with chlorosulfonic a... | 10.1021/op500222p | 1 |
Synthesis of a Carprofen Analogue Using a Continuous Flow UV-Reactor | A continuous flow UV light reactor has been constructed using commercially available equipment, and its efficiency was demonstrated by performing a photocyclodehydrogenation reaction to prepare carbazole derivatives of the drug carprofen. | 10.1021/op5002148 | 0 |
Development of a Manufacturing Process for an HCV Protease Inhibitor Candidate Molecule | The scale-up of a prototype HCV protease inhibitor ( 1 ) from gram scale in the laboratory to kilogram scale in the pilot plant is described. Key features of the optimization included the synthesis of bulk quantities of exomethylene proline intermediate 6, separation of the diastereomers of spirocycle 2 without chromat... | 10.1021/op500210w | 1 |
Enzymatic Reduction of Adamantanones to Chiral Adamantanol Intermediates for the Synthesis of 11-β-Hydroxysteroid Dehydrogenase Inhibitors | An enzymatic reduction process was developed to convert the ketone 2-(6-oxo-2-phenyladamantan-2-yl)acetic acid to the chiral alcohol 2-((2 S, 6 S )-6-hydroxy-2-phenyladamantan-2-yl)acetic acid and to convert the fluoro ketone 2-(2-(4-fluorophenyl)-6-oxoadamantan-2-yl)acetic acid to the chiral alcohol 2-((2 S,6 S )-2-(4... | 10.1021/op5002098 | 0 |
Process Intensification for the Continuous Flow Hydrogenation of Ethyl Nicotinate | Here we report a process intensification study for the selective, partial, and full hydrogenation of ethyl nicotinate using a trickle bed reactor for meso-flow transformations (HEL FlowCAT). The process achieved a throughput of 1219 g d –1 (78 g h –1 of product per g of active catalyst) for the partial hydrogenation to... | 10.1021/op500208j | 0 |
Development of a Modeling-Based Strategy for the Safe and Effective Scale-up of Highly Energetic Hydrogenation Reactions | A modeling-based strategy is disclosed for identifying reaction conditions for the safe and effective scale-up of highly energetic hydrogenation reactions. The model was developed within Scale-up Systems’s DynoChem 2011 and takes under consideration the kinetics of the reaction, the reactor heat transfer capabilities, ... | 10.1021/op500207r | 0 |
Fully Automated Continuous Meso-flow Synthesis of 5′-Nucleotides and Deoxynucleotides | The first continuous meso-flow synthesis of natural and non-natural 5′-nucleotides and deoxynucleotides is described, representing a significant advance over the corresponding in-flask method. By means of this meso-flow technique, a synthesis with time consumption and high-energy consumption becomes facile to generate ... | 10.1021/op5002066 | 0 |
Pilot-Scale Continuous Production of LY2886721: Amide Formation and Reactive Crystallization | The design, development, and implementation of a pilot-scale continuous Schotten–Baumann amide bond formation and reactive crystallization to afford LY2886721 is described. The material met all API quality attributes and was comparable to material produced by a defined batch process. The scalability of the reaction and... | 10.1021/op500204z | 1 |
Tailoring the Product Distribution with Batch and Continuous Process Options in Catalytic Hydrogenation of Furfural | Various noble metal catalysts were screened in a batch operation for a furfural (FFR) single-step decarbonylation and hydrogenation reaction to obtain THF in high selectivity. Among these, the 3% Pd/C showed complete FFR conversion with a total of 80% selectivity to ring hydrogenated products including tetrahydrofuran ... | 10.1021/op500196x | 0 |
A Scalable Route to 5-Substituted 3-Isoxazolol Fibrinolysis Inhibitor AZD6564 | A practical and chromatography-free multikilogram synthesis of a 3-isoxazolol containing antifibrinolytic agent, AZD6564, has been developed in eight steps and 7% overall yield starting from methyl 2-chloroisonicotinate. Highlights in the synthesis are a Negishi coupling and an enzymatic resolution of a racemic ester. | 10.1021/op500193s | 1 |
From Batch to Continuous Chemical Synthesis—A Toolbox Approach | A toolbox approach for the transfer of batch to continuous chemical synthesis is presented. The approach considers reaction kinetics (Type A, B, C), reacting phases (single phase, liquid–liquid, gas–liquid and liquid–solid), and the reaction network (parallel and consecutive reactions) in order to select the most appro... | 10.1021/op5001918 | 0 |
Case Studies in the Applicability of Drug Substance Design Spaces Developed on the Laboratory Scale to Commercial Manufacturing | A number of strategies have been employed within the pharmaceutical industry in order to mitigate the risk of applying design space boundaries developed on the laboratory scale to commercial drug substance manufacturing. The following communication presents a number of case histories from members of the International C... | 10.1021/op500187u | 0 |
Examples of Catalytic and Selective Routes for Fluorinated Building Blocks | Examples are presented for the catalytic fluorination of chlorinated starting materials in order to produce building blocks or HFCs. The fluorination of CF 3 CH 2 Cl, of CCl 2 ═CCl 2, of trichloromethoxylbenzenes and trichloromethoxybenzene involving nucleophilic substitution are reported. In all cases, HF was the fluo... | 10.1021/op500182w | 0 |
Development of a Continuous Plug Flow Process for Preparation of a Key Intermediate for Brivanib Alaninate | A thermal runaway potential was identified for the conversion of a tertiary alcohol to a hydroxypyrrolotriazine intermediate in the synthesis of brivanib alaninate. A continuous process was developed to mitigate the potential thermal runaway and allow for safer scale-up. This paper describes the hazard analysis, proces... | 10.1021/op500176z | 0 |
Simple Process for the Preparation of Cetyltrimethylammonium Naproxenate (Naprocet) | Specifications for cetyltrimethylammonium (CTA) naproxenate (naprocet), the active ingredient of pharmaceutical liquid preparations used as antiseptic–antinflammatory detergents, fix severe limits to the presence of residual inorganic counteranion deriving from the starting CTA salt. A new simple procedure, which avoid... | 10.1021/op500175v | 0 |
Synthesis of 1-Arylcycloalkenamines by Intramolecular Arylation of Lithiated Ureas | The deprotonation of N ′-arylurea derivatives of cyclohexenamines by alkyllithiums leads to migration of the N ′-aryl substituent from N′ to the allylic position α to N via rearrangement of a urea-stabilised allyllithium intermediate. The product ureas may be solvolysed to reveal 1-arylcyclohexenamines. | 10.1021/op500173q | 1 |
3,5-Disubstituted Piperidine Derivatives—A Scalable Route to All Four Stereoisomers | 3,5-Disubstituted piperidines are versatile building blocks that find broad application in medicinal chemistry programs. Here we describe how all four diastereoisomers of a 5-aryl-substituted nipecotic acid derivative were prepared on preparative scale in high enantiomeric purity. The piperidine core structure was form... | 10.1021/op500170d | 0 |
Continuous Flow Total Synthesis of Rufinamide | Small molecules bearing 1,2,3-triazole functionalities are important intermediates and pharmaceuticals. Common methods to access the triazole moiety generally require the generation and isolation of organic azide intermediates. Continuous flow synthesis provides the opportunity to synthesize and consume the energetic o... | 10.1021/op500166n | 1 |
Lipase Catalyzed Regioselective Lactamization as a Key Step in the Synthesis of <i>N</i>-Boc (2<i>R</i>)-1,4-Oxazepane-2-Carboxylic Acid | A synthesis of N -Boc (2 R )-1,4-oxazepane-2-carboxylic acid 1 has been developed in 39% yield over seven steps starting from methyl (2 R )-glycidate 2 . The key step was a lipase-catalyzed regioselective lactamization of amino diester 5 into seven-membered lactam 6 . The transformation was performed using SpinChem rot... | 10.1021/op5001644 | 1 |
Preparation, Properties, and Safe Handling of Commercial Organolithiums: Alkyllithiums, Lithium <i>sec</i>-Organoamides, and Lithium Alkoxides | This review includes the preparation and properties of various organolithiums, which are commercially available, up to manufacturing scale. The interdependent properties, such as pyrophoricity, solubility, stability, and aggregation, are tabulated and discussed. These properties have a direct bearing on their chemical ... | 10.1021/op500161b | 0 |
Scale-Up Investigation of the Continuous Phase-Transfer-Catalyzed Hypochlorite Oxidation of Alcohols and Aldehydes | The use of bleach to oxidize alcohols with the aid of a phase-transfer catalyst (PTC) offers several benefits over traditional oxidants: low material cost, mild reaction conditions, and no metallic waste. Mass transport limitations often dictate overall reaction rates of such PTC reactions, and continuous-flow reactors... | 10.1021/op500158h | 0 |
A Novel Synthesis of Rasagiline via a Chemoenzymatic Dynamic Kinetic Resolution | A novel synthetic route for preparing rasagiline mesylate is presented using a dynamic kinetic resolution (DKR) as the key step, catalyzed by Candida antarctica lipase B (CALB) and a Pd nanocatalyst. The chiral intermediate ( R )-2,3-dihydro-1-indanamine was obtained through the DKR of the racemic aminoindan rac -1 in ... | 10.1021/op500152g | 1 |
Development of an Enantioselective Hydrogenation Route to (<i>S</i>)-1-(2-(Methylsulfonyl)pyridin-4-yl)propan-1-amine | A highly enantioselective enamide hydrogenation route to the title amine was developed. Highlights of the synthesis include an efficient two-step synthesis of a 2-sulfonyl 4-pyridyl ethyl ketone, a simple enamide synthesis by direct condensation of propionamide with a ketone, catalytic asymmetric enamide hydrogenation ... | 10.1021/op5001513 | 1 |
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