title string | abstract string | doi string | has_route int64 |
|---|---|---|---|
Concise Large-Scale Synthesis of the Highly Active Cephalosporin Cefdaloxime | Cefdaloxime ( 1a ) is the bioactive principle of the 1-( S )-(pivaloyloxy)ethyl ester prodrug HR916K ( 1b ). To provide material for biological investigations a short and efficient large-scale synthesis of 1a was developed, which avoids chromatographic purification steps. Commercially available (6 R,7 R )-7-amino-3-(me... | 10.1021/op960025b | 1 |
Synthesis of Aldehydes by Rosenmund Reduction | Important perfumery aldehydes such as 10-undecenal could be synthesized by Rosenmund reduction. This reduction by hydrogen is usually effected in the presence of a supported Pd catalyst. The main by-product is the alcohol, and it is formed by the subsequent reduction of the aldehyde. This can be prevented by the use of... | 10.1021/op960024j | 1 |
Scale-Up Studies on Styrene−Butyl Methacrylate Copolymerization Reaction | The scale-up of the radical-initiated copolymerization of styrene with butyl methacrylate is studied here. The reaction is scaled up from 3 to 100 L scale. The problems encountered during the scale-up are agglomeration, foaming, and material loss. The techniques employed to overcome these problems are discussed in deta... | 10.1021/op960023r | 0 |
Preparation of Pure Anhydrous Solutions of Hydrogen Iodide in Acetic Acid | The presence of molecular iodine in anhydrous solutions of hydrogen iodide in acetic acid gives rise to unstable impurities during the hydriodination of isolated double bonds. This can be overcome by using aqueous hydriodic acid, as the source of hydrogen iodide, from which the iodine has been removed by washing with a... | 10.1021/op9600116 | 0 |
A Practical Synthesis of “Metabolite A<sub>1</sub>” (AAMU) of Caffeine | A three-pot, preparative scale synthesis of 5-acetamido-6-amino-3-methyluracil, “metabolite A 1 ” (AAMU) ( 2 ) of caffeine, from readily available 6-aminouracil ( 3 ) in 72% overall yield is described. | 10.1021/op960010d | 1 |
Heterogeneous Catalysis in Liquid Phase Transformations of Importance in the Industrial Preparation of Fine Chemicals | This review focuses on the use of heterogeneous catalysts in the production of fine and speciality chemicals. The major emphasis is on those systems which have been commercialised already and those which are close to commercialisation. These include the use of TS-1 for oxidation reactions including the production of hy... | 10.1021/op960008m | 0 |
A Model for Mother Liquor Recycle in Batch Processing | A simple model for the continuous recycle of mother liquors from a crystallization or precipitation is discussed. It is shown that the impurity profile of the mother liquors, at moderate recycle levels, quickly reaches a steady state according to (1 − x n +1 )/(1 − x ), where n is the number of times the process is ope... | 10.1021/op960007u | 0 |
Baeyer−Villiger Oxidation of 5-endo-(Biphenyl-4-ylmethoxy)-7-anti-piperidinobicyclo[2.2.1]heptan-2-one: Process Development and Scale-Up | The Baeyer−Villiger oxidation of 7- anti -piperidino, 5- endo -biphenyl-4-ylmethoxy substituted norbornan-2-one was developed to provide a robust, reproducible process for manufacture of the regioisomeric lactone which results from migration of the bridgehead carbon atom. Yields of 60−63% theory were obtained in a 2250... | 10.1021/op9600062 | 0 |
An Improved Large-Scale Synthesis of Benz[<i>cd</i>]indol-2(1<i>H</i>)-one and 5-Methylbenz[<i>cd</i>]indol-2(1<i>H</i>)-one | An improved synthesis of benz[ cd ]indol-2(1 H )-one ( 3 ) and a novel synthesis of 5-methylbenz[ cd ]indol-2(1 H )-one ( 4 ) utilizing analogous methodology is reported. Starting from 1,8-naphthoic anhydride and 4-nitro-1,8-naphthoic anhydride, an appropriately substituted N -(2,4-dinitrophenoxy)naphthalimide is prepa... | 10.1021/op960005+ | 0 |
Synthesis of Trimegestone: The First Industrial Application of Bakers' Yeast Mediated Reduction of a Ketone | Trimegestone (17α-methyl-17β-(2( S )-hydroxy-1-oxopropyl)estra-4,9-dien-3-one) is a new progestomimetic molecule developed by Roussel Uclaf for the treatment of postmenopausal diseases. It is produced on an industrial scale from a related 3-ketal, 17-keto norsteroid intermediate in a nine-step sequence involving hydroc... | 10.1021/op960004h | 1 |
Integration of a Highly Selective Demethylation of a Quaternized Ergoline into a One-Pot Synthesis of Pergolide | We have developed a high-yielding one-pot synthesis of pergolide ( 10 ) from dihydrolysergol ( 1 ), which was isolated as pergolide mesylate ( 6, Permax), a semisynthetic ergot alkaloid marketed for the adjunctive treatment of Parkinson's disease. The process involved the formation of quaternized amine intermediates, f... | 10.1021/op9600015 | 1 |
Cu-Based Nanoalloys in the Base-Free Ullmann Heterocyle-Aryl Ether Synthesis | We report the first liquid−liquid Ullmann etherification process mediated not only by oxidatively stable Cu but also by CuZn and CuSn nanoparticle catalysts in conjunction with microwave heating that also avoids the use of solid and expensive bases. Conditions have led to improved turnovers and excellent yields in hete... | 10.1021/op9003423 | 0 |
Development of a Scalable and Safe Process for the Production of 4-Chloro-2,3-dimethylpyridine-<i>N</i>-oxide as a Key Intermediate in the Syntheses of Proton Pump Inhibitors<sup>†</sup> | 2-(Pyridin-2-ylmethanesulfinyl)-1 H -benzimidazole-based drugs belong to the most prominent and successfully applied proton pump inhibitors. To fulfill the demand for a flexible and safe procedure for the synthesis of early-stage intermediates which are known to possess a strong exothermal decomposition potential, we h... | 10.1021/op9003357 | 1 |
Monitoring and Control of Genotoxic Impurity Acetamide in the Synthesis of Zaurategrast Sulfate | In this article we describe the strategy adopted to minimize the risk of acetamide presence in zaurategrast sulfate drug candidate. A risk of acetamide formation (a potential genotoxic impurity) was identified in the API formation step of the process during the early development phase. In order to keep the project deve... | 10.1021/op900330e | 1 |
An Improved Synthesis of Etravirine | Etravirine ( 1 ) is a novel diarylpyrimidine non-nucleoside reverse transcriptase inhibitor and has recently been approved by the U.S. Federal Drug Administsration for the treatment of AIDS. Its reported synthesis is fraught with many difficulties, the foremost being the poor yield and long reaction time required at th... | 10.1021/op9003289 | 1 |
Large-Scale Polycondensation of Lactic Acid Using Microwave Batch Reactors | Chemical processes assisted by microwave heating are attractive energy-saving processes. We applied microwave heating to the polycondensation of lactic acid, which conventionally is known as a high-energy-consuming process. We herein studied the microwave-assisted reaction at scales ranging from several tens of millili... | 10.1021/op900325e | 0 |
A Synthesis of 3,5-Disubstituted Phenols | Robust and scalable syntheses of some synthetically useful 3,5-disubstituted phenols are presented. The process involves the selective displacement of a halogen by nucleophilic aromatic substitution using a preformed mixture of potassium tert -butoxide and p -methoxybenzyl alcohol (PMB−OH), followed by deprotection of ... | 10.1021/op900322u | 1 |
Nonchromatographic Isolation of 2-Alkyl-2<i>H</i>-1,2,3-Triazoles in the Synthesis of NK3 Receptor Antagonists | A nonchromatographic isolation of a 2-alkyl-2 H -triazole from a 1:1 mixture with the corresponding 1-alkyl-1 H isomer was developed in a scalable synthesis of a synthetic intermediate for NK3 receptor antagonists. Based on the fundamental nucleophilicity difference in the isomeric triazoles, this method could be used ... | 10.1021/op900320j | 0 |
Improved Synthesis of RO4858542, a 5-HT<sub>6</sub> Receptor Antagonist | An improved synthesis of a 5-HT 6 antagonist is described. A problematic amide reduction step was avoided by a reductive amination. Overall, 2.9 kg was produced over 6 steps with an overall yield of 56%. | 10.1021/op900319p | 1 |
Kilogram Synthesis of a LFA-1/ICAM Inhibitor | The process development and the kilogram-scale synthesis of BMS-587101 ( 1 ) are described. The synthesis features a [3 + 2] azomethine ylide cycloaddition to efficiently build the spirocyclic core in a diastereoselective fashion followed by a classical resolution which affords the desired enantiomer in >98% enantiomer... | 10.1021/op9003168 | 1 |
Fulvestrant: From the Laboratory to Commercial-Scale Manufacture | The development of a commercial manufacturing process for fulvestrant (the active ingredient in ‘Faslodex’) is described. Key steps in the synthesis are stereoselective 1,6-addition of an organocuprate to a steroidal dienone followed by copper-mediated aromatisation of the A-ring. The strategy for dealing with noncryst... | 10.1021/op900315j | 1 |
Improved Process for the Preparation of Montelukast: Development of an Efficient Synthesis, Identification of Critical Impurities and Degradants | An improved and scalable process for the production of montelukast (Singulair, drug for asthma) based on a new and advantageous method of carrying out the key substitution reaction has been developed. The present procedure is distinguished from the previous solutions in the use of linear or cyclic polyethers, which ens... | 10.1021/op900311z | 1 |
Process Development of a Diacyl Glycerolacyltransferase-1 Inhibitor | A synthesis of a selective diacyl glycerolacyltransferase-1 (DGAT-1) inhibitor, 1, is described. The synthesis illustrates a diketone Favorskii reaction on 9 in place of the more common ketoester variant for generation of the dicarboxycyclopentane core, the development of an efficient classical resolution of a key cycl... | 10.1021/op900310v | 1 |
ReactIR Flow Cell: A New Analytical Tool for Continuous Flow Chemical Processing | A newly developed ReactIR flow cell is reported as a convenient and versatile inline analytical tool for continuous flow chemical processing. The flow cell, operated with ATR technology, is attached directly into a reaction flow stream using standard OmniFit (HPLC) connections and can be used in combination with both m... | 10.1021/op900305v | 0 |
A Detailed Study of Sulfonate Ester Formation and Solvolysis Reaction Rates and Application toward Establishing Sulfonate Ester Control in Pharmaceutical Manufacturing Processes | Sulfonate esters of lower alcohols possess the capacity to react with DNA and cause mutagenic events, which in turn may be cancer inducing. Consequently, the control of residues of such substances in products that may be ingested by man (in food or pharmaceuticals) is of importance to both pharmaceutical producers and ... | 10.1021/op900301n | 0 |
<i>In Situ</i> FTIR Study and Scale-Up of An Enolization−Azidation Sequence | A key step in the synthesis of an optically active aminoalcohol-containing active pharmaceutical ingredient (API) involved the diastereoselective introduction of an azido functional group on a functionalized chiral oxazolidinone. This was accomplished via a low-temperature enolization, followed by a quench with triisop... | 10.1021/op900299c | 1 |
Translating High-Temperature Microwave Chemistry to Scalable Continuous Flow Processes | A comparison between batch microwave and conventionally heated continuous flow scale-up protocols for three selected model reactions is presented. Using high-temperature/-pressure conditions as process intensification principles, reaction times for all three transformations were reduced to a few seconds or minutes at t... | 10.1021/op900297e | 0 |
Practical and Scalable Process for the Preparation of 4-Amino-1,3-dimethylpyrazole Hydrochloride | A practical and scalable process for the preparation of 4-amino-1,3-dimethylpyrazole hydrochloride 1 is described. Compound 1 is a useful starting material; its preparation is achieved via a three-step sequence from methyl hydrazine and technical grade acetaldehyde dimethylacetal. The target molecule is isolated in hig... | 10.1021/op900296p | 0 |
Ambient Pressure Desorption Ionization Mass Spectrometry in Support of Preclinical Pharmaceutical Development | The use of ambient pressure desorption ionization mass spectrometry for the rapid analytical support of process and pharmaceutical development is demonstrated. The ability of direct analysis in real time (DART) technology to analyze both active pharmaceutical ingredients (APIs) and intermediates without sample preparat... | 10.1021/op9002938 | 0 |
A Practical Synthesis of Regioisomeric 6- and 7-Methoxytetrahydro-3-benzazepines | A concise and versatile synthetic route for 6- and 7-methoxy tetrahydro-3-benzazepines is described. The key feature of the synthesis is a one-pot acylation/cyclization/elimination sequence to construct either of the isomeric dihydrobenzazepine ring systems from the same starting material. The route is high yielding an... | 10.1021/op900292j | 1 |
Towards a Process for the Reduction of Monomer Content in MDI-Based Prepolymers | The selective removal of methylene diphenylene diisocyanate (MDI) monomers from commercially important MDI-based prepolymers by means of fractionation through a semipermeable polymeric solvent-resistant nanofiltration (SRNF) membrane is demonstrated at laboratory scale. | 10.1021/op9002906 | 0 |
Scaleable Preparation of Functionalized Organometallics <i>via</i> Directed Ortho Metalation Using Mg- and Zn-Amide Bases | A range of aryl and heteroaryl organometallics are efficiently prepared in THF via directed ortho metalation by using the previously reported amide bases tmpMgCl·LiCl (tmp = 2,2,6,6-tetramethylpiperidyl), tmp 2 Mg·2LiCl and tmp 2 Zn·2MgCl 2 ·2LiCl. These metalation reactions are carried out at 80−100 mmol scale. The un... | 10.1021/op9002888 | 0 |
Exploring the Scope for Scale-Up of Organic Chemistry Using a Large Batch Microwave Reactor | A new batch microwave reactor has been evaluated in the context of palladium-mediated transformations, condensation reactions, nucleophilic aromatic substitution reactions, and alkylations. Importantly, a linear scaling approach was taken, no changes being made to the protocol when moving from the small, developmental ... | 10.1021/op900287j | 0 |
Fit for Purpose Experimental Designs and Analyses in Chemical Development | Classical experimental designs have been used as configurations of choice at GlaxoSmithKline within Chemical Development in establishing robust products and processes while achieving other goals such as reduction of cost, waste, process investigation times and most importantly improved quality. Occasionally, as in this... | 10.1021/op900286r | 0 |
Synthesis and Process Optimization of Amtolmetin: An Antiinflammatory Agent | Efforts toward the synthesis and process optimization of amtolmetin guacil 1 are described. High-yielding electrophilic substitution followed by Wolf−Kishner reduction are the key features in the novel synthesis of tolmetin 2 which is an advanced intermediate of 1 . | 10.1021/op900284w | 1 |
Selection of a Purification Process for the Removal and Recycling of Cesium Catalyst after Polyol Production | The aim of this study was the development of a crystallization process for the removal of the alkaline catalyst (cesium hydroxide) from crude polyether polyols and its recycling process. Hydrochloric, phosphoric, carbonic, and sulphuric acids were tested to choose the best neutralization agent. Sulphuric acid was chose... | 10.1021/op900282v | 0 |
Book Review of Flash Chemistry: Fast Organic Synthesis in Microsystems | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Flash Chemistry: Fast Organic Synthesis in MicrosystemsTrevor LairdCite this: Org. Process Res. Dev. 2009, 13, 6, 1432Publication Date (Web):October 30, 2009Publication History Received22 October 2009Published online30 October 2009Published inissue 20 Novem... | 10.1021/op900275q | 0 |
Development of a Biocatalytic Process as an Alternative to the (−)-DIP-Cl-Mediated Asymmetric Reduction of a Key Intermediate of Montelukast | A KetoREDuctase (KRED) engineered via directed evolution technologies catalyzed the asymmetric reduction of ( E )-methyl 2-(3-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-oxopropyl)benzoate to the corresponding ( S )-alcohol, a key intermediate in the synthesis of montelukast sodium (Singulair). Through synergistic eff... | 10.1021/op900272d | 0 |
Scale-Up of Organic Reactions in a Pharmaceutical Kilo-Lab Using a Commercial Microwave Reactor | A range of pharmaceutically relevant reactions were investigated for scale-up in a kilo-lab environment using a commercial batch microwave reactor. Typical scale-up issues are discussed, taking into account the specific limitations of microwave heating in large-scale experiments. Examples of scale-up from 15 mL to 1 L ... | 10.1021/op900269y | 0 |
Practical Application of Oxidation Using a Novel Na<sub>2</sub>WO<sub>4</sub>−H<sub>2</sub>O<sub>2</sub>System under Neutral Conditions for Scale-Up Manufacturing of 12α-Hydroxy-3-oxooleanano-28,13-lactone: Key Intermediate of Endothelin A Receptor Antagonist S-0139 | Novel alcohol oxidation using a Na 2 WO 4 −H 2 O 2 system was applied to manufacture 12α-hydroxy-3-oxooleanano-28,13-lactone which is a key intermediate of S-0139. Oxidation of the hydroxyl group of oleanolic acid was optimized based on the design of experiment (DoE) approach. Statistical analysis was used to maximize ... | 10.1021/op900265h | 1 |
Efficient Synthesis of 8-Oxa-3-aza-bicyclo[3.2.1]octane Hydrochloride | A four-step process to generate 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride starting with 5-hydroxymethyl-2-furfuraldehyde is described. Raney nickel-mediated reduction of 5-hydroxymethyl-2-furfuraldehyde afforded 2,5-bis(hydroxymethyl)tetrahydrofuran with a predominantly cis configuration. Conversion of the diol to... | 10.1021/op9002642 | 1 |
Sonogashira Reactions with Propyne: Facile Synthesis of 4-Hydroxy-2-methylbenzofurans from Iodoresorcinols | The Sonogashira reaction of terminal alkynes and ortho-halophenols with subsequent cyclization is a well-precedented method for the synthesis of substituted benzofurans. Here we describe the extension of this method to the coupling of 2-iodoresorcinols and terminal alkynes, including propyne, to give 4-hydroxy-2-substi... | 10.1021/op900263b | 1 |
Instantaneous, Facile and Selective Synthesis of Tetrabromobisphenol A using Potassium Tribromide: An Efficient and Renewable Brominating Agent | An instantaneous method for the bromination of bisphenol A has been reported using potassium tribromide for the first time as an efficient brominating agent affording the corresponding tetrabromobisphenol A in a reaction time of only 5−10 min at ambient temperature in high yields (99%) and purity (>99%), free from reac... | 10.1021/op900262f | 0 |
Improved Synthesis of the Selective Rho-Kinase Inhibitor 6-Chloro-<i>N</i>4-{3,5-difluoro-4-[(3-methyl-1<i>H</i>-pyrrolo[2,3-<i>b</i>]pyridin-4-yl)oxy]phenyl}pyrimidin-2,4-diamine | A highly potent and selective Rho-kinase inhibitor containing a 7-azaindole moiety has been developed at Bayer Schering Pharma. Herein we disclose details of a significantly improved synthesis of the compound in 8.2% overall yield. Key aspects include cost and safety considerations and the uncommon use of a trifluorome... | 10.1021/op900260k | 1 |
An Improved Process for the Production of Lansoprazole: Investigation of Key Parameters That Influence the Water Content in Final API | An improved large-scale synthesis of lansoprazole 1 an anti-ulcer drug is described. The synthesis commences with condensation of 2-mercaptobenzimadazole 3 with 2-chloromethyl-3methyl-4-(2, 2, 2-trifluoro ethoxy) pyridine hydrochloride 2 using water as a solvent to yield thioether 4 . Subsequently, 4 was selectively ox... | 10.1021/op900258b | 1 |
Flow Processing of Microwave-Assisted (Heterogeneous) Organic Reactions | A commercially available continuous-flow reactor was adapted to run three organic reactions, e.g. two heterogeneous and one homogeneous mixture under microwave heating. The setup was operated either as a batch-loop reactor for running a biocatalyzed esterification of ( R,S )-1-phenylethanol with vinyl acetate and the e... | 10.1021/op900257f | 0 |
Quaternary Chiral Center <i>via</i> Diastereoselective Enolate Amination Enables the Synthesis of an Anti-inflammatory Agent | The d -leucine amino acid residue necessary for the synthesis of BMS-561392, 1, was employed as a chiral directing group for a diastereoselective enolate amination to establish the quaternary chiral center. Enhanced diastereomeric ratios were observed while conducting the enolate amination with 1-chloro-1-nitrosocyclop... | 10.1021/op900255k | 1 |
Process Development and Pilot-Scale Synthesis of New Cyclization Conditions of Substituted Phenylacetamides to Tetrahydroisoquinoline-2-ones Using Eaton’s Reagent | Tetrahydroisoquinoline is a ubiquitous structural framework presented in numerous pharmacologically relevant molecules. Although accessible by the Pictet−Spengler cyclization, conditions commonly used for such cyclizations are often difficult to implement on scale. Herein, we report the development of a scaleable appro... | 10.1021/op9002533 | 1 |
Synthesis of an Antibacterial Compound Containing a 1,4-Substituted 1<i>H</i>-1,2,3-Triazole: A Scaleable Alternative to the “Click” Reaction | The copper-catalyzed “click” reaction of an azide with an alkyne has become a popular method to build up 1,4-substituted 1 H -1,2,3-triazoles in medicinal chemistry and this approach was used on a laboratory scale during the preparation of novel macrolide 1 . However, the manufacture of the key azide component, as well... | 10.1021/op900252a | 0 |
A New Method for Synthesis of Nolatrexed Dihydrochloride | A new synthetic method for nolatrexed dihydrochloride (thymitaq) has been developed. The synthesis was accomplished in three steps featuring the direct conversion of the starting 4-bromo-5-methylisatin into the methyl anthranilate by potassium peroxydisulfate/sodium methoxide. In the final Ullmann reaction potassium ca... | 10.1021/op9002517 | 1 |
Development of an Efficient Process Towards the Benzimidazole BYK308944: A Key Intermediate in the Synthesis of a Potassium-Competitive Acid Blocker | An entirely new synthesis of the important benzimidazole building block BYK308944 was elaborated using the Stobbe reaction as central element. BYK308944 constitutes an important intermediate for the preparation of 3,6,7,8-tetrahydrochromeno[7,8- d ]imidazoles as potassium-competitive acid blockers. The new route relies... | 10.1021/op9002505 | 1 |
An Efficient Synthesis of a Cyclic Ether Key Intermediate for 9-Membered Masked Enediyne Using an Automated Synthesizer | Naturally occurring antibiotics containing 9-membered enediynes have received considerable attention for many years due to their potent DNA-cleaving activity. We previously reported the design and synthesis of a synthetic, masked 9-membered enediyne that possesses DNA-cleaving activity. Despite the importance of the 9-... | 10.1021/op9002455 | 0 |
Attrition-Enhanced Deracemization in the Synthesis of Clopidogrel - A Practical Application of a New Discovery | The recently discovered technique of deracemization by means of attrition-induced grinding of a solid conglomerate in contact with a solution wherein racemization occurs has been used with a derivative of 2-chlorophenyl glycine, the key chiral component in the synthesis of Clopidogrel (Plavix). Deracemization of the ra... | 10.1021/op900243c | 1 |
Application of Quality by Design Principles to Support Development of a Control Strategy for the Control of Genotoxic Impurities in the Manufacturing Process of a Drug Substance | As part of the search for drugs with activity on the central nervous system (CNS) a fluoroaryl-amine was identified and developed by GlaxoSmithKline. The manufacturing process was developed and optimised by following a quality by design approach whereby a control strategy was developed, underpinned by process understan... | 10.1021/op900242x | 0 |
Development of an Extremely Efficient Oxidative Chlorination Reaction: The Value of Routine Data Collection | This contribution describes the development of an extremely efficient process for the oxidative chlorination of a benzyl, alkyl thioether to yield an alkylsulfonyl chloride. This process was subsequently run on >100 kg scale. The product alkylsulfonyl chloride was required as an intermediate, being used by several drug... | 10.1021/op900241e | 0 |
An Improved Synthetic Route for Preparative Process of Vardenafil | A new, convergent synthetic route for the process optimization of vardenafil (Levitra), a potent and effective PDE5 inhibitor, is described. Key improved steps in the preparative process are that the chlorosulfonation reaction is at the beginning and the dehydration-cyclisation reaction is at a later stage so that the ... | 10.1021/op900235p | 1 |
Comparison of Large-Scale Routes to Manufacture Chiral <i>exo</i>-2-Norbornyl Thiourea | Two routes aimed at the manufacture of chiral exo -2-norbornyl thiourea ( 1 ) on large scale are described. The first approach involves five chemical steps and hinges on a classical resolution via diastereomeric salt formation. The synthesis utilizes amine 2 as the resolution handle. The second approach includes two ch... | 10.1021/op9002328 | 1 |
Development of a Scalable Synthetic Process for DG-051B, A First-in-Class Inhibitior of LTA4H | DG-051B is a first-in-class small molecule inhibitor of leukotriene A4 hydrolase (LTA4H), currently in Phase II clinical development for the prevention of heart attack. Process optimization led from a linear seven-step synthetic procedure to a convergent four-step manufacturing sequence that has been used to manufactur... | 10.1021/op900231j | 1 |
A Practical and Efficient Synthesis of (3<i>R</i>,4<i>S</i>)-1-Benzyl-4-phenylpyrrolidine-3-carboxylic acid via an Aziridinium Ion Intermediate | A practical and efficient synthesis of (3 R,4 S )-1-benzyl-4-phenylpyrrolidine-3-carboxylic acid ( 1 ), a key chiral building block for synthesis of biologically active compounds was established by utilizing a stereospecific and regioselective chlorination of in situ generated aziridinium ion, followed by a nitrile ani... | 10.1021/op900230r | 1 |
An Efficient Large-Scale Synthesis of EDP-420, a First-in-Class Bridged Bicyclic Macrolide (BBM) Antibiotic Drug Candidate | A multistep, practical, and cost-effective synthesis of novel bridged bicyclic macrolide drug candidate EDP-420 ( 1 ) is described. Starting from inexpensive and commercially available erythromycin A 9-oxime, the current chemical process involves a series of transformations: triacetylation, Pd-catalyzed O,O -bis-allyla... | 10.1021/op900228u | 1 |
Preparation of Saxagliptin, a Novel DPP-IV Inhibitor | The commercial-scale synthesis of the DPP-IV inhibitor, saxagliptin ( 1 ), is described from the two unnatural amino acid derivatives 2 and 3 . After the deprotection of 3, the core of 1 is formed by the amide coupling of amino acid 2 and methanoprolinamide 4 . Subsequent dehydration of the primary amide and deprotecti... | 10.1021/op900226j | 1 |
Development of a Practical Biocatalytic Process for (<i>R</i>)-2-Methylpentanol | ( R )-2-Methylpentanol is an important chiral intermediate for the synthesis of certain medicinally important compounds, natural products, and liquid crystals. Here we describe the development of a practical kinetic resolution utilizing an enantiospecific biocatalytic reduction of racemic 2-methylvaleraldehyde. The pro... | 10.1021/op9002246 | 1 |
Book Review of Thermal Safety of Chemical Processes: Risk Assessment and Process Design | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Thermal Safety of Chemical Processes: Risk Assessment and Process DesignW. 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. ... | 10.1021/op900217z | 0 |
Practical Enantioselective Synthesis of a 3-Aryl-3-trifluoromethyl-2-aminopropanol Derivative | Development of a large-scale enantioselective synthesis of a lead compound containing a 3-aryl-3-trifluoromethyl-2-aminopropanol core is described. A single isomer of 3,3-disubstituted acrylic acid derivative was prepared via Perkin condensation or Horner−Wadsworth−Emmons olefination, followed by hydrolysis. The acid w... | 10.1021/op900216v | 1 |
IMRET 10: Process Intensification via New Reactor Technologies and New Ways of Processing | editorial | 10.1021/op900211d | 0 |
Understanding and Controlling the Formation of an Impurity during the Development of Muraglitazar, a PPAR Dual Agonist | Impurity A, observed during the process research and development of muraglitazar, was isolated via preparative HPLC for structural identification using one-dimensional and two-dimensional NMR techniques. The origin of impurity A was identified as arising three steps earlier as a minor contaminant present in one of the ... | 10.1021/op9002104 | 1 |
The Discovery and Development of a Safe, Practical Synthesis of ABT-869 | The discovery, development and implementation of two chemical routes to ABT-869 is reported. Optimization of the first-generation heterocycle formation and Suzuki coupling is briefly described. Key features of the second-generation synthesis include the development of a safe hydrazine condensation by utilizing an inorg... | 10.1021/op900208y | 1 |
Straightforward Enzymatic Process Based on HNL CLEA-Catalysis towards Cyanohydrin Derivatives | An efficient enzymatic process based on HNL-CLEA catalysis in buffer-saturated organic media was developed to limit the amount of overall waste generated and the number of safety issues incurred by handling HCN-containing waste. Starting from benzaldehyde as a model substrate, ( R )- and ( S )-mandelonitrile can be obt... | 10.1021/op900207n | 0 |
The Development of a New Manufacturing Route to the Novel Anticonvulsant, SB-406725A | The development of an efficient manufacturing route to 3-acetyl- N -(5,8-dichloro-1,2,3,4-tetrahydro-7-isoquinolinyl)-4-(1-methylethoxy)-benzamide hydrochloride SB-406725A ( 1 ) is described. The synthesis begins with dichlorination of isoquinoline, followed by nitration using nitronium tetrafluoroborate in sulpholane.... | 10.1021/op9002054 | 1 |
Synthesis of the NK1 Receptor Antagonist GW597599. Part 3: Development of a Scalable Route to a Key Chirally Pure Arylpiperazine Urea, A Happy End | GW597599 1 is a novel NK-1 antagonist currently under investigation for the treatment of central nervous system disorders and emesis. The initial chemical development synthetic route, derived from the one used by medicinal chemistry, involved several hazardous reagents, gave low yields and produced high levels of waste... | 10.1021/op9002032 | 1 |
An Efficient Kilogram-Scale Synthesis of <i>N</i>,<i>N</i>′-Bis(4,6-disubstituted 1,3,5-triazin-2-yl)-4-aminophenetylamine | A practical large-scale synthesis was developed for the preparation of N, N ′-bis(4,6-disubstituted 1,3,5-triazin-2-yl)-4-aminophenethylamine derivatives exemplified by compound 2 . This route is a six-step procedure starting from commercially available cyanuric chloride and 3-( tert- butoxycarbonylamino) aniline based... | 10.1021/op900202b | 1 |
Development of a Scalable Synthesis of Dipeptidyl Peptidase-4 Inhibitor ABT-279 | A convergent, scalable synthesis of dipeptidyl peptidase-4 inhibitor, ABT-279, has been developed and demonstrated on multikilogram scale. The cis -2,5-disubstituted pyrrolidine is generated by cyclization of a Boc-amine onto an alkynyl ketone followed by stereospecific reduction of the resulting acyliminium intermedia... | 10.1021/op900197r | 1 |
Short and Efficient Process for the Synthesis of <i>trans-</i>4-Aminocyclohexanecarboxylic Acid Derivatives | This contribution relates to an industrially feasible process for the preparation of isomerically pure trans -4-amino-1-cyclohexanecarboxylic acid derivatives that are useful building blocks in the synthesis of several pharmacologically active compounds such as glimepiride, L-370518. | 10.1021/op900195w | 1 |
On Scale Up of Organic Reactions in Closed Vessel Microwave Systems | Scale up of reactions with existing laboratory-scale microwave technologies and factors affecting extension of the scope, including the influences of putative nonthermal microwave “effects,” mechanisms of energy transfer, interactions of microwaves with materials, temperature measurement, and reproducibility between sy... | 10.1021/op900194z | 0 |
A Multidisciplinary Approach Toward the Rapid and Preparative-Scale Biocatalytic Synthesis of Chiral Amino Alcohols: A Concise Transketolase-/ω-Transaminase-Mediated Synthesis of (2<i>S</i>,3<i>S</i>)-2-Aminopentane-1,3-diol | Chiral amino alcohols represent an important class of value-added biochemicals and pharmaceutical intermediates. Chemical routes to such compounds are generally step intensive, requiring environmentally unfriendly catalysts and solvents. This work describes a multidisciplinary approach to the rapid establishment of bio... | 10.1021/op900190y | 0 |
Investigation of Synthetic Routes to a Key Benzopyran Intermediate of a 5HT<sub>4</sub> Agonist | The supply route to GlaxoSmithKline’s 5HT 4 receptor agonist 1 centred on the construction of key benzopyran fragment 2 . Our attempts to define the final manufacturing route for this component are described through a series of disconnections. The systematic approach undertaken towards the construction of the benzopyra... | 10.1021/op900188v | 1 |
Process Development and Scale Up of a Glycine Antagonist | A synthetic route amenable to large-scale synthesis of the glycine antagonist (2 R,4 E )-7-chloro-4-(2-oxo-1-phenyl-pyyrrolidin-3-ylidene)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid, (2 R,3 R,4 R,5 S )-6-(methylamino)hexane-1,2,3,4,5-penta-ol 12 is presented. The route consists of four stages of chemistry. Stage 1 s... | 10.1021/op9001824 | 1 |
Book Review of Validation of Pharmaceutical Processes, edited by J. Agalloco and F. J. Carleton | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Validation of Pharmaceutical Processes, edited by J. Agalloco and F. J. CarletonTrevor LairdCite this: Org. Process Res. Dev. 2009, 13, 5, 1034Publication Date (Web):July 23, 2009Publication History Received15 July 2009Published online23 July 2009Published ... | 10.1021/op900181h | 0 |
Response to the Comments by Bercu and Callis on our communication “Controlling the Genotoxins Ethyl Chloride and Methyl Chloride Formed During the Preparation of Amine Hydrochloride Salts from Solutions of Ethanol and Methanol” [<i>Org. Process Res. Dev</i>. <b>2009</b>, <i>13</i>, 786−791; DOI: 10.1021/op9000737] | ADVERTISEMENT RETURN TO ISSUEPREVLetter to the EditorNEXTResponse to the Comments by Bercu and Callis on our communication "Controlling the Genotoxins Ethyl Chloride and Methyl Chloride Formed During the Preparation of Amine Hydrochloride Salts from Solutions of Ethanol and Methanol" [Org. Process Res. Dev. 2009, 13, 7... | 10.1021/op900179n | 0 |
Development of a Practical Large-Scale Synthesis of Denagliptin Tosylate | A large-scale synthesis of denagliptin tosylate has been developed. The efficiency of the synthesis has been improved from the initially scaled route by changing the order of steps (performing a dehydration at a late stage). The key step of the synthesis is a single-step peptide coupling/dehydration, mediated by n -pro... | 10.1021/op900178d | 0 |
Microreactor-Based Synthesis of Molecularly Imprinted Polymer Beads Used for Explosive Detection | Molecularly imprinted polymer (MIP) beads based on acrylate formulations have been successfully synthesized in two different types of microreactors capable of generating spherical prepolymer droplets of controlled size in continuous segmented flow processes. After polymerizing and curing the droplets monodisperse acryl... | 10.1021/op9001774 | 0 |
Pilot-Plant Preparation of an α<sub>v</sub>β<sub>3</sub> Integrin Antagonist. Part 3. Process Research and Development of a Diisopropylcarbodiimide and Catalytic 1-Hydroxybenzotriazole Peptide Coupling | Studies directed toward the process research, development, and scale-up preparation of the potential α v β 3 integrin antagonist 1 are described. A convergent approach is detailed wherein tetrahydropyrimidine hydroxybenzoic acid 2 is linked to the β-amino acid ester 3 via a diisoproylcarbodiimide, catalytic HOBt coupli... | 10.1021/op900173f | 0 |
Development of a Multikilogram Synthesis of a Chiral Epoxide Precursor to a CCR1 Antagonist. Use of in Situ Monitoring for Informed Optimisation via Fragile Intermediates | The optimisation and scale up of a manufacturing route to a key intermediate, acetic acid 4-acetylamino-3-(2-methyl-oxiranylmethoxy)phenyl ester ( 2 ), utilising a S N Ar coupling, the hydrogenation of a nitro moiety and the conversion of a chiral acetonide into a chiral epoxide is described along with other routes to ... | 10.1021/op900172t | 1 |
Polymorphism in Processes of Crystallization in Solution: A Practical Review | Here we review the polymorphism of organic molecules, obtained through batch crystallization in solution carried out in a stirred vessel. Preferential formation of a polymorph, crystal habit, and size depend strongly on the kinetics of the mechanisms involved. First, we recall the concepts of crystallization from solut... | 10.1021/op900168f | 0 |
A Continuously Operated Bimembrane Reactor Process for the Biocatalytic Production of (2<i>R</i>,5<i>R</i>)-Hexanediol | Alcohol dehydrogenase-catalyzed reductions of prochiral ketones to chiral alcohols require the regeneration of consumed cofactors such as NADH or NADPH. In the substrate-coupled cofactor regeneration approach, where 2-propanol is oxidized to acetone, complete conversion is inhibited by a thermodynamic limitation. This ... | 10.1021/op9001643 | 0 |
Routes for the Synthesis of (2<i>S</i>)-2-Methyltetrahydropyran-4-one from Simple Optically Pure Building Blocks | Routes to (2 S )-2-methyltetrahydropyran-4-one of high optical purity starting from readily available chiral pool precursors and suitable for large-scale manufacture are described. In one approach, the key step is cyclisation of ( S )-5-hydroxyhex-1-en-3-one, derived either from an alkyl ( S )-3-hydroxybutyrate or ( S ... | 10.1021/op900163a | 1 |
Utilization of Sequential Palladium-Catalyzed Cross-Coupling Reactions in the Stereospecific Synthesis of Trisubstituted Olefins | A stereospecific synthesis of the drug-candidate <b>1</b> is described. The synthetic sequence, aimed at accomplishing modularity and cost savings, features a series of organometallic steps to afford stereospecifically the desired trisubstituded olefin active pharmaceutical ingredient. Key developments cons... | 10.1021/op9001609 | 0 |
Development of Manufacturing Processes for a New Family of 2,6-Dihaloaryl 1,2,4-Triazole Insecticides | Details are presented on the process development work for the new 2,6-dihaloaryl-1,2,4-triazole insecticide 1, and the development of a one-pot process toward a potential commercial manufacturing process. | 10.1021/op9001577 | 1 |
The Challenges of Developing an API Crystallization Process for a Complex Polymorphic and Highly Solvating System. Part I | Developing a robust crystallization process for an active pharmaceutical ingredient (API) molecule with a complex polymorphic profile can present a significant challenge. The presented case illustrates an unusual crystallization development problem where a polymorphically complex API has the additional obstacles of poo... | 10.1021/op9001559 | 0 |
An Efficient Laboratory Automation Concept for Process Chemistry | This concept article presents and outlines a successful strategy to roll out an automation concept on a broad basis to AstraZeneca Process R&D laboratories. Examples of hardware and software are presented as well as a couple of examples related to process safety. | 10.1021/op900154c | 0 |
An Improved Process for the Production of Rabeprazole Sodium Substantially Free from the Impurities | The present work details the journey towards development of a simple and cost-viable process for large-scale synthesis of rabeprazole sodium substantially free from the impurities. The detailed study of different parameters affecting the quality and yield percentage of the compound has been presented. Yield is increase... | 10.1021/op900148x | 1 |
Large-Scale Synthesis of a Selective Inhibitor of the Norepinephrine Transporter: Mechanistic Aspects of Conversion of Indolinone Diol to Indolinone Aminoalcohol and Process Implications | Development of a scalable synthesis of WAY-315193 is described. Use of LiHMDS as a base and Ti(O- i -Pr) 4 as a Lewis acid was optimal for efficient and reproducible addition of indolinone anion to epoxyalcohol. Conversion of indolinone diol to indolinone aminoalcohol was achieved via monotosylation−methylamination. Th... | 10.1021/op900141r | 1 |
Scalable Process for the Premix of Esomeprazole | An efficient, scalable process for the premix of unstable esomeprazole base is described that allows accessibility to the stable amorphous form of esomeprazole 1 . | 10.1021/op9001406 | 0 |
A Practical Solid Form Screen Approach To Identify a Pharmaceutical Glutaric Acid Cocrystal for Development | Pharmaceutical cocrystals could be used to improve the physicochemical properties of active pharmaceutical ingredients. Here, a practical solid form screen approach to identify pharmaceutical cocrystals in the early development stage is proposed. This approach first used a cogrinding screen to identify potential cocrys... | 10.1021/op900137j | 0 |
From Batch to Flow Processing: Racemization of <i>N</i>-Acetylamino Acids under Microwave Heating | The racemization of N -acetylindoline-2-carboxylic acid in p -xylene revealed beneficial rate enhancements due to microwave effects, by comparing conventional and microwave heating. The magnitude of this effect was governed by the degree of heterogeneity of the reaction system. The amount of catalyst, the temperature a... | 10.1021/op9001356 | 0 |
An Improved Process for Pioglitazone and Its Pharmaceutically Acceptable Salt | An improved process for pioglitazone ( 1 ) is described. The process features high-yielding transformations employing inexpensive reagents and recoverable solvents. | 10.1021/op900131m | 1 |
An Improved Procedure for Preparation and Isolation of Cephalosporin Antibiotic: Cefozopran as Free Base | An efficient synthesis of cephalosporin antibiotic, cefozopran is described. The present process does not involve chromatographic purification for isolation and is cost-effective and amenable to large-scale synthesis. | 10.1021/op900128z | 0 |
A New Industrial Process for 10-Methoxyiminostilbene: Key Intermediate for the Synthesis of Oxcarbazepine | A new industrial process, involving only two isolation and drying steps, for 10-methoxyiminostilbene (MISB), an advance intermediate of widely prescribed antiepileptic drug, oxcarbazepine, has been developed. A salient feature of this process is the novel use of 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) to afford bromo... | 10.1021/op900127v | 1 |
Crystallisation from Water-in-Oil Emulsions As a Route to Spherical Particulates: Glycine and the Hydrochloride Salts of Glutamic Acid and Ephedrine | Emulsion crystallization has been reported as an approach to controlling particle properties, and is part of a wider set of techniques that can be used to form spherical particles. In the pharmaceutical industry, spherical particles are known to present distinctive advantages in terms of flow and compression properties... | 10.1021/op900123n | 0 |
Development of a Practical Synthesis of a Purine Nucleoside Phosphorylase Inhibitor: BCX-4208 | A practical synthesis of the purine nucleoside phosphorylase (PNP) inhibitor BCX-4208 ( 1) was accomplished in three telescoped steps. Mannich condensation of the 4-benzyloxy-9-deazahypoxanthine with (3 R,4 R )-3-hydroxy-4-(hydroxymethyl)pyrrolidine and formaldehyde followed by removal of the protecting group and cryst... | 10.1021/op9001142 | 1 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.