title string | abstract string | doi string | has_route int64 |
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Heavy-Metal-Free Reduction Methodology for Large-Scale Synthesis Applicable to Heterocyclic and Arylhydrazines | A green chemistry methodology that uses a heavy-metal-free reduction in aqueous medium is described to produce 5-hydrazinoquinoline [1-(quinolin-5-yl)hydrazine] ( 6a ) as the anhydrous dihydrochloride salt at large scale. The process is entirely aqueous and utilizes l -ascorbic acid to reduce the diazonium salt ( 2a ) ... | 10.1021/op8002163 | 0 |
Syntheses of a Selective Peroxisome Proliferator Activated Receptor Modulator and Practical New Preparations of 2-(4-Alkoxyphenyl)ethylamines | This article describes chemistry that was developed to give access to multigram quantities of the selective peroxisome proliferator activated receptor modulator (SPPARM), compound 1 . 1 Fischer esterifications, phase transfer-catalyzed alkylations, amide couplings, crystallizations, and a new synthesis were developed t... | 10.1021/op800215a | 1 |
Process Development and Scale-Up of a PPARγ Agonist: Selection of the Manufacture Route | Two short, high-yielding routes to the selective PPARγ agonist GSK376501A were developed and carried out on scale. The key bond -forming reaction in each synthesis was the substitution of a 3,5-difluoro or 3,5-dibromo aryl intermediate with 2-methoxyethanol. A nucleophilic aromatic (S N Ar) substitution reaction under ... | 10.1021/op800211c | 1 |
Development of an Acyl Sulfonamide Anti-Proliferative Agent, LY573636·Na | The synthesis of 5-bromo-thiophene-2-sulfonic acid 2,4-dichlorobenzoylamide sodium salt on multikilogram scale is described. The initial clinical supplies were made using carbonyl diimidazole to converge the two fragments. A more efficient acid chloride process has been developed, which also provides better control of ... | 10.1021/op800210x | 1 |
First Scale-Up Synthesis of WAY-262398, a Novel, Dual-Acting SSRI/5HT1a Antagonist | An alternative synthesis of WAY-262398, 1, a novel, dual-acting SSRI/5-HT 1A antagonist, has been developed. The target compound was initially synthesized as a part of diastereomeric mixture which was separated by chiral preparative HPLC. The new route was designed around intermediates suitable for chiral resolution an... | 10.1021/op8002085 | 1 |
Response to Dancer’s Comments on Our Article “Substrate Modification Approach to Achieve Efficient Resolution: Didesmethylcitalopram: A Key Intermediate for Escitalopram” [<i>Org. Process Res. Dev.</i> <b>2007</b>, <i>11</i>, 289−292] | Recently, we published a synthesis of escitalopram ( S - 1 ) consisting of the resolution of didesmethylcitalopram ( 3 ) and subsequent methylation of S -didesmethylcitalopram ( S-3 ) ( Org. Process Res. Dev. 2007, 11, 289−292). Some of our observations regarding citalopram resolution and C-alkylation of a benzofuran a... | 10.1021/op8002079 | 1 |
Microwave-Irradiated Synthesis of Nitrophen Using PEG 400 as Phase Transfer Catalyst and Solvent | Nitrophen is a widely used herbicide which is commonly produced by an energy intensive process using high temperature and pressure. In the current work, nitrophen is synthesized by using PEG-400 as a phase transfer catalyst in a solid−liquid (S-L) system from potassium 2,4-nitrophenolate and p -nitrochlorobenzene using... | 10.1021/op800206c | 0 |
Practical Syntheses of Oxindole Derivatives: Chemical Development towards 2-(5-Chloro-2-oxo-2,3-dihydroindol-1-yl)acetamide and (<i>S</i>)-2-(5-Chloro-2-oxo-2,3-dihydroindol-1-yl)propionamide | We describe development of scalable syntheses of novel oxindole-type SV2A ligands with improved potency towards seizure suppression. | 10.1021/op800203p | 1 |
Book Review of Process Chemistry in the Pharmaceutical Industry, Vol. 2 | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Process Chemistry in the Pharmaceutical Industry, Vol. 2W. J. WatsonView Author Information Scientific Update, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, United Kingdom.E-mail: [email protected]Cite this: Org. Process Res. Dev. 2008, 12, 6... | 10.1021/op8001992 | 0 |
A Facile Two-Step Synthesis of 3-Fluoro-6-methoxyquinoline | A facile two-step synthesis of 3-fluoro-6-methoxyquinoline is described. p -Anisidine was heated at reflux with 2-fluoromalonic acid in the presence of phosphorus oxychloride to produce 2,4-dichloro-3-fluoro-6-methoxyquinoline. This was followed by hydrogenolysis to produce 3-fluoro-6-methoxyquinoline. | 10.1021/op800198b | 1 |
Book Review of Asymmetric Organic Synthesis with Enzymes | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Asymmetric Organic Synthesis with EnzymesCite this: Org. Process Res. Dev. 2008, 12, 6, 1313–1314Publication Date (Web):September 13, 2008Publication History Received15 August 2008Published online13 September 2008Published inissue 21 November 2008https://pu... | 10.1021/op800197f | 0 |
Measurement of Gas Flow Rates from Small-Scale Reactions | The rate and total volume of noncondensable gas generation are important parameters in the safe, successful scale-up of chemical processes. Information regarding the evolution of noncondensable gas is used to (1) ensure the gas can be vented from the reactor without overpressurization, (2) calculate the concentration o... | 10.1021/op800194g | 0 |
Mechanism and Processing Parameters Affecting the Formation of Methyl Methanesulfonate from Methanol and Methanesulfonic Acid: An Illustrative Example for Sulfonate Ester Impurity Formation | Sulfonate salts offer useful modification of physicochemical properties of active pharmaceutical ingredients (APIs) containing basic groups, but there are regulatory concerns over the presence of sulfonate esters as potential genotoxic impurities (PGIs). Whilst sulfonate esters could theoretically result from interacti... | 10.1021/op800192a | 0 |
High Conversion, Solvent Free, Continuous Synthesis of Imidazolium Ionic Liquids In Spinning Tube-in-Tube Reactors | A spinning tube-in-tube (STT) reactor has been used for the accelerated solvent-free synthesis of a number of 1-methylimidazole-based ionic liquids with excellent conversions (>99%) and high throughputs (tens of kg/day). | 10.1021/op8001917 | 0 |
Calcium Pantothenate. Part 3. Process for the Biologically Active Enantiomer of the Same via Selective Crystallization and Racemization | Optically pure calcium ( R )-pantothenate has been obtained from the racemic compound via direct fractional crystallization of the single enantiomer. Efficient racemization of the biologically inactive calcium ( S )-pantothenate without its decomposition to pantolactone has been developed, resulting in a simple, comple... | 10.1021/op800189g | 0 |
Continuous Processes | ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTContinuous ProcessesTrevor LairdCite this: Org. Process Res. Dev. 2008, 12, 5, 904Publication Date (Web):August 12, 2008Publication History Received1 August 2008Published online12 August 2008Published inissue 19 September 2008https://doi.org/10.1021/op800183cCopyright © 200... | 10.1021/op800183c | 0 |
Isolation, Synthesis, and Characterization of Impurities and Degradants from the Clofarabine Process | The identification of clofarabine process impurities and their subsequent isolation, synthesis, and characterization is described. Two isomeric process impurities resulting from N 6 -attachment of a fluoroarabinose to clofarabine were found. Clofarabine’s base degradation products, which were different from the process... | 10.1021/op800182x | 1 |
A Large Scale Process for the Preparation of Thymitaq | The large scale manufacturing of the anticancer agent 2-amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3 H -quinazolin-4-one dihydrochloride (thymitaq) from 6-bromo-5-methylanthranilic acid is described. The chemical route consists of two chemical steps: formation of a bromoquinazolinone and a copper-mediated Ullman-like coup... | 10.1021/op800181e | 1 |
A Catalyzed and Highly Selective Ester Reduction in the Synthesis of an<i>N</i>-Acylpyrrolidine: Safe Design through Reaction Calorimetry and Modeling | The asymmetric synthesis of an N -acylpyrrolidine for HCV inhibition features a unique and highly selective reduction of an ester to an alcohol with NaBH 4 −MeOH catalyzed by NaB(OAc) 3 H. This reagent combination provides excellent chemoselectivity while avoiding formation of the thermodynamically favored but undesire... | 10.1021/op8001799 | 1 |
Large-Scale Asymmetric Synthesis of the 3,6,7,8-Tetrahydrochromeno[7,8-<i>d</i>]imidazole BYK 405879: A Promising Candidate for the Treatment of Acid-Related Diseases | A process for the synthesis of the potassium-competitive acid blocker BYK 405879 ( 8 ) was established based on the approach used in medicinal chemistry (asymmetric hydrogenation of prochiral ketone 15 and Mitsunobu cyclization of the resulting alcohol 34 ). Several critical reaction steps were optimized. The synthesis... | 10.1021/op800177x | 1 |
A Rapid, Large-Scale Synthesis of a Potent Cholecystokinin (CCK) 1R Receptor Agonist | The development of a scalable synthesis of a potent cholecystokinin (CCK) 1R receptor agonist is described. The focus on a rapid short-term delivery rather than longer-term development allowed for the preparation of multihundred gram quantities to support aggressive timelines and evaluate safety and pharmacological stu... | 10.1021/op800176e | 1 |
An Improved Synthesis of Antiulcerative Drug: Tenatoprazole | An efficient, cost-effective and multikilogram-scale process for the synthesis of tenatoprazole 1, an antiulcerative drug, is described. The key steps in this synthesis involve the coupling of 2-mercapto-5-methoxyimidazo[4,5- b ]pyridine 2 with 2-chloromethyl-4-methoxy-3,5-dimethyl pyridine hydrochloride 3 to yield 4 a... | 10.1021/op800173u | 1 |
Mild and Selective Synthesis of an Aryl Boronic Ester by Equilibration of Mixtures of Boronic and Borinic Acid Derivatives | Quenching of aryl Grignard reagents with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (isopropyl pinacol borate) under noncryogenic conditions can lead to mixtures of the corresponding boronic ester along with, generally undesired, borinic acid derivatives. We have found that in certain cases gentle heating of ... | 10.1021/op800169s | 1 |
Pharmaceutical Manufacturing Handbook . Edited by Shayne Cox Gad . Wiley-Interscience . 2008 . 1370 + xiii pp £103. ISBN 978-0-470-25958-0 . | ADVERTISEMENT RETURN TO ISSUEPREVArticleCite this: Org. Process Res. Dev. 2008, 12, 5, 1016–1017Publication Date (Web):August 22, 2008Publication History Received21 July 2008Published online22 August 2008Published inissue 19 September 2008https://doi.org/10.1021/op800168uCopyright © 2008 American Chemical SocietyReques... | 10.1021/op800168u | 0 |
An Improved and Scalable Process for Celecoxib: A Selective Cyclooxygenase-2 Inhibitor | An improved, scalable and commercially viable process is developed for an active pharmaceutical ingredient, celecoxib. | 10.1021/op800158w | 1 |
Global Green Chemistry Metrics Analysis Algorithm and Spreadsheets: Evaluation of the Material Efficiency Performances of Synthesis Plans for Oseltamivir Phosphate (Tamiflu) as a Test Case | This work discloses an easy-to-use algorithm to evaluate the global material efficiency performance of any kind of synthesis plan regardless of complexity to a given target molecule according to green metrics criteria. The algorithm is robust and has been adapted to Excel spreadsheets for rapid calculation and graphing... | 10.1021/op800157z | 1 |
Practical Synthesis of a HIV Integrase Inhibitor | A practical and efficient synthesis of the potent HIV integrase inhibitor 1 is described. Starting from readily available 3,4-dihydro-2 H -pyran, the six-step synthesis features a through process without purification of any of the intermediates until the isolation of crystalline intermediate 7 . After deprotection and ... | 10.1021/op800153y | 1 |
Optimization of Solvent Chasing in API Manufacturing Process: Constant Volume Distillation | Solvent exchange by distillation is a common unit operation in active pharmaceutical ingredient (API) manufacturing processes. Either a stepwise solvent displacement mode or a constant volume solvent displacement mode can be used to carry out the solvent exchange. The constant volume mode can be more efficient as the c... | 10.1021/op800152n | 0 |
Use of a Fiber-Optic Turbidity Probe to Monitor and Control Commercial-Scale Unseeded Batch Crystallizations | This article describes how a fiber-optic turbidity probe may be used as an inferential sensor to aid in the control of commercial-scale batch crystallizations. The discussion focuses on several unseeded crystallization examples involving cooling or cooling plus addition of antisolvent. In a typical control scheme, the ... | 10.1021/op8001504 | 0 |
Enzymatic Preparation of a<scp>d</scp>-Amino Acid from a Racemic Amino Acid or Keto Acid | The d -amino acid ( R )-2-amino-3-(7-methyl-1 H -indazol-5-yl)propanoic acid ( 3 ) is a key intermediate needed for synthesis of a drug candidate compound. Enzymatic routes to 3 were explored. d -Amino acid 3 was prepared in 68% isolated yield with >99% ee from racemic amino acid 1 using l -amino acid deaminase from Pr... | 10.1021/op800149q | 0 |
Synthesis of the NK1 Receptor Antagonist GW597599. Part 1: Development of a Scalable Route to a Key Chirally Pure Arylpiperazine | GW597599 1 is a novel NK-1 antagonist currently under investigation for the treatment of CNS disorders and emesis. The initial synthetic route devised from the medicinal chemistry one, used several hazardous reagents, gave low yields, and produced high levels of wastes. By targeted process of research and development, ... | 10.1021/op800146d | 1 |
A Practical Synthesis of a Chiral Analogue of FTY720 | A practical synthesis of 1 involving a catalytic enantioselective construction of the quaternary carbon from imine 10 (derived from 13 and 14 ) and alkyl iodide 5 using Maruoka’s chiral catalyst 11 is described. This asymmetric alkylation followed by hydrolysis to amino acid 9 was accomplished in good yield with high c... | 10.1021/op800144h | 1 |
A Practical Synthesis of a Diazepinylbenzoic Acid, a Retinoid X Receptor Antagonist | An optimized convergent synthetic route for the preparation of retinoid X receptor (RXR) antagonist ( 1 ) in an overall yield of 35% is described. The formation of the benzodiazepine was achieved in 85% yield using POCl 3 in toluene. The drug substance 14 was obtained by treatment of aryl bromide with vinyl butyl ether... | 10.1021/op800142b | 1 |
An Improved and Scalable Process for Zafirlukast: An Asthma Drug | An improved and scalable process for the large-scale production of zafirlukast (Accolate), an important drug for asthma, is discussed along with impurity and scale-up-related issues. | 10.1021/op800137b | 1 |
Green Chemistry with a Novel 5.8-GHz Microwave Apparatus. Prompt One-Pot Solvent-Free Synthesis of a Major Ionic Liquid: The 1-Butyl-3-methylimidazolium Tetrafluoroborate System | This article reports for the first time the rapid one-pot solvent-free synthesis of 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF 4 ), a major ionic liquid, in good yields (87%) after 30 min of microwave irradiation with microwaves at a frequency of 5.8 GHz in a batch-mode reactor. By contrast, the yields of ... | 10.1021/op800135t | 0 |
Continuous Reaction/Crystallization Process for Production of a Hazardous Intermediate | Perchloric acid appears unique in its ability to catalyze stereoselective trans-acetalizations of steroids. However, the requisite recipes result in an intermediate phase enriched in perchlorate and organic material with the potential for catastrophic decomposition. We present here a discussion of the relevant chemistr... | 10.1021/op800128g | 0 |
Microreactor Technology and Continuous Processes in the Fine Chemical and Pharmaceutical Industry: Is the Revolution Underway? | Microreactors have shown their ability to improve chemical processes and routes; however, their integration into chemical production processes depends not only on technical advances. Cost issues and productions logistics play a crucial role, too, and are highlighted with two different case studies. Economical drivers f... | 10.1021/op8001273 | 0 |
Scale-Up of Microwave-Promoted Reactions to the Multigram Level Using a Sealed-Vessel Microwave Apparatus | A range of synthetic transformations have been scaled up successfully using a sealed-vessel multimode microwave unit. These include metal-catalyzed couplings, synthesis of heterocycles, reactions under an atmosphere of reactive gas and two-step one-pot procedures. Also, observations have been made along the way that ar... | 10.1021/op8001239 | 0 |
Development of a Synthesis For a Long-Term Oxazolidinone Antibacterial | Linezolid, compound 1, is a member of the oxazolidinone class of antibacterials and has had recent clinical interest due to its potential use as a long-term treatment for bacterial infection. Detailed herein are improvements to the original synthesis to enable phase I clinical trials. Of particular interest is the prep... | 10.1021/op8001195 | 1 |
The Synthesis of (<i>S</i>)-5-Fluoro-1-(2-fluorophenyl)-3-(piperidin-3-ylmethoxy)-1<i>H</i>-indazole, a Norepinephrine/Serotonin Reuptake Inhibitor for the Treatment of Fibromyalgia | Compound 1, a norepinephrine/serotonin reuptake inhibitor (NSRI) for the treatment of fibromyalgia, has been synthesized in optically pure form in six linear steps and 48% overall yield with no chromatography. This route features a novel and efficient intramolecular cyclization to generate the indazolone core via a dia... | 10.1021/op800113s | 1 |
A Practical, Efficient Synthesis of 1,1-Dioxo-hexahydro-1λ<sup>6</sup>-thiopyran-4-carbaldehyde | A practical, efficient, and scalable procedure for the preparation of 1,1-dioxo-hexahydro-1λ 6 -thiopyran-4-carbaldehyde is reported. Synthesis of this aldehyde was complicated by high aqueous solubility of the product and the intermediates. The isolation and purification of the aldehyde was accomplished by conversion ... | 10.1021/op800108s | 1 |
Microscale HPLC Predicts Preparative Performance at Millionfold Scale | The use of microscale HPLC for piloting the large-scale preparative chromatographic resolution of the enantiomers of a chiral pharmaceutical intermediate is reported with an example of a millionfold scale-up from a 300 μm i.d. column to a 30 cm i.d column. Performance and productivity at scale are accurately predicted ... | 10.1021/op800107u | 0 |
Improved Process for the Preparation of 6-Chloro-5-(2-chloroethyl)oxindole | The current process for ziprasidone involves preparation and isolation of the key intermediate 6-chloro-5-(2-chloroethyl)oxindole. An improved process for the synthesis of this intermediate is reported here. The new process involves use of a novel Lewis acid-mediated selective deoxygenation of the precursor ketone with... | 10.1021/op800105j | 1 |
An Improved Preparation Process for Gemcitabine | An improved, cost-effective, and convenient process, using cinnamoyl as hydroxyl protective group and tosyl as the leaving group for gemcitabine ( 1 ) is described. The overall yield obtained from this newly developed process is around 10%, including two stereospecific crystallizations, and the quality of the product c... | 10.1021/op800104r | 1 |
AMD070, a CXCR4 Chemokine Receptor Antagonist: Practical Large-Scale Laboratory Synthesis | An efficient and convergent four-step synthetic route to the CXCR4 chemokine receptor antagonist AMD070 ( 1 ) has been developed which employs only a single chromatographic step in the entire sequence. Novel reductive amination methods have been developed for the coupling of 2 and 3 in which a dehydrative imine formati... | 10.1021/op8000993 | 1 |
Development of a New Variant of the Migita Reaction for Carbon−Sulfur Bond Formation Used in the Manufacture of Tetrahydro-4-[3-[4-(2-methyl-1<i>H</i>-imidazol-1-yl)phenyl]thio]phenyl-2<i>H</i>-pyran-4-carboxamide | Palladium-catalyzed carbon−sulfur bond formation using modified Migita reaction conditions was explored and applied to the synthesis of a former antiasthma drug candidate, tetrahydro-4-[3-[4-(2-methyl-1 H -imidazol-1-yl)phenyl]thio]phenyl-2 H -pyran-4-carboxamide ( 5 ). The reaction was developed into a general method ... | 10.1021/op800098a | 1 |
Preparation of a HMG-CoA Reductase Inhibitor via an Optimized Imidazole-Forming Condensation Reaction | Development work toward an enabling synthesis of preparative scale batches of an imidazole-based HMG-CoA reductase inhibitor is described. The desired target was synthesized in 16% yield over 7 steps, highlighted by an imidazole-forming condensation reaction in which the yield was improved from 20% to >70% via modifica... | 10.1021/op800092e | 1 |
Development of a Suitable Process for the Preparation of a TNF-α Converting Enzyme Inhibitor, WAY-281418 | A suitable process for the preparation of kilogram quantities of a TNF-α converting enzyme (TACE) inhibitor (WAY-281418) was developed using isatin 13 as starting material and an efficient coupling step for the formation of sulfonamide 8 in a 15% overall yield. Process preparation of (+)-(1 S,2 R )-2-aminocyclopentane-... | 10.1021/op800090s | 1 |
Development and Scale-Up of Three Consecutive Continuous Reactions for Production of 6-Hydroxybuspirone | This paper describes the development of a continuous, high yielding, and scalable enolization, oxidation, and quench process for the hydroxylation of the azapirone psychtropic agent buspirone to afford 6-hydroxybuspirone (6-hydroxy-8-[4-(4-pyrimidin-2-yl-piperazin-1-yl)-butyl]-8-aza-spiro[4.5]decane-7,9-dione). Two fee... | 10.1021/op800079u | 0 |
Development of a Kilogram-Scale Synthesis of <i>cis</i>-LC15-0133 Tartrate, a Potent Dipeptidyl Peptidase IV Inhibitor | (4 S )- N -Boc-4-fluoro- l -proline methyl ester ( 4 ) was prepared from the following sequence of reactions: esterification of trans -4-hydroxy- l -proline ( 2 ), Boc protection, and fluorination by DAST. Reaction of 4 with lithiated oxadiazole provided oxadiazolyl ketone 7 . Deprotection of the Boc group of 7 and sub... | 10.1021/op800076r | 1 |
Development of a Pilot-Plant Process for a Nevirapine Analogue HIV NNRT Inhibitor | The pilot-plant synthesis of nevirapine analogue 1 is described. The compound was prepared in eight steps from substituted pyridine raw materials and 4-hydroxyquinoline. The key transformation involves a novel one-pot conversion of an arylhalide to arylacetic acid under palladium catalysis, followed by regioselective r... | 10.1021/op8000756 | 1 |
A Scalable Synthesis of MN-447, an Antagonist for Integrins α<sub>v</sub>β<sub>3</sub> and α<sub>IIb</sub>β<sub>3</sub> | (2 S )-Benzenesulfonylamino-3-[3-methoxy-4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]propionic acid, MN-447, is a potent antagonist of the integrins α v β 3 and α IIb β 3 . Herein, we report a novel synthetic protocol that produces MN-447 in an overall yield of 45%. This protocol, when compa... | 10.1021/op800073z | 1 |
Chemical Development of NBI-75043. Use of a Flow Reactor to Circumvent a Batch-Limited Metal−Halogen Exchange Reaction | The discovery route and subsequent scale-up routes for NBI-75043 are presented. When traditional batch chemistry was found to limit the scale of a key reaction, a flow reactor was designed and optimized to provide an alternate method of production. | 10.1021/op800071m | 1 |
Identification of Critical Process Impurities and Their Impact on Process Research and Development | The identification of low-level critical process impurities and degradants encountered during pharmaceutical development is crucial to the process development, but can often be challenging and can negatively impact the timeline of the developmental program. This is demonstrated during the early stage of process researc... | 10.1021/op800067v | 1 |
An Improved and Efficient Process for the Production of Donepezil Hydrochloride: Substitution of Sodium Hydroxide for <i>n</i>-Butyl Lithium via Phase Transfer Catalysis | A simple, efficient and highly economic process for the production of donepezil hydrochloride ( 1 ), an anti-Alzheimer drug is reported. The process relies upon improved and large-scale synthesis of a key intermediate: 1-benzylpiperidine-4-carboxaldehyde ( 2 ), and the introduction of operationally simple chemistry at ... | 10.1021/op800066m | 1 |
A Convergent Process for the Preparation of Adamantane 11-β-HSD-1 Inhibitors | A convergent, scalable process was developed for the synthesis of adamantane 11-β-hydroxysteroid dehydrogenase-1 inhibitors E -4-(2-methyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propionylamino)adamantane-1-carboxylic acid ( 1 ) and E -4-(2-methyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propio... | 10.1021/op800065q | 1 |
Optimization and Scale-Up of a Suzuki−Miyaura Coupling Reaction: Development of an Efficient Palladium Removal Technique | A ligand−solvent−base screen was performed on a Suzuki−Miyaura coupling reaction, and the screening data, followed by a set of focused experiments, helped to optimize reaction conditions. Further work was carried out that centered on reducing the level of residual palladium in the isolated product. Treatment of the rea... | 10.1021/op800064y | 0 |
Process Research and Scale-up of a Commercialisable Route to Maraviroc (UK-427,857), a CCR-5 Receptor Antagonist | A six-step synthetic route to the CCR-5 receptor antagonist, Maraviroc (UK-427,857) ( 1 ) has been developed and demonstrated at scale in a pilot plant. The route has supported four Pilot-Plant campaigns and has produced multikilogram quantities of 1 . Continued development of the synthetic route has resulted in a robu... | 10.1021/op800062d | 1 |
Development of a Bulk Enabling Route to Maraviroc (UK-427,857), a CCR-5 Receptor Antagonist | A bulk enabling synthesis of the CCR-5 receptor antagonist, Maraviroc (UK-427,857) ( 1 ), is presented. Synthesis of the three key fragments, β-amino ester 3, 4,4-difluorohexanecarboxylic acid ( 2 ), and 1,3,4-triazole-substituted tropane fragment 4 are described. Coupling strategies for these fragments are discussed a... | 10.1021/op8000614 | 1 |
Development and Manufacture of the Inosine Monophosphate Dehydrogenase Inhibitor Merimepodib, VX-497 | A process for the manufacture of merimepodib (VX-497), an inosine monophosphate dehydrogenase (IMPDH) inhibitor, has been developed and efficiently scaled to produce clinical supply. The process comprises five steps, incorporating simple and robust chemistry that ultimately yielded 96.5 kg with a purity of 100% (by HPL... | 10.1021/op800060h | 1 |
Scale-Up Synthesis of Swainsonine: A Potent α-Mannosidase II Inhibitor | The large-scale synthesis of Swainsonine 1, a potent α-mannosidase II inhibitor, has been achieved with several improvements. The key modifications were (a) performing the Wittig olefination under mild conditions and isolation of the product 4 with modified workup conditions, (b) introduction of the azido group on a la... | 10.1021/op800059y | 1 |
Solving a Scale-Up Problem in the <i>O</i>-Alkylation of Isovanillin Under Phase-Transfer Catalysis Conditions | The alkylation of isovanillin with cyclopentyl bromide in the presence of potassium carbonate and a phase-transfer catalyst in THF is investigated. Successful completion of the reaction depends on the particle size of potassium carbonate. | 10.1021/op800058n | 0 |
The Swern Oxidation: Development of a High-Temperature Semicontinuous Process | The Swern oxidation has been widely exploited for the oxidation of alcohols to their respective carbonyl compounds. The cryogenic operating conditions (<−60 °C) employed for the Swern oxidation, however, limit its utility for scale-up operations. Process development efforts on the Swern oxidation have demonstrated that... | 10.1021/op800057d | 0 |
Microwaves in Organic Synthesis, Volumes 1 and 2. Edited by André Loupy. Wiley-VCH, Verlag GmbH and Co. KGaA: Weinheim. 2006. $375. Vol 1, 517 pp, Vol 2, 466 pp. Hard back. ISBN 978-3-527-31452-2 . | ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTJohn KnightView Author Information Scientific Update LLP, Maycroft Place, Stone Cross, Mayfield TN20 6EW, U.K.Cite this: Org. Process Res. Dev. 2008, 12, 3, 545–546Publication Date (Web):April 5, 2008Publication History Received11 March 2008Accepted11 March 2008Published onli... | 10.1021/op8000564 | 0 |
Commercialization and Late-Stage Development of a Semisynthetic Antifungal API: Anidulafungin/<scp>d</scp>-Fructose (Eraxis) | Many years ago anidulafungin 1 was identified as a potentially useful medicine for the treatment of fungal infections. Its chemical and physical properties as a relatively high molecular weight semisynthetic derived from echinocandin B proved to be a significant hurdle to its final presentation as a useful medicine. It... | 10.1021/op800055h | 0 |
Continuous Organic Synthesis in a Spinning Tube-in-Tube Reactor: TEMPO-Catalyzed Oxidation of Alcohols by Hypochlorite | Continuous production of aldehydes in high yields (≥90%) can be accomplished by feeding aqueous (sodium hypochlorite/sodium bicarbonate, pH 8.5) and organic (TEMPO/tetrabutylammonium bromide/primary alcohol/toluene or CH 2 Cl 2 ) solutions through the inlets of a spinning tube-in-tube reactor (STT reactor manufactured ... | 10.1021/op800051t | 0 |
A Concise Synthesis of Racemic 1-(6,7-Dimethoxy-2-naphthyl)-1-(1<i>H</i>-imidazol-4-yl)-2-methylpropan-1-ol for a Potent C<sub>17</sub>,<sub>20</sub>-Lyase Inhibitor | ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionA Concise Synthesis of Racemic 1-(6,7-Dimethoxy-2-naphthyl)-1-(1H-imidazol-4-yl)-2-methylpropan-1-ol for a Potent C17,20-Lyase InhibitorJun-ichi Kawakami, Kazuhiro Kimura, and Masayoshi YamaokaCite this: Org. Process Res.... | 10.1021/op800050k | 0 |
The First 200-L Scale Asymmetric Baeyer−Villiger Oxidation Using a Whole-Cell Biocatalyst | Biocatalytic Baeyer−Villiger oxidations using oxygen as an environmentally friendly oxidant in aqueous media have been shown to proceed with excellent stereo- and enantioselectivity for a large number of substrates at laboratory scale. These are good starting boundary conditions for process research and development com... | 10.1021/op800046t | 0 |
A High-Throughput Impurity-Free Process for Gatifloxacin | An improved process to obtain gatifloxacin ( 1 ) through use of boron chelate intermediates has been developed. The methodology involves an initial activation step which accelerates the formation of the first chelate under low-temperature conditions and prevents demethylation of the starting material. To increase the o... | 10.1021/op800042a | 1 |
Ligandless Heck Coupling between a Halogenated Aniline and Acrylonitrile Catalyzed by Pd/C: Development and Optimization of an Industrial-Scale Heck Process for the Production of a Pharmaceutical Intermediate | The aniline derivative 3 is a key building block of rilpivirine (TMC278) 2, a new potent NNRTI compound under clinical evaluation. In this paper we describe the development of a new synthesis of 3 based on a Heck coupling between a halogenated aniline and acrylonitrile using low loading of Pd/C (0.5 mol %) as catalyst.... | 10.1021/op8000383 | 0 |
Kepner-Tregoe Decision Analysis as a Tool To Aid Route Selection. Part 3. Application to a Back-Up Series of Compounds in the PDK Project | Kepner-Tregoe Decision Analysis was used to rank 22 potential routes to a back-up series of compounds in the PDK project. The ten highest scoring routes were evaluated practically, affording four new synthetic sequences for preparing the target compounds. | 10.1021/op8000355 | 1 |
Kepner-Tregoe Decision Analysis as a Tool to Aid Route Selection. Part 1 | Kepner-Tregoe Decision Analysis is a logic-based tool that has been used by AstraZeneca to prioritise the investigation of alternative routes to drug candidates. This paper describes how the tool can be used in route selection work, with subsequent papers discussing application to AstraZeneca projects. | 10.1021/op8000349 | 0 |
Kepner-Tregoe Decision Analysis as a Tool To Aid Route Selection. Part 2. Application to AZD7545, a PDK Inhibitor | Kepner-Tregoe decision analysis was formally used as an aid to route selection, as outlined in the preceding paper. Over 40 paper routes were assessed for suitability for both immediate and longer term manufacture of AZD7545, a compound in the early stages of development. Eight routes were then investigated in full in ... | 10.1021/op800033c | 1 |
An Integrated Microreactor for the Multicomponent Synthesis of α-Aminonitriles<sup>1</sup> | Initial steps have been taken to develop an integrated microreactor, capable of performing multicomponent reactions consisting of both solution phase and heterogeneously catalyzed steps. Using the multicomponent Strecker reaction as a model, five α-aminonitriles were synthesized in excellent yields (>99.5%) and analyti... | 10.1021/op800025p | 1 |
Using Potassium Carbonate to Scavenge Hydrogen Fluoride: A Scale-Up Process for Quantitative Production of (1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-(oxo-κO)-3-quinolinecarboxylato-κO3)difluoro−Boron | Hydrogen fluoride is a byproduct from the reaction of treating 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( 4, 1.0 equiv) with borontrifluoride etherate (1.15−1.35 equiv) in refluxing THF solution. Scavenging the hydrogen fluoride evolved with potassium carbonate (1.15 equiv, 325 ... | 10.1021/op8000228 | 0 |
Development of a Mild and Robust Method for Large-Scale Palladium-Catalysed Cyanation of Aryl Bromides: Importance of the Order of Addition | A mild and robust method for the large-scale palladium-catalysed cyanation of aryl bromides has been developed. The reaction is sensitive to cyanide poisoning of the catalyst, and it was found that the order of adding the reagents had a strong impact on the performance of the reaction. Addition of the cyanide source to... | 10.1021/op800020r | 0 |
UnyLinker: An Efficient and Scaleable Synthesis of Oligonucleotides Utilizing a Universal Linker Molecule: A Novel Approach To Enhance the Purity of Drugs | A novel universal linker (UnyLinker) molecule which has a conformationally rigid and chemically stable bridge head ring oxygen atom carrying a conventional 4,4′-dimethoxytrityl (DMT) and succinyl groups locked in a syn orientation has been developed to carry out oligonucleotide synthesis efficiently and smoothly. The g... | 10.1021/op8000178 | 1 |
Optimization and Scale-up of a Pd-Catalyzed Aromatic C−N Bond Formation: A Key Step in the Synthesis of a Novel 5-HT<sub>1B</sub> Receptor Antagonist | Searching for the best synthetic route for a given target molecule is a complex task and, by the same token, a key deliverable from a process R&D department. In this vein the challenge for our group was to identify a sustainable manufacturing process for a chiral compound, AR-A2, to be developed for the treatment of ce... | 10.1021/op8000146 | 1 |
Particle Shape Characterisation via Image Analysis: from Laboratory Studies to In-process Measurements Using an in Situ Particle Viewer System | A recent evaluation of a new in situ particle viewer (ISPV) system for the examination of particle shape and its subsequent development during crystal growth is presented. Precharacterization studies using conventional and hot-stage microscopy reveal that the ISPV probe system together with a commercial image analysis ... | 10.1021/op800011v | 0 |
Development of One-Pot Synthesis of New Antiarthritic Drug Candidate S-2474 with High <i>E</i>-Selectivity | A one-pot synthesis of S-2474 was developed to overcome the problems of a large number of steps, low stereoselectivity, low yield, a large amount of waste, and severe reaction conditions. Aldol-type condensation of 3,5-di- tert -butyl-4-hydroxybenzaldehyde and N -ethyl-γ-sultam was carried out with LDA and then quenche... | 10.1021/op800008w | 1 |
Concise Synthesis of Vinylheterocycles through β-Elimination under Solventless Phase Transfer Catalysis Conditions | Various vinylheterocycles compounds have been prepared in excellent yields through β-elimination of the corresponding sulfonate esters with 50% aq NaOH under phase transfer catalysis conditions without organic solvent. The new approach provides an economic and environmentally friendly solution to removal of hazardous b... | 10.1021/op800001d | 0 |
Large-Scale Synthesis of the Glucosylceramide Synthase Inhibitor <i>N</i>-[5-(Adamantan-1-yl-methoxy)-pentyl]-1-deoxynojirimycin | A synthetic route for the preparation of glucosylceramide synthase inhibitor N -[5-(adamantan-1-yl-methoxy)-pentyl]-1-deoxynojirimycin methanesulfonic acid salt (AMP-DNM) has been developed. Herein we report the development and optimization of this synthetic route from its initial version in an academic research labora... | 10.1021/op700295x | 1 |
Industrial Applications of Online Monitoring of Drying Processes of Drug Substances Using NIR | Drying is an important part of manufacturing processes in the chemical and pharmaceutical industry. The product quality often depends on the drying conditions and efficiency. Moreover, this unit operation frequently represents the bottleneck of the whole process. Therefore, online monitoring of the drying operation can... | 10.1021/op700293p | 0 |
Chemical Reactions with a Novel 5.8-GHz Microwave Apparatus. 1. Characterization of Properties of Common Solvents and Application in a Diels–Alder Organic Synthesis | Microwave radiation emitted at a frequency of 5.8 GHz in a novel fabricated apparatus is herein proposed for carrying out organic syntheses. Temperature profiles (rates of increase of temperature and superheating) and dielectric parameters are reported for water and 22 common organic solvents. For comparison, solvent p... | 10.1021/op700292s | 0 |
Microreactor Technology: Continuous Synthesis of 1<i>H</i>-Isochromeno[3,4-<i>d</i>]imidazol-5-ones | A synthetic method was evaluated to form 1 H -isochromeno[3,4- d ]imidazol-5-ones via ring closure starting from 3-amino-4-(arylamino)-1 H -isochromen-1-ones. The method was implemented and optimized in a microreactor environment. It was possible to synthesize these compounds in a continuous mode with an output up to 2... | 10.1021/op700289e | 0 |
Development of a Robust Ring-Closing Metathesis Reaction in the Synthesis of SB-462795, a Cathepsin K Inhibitor | The development of a robust and high-yielding ring-closing metathesis (RCM) reaction and its demonstration on multikilogram scale are described. A detailed understanding of the impact of impurities on the RCM reaction was achieved using a variety of chemical and statistical methods. Specifically, individual impurities ... | 10.1021/op700288p | 1 |
A Practical and Improved Copper-Catalyzed Synthesis of the Central Intermediate of Diafenthiuron and Related Products | A bioinspired Cu(I)/ N -methylimidazole catalyst system is used for the synthesis of the diaryl ether part of diafenthiuron, a widely used insecticide. The convenient protocol proceeds smoothly with high selectivity and quantitative yield. Applying the optimized procedure various diaryl ether analogs are synthesized in... | 10.1021/op700287s | 0 |
Synthesis of Enantiopure Fmoc-α-Methylvaline | An efficient synthesis of enantiopure Fmoc-α-methylvaline has been developed. The racemate was prepared in two steps from 3-methyl-2-butanone and was resolved using a chiral amine, ( S )-1,2,3,4-tetrahydro-1-naphthylamine to give the desired, enantiopure S -isomer in 23% overall yield. | 10.1021/op700286u | 1 |
Streamlined Synthesis of the Bippyphos Family of Ligands and Cross-Coupling Applications | We describe the efficient preparation of Bippyphos, 1 . The key precursor to Bippyphos, 5, was prepared via a one-pot bromination of diketone 2 followed by alkylation with pyrazole and condensation with phenylhydrazine. Lithiation of 5 and trapping with di- tert -butylchlorophosphine afforded Bippyphos, 1 . Using this ... | 10.1021/op7002858 | 1 |
Process Development for the Sulfonamide Herbicide Pyroxsulam | The development of a manufacturing process for the initial commercial production of pyroxsulam sulfonamide herbicide is described. The process encompasses seven reaction steps, and includes a new route to 4-(trifluoromethyl)pyridines, a scaleable method of lithiating a pyridine intermediate, and a sulfilimine-catalyzed... | 10.1021/op700281w | 1 |
Development of a Scalable Synthetic Route to GSK369796 (<i>N-tert</i>-Butyl Isoquine), a Novel 4-Aminoquinoline Antimalarial Drug | An improved process to the novel 4-aminoquinoline antimalarial GSK369796 is described. Although the initial synthetic route consisted of only two steps from readily available starting materials, the product isolated via the key Mannich reaction was hampered by both low yields and low purity. In addition to instability ... | 10.1021/op7002776 | 1 |
A Facile Total Synthesis of Imatinib Base and Its Analogues | Imatinib and its analogues were successfully synthesized by an improved method in 19.5– 46.2% total yield of six main steps. Pyrimidinyl amine was prepared by the reaction of enaminone and guanidine nitrate without the use of a toxic cyanamide. N -(2-Methyl-5-nitrophenyl)-4-(pyridin-3-yl) pyrimidin-2-amine as a key int... | 10.1021/op700270n | 1 |
Practical Synthesis of a Peptide Deformylase (PDF) Inhibitor | A practical chromatography-free synthesis of an N -formylated hydroxylamine peptide deformylase inhibitor LCD320 is described. A diastereoselective Michael reaction of (4 S )-3-[2-(cyclobutylmethyl)-1-oxo-2-propenyl]-4-(phenylmethyl)-2-oxazolidinone with O -benzyl hydroxylamine was used to establish the key stereogenic... | 10.1021/op700265n | 1 |
Practical Asymmetric Synthesis of Trifluoromethyl-Containing Aminoester Using a Modified Davis Protocol | Practical synthesis of aminoester 1 starting from 1,1,1-trifluoro-3-iodopropane is presented. Use of Ti(O i -Pr) 4 as a Lewis acid for condensation of intermediate aldehyde 8 with ( S )-(+)- p -toluenesulfinamide was found to be critical. Conditions for a reproducible and high-yielding Wittig reaction of aldehyde hydra... | 10.1021/op700259d | 1 |
Route Scouting and Process Development of Lu AA26778 | Route scouting and process development for the synthesis of ( S )-2-({3-[( S )-5-chloro-1-(4-chloro-phenyl)indan-1-yl]propyl}methylamino)propionic acid, Lu AA26778, are described. The strategy is based on a short synthesis and SMB resolution of a key chiral intermediate for the introduction of one of the two stereocent... | 10.1021/op7002584 | 1 |
Reduction of Ethyl Benzoylacetate and Selective Protection of 2-(3-Hydroxy-1-phenylpropyl)-4-methylphenol: A New and Facile Synthesis of Tolterodine | A new and facile synthesis of tolterodine using ethyl benzoylacetate as the starting material was developed. Reduction using sodium borohydride in methanol followed by Friedel–Crafts alkylation utilizing FeCl<sub>3</sub>·6H<sub>2</sub>O as catalyst lead to the known 2-(3-hydroxy-1-phenylpropyl)-... | 10.1021/op7002562 | 0 |
Preparative Asymmetric Synthesis of 4,4-Dimethoxytetrahydro-2H-pyran-3-ol with a Ketone Reductase and in Situ Cofactor Recycling using Glucose Dehydrogenase | The asymmetric enzymatic ketone reduction of 4,4-dimethoxytetrahydro-2H-pyran-3-one provided the ( R )-α-hydroxyketal, an important chiral precursor for a pharmaceutical intermediate, with high enantioselectivity (>99% ee). An economical process including in situ NADPH-cofactor regeneration using glucose dehydrogenase ... | 10.1021/op700255b | 0 |
Synthesis of Tetracyclic Heterocompounds as Selective Estrogen Receptor Modulators. Part 2. Process Improvement for Scale-Up of 2,5,8-Substituted 11,12-Dihydro-5<i>H</i>-6,13-dioxabenzo[3,4]cyclohepta-[1,2-<i>a</i>]naphthalene Derivatives | ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionSynthesis of Tetracyclic Heterocompounds as Selective Estrogen Receptor Modulators. Part 2. Process Improvement for Scale-Up of 2,5,8-Substituted 11,12-Dihydro-5H-6,13-dioxabenzo[3,4]cyclohepta-[1,2-a]naphthalene Derivati... | 10.1021/op700254f | 0 |
Chemoenzymatic Deracemization of Chiral Secondary Alcohols: Process Optimization for Production of (<i>R</i>)-1-Indanol and (<i>R</i>)-1-Phenylethanol | A process for preparing chiral secondary alcohols by chemoenzymatic deracemization was optimized. First, the transesterification process of 1-indanol and 1-phenylethanol with vinyl acetate as the acyl donor was optimized using lipase Novozym 435 as biocatalyst. The effects of acyl donors, substrate concentration, solve... | 10.1021/op700253t | 0 |
A Highly Practical and General Route for α-Arylations of Ketones Using Bis-phosphinoferrocene-Based Palladium Catalysts | Well-defined, air-stable Pd complexes of bis-phosphinoferrocene family of catalysts have been studied in the arylation of various ketones with aryl chlorides and aryl bromides. Bis(di- tert -butyl)phosphinoferrocene (DtBPF)-based catalysts such as (DtBPF)PdCl 2 and (DtBPF)PdBr 2 have been identified as two of the most ... | 10.1021/op7002503 | 0 |
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