title string | abstract string | doi string | has_route int64 |
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Chiral Supercritical Fluid Chromatography in the Preparation of Enantiomerically Pure (<i>S</i>)-(+)-<i>tert</i>-Butyl-3-hydroxyazepane-1-carboxylate | We report herein the isolation and characterization of ( S )-(+)- tert -butyl-3-hydroxyazepane-1-carboxylate via resolution of the commercially available racemate, using chiral supercritical fluid chromatography (SFC). After optimization of the experimental chromatographic conditions, preparative scale separation using... | 10.1021/op400274b | 0 |
Development of an Efficient Process for the Decomposition of the Borate Complexes Formed during the Large-Scale Synthesis of (<i>S</i>)-1,2,4-Butanetriol | An improved multikilogram-scale process for the production of ( S )-1,2,4-butanetriol has been developed. This process involves the efficient removal of residual boric acid and the decomposition of the borate complexes formed during the reduction of (−)-dimethyl malate with sodium borohydride by methanolysis using a ci... | 10.1021/op400271k | 0 |
Diastereospecific Enolate Addition and Atom-Efficient Benzimidazole Synthesis for the Production of L/T Calcium Channel Blocker ACT-280778 | A scalable access to 1 ( ACT-280778 ), a potent L/T calcium channel blocker, has been developed. The synthesis, amenable to kilogram manufacturing, comprises 10 chemical steps from enantiomerically pure 5-phenylbicyclo[2.2.2]oct-5-en-2-one ( 3 ) and 1,4-dimethoxybenzene with a longest linear sequence of 7 steps. Key to... | 10.1021/op400269b | 1 |
Catalytic Asymmetric Reduction of a 3,4-Dihydroisoquinoline for the Large-Scale Production of Almorexant: Hydrogenation or Transfer Hydrogenation? | Several methods are presented for the enantioselective synthesis of the tetrahydroisoquinoline core of almorexant (ACT-078573A), a dual orexin receptor antagonist. Initial clinical supplies were secured by the Noyori Ru-catalyzed asymmetric transfer hydrogenation (Ru-Noyori ATH) of the dihydroisoquinoline precursor. Bo... | 10.1021/op400268f | 1 |
Synthesis of Enantiomerically Pure 4-Hydroxy-2-cyclopentenones | Conversion of furfuryl alcohol to 4-hydroxy-2-cyclopentenone was studied in a microreactor channel of 0.5 mm diameter and 1.5 m length. Addition of 1 M N -methylpyrrolidinone as a cosolvent significantly reduces the polymeric material normally formed during the reaction in purely aqueous solution. The reaction follows ... | 10.1021/op400266k | 1 |
Process for Producing Optically Active (<i>R</i>)-Tetrahydrothiophene-3-ol with High Optical Purity and High Purity: Bioconversion and Crystallization | ( R )-Tetrahydrothiophene-3-ol ( 1 ) is a key intermediate in the synthesis of penem-based antibiotics. However, it is a viscous liquid at room temperature, which makes it impossible to purify the ( R )-isomer especially in the presence of the ( S )-isomer. In this study, we successfully developed a process for produci... | 10.1021/op4002627 | 0 |
Improved Process for Pilot-Scale Synthesis of Danshensu ((±)-DSS) and Its Enantiomer Derivatives | A pilot-scale process has been developed for green and scalable synthesis of (±)-β-(3,4-dihydroxyphenyl) lactic acid ((±)-DSS) and their two important derivatives, namely, (±)-IDHP [(±)-isopropyl 2-hydroxy-3-(3,4-dihydroxyphenyl)propanoate] and (±)-DBZ [(±)-bornyl 2-hydroxy-3-(3,4-dihydroxyphenyl)propanoate]. Subsequen... | 10.1021/op4002593 | 1 |
Safe Scale-Up of a Hydrazine Condensation by the Addition of a Base | Herein we describe an observation where an exothermic event encountered during the safety evaluation of the scale-up of the synthesis of 4-chloro-1 H -indazol-3-amine was mitigated upon the addition of a base. The 100 °C adiabatic temperature rise was attributed to the hydrazine condensation reaction, which could cause... | 10.1021/op4002577 | 0 |
Sanofi’s Solvent Selection Guide: A Step Toward More Sustainable Processes | Sanofi’s solvent selection guide helps chemists in early development select sustainable solvents that will be accepted in all production sites. Solvents are divided into four classes, from “recommended” to “banned”. This ranking is derived from Safety, Health, Environmental, Quality, and Industrial constraints. Each so... | 10.1021/op4002565 | 0 |
Use of a Miniature Mass Spectrometer To Support Pharmaceutical Process Chemistry | In this study we describe the evaluation of a recently developed miniaturized single-quadrupole mass spectrometer to support pharmaceutical process research investigations. Mass spectrometry is becoming an indispensable tool for analytical support of synthetic chemistry; however, current mass spectrometers are too expe... | 10.1021/op400253x | 0 |
Women in Process R&D | ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTWomen in Process R&DTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 10, 1220Publication Date (Web):September 17, 2013Publication History Published online17 September 2013Published inissue 18 October 2013https://doi.org/10.1021/op400251pCopyright © 2013 American Chem... | 10.1021/op400251p | 0 |
A Scalable Synthesis of an Atropisomeric Drug Substance via Buchwald–Hartwig Amination and Bruylants Reactions | A practical, chromatography-free synthesis for a chemokine receptor antagonist NIBR-1282 ( 1 ) is described. Highlights of this scalable synthesis include (1) Buchwald–Hartwig amination reaction using ( t -Bu) 3 P as the ligand and 5–12 mol % of water as an additive affording 6 with yield increase of more than 2-fold; ... | 10.1021/op400250s | 1 |
Special Feature Section: Engineering Contributions to Chemical Process Development | U pon initial consideration, the idea of a special Organic Process Research & Development (OPRD) feature devoted to "Engineering Contributions to Chemical Process Development" may seem unnecessary.After all, chemical engineering principles are deeply embedded in the strategy of process development, especially as it rel... | 10.1021/op400248x | 0 |
Pharmaceutical Roundtable Study Demonstrates the Value of Continuous Manufacturing in the Design of Greener Processes | The American Chemical Society (ACS) Green Chemistry Institute (GCI) Pharmaceutical Roundtable conducted a study to elucidate the value of continuous processing, which had been defined as a key research area for green engineering. In the course of defining the business case for continuous processing, individual cases we... | 10.1021/op400245s | 0 |
Commercial Synthesis of a Pyrrolotriazine–Fluoroindole Intermediate to Brivanib Alaninate: Process Development Directed toward Impurity Control | The development of a practical, commercial process for the preparation of 4-fluoro-2-methyl-indol-5-ol and its subsequent coupling with a pyrrolotriazine to form an advanced intermediate of the oncology therapy brivanib alaninate is described. A key aspect is the multikilogram-scale preparation of the fluoroindole inte... | 10.1021/op400242j | 1 |
Synthesis of Filibuvir. Part III. Development of a Process for the Reductive Coupling of an Aldehyde and a β-Keto-lactone | Development of a reductive coupling of a β-keto-lactone and an aldehyde is described, in which the Hantzsch ester serves as an inexpensive and convenient reducing agent. Structural features in the β-keto-lactone rendered standard reductive coupling conditions ineffective, requiring development of a specific addition an... | 10.1021/op400237j | 1 |
Synthesis of Filibuvir. Part II. Second-Generation Synthesis of a 6,6-Disubstituted 2<i>H</i>-Pyranone via Dieckmann Cyclization of a β-Acetoxy Ester | This paper describes an improved sequence for the conversion of an oxazolidinone ( 3 ) to a β-keto lactone ( 5 ). The primary drivers behind this change were the modest and variable yields observed in the intramolecular cyclization to generate the β-keto lactone. Changing the cyclization substrate from oxazolidinone to... | 10.1021/op400236r | 1 |
Synthesis of Filibuvir. Part I. Diastereoselective Preparation of a β-Hydroxy Alkynyl Oxazolidinone and Conversion to a 6,6-Disubstituted 2<i>H</i>-Pyranone | This is the first in a series of three papers describing the identification and development of a commercial synthesis of filibuvir ( 1 ). This contribution describes development of an Evans aldol reaction to control the tertiary alcohol stereocenter, a challenging variant of that strategy in that both reacting partners... | 10.1021/op4002356 | 1 |
Process Safety Evaluation To Identify the Inherent Hazards of a Highly Exothermic Ritter Reaction Using Adiabatic and Isothermal Calorimeters | This paper describes the process safety studies that were carried out prior to the scale-up for the initial process containing the reaction of 1,3-dimethyladamantane with sulfuric acid and acetonitrile. The reaction temperature is set at 13 °C followed by heating to 23 °C for progress of the reaction. Thermal screening... | 10.1021/op400234w | 0 |
Process Development of C–N Cross-Coupling and Enantioselective Biocatalytic Reactions for the Asymmetric Synthesis of Niraparib | Process development of the synthesis of the orally active poly(ADP-ribose)polymerase inhibitor niraparib is described. Two new asymmetric routes are reported, which converge on a high-yielding, regioselective, copper-catalyzed N -arylation of an indazole derivative as the late-stage fragment coupling step. Novel transa... | 10.1021/op400233z | 1 |
Introduction to Biological and Small Molecule Drug Research and Development: Theory and Case Studies | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewIntroduction to Biological and Small Molecule Drug Research and Development: Theory and Case StudiesTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 9, 1218Publication Date (Web):September 4, 2013Publication History Published online4 September 2013Published inissue 20 ... | 10.1021/op400230q | 1 |
Copper-Catalyzed C–N Coupling in the Synthesis of Integrase Inhibitors of Immunodeficiency Viruses | This contribution describes the total synthesis of a complex macrocyclic integrase inhibitor, a key enzyme involved in the infection process of various immunodeficiency viruses. The key transformation of the synthetic strategy was the selective C–N coupling of a sulfonamide to a heteroaryl bromide in the presence of po... | 10.1021/op400228z | 1 |
Use of Modeling and Process Analytical Technologies in the Design of a Catalytic Amination Reaction: Understanding Oxygen Sensitivity at the Lab and Manufacturing Scales | A mechanistic approach was undertaken to understand the oxygen sensitivity of a Pd-catalyzed amination reaction used in the synthesis of an active pharmaceutical ingredient. FlowNMR and dissolved oxygen probes were used as process analytical technology alongside kinetic and unit operation models to better characterize ... | 10.1021/op400226m | 0 |
Preparation of Phosphonooxymethyl Prodrugs of HIV-1 Attachment Inhibitors | A practical and scalable synthesis of phosphonooxymethyl prodrugs of HIV-1 attachment inhibitors is described. Starting from azaindoles 1 and 2, this two-step sequence features an efficient alkylation using chloromethyl phosphate 5 and an exceptionally mild deprotection for tert -butyl phosphates. After a salt formatio... | 10.1021/op400225q | 0 |
Virtual Issue on Crystallisation and Polymorphism in Organic Process Development: 25 Papers Specially Selected by the Editor | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTVirtual Issue on Crystallisation and Polymorphism in Organic Process Development: 25 Papers Specially Selected by the EditorTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 10, 1219Publication Date (Web):September 20, 2013Publication History Published online20 September ... | 10.1021/op400220h | 0 |
Convergent Asymmetric Synthesis of a Renin Inhibitor: A Highly Efficient Construction Method of Three Stereogenic Centers | An improved asymmetric synthesis of renin inhibitor DS-8108b (1) is described. This compound consists of three intermediates: 4-aminoadamantan-1-ol, ketopiperazine, and chiral lactone which contains three stereogenic centers. Especially, the chiral lactone is a key intermediate, and development of a scalable synthetic ... | 10.1021/op400219y | 1 |
Process Understanding: For Scale-Up and Manufacture of Active Ingredients | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTProcess Understanding: For Scale-Up and Manufacture of Active IngredientsJörgen BlixtView Author Information Chemovix AB Lostigen 25, SE-151 50 Enhörna, SwedenE-mail: [email protected]Cite this: Org. Process Res. Dev. 2013, 17, 9, 1216Publication Date (Web):September 4, 2... | 10.1021/op400218n | 0 |
Glucokinase Activator: Practical Asymmetric Hydrogenation and Scalable Synthesis of an API Fragment | The enantioselective synthesis of ( R )-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl propionic acid ( R )- 2 is described. The key intermediate ( E )- 7, a trisubstituted α-aryl β-alkyl acrylic acid, was conveniently accessed as its dicyclohexylamine salt by Perkin reaction in good yield and purity. Subsequent a... | 10.1021/op4002164 | 1 |
Exploratory Process Development of a Novel Diacylglycerol Acyltransferase-1 (DGAT-1) Inhibitor | A practical large-scale synthesis was developed for 1, a DGAT-1 inhibitor, involving an aza-Michael reaction, amidation, Dieckman cyclization, and conjugate addition of cyanamide followed by cyclization, to form the fused 4-amino-7,8-dihydropyrido[4,3- d ]pyrimidin-5-one scaffold. The enabled process presented here sub... | 10.1021/op400215h | 1 |
Development of a Practical and Scalable Synthesis of the Side Chain for ASP9726, a Successor of Micafungin | Here, we describe a practical and scalable synthesis of 1, which is a useful side chain of ASP9726 ( 2 ), a successor of Micafungin. For large-scale synthesis of 1, reaction conditions were optimized to control impurities and increase yield. In particular, we utilized a high-yield thiadiazole ring formation to prepare ... | 10.1021/op400211t | 1 |
A Scalable Route to the SMO Receptor Antagonist SEN826: Benzimidazole Synthesis via Enhanced in Situ Formation of the Bisulfite–Aldehyde Complex | A practical and scalable route to the SMO antagonist SEN826 1 is described herein, including the discussion of an alternative approach to the synthesis of the target molecule. The optimized route consists of five chemical steps. A new and efficient access to the key intermediate 6 via the bisulfite–aldehyde complex was... | 10.1021/op4002092 | 1 |
Safer Preparation of <i>m-</i>CPBA/DMF Solution in Pilot Plant | The usage of m -CPBA ( meta -chloroperbenzoic acid) is limited on large scale due to its thermal instability, although it is a good oxidant and well-accepted in laboratory scale. In our recent project, m -CPBA was used for an oxidation reaction, and an explosion hazard was identified. To ensure the safe use of m -CPBA ... | 10.1021/op400208b | 0 |
An Improved and Economical Process for the Manufacture of the Key Intermediate of Aliskiren, a New Potent Renin Inhibitor | An improved, practical, economical and efficient process for the production of (2 S,4 S )-2-amino-4-(4-methoxy-3-(3-methoxypropoxy)benzyl)-5-methylhexanoic acid, a key intermediate of the new potent renin inhibitor of aliskiren, in a total yield over 30% is described. This process avoids expensive reagents and chromato... | 10.1021/op400205k | 1 |
Practical and Scalable Synthesis of a Benzonitrile Derivative via Palladium-Catalyzed Cyanation with Potassium Ferrocyanide | A practical and reproducible synthetic method for the preparation of a benzonitrile derivative ( 1 ) from an aryl bromide ( 2 ) via Pd-catalyzed cyanation was established with dimethylacetamide (DMAc)–toluene as a mixed solvent. Optimization was examined by a design of experiments (DoE) technique to enhance reaction co... | 10.1021/op400204g | 1 |
Merck’s Reaction Review Policy: An Exercise in Process Safety | Process safety is an important consideration not only when conducting reactions on manufacturing scale, but also on lab and kilo lab scale. This contribution presents a discussion of Merck’s Reaction Review policy, originally specific to Process Chemistry and now applied broadly across the whole chemistry organization.... | 10.1021/op4002033 | 0 |
A Stereoselective Process for the Manufacture of a 2′-Deoxy-β-<scp>d</scp>-Ribonucleoside Using the Vorbrüggen Glycosylation | A practical and scalable process for the manufacture of cladribine ( 1 ) is described. Vorbrüggen glycosylation of doubly silylated 2-chloroadenine 2 with protected 1- O -acetyl-2-deoxy-α,β- d -ribofuranose 3 under reversible conditions in the presence of 20 mol % triflic acid in a solvent that selectively precipitated... | 10.1021/op4002005 | 0 |
Development of an Improved and Scalable Process for 2-(5-Ethylpyridin-2-yl)ethan-1-ol: Solvent-Free Reaction and Recycling of the Starting Material 5-Ethyl-2-picoline | The main objective of this exercise was to develop a more efficient process for 2-(5-ethylpyridin-2-yl)ethan-1-ol ( 1 ), which is the key intermediate in the synthesis of pioglitazone hydrochloride. This process not only features the yield improvement of ( 1 ) by optimizing reaction variables in solvent-free conditions... | 10.1021/op400196y | 0 |
Evolution and Application of an Automated Platform for the Development of Crystallization Processes | An automated crystallization platform enabled by FTIR and FBRM in combination with automation and chemometrics has provided a versatile tool for efficient crystallization process development. This system allows users to perform a “walkup” operation for routine process evaluation and also execute automated feedback cont... | 10.1021/op400187h | 0 |
Asymmetric Synthesis of a TRPV1 Antagonist via <i>tert</i>-Butanesulfinamide-Directed Reductive Amination with a Chromanone | An expedient asymmetric synthesis of TRPV1 antagonist 1 has been developed and demonstrated on multikilogram scale. The enabling route to 1 is detailed herein and characterized by the following key transformations: an aldol-cyclodehydration sequence to install the chromanone, and an auxiliary-mediated diastereoselectiv... | 10.1021/op400184f | 1 |
Pilot-Scale Production of Dimethyl 1,4-Cubanedicarboxylate | A scalable process for the preparation of high purity dimethyl 1,4-cubanedicarboxylate ( 3 ) is reported. The work described herein builds on previous synthetic work from this and other laboratories, to provide a reliable process that can be used to prepare multigram quantities of 3 in a partially telescoped, 8 step pr... | 10.1021/op400181g | 1 |
Application of Ultrasound Measurements as PAT Tools for Industrial Crystallization Process Development of Pharmaceutical Compounds | Within this work, 12 different pharmaceutical compounds were analyzed by the single-frequency ultrasound measurement technique for its applicability to determine concentrations, as an important process parameter during crystallization processes, or to determine the metastable zone widths, as an important precondition f... | 10.1021/op4001803 | 0 |
Improved Continuous Flow Processing: Benzimidazole Ring Formation via Catalytic Hydrogenation of an Aromatic Nitro Compound | In the development of a new route to bendamustine hydrochloride, the API in Treanda, the key benzimidazole intermediate 5 was generated via catalytic heterogeneous hydrogenation of an aromatic nitro compound using a batch reactor. Because of safety concerns and a site limitation on hydrogenation at scale, a continuous ... | 10.1021/op400179f | 1 |
Right First Time in Fine-Chemical Process Scale-Up: Avoiding Scale-Up Problems: The Key to Rapid Success | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTRight First Time in Fine-Chemical Process Scale-Up: Avoiding Scale-Up Problems: The Key to Rapid SuccessJohn BlackerView Author Information Institute of Process R&D, University of Leeds, U.K.Cite this: Org. Process Res. Dev. 2013, 17, 9, 1214–1215Publication Date (Web):Au... | 10.1021/op400176g | 0 |
Evaluation of Novel Synthetic Methods for the Preparation of the Sodium Channel Inhibitor, GW273225X | The evaluation of efficient synthetic methods for the preparation of ( R )-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine, GW273225X ( 1 ), is described. The initial synthesis using ethylfluoroacetate was evaluated against three alternative routes using either nucleophilic fluorination, electrophilic fluor... | 10.1021/op4001753 | 1 |
Practical Nonazide Synthesis of a <scp>d</scp>-Amino Acid Oxidase Inhibitor via a Sequential Erlenmeyer–Plöchl Reaction and Ligand-Free Copper(I) Amination Protocol | A synthetic route to fused heterocycle 5 (R 1 = Et) was developed that avoids the use of troublesome azido functionality. In this approach, 3-bromofuran aldehyde 7 was synthesized from 3-bromofuran 6 using highly regioselective formylation conditions. The crude solution of 7 was treated with hippuric acid under Erlenme... | 10.1021/op4001737 | 1 |
Improved “Oxazole” Method for the Practical and Efficient Preparation of Pyridoxine Hydrochloride (Vitamin B<sub>6</sub>) | Vitamin B 6, a well-studied vitamin B, has been synthesized using an oxazole method for the past 20 years. The oxazole method provided 56.2% overall yield but also generated safety, environmental, and health problems, such as using toxic benzene as solvent and unstable, corrosive, and pollutive HCl and POCl 3 as reagen... | 10.1021/op4001687 | 1 |
Advances in the Process Development of Biocatalytic Processes | Biocatalysis is already established in chemical synthesis on an industrial scale, in particular in the pharmaceutical sector. However, the wider implementation of biocatalysis is currently hindered by the extensive effort required to develop a competitive process. In order that resources spent on development are used i... | 10.1021/op4001675 | 0 |
The Fit For Purpose Development of S1P<sub>1</sub> Receptor Agonist GSK2263167 Using a Robinson Annulation and Saegusa Oxidation to Access an Advanced Phenol Intermediate | A fit for purpose approach has been adopted in order to develop a robust, scalable route to the S1P 1 receptor agonist, GSK2263167. The key steps include a Robinson ring annulation followed by a Saegusa oxidation, providing rapid access to an advanced phenol intermediate. Despite the use of stoichiometric palladium ace... | 10.1021/op400162p | 1 |
Use of Computational Fluid Dynamics for Development and Scale-Up of a Helical Coil Heat Exchanger for Dissolution of a Thermally Labile API | Computational fluid dynamics (CFD) is well established as a tool of choice for solving complex problems that involve interplay of the various transport phenomena (fluid flow, heat transfer, mass transfer) and/or chemical reaction. CFD modelling in such applications can be an effective tool for understanding the process... | 10.1021/op400161s | 0 |
A Scalable Process to the Key Intermediate of Cilazapril, (<i>S</i>)-1-Benzyloxycarbonylhexahydropyridazine-3-carboxylic Acid, Through a Novel Cascade Course | A novel and efficient manufacturing technology is disclosed in the present work for the preparation of ( S )-1-benzyloxycarbonylhexahydropyridazine-3-carboxylic acid, which is a key intermediate of cilazapril. The whole process includes only three steps; the first two steps were conducted in one pot, followed by a nove... | 10.1021/op400155u | 1 |
Continuous Flow-Processing of Organometallic Reagents Using an Advanced Peristaltic Pumping System and the Telescoped Flow Synthesis of (<i>E/Z</i>)-Tamoxifen | A new enabling technology for the pumping of organometallic reagents such as n -butyllithium, Grignard reagents, and DIBAL-H is reported, which utilises a newly developed, chemically resistant, peristaltic pumping system. Several representative examples of its use in common transformations using these reagents, includi... | 10.1021/op4001548 | 0 |
Scaling Up of Continuous Flow Processes with Gases Using a Tube-in-Tube Reactor: Inline Titrations and Fanetizole Synthesis with Ammonia | The development of a tube-in-tube reactor based on a semipermeable polymer membrane has enabled the efficient transfer of gases into liquid flow streams. In this work we describe the scalability and throughput of this reactor when applied to ammonia gas. This is made possible by a convenient titration method to rapidly... | 10.1021/op400152r | 0 |
Practical Asymmetric Synthesis of a Chiral Piperazinone Derivative | A practical asymmetric route to a chiral piperazinone derivative, a fragment of MK-3207, is reported. The amine-bearing benzylic stereocenter is introduced via an asymmetric Pd-catalyzed hydrogenation of a cyclic sulfimidate in the presence of a chiral phosphine ligand. An efficient synthesis of the hydrogenation subst... | 10.1021/op400150w | 1 |
Process Development and Scale-Up for the Preparation of the 1-Methyl-quinazoline-2,4-dione Wnt Inhibitor SEN461 | A practical and scalable route to the Wnt inhibitor SEN461 1 is described herein. The optimized route consists of nine chemical steps. The intermediates are solids and were isolated by filtrations. Critical reactions steps in the medicinal chemistry route were modified for an initial scale-up process, and as a result, ... | 10.1021/op400145w | 1 |
Improved Process for Preparation of (3<i>R</i>,4<i>R</i>)-3-(3,4-Dimethyl-4-piperidinyl)phenol, A Key Intermediate for the Synthesis of Alvimopan | This report discloses an industrially feasible and cost efficient process for the preparation of the compound [(3 R, 4 R )-3-(3,4-dimethyl-4-piperidinyl)phenol] ( 1 ), which is used as the key intermediate for preparation of the opioid drug Alvimopan. The overall yield in this process is increased from 15 to 30%, mainl... | 10.1021/op400144z | 1 |
Process Development and Multikilogram Syntheses of XL228 Utilizing a Regioselective Isoxazole Formation and a Selective S<sub>N</sub>Ar Reaction to a Pyrimidine Core | Route scouting, process development, and multikilogram syntheses of an IGF-1R/Src/Bcr-Abl inihibitor are reported. Key aspects of the developed route are a regioselective [3 + 2] isoxazole formation on a pyrimidine core and a selective S N Ar addition of an aryl amine to a symmetrical dichloro substituted pyrimidine. T... | 10.1021/op400137m | 1 |
Lipase-Catalyzed One-Step and Regioselective Synthesis of Clindamycin Palmitate | Chemical synthesis of clindamycin palmitate, a prodrug with taste greatly improved more than that of clindamycin, involves laborious steps of protection and deprotection to achieve the monoacylation only at 2-hydroxyl group of clindamycin and gives an overall yield below 50%. Here we report the first example of one-ste... | 10.1021/op400135y | 0 |
Use of ω-Transaminase Enzyme Chemistry in the Synthesis of a JAK2 Kinase Inhibitor | ω-Transaminase enzyme chemistry provides an excellent methodology to build synthetically useful chiral amines from their corresponding ketones. An application of this methodology, providing a long-term commercial manufacturing route to a JAK2 kinase inhibitor, is reported herein. | 10.1021/op400133d | 1 |
Efficient Synthesis of (<i>S</i>)-1-(5-Fluoropyrimidin-2-yl)ethylamine Using an ω-Transaminase Biocatalyst in a Two-Phase System | Screening of 60 transaminases using three different amine donors found that the ω-transaminase from Vibrio fluvialis together with ( S )-α-methylbenzylamine to be the most promising combination to deliver the desired ( S )-1-(5-fluoropyrimidin-2-yl)-ethylamine ( 2 ) in almost quantitative conversion. The process was fu... | 10.1021/op400131h | 0 |
Engineering Reaction and Crystallization and the Impact on Filtration, Drying, and Dissolution Behaviors: The Study of Acetaminophen (Paracetamol) by In-Process Controls | Acetaminophen was synthesized by reacting p -aminophenol with acetic anhydride. Overall materials balance was compiled. Three different crystallization paths (i.e., cases I, II, and III) involving various modes in agitation and addition of sodium hydroxide were taken to produce acetaminophen particles with different pa... | 10.1021/op400129n | 0 |
The Literature of Organic Process Research & Development | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTThe Literature of Organic Process Research & DevelopmentTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 6, 885Publication Date (Web):May 24, 2013Publication History Published online24 May 2013Published inissue 21 June 2013https://pubs.acs.org/doi/10.1021/op400124bhttps:... | 10.1021/op400124b | 0 |
An Efficient, Selective Process for the Conversion of Glycerol to Propylene Glycol Using Fixed Bed Raney Copper Catalysts | Propylene glycol is formed in yields of up to 95% at 100% conversion using a Raney Cu catalyst in a fixed bed reactor. The reaction uses an 80% aqueous glycerol solution and a hydrogen pressure of 600 psi. The primary byproduct is ethylene glycol formed in 1–3% yield. In a reaction run continuously for 24 d using a sam... | 10.1021/op400123f | 0 |
Hydrazine and Aqueous Hydrazine Solutions: Evaluating Safety in Chemical Processes | This contribution provides a summary of the hazards of hydrazine and its aqueous solutions and an understanding of the important role dilution plays in increasing the inherent safety of aqueous hydrazine solutions. Rather than provide an extensive description of the hazardous properties of hydrazine, the intent is to p... | 10.1021/op400120g | 0 |
Identification, Synthesis, and Strategy for Minimization of Potential Impurities in the Preclinical Anti-HBV Drug <b>Y101</b> | The identification of actual, potential, and theoretical impurities of N -[ N -benzoyl- O -(2-dimethylaminoethyl)- l -tyrosyl]- l -phenylalaninol ( Y101 ), a preclinical anti-HBV drug, is described in this article. The impurities were monitored by HPLC, and their structures were established on the basis of NMR, IR, and... | 10.1021/op400119b | 1 |
Greening the Valsartan Synthesis: Scale-up of Key Suzuki–Miyaura Coupling over Silia<i>Cat</i> DPP-Pd | The study of the scale-up of the heterogeneous Suzuki-Miyaura coupling reaction in batch conditions between 2-chlorobenzonitrile and 4-tolylboronic acid, a key step in valsartan synthesis, to produce 4′-methyl-2-biphenylcarbonitrile over the Silia Cat DPP-Pd catalyst in ethanol under reflux allows to identify the optim... | 10.1021/op400118f | 0 |
Process Development and Scale-up of a β-Secretase Inhibitor via a Stereospecific Jocic Reaction | A scalable process for the synthesis of a spiropiperidine β-secretase inhibitor is described. Key stereochemical transformations utilized are a diastereoselective trichloromethyl addition followed by an unprecedented stereospecific Jocic reaction with an aniline nucleophile. Simplified processing was developed for a Di... | 10.1021/op400115g | 1 |
An Improved Process for Trimethobenzamide Hydrochloride | An improved process for the preparation of trimethobenzamide hydrochloride conforming to regulatory specification is reported. Specifically, a process for the preparation of trimethobenzamide hydrochloride, which is free from the associated impurities that are normally encountered during coupling of 4-(2-dimethylaminoe... | 10.1021/op400113a | 1 |
Model-Based Scale-up and Design Space Determination for a Batch Reactive Distillation with a Dean–Stark Trap | Batch reactive distillations are commonly used unit operations in the pharmaceutical industry to drive chemical equilibrium reactions to completion. Their scale-up and transfer to manufacturing is not straightforward due to the interplay of scale dependent and scale independent phenomena. The increased process knowledg... | 10.1021/op4001127 | 0 |
I-MR Control Chart: A Tool for Judging the Health of the Current Manufacturing Process of an API and for Setting the Trial Control Limits in Phase I of the Process Improvement | It has been observed that the main focus during the process development and manufacturing of an API is to meet the customer’s specifications (LSL and USL) rather than estimating and improving the natural control limits (LCL and UCL) of the process. It results in the overlap of the natural control limit and customer’s s... | 10.1021/op4001093 | 0 |
Development of a Scalable Synthesis of a Bruton’s Tyrosine Kinase Inhibitor via C–N and C–C Bond Couplings as an End Game Strategy | A scalable and convergent synthesis of a BTK (Bruton’s tyrosine kinase) inhibitor has been developed. Synthetic routes to key intermediates were explored for the scale-up campaign, especially the process for 6-dimethylaminodihydroisoquinolinone, which was prepared via a regioselective cyclization of an isocyanate, medi... | 10.1021/op4001077 | 1 |
Synthesis of a <i>cis</i> 2,5-Disubstituted Morpholine by De-epimerization: Application to the Multigram Scale Synthesis of a Mineralocorticoid Antagonist | A convergent route to multigram quantities of a mineralocorticoid antagonist 3 is described. Starting from ( R )-phenylglycinol, the synthesis of cis 2,5-morpholine 2 is accomplished utilizing a de-epimerization to install the second stereogenic center. The multigram synthesis of 3 was completed through a sequence of a... | 10.1021/op400101p | 1 |
A New Efficient Synthetic Process for an Endothelin Receptor Antagonist, Bosentan Monohydrate | A new and efficient synthetic process for the synthesis of an endothelin receptor antagonist, bosentan monohydrate, involves the coupling of p - tert -butyl- N -(6-chloro-5-(2-methoxy phenoxy)-2,2′-bipyrimidin-4-yl)benzenesulfonamide ( 7 ) with (2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanol ( 14 ) as a key step. This ... | 10.1021/op400100s | 1 |
Formulation and Process Development Strategies for Manufacturing Biopharmaceuticals | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTFormulation and Process Development Strategies for Manufacturing BiopharmaceuticalsTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 5, 883Publication Date (Web):May 6, 2013Publication History Published online6 May 2013Published inissue 17 May 2013https://pubs.acs.o... | 10.1021/op400098h | 0 |
Understanding and Avoidance of Agglomeration During Drying Processes: A Case Study | A systematic investigation into possible causes of agglomeration during drying was carried out, with a view to reduce the amount of agglomerates present in an active pharmaceutical ingredient. Several tools used in this study are described, including rheology to elucidate how the interplay of agitation (during drying a... | 10.1021/op4000972 | 0 |
An Improved Kilogram-Scale Synthesis of 2-Bromo-4-nitro-1<i>H</i>-imidazole: A Key Building Block of Nitroimidazole Drugs | An efficient two-step method for the synthesis of 2-bromo-4-nitroimidazole, 6, a key building block for nitroimidazole drugs, has been developed. The synthesis involves dibromination of 4-nitroimidazole 10 followed by selective debromination using in situ reductive deiodination strategy. The reactions are facile, safe,... | 10.1021/op400095f | 1 |
Book Review of Modern Gold Catalyzed Synthesis | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Modern Gold Catalyzed SynthesisTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 5, 882Publication Date (Web):April 19, 2013Publication History Published online19 April 2013Published inissue 17 May 2013https://pubs.acs.org/doi/10.1021/op400093khttps:/... | 10.1021/op400093k | 0 |
The Synthesis of Bromomethyltrifluoroborates through Continuous Flow Chemistry | A continuous flow process was developed for the synthesis of potassium bromomethyltrifluoroborate, a key precursor for Suzuki–Miyaura coupling reagents. The continuous flow process was used to produce potassium bromomethyltrifluoroborate on scales from grams to kilograms, and the successful process utilized a fraction ... | 10.1021/op400090a | 0 |
Development of an Efficient Pd-Catalyzed Coupling Process for Axitinib | The manufacturing process of axitinib ( 1 ) involves two Pd-catalyzed coupling reactions, a Migita coupling and a Heck reaction. Optimization of both of these pivotal bond-formation steps is discussed as well as the approach to control impurities in axitinib. Essential to the control strategy was the optimization of th... | 10.1021/op400088k | 1 |
Development and Application of Laboratory Tools To Predict Particle Properties upon Scale-Up in Agitated Filter-Dryers | Agitated filter-dryers (AFDs) are commonly used for performing both filtration and drying operations in the manufacture of active pharmaceutical ingredients (APIs) and intermediates. Successful scale-up from the laboratory to manufacturing AFD equipment requires that physical properties specifications such as particle ... | 10.1021/op400080x | 0 |
Book Review of Strategies for Green Organic Synthesis | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewBook Review of Strategies for Green Organic SynthesisTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 4, 721Publication Date (Web):April 11, 2013Publication History Published online11 April 2013Published inissue 19 April 2013https://pubs.acs.org/doi/10.1021/op4000785ht... | 10.1021/op4000785 | 0 |
Book Review of Organic Synthesis Using Transition Metals, 2nd edition | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Organic Synthesis Using Transition Metals, 2nd editionTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 4, 720Publication Date (Web):April 11, 2013Publication History Published online11 April 2013Published inissue 19 April 2013https://pubs.acs.org/doi... | 10.1021/op4000779 | 0 |
Full-Scale Continuous Mini-Reactor Setup for Heterogeneous Grignard Alkylation of a Pharmaceutical Intermediate | A reactor setup consisting of two reactors in series has been implemented for a full-scale, heterogeneous Grignard alkylation. Solutions pass from a small filter reactor into a static mixer reactor with multiple side entries, thus combining continuous stirred tank reactor (CSTR) and plug flow reactor (PFR) technologies... | 10.1021/op400069e | 0 |
Book Review of Enzyme Catalysis in Organic Synthesis | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Enzyme Catalysis in Organic SynthesisTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 4, 718Publication Date (Web):April 11, 2013Publication History Published online11 April 2013Published inissue 19 April 2013https://doi.org/10.1021/op400067sCopyrigh... | 10.1021/op400067s | 0 |
Development of a Safe and Economical Synthesis of Methyl 6-Chloro-5-(trifluoromethyl)nicotinate: Trifluoromethylation on Kilogram Scale | Reported herein is a safe and economical synthesis of methyl 6-chloro-5-(trifluoromethyl)nicotinate, an intermediate in the synthesis of novel anti-infective agents. The key to this process is the trifluoromethylation of an aryl iodide using an inexpensive methyl chlorodifluoroacetate (MCDFA)/KF/CuI system, with an emp... | 10.1021/op400061w | 1 |
Development of a Practical and Efficient Synthesis of SIPI-4884, a HMG CoA Reductase Inhibitor for the Treatment of Hypercholesterolemia | An improved process of the novel HMG CoA reductase inhibitor SIPI-4884 has been developed for early preclinical pharmacology and safety studies, and it was made up with an efficient nine-step and scalable process. Significant improvements in the nucleophilic substitution, reduction, Wittig–Horner reaction, and preparat... | 10.1021/op400060z | 1 |
Acidity Removal and Cesium Catalyst Recovery from Polyol Synthesis Process | In this work, a suitable method for removing the final acidity of the polyol and for recovering cesium hydroxide from polyols synthesis has been developed. Different treatments were performed in order to remove the final acidity of the polyol: adsorption with two different adsorbents (Ambrosol and basic alumina) and io... | 10.1021/op400056w | 0 |
The P-Chiral Phosphane Ligand (MeO-BIBOP) for Efficient and Practical Large-Scale Rh-Catalyzed Asymmetric Hydrogenation of <i>N</i>-Acetyl Enamides with High TONs | A highly electron-rich P-chiral bis(trialkylphosphane) ligand MeO-BIBOP ( 1 ) was efficiently synthesized on large scale. The MeO-BIBOP–rhodium complex exhibited remarkably high reactivities (up to 200,000 TON) for the hydrogenation of N -acetyl enamides to provide chiral acetamides on kilogram scale. In the meantime, ... | 10.1021/op400055z | 0 |
A Practical Synthesis of an Aminopyridine as a Component of a BTK Inhibitor | Development of a new route to the BTK intermediate, 5-(1-(azetidin-1-yl)-2-methylpropan-2-yloxy)pyridin-2-amine ( 7 ), has resulted in significant improvements in terms of yield, purity, and operability over the previously known synthesis. The new route was demonstrated on a multihundred-gram scale, and the overall yie... | 10.1021/op400046y | 1 |
Optimization of a Crude Deoxyribose-5-phosphate Aldolase Lyzate-Catalyzed Process in Synthesis of Statin Intermediates | A process for providing intermediate compounds as building blocks for effectively producing statins is described. The presented process is based on acetoxyacetaldehyde and acetaldehyde as substrates, which are presented in an aldol reaction catalyzed by a crude deoxyribose-5-phosphate aldolase (DERA) expressing culture... | 10.1021/op400040b | 0 |
Development and Scale-Up of an Optimized Route to the Pyridazin-3-one Histamine H3 Receptor Antagonist CEP-32215 | The evolution of the process to prepare CEP-32215, 3-(1′-cyclobutylspiro[4H-1,3-benzodioxine-2,4′-piperidine]-6-yl)-5,5-dimethyl-1,4-dihydropyridazine-6-one, is presented. Two routes detailing preparation of supplies for biological screening are discussed along with the optimized fit-for-purpose process used to prepare... | 10.1021/op400039d | 1 |
Improved Synthesis of the C16–C20 Segment of Resolvin E1 Using Enantioselective Ketone Reduction and Lipase-Catalyzed Resolution | A practical synthesis targeting the C16–C20 segment of the endogenous metabolite Resolvin E1 (RvE1) is described. The original route was revised to avoid the use of source-constrained raw materials and chemistries that were problematic on larger scale. The revised route utilizes commercially available ( E )-1-chloropen... | 10.1021/op4000384 | 1 |
Improved Process for Preparation of Gemfibrozil, an Antihypolipidemic | An improved process for the preparation of gemfibrozil, an antihypolipodimic drug substance, with an overall yield of 80% and ∼99.9% purity (including three chemical reactions) is reported. Formation and control of possible impurities are also described. Finally, gemfibrozil is isolated from water without any additiona... | 10.1021/op400034f | 1 |
In Praise of the Peer Review Process and Reviewers/Referees | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTIn Praise of the Peer Review Process and Reviewers/RefereesTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 3, 317Publication Date (Web):February 18, 2013Publication History Published online18 February 2013Published inissue 15 March 2013https://pubs.acs.org/doi/10.1021/o... | 10.1021/op400029f | 0 |
A New Scalable Route to 4-(2-Hydroxyethyl)-1,3-dihydro-2<i>H</i>-indol-2-one: A Key Intermediate for Ropinirole Hydrochloride | A new and efficient manufacturing technology is disclosed in the present work for the preparation of 4-(2-hydroxyethyl)-1,3-dihydro-2 H -indol-2-one, which is a key intermediate for ropinirole hydrochloride. The whole process gives the target molecule in 71% overall yield with 99% purity. In the final step, a novel nit... | 10.1021/op400024a | 1 |
Asymmetric Preparation of <i>prim</i>-, <i>sec</i>-, and <i>tert</i>-Amines Employing Selected Biocatalysts | High Resolution Image Download MS PowerPoint Slide This account focuses on the application of ω-transaminases, lyases, and oxidases for the preparation of amines considering mainly work from our own lab. Examples are given to access α-chiral primary amines from the corresponding ketones as well as terminal amines from ... | 10.1021/op4000237 | 1 |
Process R&D of Eravacycline: The First Fully Synthetic Fluorocycline in Clinical Development | Process research and development of the first fully synthetic broad spectrum 7-fluorotetracycline in clinical development is described. The process utilizes two key intermediates in a convergent approach. The key transformation is a Michael–Dieckmann reaction between a suitable substituted aromatic moiety and a key cyc... | 10.1021/op4000219 | 1 |
The Large-Scale Synthesis of (<i>S</i>)-2,4-Dichloro-1-(1,2-dichloroethyl)benzene | ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTThe Large-Scale Synthesis of (S)-2,4-Dichloro-1-(1,2-dichloroethyl)benzeneWeiguo Liu*, Canhui Wang, Qianying Liu, Yucheng Jiang, and Peng GuoCite this: Org. Process Res. Dev. 2013, 17, 5, 881Publication Date (Web):March 14, 2013Publication History Received24 Janua... | 10.1021/op4000187 | 1 |
Latest Highlights in Liquid-Phase Reactions for Organic Synthesis in Microreactors | The attention for microreactors for organic synthesis reactions, in both academia and industry, has considerably increased over the past few years, as indicated by the progressively growing number of publications. A review of articles on liquid-phase organic syntheses in microreactors in 2011–2012 is presented in this ... | 10.1021/op4000169 | 1 |
Enzymatic Preparation of an<i>R</i>-Amino Acid Intermediate for a γ-Secretase Inhibitor | ( R )-5,5,5-Trifluoronorvaline, an intermediate for a γ-secretase inhibitor (BMS-708163) under development, was initially prepared from the corresponding keto acid using a commercially available d -amino acid dehydrogenase for reductive amination and glucose dehydrogenase for cofactor recycling. This amino acid could a... | 10.1021/op400013e | 1 |
Synthetic Process Development of BMS-599793 Including Azaindole Negishi Coupling on Kilogram Scale | A new approach to the synthesis of 1 (DS003, BMS-599793), a small-molecule HIV entry inhibitor, is described. The initial medical chemistry route has been modified by rearranging the sequence of synthetic steps followed by replacement of the Suzuki coupling step by the Negishi conditions. Acylation of the resulting aza... | 10.1021/op400012p | 1 |
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