title string | abstract string | doi string | has_route int64 |
|---|---|---|---|
First Multigram Preparation of SCP-123, A Novel Water-Soluble Analgesic | A short multi-gram process for the preparation of the analgesic compound SCP-123 (4) and its sodium salt has been developed. | 10.1021/op900113b | 1 |
A Low-Waste Process To Sertraline By Diastereomeric Crystal Resolution and Waste Isomer Racemisation | A semi-continuous method for recovering waste sertraline isomers from a diastereomeric crystallisation process is described in which the mother liquors from a highly selective mandelic acid resolution for the (1 S,4 S ) isomer are treated sequentially with SCRAM, an iridium-based chiral amine racemisation catalyst, and... | 10.1021/op900112f | 0 |
Development of a Practical Synthesis of the Progesterone Receptor Antagonist 4-{[3-Cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy}-2,6-dimethylbenzonitrile | The development and implementation of a scaleable process for the manufacture of the nonsteroidal progesterone receptor antagonist 8 is described. Key aspects of the synthesis include (i) a telescoped chlorination−etherification sequence to prepare diketone 4 and (ii) separation of pyrazole regioisomers 6 and 7 through... | 10.1021/op900110k | 1 |
Practical Diastereoselective Synthesis and Scale-up Study of (+)-2-((1<i>R</i>,2<i>R</i>,3<i>R</i>,5<i>S</i>)-2-Amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)ethanol: A Key Intermediate of the Novel Prostaglandin D<sub>2</sub>Receptor Antagonist S-5751 | A new synthetic process was developed for (+)-2-((1 R,2 R,3 R,5 S )-2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)ethanol, a key intermediate of S-5751. Diastereoselective alkylation of (+)-nopinone with ethyl bromoacetate, formation of O -methyl oxime, and diastereoselective reduction with NaBH 4 −AlCl 3 could be safely... | 10.1021/op9001092 | 1 |
Development of a Supply Route for the Synthesis of an iNOS Inhibitor: Complications of the Key S<sub>N</sub>2 Reaction | The original medicinal chemistry synthesis of an iNOS inhibitor presented several challenges that had to be overcome in order to constitute a supply route suitable for operation on a multikilo scale. The key step in the synthesis is an S N 2 reaction that assembles the chiral carbon framework, but this reaction proved ... | 10.1021/op900108b | 0 |
Process Development for A Novel Pleuromutilin-Derived Antibiotic | A scalable synthesis of a novel pleuromutilin-based antibiotic is reported. The synthesis features the scale-up of an interesting skeletal rearrangement of the pleuromutilin core and isolation of a highly purified product despite starting with relatively impure pleuromutilin. The use of Design of Experiment (DoE) and P... | 10.1021/op900104g | 0 |
Removal of Heavy Metals from Organic Reaction Mixtures: Preparation and Application of Functionalized Resins | Using a toolbox, sulfur and amine ligands are attached to a variety of hydrophobic and hydrophilic resins, and the combinations were tested for the removal of heavy metals from a number of products, prepared by metal-catalyzed reactions. As a result, cheap combinations of silica resins and simple polyamines proved to b... | 10.1021/op900102a | 0 |
An Improved and Single Pot Process for the Production of Quetiapine Hemifumarate Substantially Free from Potential Impurities | An improved and single pot process for the preparation of Quetiapine hemifumarate ( 1 ), an antipsychotic drug, free from potential impurities is reported with an overall yield of 80%. The reported process for its preparation suffers from the drawback of producing potential impurities identified as 11-piperazin-1-yldib... | 10.1021/op900097q | 1 |
A Simple, Efficient, Green, Cost Effective and Chemoselective Process for the Esterification of Carboxylic Acids | Carboxylic acids have been esterified under mild and solvent-free conditions in high yield and purity using the green reagents, dimethyl carbonate and diethyl carbonate, under acid catalysis. The present methodology is free of the disadvantages of base catalysis described earlier, such as high temperatures, use of auto... | 10.1021/op900096y | 0 |
Optimisation of Permanganate Oxidation and Suzuki−Miyaura Coupling Steps in the Synthesis of a Na<sub>v</sub>1.8 Sodium Channel Modulator | The development is described of a viable kilo-scale synthesis of the Na v 1.8 sodium channel modulator, N -methyl-6-amino-5-(2,3,5-trichlorophenyl)pyridine-2-carboxamide (PF-1247324) in five steps, starting from 6-amino-5-bromo-2-picoline, in 33% overall yield. Two key steps required significant optimisation to improve... | 10.1021/op900092h | 1 |
New and Improved Manufacturing Process for Valsartan | A new and improved industrially viable manufacturing process for valsartan, an antihypertension drug, is described. | 10.1021/op9000912 | 1 |
Aqueous Process Chemistry: The Preparation of Aryl Sulfonyl Chlorides | The use of aqueous acidic conditions for the preparation of arylsulfonyl chlorides from diazonium salts in the presence of copper salts, preferably CuCl, together with thionyl chloride as the sulfur dioxide source, has considerable advantages over recommended literature procedures, whereby reactions are carried out in ... | 10.1021/op9000862 | 0 |
Renaissance of Traditional Organic Reactions under Microfluidic Conditions: A New Paradigm for Natural Products Synthesis | Continuous flow synthesis for bioactive natural products is described. Efficient procedures using the microfluidic system were developed for the large-scale synthesis of important synthetic units of asparagine-linked oligosaccharide in glycoprotein. Advantageous aspects of microfluidic conditions, i.e., efficient mixin... | 10.1021/op900084f | 0 |
Intensification of the Capillary-Based Kolbe−Schmitt Synthesis from Resorcinol by Reactive Ionic Liquids, Microwave Heating, or a Combination Thereof | The continuous Kolbe−Schmitt synthesis of 2,4-dihydroxybenzoic acid from resorcinol was carried out using a setup with a capillary reactor of mm-internals and a micro heat exchanger. The process intensification potential of microwave irradiation for heating up the reactant solution and/or of using ionic liquids as carb... | 10.1021/op9000803 | 0 |
Safety Advantages of On-Site Microprocesses | Usually large-scale capacities are preferred in process industry because of the economics of scale. However, small capacities bring along several other advantages, which are emphasized especially in on-site production. By producing on-site, the transportation of dangerous chemicals can be avoided. Moreover, smaller on-... | 10.1021/op900079f | 0 |
Controlling the Genotoxins Ethyl Chloride and Methyl Chloride Formed During the Preparation of Amine Hydrochloride Salts from Solutions of Ethanol and Methanol | The genotoxins ethyl chloride (EtCl) and methyl chloride (MeCl) were generated during the preparation of the hydrochloride salts of two tertiary amines in the presence of ethanol and methanol, respectively. In EtOH five batches of a tertiary amine hydrochloride were prepared on 0.3−18 kg scale using 37% aqueous HCl; re... | 10.1021/op9000737 | 0 |
Development of an Open-Air and Robust Method for Large-Scale Palladium-Catalyzed Cyanation of Aryl Halides: The Use of <i>i</i>-PrOH to Prevent Catalyst Poisoning by Oxygen | Palladium-catalyzed cyanation of aryl halides is an often capricious reaction and lacks robustness due to catalyst poisoning by oxygen. In this report, an open-air and robust method for large-scale cyanation was developed and the use of commercially available i -propanol as an additive was critical for achieving the op... | 10.1021/op9000725 | 0 |
A Novel Chiral Resolving Reagent, Bis((<i>S</i>)-Mandelic acid)-3-nitrophthalate, for Amlodipine Racemate Resolution: Scalable Synthesis and Resolution Process | A novel bis(( S )-mandelic acid)-3-nitrophthalate ( 1 ), a chiral resolving reagent for the separation of ( S )-(−)-isomers of amlodipine from the racemate thereof, is designed and synthesized. A simple three-step pilot-scale preparation of 1, along with the optimization of a resolution process on the racemate amlodipi... | 10.1021/op900070c | 1 |
A Convergent Synthesis of AR-C123196 Utilising Reaction Between a Cyclic Carbonate and a Phenol for Aryl Alkyl Ether Formation | The development of a convergent synthesis of AR-C123196 is reported in which the alkyl aryl ether linkage was formed by nucleophilic attack of a phenolic hydroxyl group onto a cyclic carbonate. This approach was successfully operated on a multikilogram scale. | 10.1021/op9000687 | 1 |
Kilogram-Scale Synthesis of the CXCR4 Antagonist GSK812397 | An improved, scalable synthesis of the CXCR4 antagonist GSK812397 is described. This new route was recently scaled up in 50 L fixed equipment to afford 1.2 kg of drug substance in five steps with an overall yield of 20% and >99% chemical and enantiomeric purity. | 10.1021/op9000675 | 1 |
An Ozonolysis−Reduction Sequence for the Synthesis of Pharmaceutical Intermediates in Microstructured Devices | The advantages of microstructured reactors were utilized in a two-step process for the preparation of intermediates of vitamin D analogues, which are known to be important compounds in bone and mineral metabolism. The reaction sequence consisting of an ozonolysis step of a double bond and a subsequent reduction was suc... | 10.1021/op9000669 | 0 |
The Process Development of Ravuconazole: An Efficient Multikilogram Scale Preparation of an Antifungal Agent | The development of a safe, robust process for the preparation of ravuconazole ( 1 ), an antifungal agent, is described. The discovery and development of procedures enabling the efficient synthesis of multikilogram quantities of 1 and the process demonstration through plant scale preparations are presented. A controlled... | 10.1021/op900065c | 1 |
An Efficient Process of Racemization of 3-(Carbamoylmethyl)-5-methylhexanoic acid: A Pregabalin Intermediate | A simple and cost-effective process for racemization of undesired ( S )-3-(carbamoylmethyl)-5-methylhexanoic acid ( 9 ), produced during the resolution step, is described. The literature procedure is fraught with many difficulties including number of steps and hazardous reagents. We have developed a one pot process for... | 10.1021/op900064x | 1 |
An Improved Process for the Preparation of Diphenylmethyl 7β-Phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate | An efficient and improved process for the preparation of diphenylmethyl 7β-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate was developed. With the commercially available 7-aminocephalosporanic acid (7-ACA) as starting material, up to 73.5% overall isolated yield of the titled compound was synthesized in two step... | 10.1021/op900063e | 1 |
Efficient Synthesis of 1,4-Diaryl-5-methyl-1,2,3-triazole, A Potential mGluR1 Antagonist, and the Risk Assessment Study of Arylazides | A concise and practical synthesis of a 1,4-diaryl-5-methyl-1,2,3-triazole is described. A mGluR1 antagonist 1 was prepared with one-pot operation by the Negishi coupling reaction between two building blocks, 5-bromophthalimidine ( 2 ) and 1-aryl-5-methyl-4-triazolylzinc ( 3- Zn ). Bromide 2 was synthesized via N -selec... | 10.1021/op900062p | 1 |
Practical Synthesis of 5-Fluoro-2-(piperidin-4-yloxy)pyrimidin-4-amine, a Key Intermediate in the Preparation of Potent Deoxycytidine Kinase Inhibitors | A practical synthesis of 5-fluoro-2-(piperidin-4-yloxy)pyrimidin-4-amine, a key intermediate in the preparation of a new class of potent deoxycytidine kinase (dCK) inhibitors, is described. The commercially available 2,4-dichloro-5-fluoropyrimidine ( 12 ) is converted in four telescoped steps to tert -butyl 4-(4-amino-... | 10.1021/op900060u | 1 |
Model-Based Solvent Selection during Conceptual Process Design of a New Drug Manufacturing Process | Using models, we have demonstrated an efficient approach to identify optimal solvent compositions during conceptual design of an active pharmaceutical ingredient (API) process. A ternary solvent system was considered for a reaction, extraction, distillation, and crystallization sequence. Two thermodynamic models, NRTL-... | 10.1021/op900058e | 0 |
A Facile, One-Pot Synthesis of Lacidipine Using in Situ Generation of Wittig Intermediates | An improved, one-pot process for the preparation of lacidipine ( 1 ) via an efficient in situ generation of Wittig intermediates is reported. Generation of ylide ( 4 ) by dehydrobromination of phosphonium salt ( 3 ) followed by in situ condensation of 4 with o- phthalaldehyde ( 5 ) to yield corresponding olefin ( 6 ) a... | 10.1021/op900055u | 1 |
An Improved and Scaleable Preparation of 7-Amino-3-vinylcephem-4-carboxylic acid | A practical and efficient multikilogram-scale preparation of 7-amino-3-vinylcephem-4-carboxylic acid (7-AVCA), a key intermediate used in the synthesis of cefixime and cefdinir, is described utilizing p -methoxybenzyl 7-phenylacetamido-3-chloromethylcephem-4-carboxylate (GCLE) as a starting material. Reaction condition... | 10.1021/op900053j | 1 |
Adaptation of an Exothermic and Acylazide-Involving Synthesis Sequence to Microreactor Technology | The original three-step batchwise synthesis of the pharmaceutical intermediate (1 R,2 S,4 S )-(7-oxa-bicyclo[2.2.1]hept-2-yl)-carbamic acid ethyl ester ( 4 ) from (1 R,2 S,4 S )-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester ( 1 ) encompassed a highly exothermic hydrazine quenching step as well as an acylazid... | 10.1021/op9000516 | 0 |
An Efficient Synthetic Process for Scale-Up Production of 4,5-Diamino-2-(trifluoromethyl)benzonitrile and 5-Bromo-3-(trifluoromethyl)benzene-1,2-diamine | Starting from 4-amino-2-(trifluoromethyl)benzonitrile ( 6 ), an efficient and nonchromatographic process was developed for multihundred gram production of 4,5-diamino-2-(trifluoromethyl)benzonitrile ( 1 ) in 73% yield and 98 HPLC area% purity over four synthetic steps. The same synthetic strategy was applied to 4-bromo... | 10.1021/op9000498 | 1 |
Preparation and Characterization of Theophylline−Nicotinamide Cocrystal | Cocrystals have been increasingly recognized as an attractive alternative for solid forms of drug products. In this work, nicotinamide (NCT) was employed as a cocrystal former with the active pharmaceutical ingredient theophylline (TP). The theophylline−nicotinamide cocrystal (hereafter TP-NCT cocrystal) was prepared b... | 10.1021/op900047r | 0 |
Special Issue Dedicated to Chris Schmid, Former Associate Editor of <i>Organic Process Research and Development</i>, Who Died in 2007 | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTSpecial Issue Dedicated to Chris Schmid, Former Associate Editor of Organic Process Research and Development, Who Died in 2007Trevor LairdCite this: Org. Process Res. Dev. 2009, 13, 2, 127Publication Date (Web):March 3, 2009Publication History Received27 February 2009Published ... | 10.1021/op900042m | 0 |
Response to the Comments by Snodin on Our Article “Approaches to Assessment, Testing Decisions, and Analytical Determination of Genotoxic Impurities in Drug Substances” [<i>Org. Process Res. Dev</i>. Web publication November 13, 2008; DOI: 10.1021/op8002129; <b>2009</b>, <i>13</i>, 285−291.] | ADVERTISEMENT RETURN TO ISSUEPREVLetter to the EditorNEXTResponse to the Comments by Snodin on Our Article "Approaches to Assessment, Testing Decisions, and Analytical Determination of Genotoxic Impurities in Drug Substances" [Org. Process Res. Dev. Web publication November 13, 2008; DOI: 10.1021/op8002129; 2009, 13, 2... | 10.1021/op900041q | 0 |
Formation of 2-Trifluoromethylphenyl Grignard Reagent via Magnesium−Halogen Exchange: Process Safety Evaluation and Concentration Effect | The thermal stability profile for a solution of 2-trifluoromethylphenyl magnesium chloride at 1.5 M concentration in THF was determined using an Advanced Reactive System Screening Tool (ARSST). The solution generated by employing Knochel’s magnesium−halogen exchange protocol showed highly exothermic decomposition. The ... | 10.1021/op900040y | 0 |
An Improved and Scalable Process for the Synthesis of Ezetimibe: An Antihypercholesterolemia Drug | An efficient, cost-effective and large-scale synthesis of ezetimibe 1, an antihypercholesterolemia drug, is described. Chiral oxazolidinone chemistry was used to fix the required stereochemistry of the β-lactam ring, and the chiral oxazaborolidine chemistry was used to fix the hydroxyl group stereochemistry. The synthe... | 10.1021/op900039z | 1 |
A Simple and Efficient Large-Scale Synthesis of Metal Salts of Medium-Chain Fatty Acids | A simple, inexpensive, one-step general procedure was developed for the preparation of medium-chain fatty acid (MCFA) metal salts. This approach offers the advantage of a practical route and is superior to literature methods. Also, it overcomes many of the limitations previously reported for the preparation of fatty ac... | 10.1021/op900038v | 0 |
Preparative Chromatography with Extreme Productivity: HPLC Preparation of an Isomerically Pure Drug Intermediate on Multikilogram Scale | A highly productive method for HPLC preparation of 7.5 kg of an isomerically pure drug intermediate is described. The method employs an IPA/heptane eluent with a Chromegabond Nitro stationary phase, and affords an unusually large productivity of 5.5 kkd (kilograms of desired product per kilogram of stationary phase per... | 10.1021/op900035y | 0 |
Development of an Acid-Washable Tag for the Separation of Enantiomers from Bioresolutions | A separation tool involving the use of a vinyl ester amino acid as acyl donor in a bioresolution has been developed. The acid-washable acyl group acts as a removable tag, facilitating separation of the secondary alcohol from the bioresolution product mixture. The use of these acyl donors from cheap, commercially availa... | 10.1021/op900028d | 0 |
A Practical, Kilogram-Scale Implementation of the Wolff−Kishner Reduction | A safe and practical strategy has been developed for the large-scale preparation of imidazole 7 . The key transformation involved the Wolff−Kishner reduction of the sterically demanding neopentyl-trifluoromethylcyclopropyl imidazole ketone 8 . The described process provided the desired product in 74% overall yield with... | 10.1021/op9000274 | 0 |
Book Review of Inherently Safer Chemical Process: A Life Cycle Approach | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Inherently Safer Chemical Process: A Life Cycle ApproachCite this: Org. Process Res. Dev. 2009, 13, 3, 656Publication Date (Web):March 18, 2009Publication History Received5 February 2009Published online18 March 2009Published inissue 15 May 2009https://doi.o... | 10.1021/op900026h | 0 |
Endoscopy-Based in Situ Bulk Video Imaging of Batch Crystallization Processes | External bulk video imaging (eBVI) of crystallization processes has proven to be a promising technique for metastable zone determination. In this contribution the endoscopy-based in situ bulk video imaging (iBVI) method is introduced. The video data are processed using the mean gray intensity method and by a digital im... | 10.1021/op900019b | 0 |
Utilization of Sequential Palladium-Catalyzed Cross-Coupling Reactions in the Stereospecific Synthesis of Trisubstituted Olefins | A stereospecific synthesis of the drug-candidate 1 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 consist of a mild Sonog... | 10.1021/op900015g | 1 |
Scale-Up of Trisodium [(3β,5β,12α)-3-[[4(<i>S</i>)-4-[Bis[2-[bis[(carboxy-<i>kO</i>)methyl]amino-<i>kN</i>]ethyl]amino-<i>kN</i>]-4-(carboxy-<i>kO</i>)-1-oxobutyl]amino]-12-hydroxycholan-24-oato(6-)]gadolinate(3-)], a Gd(III) Complex under Development As a Contrast Agent for MRI Coronary Angiography | Process chemistry involved in the discovery and development routes to trisodium [(3β,5β,12α)-3-[[4( S )-4-[bis[2-[bis[(carboxy- kO )methyl]amino- kN ]ethyl]amino- kN ]-4-(carboxy- kO )-1-oxobutyl]amino]-12-hydroxycholan-24-oato(6-)]gadolinate(3-)] ( B22956/1 ) starting from l -glutamic acid and (3α,5β,12α)-3,12-dihydro... | 10.1021/op900008a | 1 |
Research and Development of the Catalytic Oxidation of Methylacrylate to 3,3-Dimethoxy Methyl Propionate | A selective synthesis of 3,3-dimethoxy methyl propionate has been developed using a green approach, in which the key step is a palladium-catalyzed oxidation of methylacrylate in methanol using oxygen as oxidant. The relationship between several reaction parameters including catalyst composition, oxygen pressure, substr... | 10.1021/op900001p | 0 |
Orthogonal Experiments in the Development of Organic Synthetic Processes | A new strategy is presented for the design of explorative experiments in synthetic chemistry when the objective is to identify the important experimental variables. The methodology is based on Taylor expansion (response surface) models, and the principles are: A grid of possible settings of the experimental variables i... | 10.1021/op800322h | 0 |
Process Development of a Potent Bradykinin 1 Antagonist | As part of Merck’s continued research effort on inflammation and pain, a safe synthesis of an orally bioavailable and CNS penetrant bradykinin 1 antagonist was developed and demonstrated on kilogram scale. The key step included a novel regioselective metal−halogen exchange reaction on 1,2-dibromo-5-chloro-3-fluorobenze... | 10.1021/op8003184 | 1 |
Continuous Biocatalytic Processes | In this review article, recently developed continuous biotransformation processes are discussed. The processes are used to carry out resolution, redox reactions, hydrolysis/esterification, C−C bond formation, and other reactions. Examples of continuous downstream processing are also included. | 10.1021/op800314f | 0 |
A Convenient One-Step Synthesis of Methyl 2-Benzamidomethyl-3-oxobutanoate | A convenient one-step process for the preparation of methyl 2-benzamidomethyl-3-oxobutanoate ( 1 ), a raw material used in the synthesis of (2 R,3 R )-3-(( R )-1-( tert -butyldimethylsilyloxy)ethyl)-2,3-dimethyl-4-oxoazetidin-2-yl acetate ( 2 ), a key intermediate for carbapenem synthesis is reported. The process is ca... | 10.1021/op800313t | 1 |
Development and Large-Scale Preparation of an Oral TACE Inhibitor | An efficient, expedient synthesis of BMS-561392, 1, which enabled rapid delivery of drug substance for clinical development is described. The key features of the synthesis include an efficient synthesis of a phenolic α,α-disubstituted amino ester via carbon alkylation without protection of the phenol, an effective enzy... | 10.1021/op800308t | 1 |
The Synthesis of a Dopamine D<sub>2</sub> Partial Agonist for the Treatment of Schizophrenia | The synthesis of the phosphoric acid salt of dopamine D 2 partial agonist 2-{4-[4-(7-fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-5,6,7,9-tetrahydro-1,7,9-triaza-benzocyclohepten-8-one ( 1 ) is reported. The most prominent feature of the molecule is a seven-membered ring urea functionality that has been prepared via... | 10.1021/op800307k | 1 |
Book Review of Good Manufacturing Practices for Pharmaceuticals | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewBook Review of Good Manufacturing Practices for PharmaceuticalsDerek RobinsonView Author Information Little Mill, Monmouthshire, [email protected]Cite this: Org. Process Res. Dev. 2009, 13, 2, 362Publication Date (Web):January 6, 2009Publication History Received9 December 200... | 10.1021/op8003053 | 0 |
Practical One-Pot and Large-Scale Synthesis of <i>N</i>-(<i>tert</i>-Butyloxycarbonyl)-3-pyrroline | N -( tert -Butyloxycarbonyl)-3-pyrroline was prepared with high purity in large scale starting from cis -1,4-dichloro-2-butene via delepine reaction and subsequent cyclization in the presence of potassium carbonate followed by N- Boc protection in methanol. Judicious selection of base and solvent led to the use of a si... | 10.1021/op8003037 | 1 |
Application of a Batch Microwave Unit for Scale-Up of Alkoxycarbonylation Reactions Using a Near-Stoichiometric Loading of Carbon Monoxide | The ethoxycarbonylation of iodobenzene was performed on the 1 mol scale in batch mode using microwave heating. The reaction was performed using both an excess and a near stoichiometric loading of carbon monoxide, comparable yields being obtained. Six different alkoxycarbonylation reactions were then performed simultane... | 10.1021/op800296d | 0 |
Development of a Multigram Asymmetric Synthesis of 2-(<i>R</i>)-2-(4,7,10-Tris <i>tert</i>-Butylcarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)-pentanedioic Acid, 1-<i>tert</i>-Butyl Ester, (<i>R</i>)-<i>tert</i>-Bu<sub>4</sub>-DOTAGA | A process for the multigram asymmetric synthesis of the chiral tetraazamacrocycle 2-( R )-2-(4,7,10-tris tert -butylcarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)-pentanedioic acid, 1- tert -butyl ester (( R )- tert -Bu 4 -DOTAGA, 4 ) has been devised and demonstrated. The nine-step synthesis features an improved synt... | 10.1021/op8002932 | 1 |
A New Approach to the Synthesis of 4-Hydroxyethylsulfonylstyrene | A new, more environmentally benign route to hydroxyethylsulfonylstyrene has been developed, starting from 4-bromobenzenethiol, involving a solventless thioether formation, water-based perborate oxidation, and Suzuki−Miyaura cross coupling with a vinylborate reagent. | 10.1021/op800292b | 1 |
Development of a Scaleable Synthesis of a Partial Nicotinic Acid Receptor Agonist | A practical and efficient synthesis of 1,4,5,6-tetrahydro-3-(1 H -tetrazol-5-yl)cyclopenta[ c ]pyrazole, 1, is described. A new one-pot process has been developed, starting from the commercially available 1 H -tetrazole-5-carboxylic acid-ethyl ester sodium salt which is reacted in a pseudo -Claisen condensation reactio... | 10.1021/op800290t | 1 |
An Investigation on Key Parameters that Influence the Synthesis of (<i>S</i>)-(+)-<i>N</i>,<i>N</i>-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propylamine: A Key Intermediate for Duloxetine | This document highlights the systematic study of influencing factors such as temperature, base, catalyst, and solvent volume in the synthesis of ( S )-(+)- N, N -dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propylamine oxalate 11a, without affecting the chiral purity. | 10.1021/op800289h | 1 |
Practical, Highly Convergent, Asymmetric Synthesis of a Selective PPARγ Modulator | A practical, highly convergent, asymmetric synthesis of a selective PPARγ modulator 1 is described. The inhibitor contains two key components, a 6-trifluoromethoxy-3-acylindole ( 6 ) and ( R )-α-aryloxybutanoic acid derivative ( 10 ). Two methods were developed to overcome the regioselectivity issues encountered in the... | 10.1021/op8002882 | 1 |
Book Review of Clean-In-Place for Biopharmaceutical Processes | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewBook Review of Clean-In-Place for Biopharmaceutical ProcessesDerek RobinsonView Author Information 38 Millbrook Court, Little Mill, Pontypool NP4 0HT, United KingdomCite this: Org. Process Res. Dev. 2009, 13, 1, 125Publication Date (Web):December 18, 2008Publication History R... | 10.1021/op800287b | 0 |
A Simple and Efficient Process for the Preparation of 1,6-Dimethoxynaphthalene | 1,6-Dimethoxynaphthalene (1,6-DMN) was prepared by the O -dimethylation of 1,6-dihydroxynaphthalene (1,6-DHN) with dimethyl sulfate (DMS) in the presence of sodium hydroxide and additives in different solvents. The main reaction determining factors were divided into three categories with respect to yield and purity of ... | 10.1021/op800285t | 1 |
Practical Synthesis of Roscovitine and CR8 | Roscovitine and CR8 are potent inhibitors of cyclin-dependent kinases. A scalable synthesis of both inhibitors is described. In the case of CR8, the biarylmethylamine moiety was obtained as a stable and high-purity salt. | 10.1021/op800284k | 1 |
Synthesis of the NK1 Receptor Antagonist GW597599. Part 2: 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 chemical development synthetic route, derived from the one used by medicinal chemistry, involved several hazardous reagents, gave low yields, and produced high levels of wastes. Through a targe... | 10.1021/op8002823 | 1 |
Lipase-Catalyzed Polycondensation in Water: A New Approach for Polyester Synthesis | The lipase-catalyzed polycondensation of sebacic aid and 1,4-butanediol can be performed in a biphasic reaction system composed of an aqueous reaction phase and an organic extraction phase. The shift of the equilibrium to higher product yields can be realized by the integrated product removal (IPR). In this biphasic re... | 10.1021/op8002807 | 0 |
A Practical Palladium-Catalyzed Telomerization for the Synthesis of Functionalized Alcohols | The synthesis of octadienyl-substituted alcohols via palladium-catalyzed telomerization is described. 2- N -Methylaminoethanol, ethylene glycol, and 1,2-propylenediol react smoothly with 1,3-butadiene to give valuable intermediates for speciality polymers in high selectivity and quantitative yield on multi-100 g-scale. | 10.1021/op800278g | 0 |
A Scalable Synthesis of the INOS Inhibitor PHA-399733 | This contribution describes a scalable synthesis of the INOS inhibitor PHA-399733 using the Bucherer−Bergs hydantoin synthesis to introduce the amino acid function. | 10.1021/op8002745 | 1 |
Development of a Sequential Tetrahydropyran and Tertiary Butyl Deprotection: High-Throughput Experimentation, Mechanistic Analysis, and DOE Optimization | The synthesis of compound 1 by deprotection of the THP, tert -butyl protected amino-pyrazolopyridine ( 2 ), is described. The original conditions for this transformation were conducted in a one-pot procedure and necessitated the use of large quantities of either TsOH or benzenesulfonic acid (5 equiv) and trifluoroaceti... | 10.1021/op8002739 | 0 |
New Efficient Asymmetric Synthesis of Taranabant, a CB1R Inverse Agonist for the Treatment of Obesity | Taranabant ( 1 ) is a cannabinoid-1 receptor (CB1R) inverse agonist that was recently in late-stage clinical development for the treatment of obesity. The previously employed synthesis exhibited a number of shortcomings for continuing development, and in this paper we report an improved synthesis of the target molecule... | 10.1021/op800270e | 1 |
Facile, Fast and Safe Process Development of Nitration and Bromination Reactions Using Continuous Flow Reactors | Chemists working in a pilot plant often face safety issues during scale-up operations. With the help of emerging microfluidic applications and microdevices, running hazardous, highly exothermic or potentially unstable reactions can be easily transposed into a safe continuous flow mode. This paper describes how a potent... | 10.1021/op8002695 | 0 |
A Scalable, Enantioselective Synthesis of the α<sub>2</sub>-Adrenergic Agonist, Lofexidine | A scalable and high-yielding synthetic route toward pure enantiomers of the α 2 -adrenergic agonist, lofexidine hydrochloride, is presented. Salient features include a rapid one-pot amide alkylation-imidazoline formation sequence on the carboxamide function of α-(2,6-dichlorophenoxy)propionamide, while preserving the s... | 10.1021/op8002689 | 1 |
Preparation of a Corticotropin-Releasing Factor Antagonist by Nucleophilic Aromatic Substitution and Copper-Mediated Ether Formation | Several synthetic approaches to a corticotropin-releasing factor (CRF) antagonist containing a tetrasubstituted pyridine were evaluated. In particular, nucleophilic aromatic substitutions on 2,4-dichloropyridine derivatives were attempted using 2,6-dimethyl-4-chlorophenol ( 4 ), ( S )-2-aminobutanol ( 7 ), and several ... | 10.1021/op800266x | 1 |
Improved Synthesis of 1-(Azidomethyl)-3,5-bis-(trifluoromethyl)benzene: Development of Batch and Microflow Azide Processes | A batch process was developed to produce 1-(azidomethyl)-3,5-bis-(trifluoromethyl)benzene, 1, in 94% yield by an efficient nucleophilic substitution reaction between 3,5-bis-(trifluoromethyl)benzyl chloride, 4, and sodium azide. Hydrazoic acid (HN 3 ), a toxic volatile compound with explosive properties, can be formed ... | 10.1021/op800265e | 1 |
Preparation, Use, and Safety of <i>O</i>-Mesitylenesulfonylhydroxylamine | The aminating reagent O -mesitylsulfonylhydroxylamine (MSH) has a known potential hazard since it contains high-energy functional groups in its structure. There are references in the literature that report several incidents involving the use of pure and crystalline MSH. The preparation and safe use of this reagent at k... | 10.1021/op800264p | 0 |
Loss Prevention and Waste Minimization with Cascade-Engineered Green Synthesis of Bisphenol-A from Cumene Hydroperoxide and Phenol using Heteropoly Acid-Supported Clay Catalysts | Bisphenol-A (BPA), an important raw material for the synthesis of epoxy resins and other polymers, is conventionally synthesised by acid-catalysed condensation of phenol and acetone, which produces 28 known byproducts. This leads to heavy costs for purification of the final product and loss of raw material. Phenol itse... | 10.1021/op800262u | 0 |
Synthesis of 2-Methyl-2,5-diazabicyclo[2.2.1]heptane, Side Chain to Danofloxacin | Various syntheses of the side chain of the quinolone antibiotic danofloxacin are described. The realization that the N -methyl substitution on the side chain 2-methyl-2,5-diazabicyclo[2.2.1]heptane can reside on either nitrogen, due to the symmetry of the molecule, played a major role in the design of the commercial sy... | 10.1021/op8002618 | 1 |
Efficient Synthesis of (2<i>S</i>,3<i>S</i>)-2-Ethyl-3-methylvaleramide Using (1<i>S</i>,2<i>S</i>)-Pseudoephedrine as a Chiral Auxiliary | An efficient and scaleable synthesis of (2 S,3 S )-2-ethyl-3-methylvaleramide ( 1 ) has been developed starting from inexpensive and readily available l -isoleucine. The key step in this process is an asymmetric alkylation using (1 S,2 S )-pseudoephedrine as a chiral auxiliary. A practical procedure was developed to re... | 10.1021/op800260j | 1 |
The Impact of Process Chemists and Engineers on Green Chemistry | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTThe Impact of Process Chemists and Engineers on Green ChemistryNealG. AndersonView Author Information Anderson's Process Solutions LLC, 7400 Griffin Lane, Jacksonville, Oregon 97530, U.S.A. E-mail: [email protected]Cite this: Org. Process Res. Dev. 2008, 12, 6, 1019–1020Publica... | 10.1021/op800259p | 0 |
An Efficient Synthesis of a Multipotent Eicosanoid Pathway Modulator | An efficient, scalable synthesis of the multipotent eicosanoid pathway modulator 2-[3-[3[[5-ethyl-4′-fluoro-2-hydroxyl[1,1′-biphenyl]-4-yl]oxy]-propoxy]2-propoxylphenoxy]benzoic acid ( 1 ) is described. The process consists of nine chemical steps with the longest linear sequence having six isolations. Palladium metal-m... | 10.1021/op800257u | 1 |
Development of a Practical and Efficient Synthesis of CP-945,598-01, a CB<sub>1</sub> Antagonist for the Treatment of Obesity | Development of an efficient bond-forming sequence and optimization of reaction conditions are described for the synthesis of CP-945,598-01 ( 1 ·HCl), a CB 1 antagonist in clinical studies for the treatment of obesity. Reordering of the bond-forming sequence provided a more efficient synthesis and avoided the use of pho... | 10.1021/op800255j | 1 |
Development of Scaffold Synthesis for the Preparation of New Insulin-Like Growth Factor 1 Receptor Inhibitors | The synthesis of new insulin-like growth factor 1 receptor (IGF-1R) inhibitors is reported. The described molecules have a new sulfonyl-indazole structure. We describe the process research and development for the scaffold synthetic procedure in order to provide the large amount of product required for lead optimization... | 10.1021/op8002536 | 1 |
Development of a Practical Synthesis of a p38 MAP Kinase Inhibitor | A practical synthesis of the phthalazine-based p38 MAP kinase inhibitor [( S )- 2 ] was needed for an ongoing program. Vibrational circular dichroism provided the assignment of the absolute stereochemistry of the target compound. The selected synthetic route for ( S )- 2 required identification of efficient reaction co... | 10.1021/op800250v | 1 |
Crystallisation Design Space: Avoiding a Hydrate in a Water-Based Process | Many compounds can exist in either hydrated or anhydrous crystalline forms. The demands of robust processing and consistent product performance usually mean that only one of these two forms is desired, and that mixtures are unacceptable. Where the crystallisation is preceded by a phase separation and a distillation, li... | 10.1021/op800249r | 0 |
The Role of New Technologies in Defining a Manufacturing Process for PPARα Agonist LY518674 | The impact of several new technologies on the development of a manufacturing process for LY518674 is described. Extensive use of process analytical technology (PAT) throughout development, both at laboratory and pilot-plant scale, enabled data-rich experiments, shortened development cycle times, and obviated the requir... | 10.1021/op8002486 | 1 |
Practical Synthesis of Chiral 2-Morpholine: (4-Benzylmorpholin-2-(<i>S</i>)-yl)-(tetrahydropyran-4-yl)methanone Mesylate, a Useful Pharmaceutical Intermediate | A commercial synthesis was developed for the production of (4-benzylmorpholin-2-( S )-yl)-(tetrahydropyran-4-yl)methanone mesylate, 1a, a key starting material for a phase 2, new investigational drug candidate at Eli Lilly and Company. The target compound was produced in the clinical pilot plant by the combination of t... | 10.1021/op800247w | 1 |
Scalable Non-Aqueous Process to Prepare Water Soluble 3-Amino-pentan-1,5-diol | The development of a nonaqueous process for the synthesis of 3-amino-pentan-1,5-diol is described. Beginning with dimethyl acetone-1,3-dicarboxylate, a telescoped sequence of reductive amination, Boc protection, sodium borohydride reduction, and acidic resin-mediated deprotection generates the title compound. The key t... | 10.1021/op800245v | 1 |
The Newman−Kwart Rearrangement Revisited: Continuous Process under Supercritical Conditions | A continuous process that is suitable for large-scale manufacture of the biphenylthiol 1 using dimethoxyethane as solvent at 320 °C and 1000 psi under supercritical conditions has been developed. Due to the use of the low-boiling solvent, the workup through a solvent switch to heptane makes the process suitable for con... | 10.1021/op800244m | 0 |
Development of a Practical Synthesis of an Aminoindanol-Derived M1 Agonist | An efficient and scalable synthesis of the clinical candidate 1 is described. The first-generation synthesis built the enantioenriched nitro-aminoindanol core from 6-nitroindanone using a five-step literature route. The second-generation route used a safe aromatic nitration protocol in the presence of the unprotected a... | 10.1021/op800243q | 1 |
Crystallization Process Development for a Stable Polymorph of Treprostinil Diethanolamine (UT-15C) by Seeding | Process development of treprostinil diethanolamine salt ( UT-15C ) involved the development of crystallization and slurry protocols to address the polymorph and morphology control issues. Two forms of UT-15C were evaluated by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and thermogravimetric... | 10.1021/op800239m | 0 |
Identification and Suppression of a Dimer Impurity in the Development of Delafloxacin | Delafloxacin is a 6-fluoroquinolone antibiotic which is under development at Rib-X Pharmaceuticals. During initial scale-up runs to prepare delafloxacin, up to 0.43% of a new impurity arose in the penultimate chlorination step. This was identified as a dimeric adduct of delafloxacin. Subsequent application of design of... | 10.1021/op800238q | 1 |
Synthesis of Tetracyclic Heterocompounds as Selective Estrogen Receptor Modulators. Part 3. Development of an Acid-Catalyzed Racemization Process for (<i>S</i>)-2,8-(Dimethoxy)-5-{4-[2-(1-piperidinyl)ethoxy]phenyl}−11,12-dihydro-<i>5H</i>-6,13-dioxabenzo[3,4]cyclohepta[1,2-<i>a</i>]naphthalene | A novel and economical process was developed for recycling the undesired enantiomer, ( S )-2,8-dimethoxy-5-{4-[2-(1-piperidinyl)ethoxy]phenyl}-11,12-dihydro- 5H -6,13-dioxabenzo[3,4]cyclohepta[1,2- a ]naphthalene ( 1b ) obtained from chiral chromatographic separation, by refluxing 1b with HCl (4.0 equiv) in EtOH for 76... | 10.1021/op800237y | 0 |
Identifying Scale Sensitivity for API Crystallizations from Desupersaturation Measurements | The present report details a methodology for discriminating between mass transfer- and surface integration-controlled crystallizations. Initial desupersaturation rates were measured, and a simple kinetic model was developed as a diagnostic tool for identifying scale sensitivity. The model was further extended to evalua... | 10.1021/op8002344 | 0 |
Development of an Efficient Palladium-Catalyzed Intramolecular Carbometalation Reaction for the Synthesis of a Dibenzoxapine Containing Tetra-substituted Exocyclic Alkene | A practical and scaleable synthesis of ( Z )-3-(1-(8-bromodibenzo[ b, e ]oxepin-11(6 H )-ylidene)ethyl)aniline hydrochloride ( 1 · HCl ), a key intermediate in the synthesis of a selective nuclear hormone receptor modulator, is described. The target compound is prepared in five steps from commercially available (5-brom... | 10.1021/op800231b | 1 |
An Improved Process for the Synthesis and Isolation of (<i>S</i>)-<i>N</i>-(1-Phenylethyl)hydroxylamine | A three-step, single-solvent telescoped process amenable to the large-scale manufacture of ( S )- N -(1-phenylethyl)hydroxylamine p -toluenesulfonic acid salt is reported. This synthetic protocol has been applied to the preparation of other chiral hydroxylamines. | 10.1021/op800230f | 0 |
Process Development for Sodelglitazar: A PPAR Panagonist | Three efficient syntheses of sodelglitazar ( 1 ) have been developed. In particular, the third synthesis avoids the use of zinc and eliminates the resulting heavy metal waste stream as well as the potential genotoxic methanesulfonate in the two earlier syntheses. This process produces sodelglitazar in 74% overall yield... | 10.1021/op8002294 | 1 |
A Novel Method for Large-Scale Synthesis of Lamivudine through Cocrystal Formation of Racemic Lamivudine with (<i>S</i>)-(−)-1,1′-Bi(2-naphthol) [(<i>S</i>)-(BINOL)] | A large-scale synthesis of (−)-[2 R,5 S ]-4-amino-1- [2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1 H )-pyrimidin-2-one (lamivudine) through resolution of racemic lamivudine by cocrystal formation with ( S )- BINOL has been demonstrated. Lamivudine of very high purity with an enantiomeric excess of more than 99.9% was obt... | 10.1021/op800228h | 1 |
Large-Scale Preparation of (+)-<i>p</i>-Menth-2-ene-1,8-diol, a Key Intermediate in the Synthesis of Δ-9-Tetrahydrocannabinol | A manufacturing-scale process for the preparation of p -menth-2-ene-1,8-diol, a key intermediate for the preparation of Δ-9-tetrahydrocannabinol (Δ-9-THC), was developed. The process entails a large-scale olefin migration/epoxidation and hydrolytic epoxide opening in organic solvent. The water-soluble product is isolat... | 10.1021/op8002272 | 0 |
Second-Generation Process for the HCV Protease Inhibitor BILN 2061: A Greener Approach to Ru-Catalyzed Ring-Closing Metathesis | The ring-closing metathesis (RCM) step, a key reaction in our process to BILN 2061, was dramatically improved from the first-generation process by the selection of a more appropriate substrate as well as the use of a more effective catalyst. The two RCM reactions are compared in detail using criteria that are of high s... | 10.1021/op800225f | 0 |
Book Review of Process Systems Engineering: Volumes 3 and 4: Supply Chain Optimization - parts I and II | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Process Systems Engineering: Volumes 3 and 4: Supply Chain Optimization - parts I and IICite this: Org. Process Res. Dev. 2008, 12, 6, 1315Publication Date (Web):October 10, 2008Publication History Received11 September 2008Published online10 October 2008Pub... | 10.1021/op800223k | 0 |
Pilot-Plant Preparation of an α<sub>v</sub>β<sub>3</sub> Integrin Antagonist: Process Development of a Carbonyldiimidazole Peptide Coupling | The process development of a peptide coupling with CDI is discussed. Various solvents, addition orders, stoichiometries, and reaction temperatures were investigated. A reliable crystallization procedure was also developed. The new process was piloted to provide 342 kg of product in two batches with an average 85% yield... | 10.1021/op8002213 | 0 |
Book Review of The Management of Chemical Process Development in the Pharmaceutical Industry | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of The Management of Chemical Process Development in the Pharmaceutical IndustryJohn KnightView Author Information Scientific Update LLP, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, United Kingdom, E-mail: [email protected]Cite this: Org. Proc... | 10.1021/op800219t | 0 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.