title string | abstract string | doi string | has_route int64 |
|---|---|---|---|
Cu-Catalyzed Formation of Triazole-Linked Glycoamino Acids and Application in Chemoenzymatic Peptide Synthesis | Novel stable triazole-linked glycoamino acids have been prepared, with the heterocyclic moiety being established by efficient Cu-mediated cycloaddition between the corresponding azido and acetylene moieties. Selected reactions were scaled up and successfully subjected to chemoenzymatic peptide-coupling reactions involv... | 10.1021/op700249f | 0 |
Development of a Scaleable Process for the Synthesis of the A2a Agonist, UK-371,104 | The development and utilization of a scaleable process for the manufacture of the A2a agonist UK-371,104 ( 1 ) is described. Key steps in the synthesis include (i) a palladium-catalyzed cyanation reaction to prepare the nitrile 10, (ii) a telescoped conversion of the acid 11 to the glycosidation substrate 9, and (iii) ... | 10.1021/op700248t | 1 |
Development of an Enantioselective, Kilogram-Scale, Rhodium-Catalysed 1,4-Addition | A rhodium-catalysed 1,4-addition of an arylboron species to an α,β-unsaturated ester was the key chirality-inducing step in the synthesis of an API. We describe herein the development of this chemistry, including optimization of reagent charges, reaction conditions, and metal recovery, in order to allow manufacture at ... | 10.1021/op700246g | 1 |
Debottlenecking the Synthesis Route of Asenapine | The discovery synthesis of asenapine that was used for the manufacture of drug substance batches up to 10 kg contained two chemical steps that were major bottlenecks for scale-up. One of these steps involved a magnesium/methanol reduction of an enamide moiety that was severely hampered by safety and efficiency problems... | 10.1021/op700240c | 1 |
Engineering Selectivity in Novel Synthesis of 3-(Phenylmethoxy)phenol from Resorcinol and Benzyl Chloride under Liquid–Liquid−Liquid Phase Transfer Catalysis | Monobenzyl ether of resorcinol, namely, 3-(phenylmethoxy)phenol is used as an intermediate for the synthesis of various chemically and biologically active molecules. The synthesis of 3-(phenylmethoxy)phenol can be accomplished by using phase transfer catalysis (PTC), either as liquid–liquid (L−L) or solid–liquid (S−L) ... | 10.1021/op7002369 | 0 |
Development of a Practical Synthesis of DPP IV Inhibitor LY2497282 | A new synthetic route to LY2497282 ( 1 ), a potent and selective DPP IV inhibitor for the potential treatment of diabetes, suitable for the preparation of multikilogram quantities is described. The key step involved a stereoselective addition of the dianion of nicotinamide 8 to N -dibenzyl-protected α-amino aldehyde 12... | 10.1021/op700235c | 1 |
Continuous Processes in Small-Scale Manufacture | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTContinuous Processes in Small-Scale ManufactureTrevor LairdCite this: Org. Process Res. Dev. 2007, 11, 6, 927Publication Date (Web):October 31, 2007Publication History Published online31 October 2007Published inissue 1 November 2007https://pubs.acs.org/doi/10.1021/op700233ehttp... | 10.1021/op700233e | 0 |
Sulfur Contamination Due to Quenching of Halogenation Reactions with Sodium Thiosulfate: Resolution of Process Problems via Improved Quench Protocols | Many metal-mediated cross-couplings involve the use of organic halides, which are usually accessed by halogenation reactions. Cross-couplings are sensitive to the presence of impurities in the halides. This paper describes the origin of one such problematic impurity (sulfur) during the synthesis of organic halides and ... | 10.1021/op700227p | 1 |
Continuous Flow Microwave-Assisted Reaction Optimization and Scale-Up Using Fluorous Spacer Technology | Microwave-assisted organic synthesis in a laboratory-scale monomodal microwave reactor is investigated for continuous flow applications using fluorous spacer technology. The benchtop continuous flow microwave described allows sequential processing of multiple plugs using small amounts of reagents for reaction optimizat... | 10.1021/op700225u | 0 |
Development of a Chemoenzymatic Manufacturing Process for Pregabalin | A new manufacturing process for ( S )-3-(aminomethyl)-5-methylhexanoic acid (Pregabalin), the active ingredient in Lyrica, has been developed. Using Lipolase, a commercially available lipase, rac -2-carboxyethyl-3-cyano-5-methylhexanoic acid ethyl ester ( 1 ) can be resolved to form 2-carboxyethyl-3-cyano-5-methylhexan... | 10.1021/op7002248 | 1 |
Development of a Practical Route for the Manufacture of <i>N</i>-[5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]acetamide | An efficient synthesis of a potent candidate in our respiratory program is described. The synthesis based on a key Darzens condensation−α,β-epoxide rearrangement circumvented the toxicity and safety issues encountered in the original synthesis route. Subsequent functionalization and formation of an heterocyclic moiety ... | 10.1021/op700222r | 1 |
Process Development of TRI-999, a Fatty-Acid-Modified HIV Fusion Inhibitory Peptide | TRI-999 is a HIV fusion inhibitory peptide designed to improve upon the efficacy and convenience of Enfuvirtide (ENF, Fuzeon), the first approved HIV entry inhibitor. Derived from a gp41 HR2 region partially overlapping the ENF sequence, TRI-999 is modified using a fatty acid conjugation strategy through a poly(ethylen... | 10.1021/op7002198 | 0 |
Application of an Enantiomerically Pure Bicyclic Thiolactone in the Synthesis of a Farnesyl Transferase Inhibitor | An efficient manufacturing route to a novel farnesyl transferase inhibitor is described. The target molecule is a pro-drug, and its synthesis is complicated by the presence of labile functionality. The Medicinal Chemistry synthesis required trityl mercaptan to introduce a thiol group stereospecifically. An important ob... | 10.1021/op700218j | 1 |
Modeling-Based Approach towards On-Scale Implementation of a Methanethiol-Emitting Reaction | Utilizing kinetic process modeling, the conditions for a pharmaceutical guanylation reaction were optimized to promote controlled generation of methanethiol and efficient removal from the off-gas stream via wet scrubbing. Optimization of the kinetic model identified two guanylation reaction temperature profiles that re... | 10.1021/op7002166 | 0 |
Catalysts for Fine Chemical Synthesis, Volume 5: Regio- and Stereo-Controlled Oxidations and Reductions. Stanley M. Roberts and John Whittall , Eds. Wiley : West Sussex, U.K. 2007 . 312 + xxii pages. £100. ISBN 978-0-470-09022-0 . | ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCite this: Org. Process Res. Dev. 2007, 11, 6, 1151Publication Date (Web):November 16, 2007Publication History Published online16 November 2007Published inissue 1 November 2007https://doi.org/10.1021/op700213vCopyright © 2007 American Chemical SocietyRIGHTS & PERMISSIONSArtic... | 10.1021/op700213v | 0 |
Implementation on Pilot-Plant Scale of the Titanocene-Catalyzed Reduction of a Lactone with Poly(methylhydrosiloxane) | The titanocene-catalyzed reduction of the lactone 1 into the lactol 2 was studied. This process uses poly(methylhydrosiloxane) as stoichiometric reductant. Thermodynamic and safety data was collected in order to develop a reliable, safe and scalable process that was successfully implemented in the pilot plant. Using th... | 10.1021/op700207m | 0 |
Encyclopedic Dictionary of Named Processes in Chemical Technology, 3rd ed . By Alan E. Comyns . CRC Press/Taylor and Francis : Boca Raton . 2007 . £85. ISBN 978-0-8493-9163-7 . | ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCite this: Org. Process Res. Dev. 2007, 11, 6, 1149–1150Publication Date (Web):October 19, 2007Publication History Received6 September 2007Published online19 October 2007Published inissue 1 November 2007https://pubs.acs.org/doi/10.1021/op700205yhttps://doi.org/10.1021/op70020... | 10.1021/op700205y | 0 |
Process Research on the Preparation of 1-(3-Trimethylsilylphenyl)-2,2,2-trifluoroethanone by a Friedel–Crafts acylation Reaction | Zifrosilone (1-(3-trimethylsilylphenyl)-2,2,2-trifluoroethanone) ( 3 ) is a cholinesterase inhibitor that has been studied for the treatment of Alzheimer’s disease. Process research has been carried out on a route to convert phenyltrimethylsilane to 3 by Friedel–Crafts acylation using trifluoroacetic anhydride. Kinetic... | 10.1021/op700199p | 0 |
Large-Scale Preparation of 2-Methyloxazole-4-carboxaldehyde | The large-scale preparation of 2-methyloxazole-4-carboxaldehyde presents a significant challenge due to the physical characteristics of the molecule. A method for the preparation of 10-kg batches of 2-methyloxazole-4-carboxaldehyde is described. The key reaction is the reduction of the corresponding N -methoxy- N -meth... | 10.1021/op700198s | 1 |
Efficient Multikilogram Synthesis of 5-Bromo-2-cyclopropyl-1-methyl-1<i>H</i>-imidazole | Herein we describe the optimization and application of a copper(I) chloride-mediated protocol for the multikilogram synthesis of 5-bromo-2-cyclopropyl-1-methyl-1 H -imidazole hydrochloride ( 1 ), a key building block used in the preparation of several biologically active small molecules. | 10.1021/op700195j | 1 |
Process Research and Development of an NK-1 Receptor Antagonist. Enantioselective Trifluoromethyl Addition to a Ketone in the Preparation of a Chiral Isochroman | CJ-17,493 ( 4 ) is a chiral NK-1 receptor antagonist. It was first prepared through a diastereoselective crystallization, then through chiral chromatography of a key intermediate, and ultimately via asymmetric synthesis. Multiple routes for the preparation of a key isochroman were demonstrated, and conditions for impro... | 10.1021/op7001886 | 1 |
Approaches for Scale-Up of Microwave-Promoted Reactions | In this report, we look at a range of classes of reaction involving microwave heating and show how different processing techniques can be used to address scale-up needs. We look at both batch and continuous-flow processing. We have shown that when using batch methodologies working using an open reaction vessel offers o... | 10.1021/op700187w | 0 |
A Comparison of Commercial Microwave Reactors for Scale-Up within Process Chemistry | Seven commercially available microwave reactors designed for limited scale-up have been investigated using a highly reliable and robust reaction (the Newman−Kwart rearrangement). The use of a single reaction has enabled the comparison to be made across the range of different reactor types and scales. Overall, all react... | 10.1021/op700186z | 1 |
A Synthesis Is Not the Same as a Process | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTA Synthesis Is Not the Same as a ProcessTrevor LairdCite this: Org. Process Res. Dev. 2007, 11, 5, 783Publication Date (Web):September 6, 2007Publication History Received14 August 2007Accepted14 August 2007Published online6 September 2007Published inissue 1 September 2007https:... | 10.1021/op700185v | 0 |
A Practical Synthesis of Enantiopure 7-Alkoxy-4-aryl-tetrahydroisoquinoline, a Dual Serotonin Reuptake Inhibitor/Histamine H<sub>3</sub> Antagonist | An efficient synthesis of compound 1 featuring a novel sequential Friedel–Crafts alkylation strategy to construct the 4-aryl-tetrahydroisoquinoline core structure has been developed. Resolution with ( d / l )-di- p -toluoyl-tartaric acid is utilized to provide the enantiomerically pure material. Overall, the route is c... | 10.1021/op700183q | 1 |
First Scale-Up: Problems and Resolutions on the Synthesis of WAY-253752, a Novel, Dual-Acting SSRI/5HT<sub>1A</sub> Antagonist | An alternative synthesis of WAY-253752, 1, a novel, dual-acting SSRI/5HT 1A antagonist, was developed and used for the first scale-up. Initially, the target compound was synthesized as part of a diasteromeric mixture separated by chiral preparative HPLC. The new route was designed around intermediates suitable for chir... | 10.1021/op700181n | 1 |
Development of a Phase Transfer Catalyzed Asymmetric Synthesis for an Estrogen Receptor Beta Selective Agonist | A practical asymmetric synthesis of the estrogen receptor beta selective agonist (7β-9aβ)-1,4-dichloro-2-hydroxygibba-1(10a),2,4,4b-tetraen-6-one ( 1 ), proceeding by way of six isolated intermediates and without recourse to chromatography, is described. Highlights of the process route developed are two chemoselective ... | 10.1021/op700178q | 1 |
pH Control in Aqueous Processes: <i>N</i>-4-Methylsulfonylphenylguanidine | The kinetics and mechanism of the synthesis of the sulfonylguanidine 2 by reaction of the corresponding aniline, 1, with cyanamide have been investigated in aqueous acid solution. The reaction is acid-catalysed, but at low pH, where substantial protonation of 1 occurs, the dominant reaction occurring is a competing hyd... | 10.1021/op700175d | 0 |
The Art of Drug Synthesis. By Douglas S. Johnson and Jie Jack Li . Wiley-Interscience: New York . 2007 . 276 pp. £50.50, $89.95. ISBN 978-0-471-75215-8 . | ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCite this: Org. Process Res. Dev. 2007, 11, 5, 925Publication Date (Web):August 22, 2007Publication History Received2 August 2007Accepted2 August 2007Published online22 August 2007Published inissue 1 September 2007https://pubs.acs.org/doi/10.1021/op7001744https://doi.org/10.1... | 10.1021/op7001744 | 0 |
Arylethenylbenzofuroxan Derivatives as Drugs for Chagas Disease: Multigram Batch Synthesis using a Wittig−Boden Process | In the present work, we developed robust processes for the preparation of new antitrypanosomal benzofuroxans, E and Z isomers of 5-arylethenylbenzo[1,2- c ]1,2,5-oxadiazole N 1 -oxide 1 – 6, in multigram batch through Wittig−Boden conditions as the key synthetic step. In these conditions, the generation of the benzofur... | 10.1021/op7001722 | 1 |
Comparison of the Crystal Chemistry, the Process Conditions for Crystallization and the Relative Structural Stability of Two Polymorphic Forms of<i>N</i><sup>G</sup>-monomethyl-<scp>l</scp>-arginine Hydrochloride | Crystal structures of two conformational polymorphs (Form A and Form D) of N G -monomethyl- l -arginine hydrochloride, a drug developed to treat septic shock, are presented. Form A is orthorhombic in a tetra-molecular unit cell and Form D is monoclinic in a bimolecular unit cell (space groups P 2 1 2 1 2 1 and P2 1, re... | 10.1021/op700171b | 0 |
Discovery of the Decarboxylative Blaise Reaction and Its Application to the Efficient Synthesis of Ethyl 2,6-Dichloro-5-fluoronicotinoylacetate | An efficient synthesis of 2,6-dichloro-5-fluoronicotinoylacetate ( 1 ) has been accomplished in a single step using the unprecedented decarboxylative Blaise reaction of 3-cyano-2,6-dichloro-5-fluoropyridine ( 4 ) with potassium ethyl malonate in the presence of zinc chloride. | 10.1021/op7001694 | 0 |
Development of a Scalable Synthesis of GSK183390A, a PPAR α/γ Agonist | A scalable synthesis of GSK183390A, a PPAR α/γ agonist, is described. This synthesis is highlighted by (1) a regioselective formal 1,3-dipolar cycloaddition reaction between an enamine and a nitrile imine dipole to form a 1,3,5-trisubstituted pyrazole and (2) a regioselective amidomethylation of an ο -cresol derivative... | 10.1021/op700164t | 1 |
A Scalable Process for the Synthesis of the Bcl Inhibitor Obatoclax | Recently we created the novel indolylprodigiosin derivative 2 (obatoclax) and demonstrated its ability to antagonize multiple members of the B-cell lymphoma (Bcl) family of antiapoptotic proteins. The compound has shown potent anticancer activity in several animal tumor models. Obatoclax is now in Phase 1b and 2 clinic... | 10.1021/op7001613 | 1 |
Research and Development of an Efficient Synthesis of Hexahydrofuro[2,3-<i>b</i>]furan-3-ol Moiety—A Key Component of the HIV Protease Inhibitor Candidates | A highly efficient method for synthesizing racemic hexahydrofuro[2,3- b ]furan-3-ol has been developed utilizing a lanthanide catalyst, such as Yb(fod) 3, to promote condensation of 2,3-dihydrofuran and glycolaldehyde dimer. Access to either optically enriched enantiomer of bisfuran alcohol can be obtained by using thi... | 10.1021/op700160a | 1 |
An Efficient and Practical Synthesis of the HIV Protease Inhibitor Atazanavir via a Highly Diastereoselective Reduction Approach | An efficient and practical synthesis of the HIV-1 protease inhibitor Atazanavir was developed by employing the diastereoselective reduction of ketomethylene aza-dipeptide isostere 10 as the key and final step. The high diastereoselectivity of the amino ketone reduction by lithium tri- tert -butoxyaluminum hydride in di... | 10.1021/op7001563 | 1 |
Practical Alternative Synthesis of 1-(8-Fluoro-naphthalen-1-yl)piperazine | Convergent synthesis of 8-fluoronaphthalen-1-ylamine ( 6 ) was achieved through the reaction of 1 H -naphtho[1,8- de ][1,2,3]triazine ( 15 ) with HF-pyridine under mild conditions. This new synthesis for the preparation of 6 overcame many scale-up challenges that exist in the methods reported in the literature and prov... | 10.1021/op7001535 | 1 |
Organic Synthesis – State of the Art 2003–2005. By Douglass F. Taber . Wiley-Interscience : New York . 2006 . 216 pp. $99.95. ISBN 0-470-05331-3. | ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCite this: Org. Process Res. Dev. 2007, 11, 5, 924–925Publication Date (Web):July 31, 2007Publication History Received28 June 2007Accepted28 June 2007Published online31 July 2007Published inissue 1 September 2007https://pubs.acs.org/doi/10.1021/op700150xhttps://doi.org/10.102... | 10.1021/op700150x | 0 |
Kinetics and Process Development for Deoxofluorination of a Steroid | In this paper investigations for developing a continuous process for the fluorination of a steroid derivative with bis(methoxyethyl)-aminosulfurtrifluoride are presented. A kinetic model is suggested for this reaction. A simulation-based experimental design approach was implemented to find the optimum conditions for th... | 10.1021/op7001485 | 0 |
Efficient Large-Scale Synthesis of 9-Alkylfluorenyl Phosphines for Pd-Catalyzed Cross-Coupling Reactions | The reactions of aliphatic alcohols with fluorene coupled with a transfer hydrogenation result in the facile formation of 9-alkylfluorenes, whose deprotonation with n BuLi and quenching of the fluorenyl anion with Cy 2 PCl in MTBE gave 9-alkylfluorenyl-dicyclohexyl phosphines, which are conveniently isolated as the res... | 10.1021/op7001479 | 1 |
A Chemoenzymatic Synthesis of an Androgen Receptor Antagonist | A new scalable enzymatic resolution approach to both enantiomers of trans -2-hydroxycyclohexanecarbonitrile ( 9 and 11 ) was developed. Treatment of the racemic mixture ( 4 ) with succinic anhydride in the presence of Novozym 435 led to selective acylation of one enantiomer to the corresponding hemisuccinate, which was... | 10.1021/op700146c | 1 |
Synthesis of a 5-((Aryloxy)methyl)-3-(4-(trifluoromethyl)phenyl)[1,2,4]thiadiazole Derivative: A Promising PPARα,δ Agonist | The preparation of the PPARα,δ agonist 2-methyl-2-(2-methyl-4-(3-(4-(trifluoromethyl)phenyl)[1,2,4]thiadiazol-5-ylmethoxy)phenoxy)propionic acid sodium salt ( 17 ) is described and compared with earlier in-house preparations of this important target compound. Key concerns around a large-scale synthesis of this thiadiaz... | 10.1021/op700141u | 1 |
Common Fragrance and Flavor Materials: Preparation, Properties and Uses,<b>5th ed.</b>By Horst Surburg and Johannes Panten . Wiley-VCH Verlag GmbH: Weinheim . 2006. 318 + xii pp. Euro 139.00. ISBN 3-527-31315-X. | ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCite this: Org. Process Res. Dev. 2007, 11, 5, 924Publication Date (Web):July 21, 2007Publication History Published online21 July 2007Published inissue 1 September 2007https://pubs.acs.org/doi/10.1021/op700137shttps://doi.org/10.1021/op700137sbook-reviewACS PublicationsCopyri... | 10.1021/op700137s | 0 |
Fluorination in Medicinal Chemistry: Methods, Strategies, and Recent Developments | Methods for introducing fluorine into organic molecules are reviewed, with an emphasis on preparation of compounds designed for biomedicinal applications. Electrophilic fluorination, nucleophilic fluorination, and enantioselective monofluorination procedures are discussed. This is followed by a review of the developmen... | 10.1021/op700134j | 0 |
A Scaleable Synthesis of Methyl 3-Amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate | A scaleable synthesis of methyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate ( 1b ), starting from 5-bromo-2-methoxypyridine ( 8 ) and 4-fluorobenzaldehyde ( 9 ), is described. Key steps in the process include lithium–bromine exchange of 8, addition of the resulting lithiate to aldehyde 9, regioselective nitration ... | 10.1021/op7001326 | 1 |
An Improved Synthesis of a Selective Serotonin Reuptake Inhibitor | A practical synthesis of 3-((1 S, 2 S )-2-dimethylaminomethylcyclopropyl)-1 H -indole-5-carbonitrile hydrochloride ( 1 ), a selective serotonin reuptake inhibitor (SSRI), is described. The process to prepare 1 was demonstrated on laboratory scale and highlights an enantioselective Simmons−Smith cyclopropanation of ally... | 10.1021/op700126w | 1 |
Kilogram Synthesis of a Selective Serotonin Reuptake Inhibitor | Process development of a selective serotonin reuptake inhibitor ( 1 ) is described. The synthesis features Nishiyama catalyst-mediated asymmetric cyclopropanation of vinyl indole 2 with ethyldiazoacetate to install the trans- disubstituted cyclopropane. The active pharmaceutical ingredient ( 1 ) was prepared in 13 chem... | 10.1021/op700125z | 0 |
Development of a Scaleable Synthesis for 1,2-Bis(2-aminophenylthio)ethane (APO-Link) Used in the Production of Bismaleimide Resin | The diamine reagent 1,2-bis(2-aminophenylthio)ethane is no longer commercially available but is still required for the synthesis of the bismaleimide resin, APO-BMI, used in syntactic foams. In this work, we examined the hydrolysis of benzothiazole followed by reaction with dichloroethane or dibromoethane. The deprotona... | 10.1021/op700122q | 1 |
The Synthesis of a 5HT<sub>2C</sub> Receptor Agonist | This report describes the large-scale synthesis of 1 that features a Fischer indole strategy to form an advanced intermediate followed by reduction to the indoline to construct the tetracyclic core of the molecule. Resolution using dibenzoyl- d -tartaric acid affords access to a single enantiomer, from which a Suzuki c... | 10.1021/op700121y | 1 |
A High-Throughput Process for Valsartan | With the redesign of three chemical steps, the throughput of the valsartan manufacturing process could be significantly increased, and with the substitution of chlorobenzene with cyclohexane in the bromination of 4′-methyl-biphenyl-2-carbonitrile (6) to 4′-bromomethyl-biphenyl-2-carbonitrile (5), halogenated solvents a... | 10.1021/op700120n | 1 |
Purification of Difluoromethylornithine by Global Process Optimization: Coupling of Chemistry and Chromatography with Enantioselective Crystallization | An industrial process for the purification of metric tons of enantiomerically pure difluoromethylornithine (DFMO HCl) is described. The amino acid DFMO HCl is cyclized to form the lactam, which is acylated with pivaloyl chloride to form rac - N -pivaloyl-DFMO lactam ( 4 ). The lactam 4 provides enhanced separation comp... | 10.1021/op700118m | 0 |
One-Step Synthesis of 5-(4-Fluorobenzyl)-2-furyl Methyl Ketone: A Key Intermediate of HIV-Integrase Inhibitor S-1360 | Practical one-step synthesis of 5-(4-fluorobenzyl)-2-furyl methyl ketone was accomplished by Friedel–Crafts benzylation of 2-furyl methyl ketone with 4-fluorobenzyl chloride in the presence of ZnCl 2 . Two reaction conditions and their work-up procedures are reported. The first utilizes an anhydrous condition in dichlo... | 10.1021/op700117q | 1 |
Development of HIV-Integrase Inhibitor S-1360: Selection of the Protecting Group on the 1,2,4-Triazole Ring | HIV-integrase inhibitor S-1360 was synthesized by Claisen-type reaction of 5-(4-fluorobenzyl)-2-furyl methyl ketone with N-protected 1 H -1,2,4-triazole-3-carboxylate. The protecting group on the triazole ring is essential for the reaction to proceed. Tetrahydropyranyl and 1-methoxy-1-methylethyl groups were examined f... | 10.1021/op700116y | 1 |
An Alternate Route to 2-Amino-3-nitro-5-bromo-4-picoline: Regioselective Pyridine Synthesis via 2-Nitramino-picoline Intermediate | The 2-nitramino functionality in 2-nitramino-4-picoline was successfully exploited not only as a protecting group but also as a directional handle to afford an efficient, atom-economic, and regioselective synthesis of 2-amino-5-bromo-3-nitro-4-picoline (4), a precursor for a drug candidate in development. | 10.1021/op700114d | 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 3 ·6H 2 O as catalyst lead to the known 2-(3-hydroxy-1-phenylpropyl)-4-methylphenol intermediate. Consecutive p... | 10.1021/op7001134 | 1 |
Process Research and Development and Scale-up of a 4,4-Difluoro-3,3-dimethylproline Derivative | The multikilogram production of the proline derivative 1, a key intermediate of a HIV protease inhibitor, required the design of a synthetic route able to be safely, effectively, and easily scaled up. Synthesis of the proline skeleton began with construction of racemic glycine derivative 4, via an ester enolate Claisen... | 10.1021/op7001112 | 1 |
An Improved Synthesis of Rimonabant: Anti-Obesity Drug | A novel, cost-effective, and efficient process was developed for the large-scale synthesis of Rimonabant 1, an anti-obesity drug. The process involves the conversion of 4-chloro propiophenone 2 to cyclized acid 6 as a key intermediate that afforded Rimonabant 1 in good yield. | 10.1021/op700110b | 1 |
Development of a Scalable Process for DG-041, a Potent EP<sub>3</sub> Receptor Antagonist, via Tandem Heck Reactions | DG-041 is a small molecule antagonist of the EP 3 receptor for prostaglandin E 2 that is in clinical development for treatment of peripheral artery disease (PAD). Originally produced using a six-step synthetic procedure, process optimization led to development of a four-step sequence that is readily scalable. The key s... | 10.1021/op700107h | 1 |
An Expedient and Multikilogram Synthesis of a Naphthalenoid H<sub>3</sub> Antagonist | A facile and scaleable synthesis of potent and selective histamine H 3 receptor antagonist 1 is described, starting from commercially available 6-bromo-naphthalene-2-carboxylic acid methyl ester 3a . The key intermediate, 2-(6-bromonaphthalen-2-yl)ethanol 5 was prepared in good yield (78%) and purity (99%) via a one-ca... | 10.1021/op700102k | 1 |
Kinetics for Scale-Up of a One-Pot Pathway to 5-(3-Fluorophenyl)-2,4-dihydro-2,4-dimethyl-3<i>H</i>-1,2,4-triazole-3-thione Using a Hybrid Model of Parallel and Consecutive Reactions | Kinetic results are reported for the one-pot reaction of 2,4-dimethylthiosemicarbazide (1) and 3-fluorobenzoyl chloride (2) to the unisolated benzamide intermediate (3), and on to the ring-closed product, 5-(3-fluorophenyl)-2,4-dihydro-2,4-dimethyl-3 H -1,2,4-triazole-3-thione (4). The sensitivity of the synthetic rout... | 10.1021/op700101g | 0 |
Boric Acid Catalyzed Amidation in the Synthesis of Active Pharmaceutical Ingredients | Application of a boric acid catalyzed process for the synthesis of the carboxamides, key reaction intermediates in the preparation of various active pharmaceutical ingredients (APIs), has been explored. | 10.1021/op700098w | 0 |
Optimized Synthesis of <scp>l</scp>-<i>m</i>-Tyrosine Suitable for Chemical Scale-Up | This paper demonstrates how l - m -tyrosine 1 can be synthesized on larger-scale via enzyme-catalyzed kinetic resolution of N -acyl m -tyrosine methyl ester 4 . N -Acyl m -tyrosine methyl ester 4 was prepared by a modification of Erlenmeyer’s azalactone synthesis followed by hydrogenation of the resultant dehydroamino ... | 10.1021/op700093y | 1 |
Scale-Up of the Preparation of (1<i>R</i>,2<i>R</i>,4<i>S</i>)-1-Methyl-4-(1-methylethenyl)-2-(4-morpholinyl)cyclohexanol | Chiral β-amino alcohols are widely recognized as effective chiral auxiliaries for a variety of asymmetric organic transformations. Recently, (1 R,2 R,4 S )-1-methyl-4-(1-methylethenyl)-2-(4-morpholinyl)cyclohexanol has been reported to be an effective chiral auxiliary for the asymmetric addition of diethylzinc to benza... | 10.1021/op700092n | 0 |
Development of an Alternative Process for the Manufacture of a Key Starting Material for Cefovecin Sodium | A process has been developed for the use of trimethylphosphite for the formation of the six-membered 3,6-dihydro-2 H -[1,3]thiazine ring in the cephem architecture by an intramolecular Horner−Emmons−Wadsworth condensation. The process is a suitable alternative to the traditional Wittig process, which uses trimethylphos... | 10.1021/op700091d | 1 |
Scalable Reactor Design for Pharmaceuticals and Fine Chemicals Production. 2: Evaluation of Potential Scale-up Obstacles for Asymmetric Transfer Hydrogenation | This paper is a continuation of our previous work, which reviewed the main factors that inhibit fine chemical and pharmaceutical reactor scalability. For scalable reactor design, it is suggested to first identify potential scale-up obstacles and then use shortcut calculations for their evaluation. This approach is demo... | 10.1021/op700089q | 0 |
An Improved Procedure for Preparation of Carbapenem Antibiotic: Meropenem | An efficient synthesis of a 1β-methyl carbapenem antibiotic, meropenem, is described. The present process does not involve cryogenic temperatures, chromatographic purification, or reverse osmosis and is amenable to large scale synthesis. | 10.1021/op700088y | 1 |
Process Development of the Synthetic Route to R116301 | We describe in this paper the synthesis of compound 1 (R116301), which was developed to prepare pilot scale quantities (20–50 kg) of drug substance. The synthesis involves the s BuLi deprotonation of Boc-protected piperidone acetal 2, followed by benzaldehyde addition and ring closure to cyclic carbamate 4 . Piperidine... | 10.1021/op700086d | 1 |
Development of a Scaleable Synthesis of NDT 9533750, a Key Intermediate to a Series of Novel Subtype Preferring GABA<sub>A</sub> Partial Agonists | A scaleable route to 6-chloro-4-[2-(3-fluoropyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-pyrimidine (NDT 9533750), a key intermediate to a series of novel subtype preferring GABA A partial agonists, is described in which various scaleup issues were addressed to provide an efficient and robust route for the preparation o... | 10.1021/op700084h | 1 |
<i>SPECIAL FEATURE SECTION: <u>ASYMMETRIC SYNTHESIS ON LARGE SCALE</u></i> | ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTSPECIAL FEATURE SECTION: ASYMMETRIC SYNTHESIS ON LARGE SCALEHans Jürgen Federsel and Karel M. J. BrandsView Author Information Global Process R&D, AstraZeneca E-mail: [email protected] Department of Process Research, Merck Research Laboratories E-mail: [email protected]Cite... | 10.1021/op700081f | 0 |
A Novel, Safe, and Robust Nitration Process for the Synthesis of 4-(4-Methoxy-3-nitrophenyl)morpholine | A novel nitration process was developed for the production of 4-(4-methoxy-3-nitrophenyl)morpholine. Crude 4-(4-methoxyphenyl)morpholine produced in step 1 was converted to its nitric acid salt. The nitration reaction was carried out by adding a dichloromethane solution of the isolated salt to concentrated sulfuric aci... | 10.1021/op700074k | 1 |
A Facile Preparation of an Octahydropyrrolo[2,3-<i>c</i>]pyridine Enantiomer | A facile synthesis of octahydro-pyrrolo[2,3- c ]pyridine 1 using an intramolecular [3+2]-cycloaddition of an azomethine ylide as the key step and employing DW-therm heat-transfer fluid as a solvent is disclosed. Enantiomerically pure 1 was obtained either via a chromatographic separation of the diastereoisomers 12 and ... | 10.1021/op700073g | 1 |
Mesoscale Flow Chemistry: A Plug-Flow Approach to Reaction Optimisation | In recent years, chemistry in flowing systems has become more prominent as a method of carrying out chemical transformations, ranging in scale from analytical-scale (microchemistry) through to kilogram-scale synthesis (macrochemistry). The advantages are readily apparent increased control of conditions leading to great... | 10.1021/op7000707 | 0 |
A Scaleable Synthesis of Dutasteride: A Selective 5α-Reductase Inhibitor | An improved and scaleable process for Dutasteride ( 1 ), a synthetic 4-azasteroid derivative essentially used for the treatment of prostate diseases, is described. | 10.1021/op700068g | 1 |
The Preparation of Two, Preclinical Amino-quinazolinediones as Antibacterial Agents | This paper describes the synthesis of two amino-quinazolinediones which are potent gyrase/topoisomerase inhibitors and useful as antibacterial agents. The early scale-up work to prepare a chiral side chain on multigram scale and two different amino-quinazolinedione cores is detailed. The enabling synthesis for the side... | 10.1021/op7000639 | 1 |
One-Pot Process for the Amination of Oxazolidinyl-methyl Mesylate by Sodium Diformylamide | An efficient one-pot process for the preparation of pure ( R )- N -[3-(4-iodophenyl)-2-oxo-5-oxazolidinyl]methylacetamide 1 from the mesylate 2b in 91% yield has been developed. The one-pot process makes use of commercially available sodium diformylamide 3 and avoids the use of highly hazardous reagents, simplifies wor... | 10.1021/op700062c | 1 |
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 | An improved, reproducible nonchromatographic process for scale-up synthesis of 2,5,8-substituted 11,12-dihydro-5 H -6,13-dioxabenzo[3,4]cyclohepta[1,2- a ]naphthalene derivatives as selective estrogen receptor modulators (SERMs) is described. The titled compounds were prepared in 9−21% overall yield with high chemical ... | 10.1021/op700061x | 1 |
Green Chemical Synthesis of 2-Benzenesulfonyl-pyridine and Related Derivatives | A practical synthesis of 2-benzenesulfonylpyridine, 1, is described which is a key starting material for the manufacture of an investigational new drug candidate at Eli Lilly and Company. An optimized green chemical process was developed which features a novel tandem S N Ar/oxidation under mild conditions to produce th... | 10.1021/op700060e | 0 |
Development of a Large-Scale Stereoselective Process for (1<i>R</i>,4<i>S</i>)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine Hydrochloride | A convenient, multikilogram-scale, stereoselective process for the synthesis of (1 R,4 S )-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine hydrochloride 1 is described. The key steps involve synthesis of sulfinyl imine ( R s, 4 S )-5 from ( S )-tetralone (4 S )-3 and ( R )- tert -butylsulfinamide ( R s )-4,... | 10.1021/op7000589 | 1 |
Process Intensification for Substrate-Coupled Whole Cell Ketone Reduction by In Situ Acetone Removal | Three different reactor configurations for in situ acetone removal in whole cell biotransformation processes with substrate-coupled cofactor regeneration were applied. The reduction of 2,5-hexanedione to the corresponding (2 R,5 R )-hexanediol was catalyzed by recombinant Escherichia coli cells expressing an alcohol de... | 10.1021/op700055e | 0 |
Convergent Approach for Commercial Synthesis of Gefitinib and Erlotinib | An efficient, economical and large-scale convergent synthesis of epidermal growth factor receptor- tyrosine kinase inhibitors gefitinib (1, Iressa) and erlotinib (2, Tarceva) approved by U.S. FDA for the treatment of non-small-cell lung cancer is described. The formation of 4-anilinoquinazolines are achieved in a simpl... | 10.1021/op700054p | 1 |
A Concise Synthesis of a Novel Insulin-Like Growth Factor I Receptor (IGF-IR) Inhibitor | An efficient synthesis of a potent insulin-like growth factor I receptor (IGF-IR) inhibitor AEW541 (1) is described. The key step in the synthesis is the cis -selective reductive amination of cyclobutanone, which sets up the desired 1,3-stereochemistry of the cyclobutane ring. The amino group thus generated is used as ... | 10.1021/op700052u | 1 |
Optimization and Scale-Up of the Grandberg Synthesis of 2-Methyltryptamine | An efficient, safe, and cost-effective synthesis of 2-methyltryptamine ( 2 ), a key starting material in the synthesis of the histone deacetylase inhibitor LBH589 ( 1 ) is described. The reaction of phenylhydrazine ( 7 ) with a stoichiometric amount of 5-chloro-2-pentanone ( 8 ) in aqueous ethanol at reflux furnished c... | 10.1021/op7000518 | 1 |
Improved and Practical Synthesis of 6-Methoxy-1,2,3,4- tetrahydroisoquinoline Hydrochloride | 6-Methoxy-1,2,3,4-tetrahydroisoquinoline ( 1 ) or its hydrochloride salt ( 4 ) is an expensive chemical with limited commercial availability. We report an improved and practical synthesis of 4 from inexpensive 2-(3-methoxyphenyl)ethylamine ( 2 ) using a Pictet−Spengler condensation via a novel aminal intermediate. The ... | 10.1021/op7000468 | 1 |
Generation of Fine Pharmaceutical Particles via Controlled Secondary Nucleation under High Shear Environment during Crystallization − Process Development and Scale-up | A unique semibatch crystallization process, coupling with a high-speed rotor-stator device, was developed for generation and control of fine particles. The key underlying mechanism of this process is controlled secondary nucleation under a high shear environment during crystallization, in contrast to the conventional p... | 10.1021/op700045j | 0 |
A Practical and Scaleable Synthesis of 1<i>R</i>,5<i>S</i>-Bicyclo[3.1.0]hexan-2-one: The Development of a Catalytic Lithium 2,2,6,6-Tetramethylpiperidide (LTMP) Mediated Intramolecular Cyclopropanation of (<i>R</i>)-1,2-Epoxyhex-5-ene | An efficient synthesis of 1 R,5 S -bicyclo[3.1.0]hexan-2-one from ( R )-1,2-epoxyhex-5-ene is described. Development of a catalytic intramolecular cyclopropanation of ( R )-1,2-epoxyhex-5-ene gives the key homochiral bicycle[3.1.0]hexan-1-ol, which is then oxidized to the desired ketone. This process has been successfu... | 10.1021/op700042w | 1 |
New Practical Synthesis of the Key Intermediate of Candesartan | The development of a new, practical synthesis of methyl 3-amino- N -[(2‘-cyanobiphenyl-4-yl)methyl]anthranilate, key intermediate of candesartan, is described, starting from methyl anthranilate. The features of our approach are as follows: ( i ) introduction of the 3-nitro group by acid catalysed rearrangement of the c... | 10.1021/op700041z | 1 |
A Convergent Kilogram-Scale Synthesis of the PPARα Agonist LY518674: Discovery of a Novel Acid-Mediated Triazolone Synthesis | The first kilogram-scale synthesis of the PPARα agonist LY518674 ( 1 ) is described. The de novo convergent synthetic approach involved coupling of two rapidly assembled components, triazolone formation via a novel acid-promoted cyclization reaction, and final step saponification, delivering the compound in 32.5% overa... | 10.1021/op700040v | 1 |
Execution of a Performic Acid Oxidation on Multikilogram Scale | In order to run a peracid oxidation on multikilogram scale in a pilot plant facility with an acceptable level of risk, an extensive study of the thermal characteristics of the reaction, reactants, and quench was undertaken. A number of features were engineered into the process in order to confidently run the process wi... | 10.1021/op700039r | 0 |
Route Development and Bulk Synthesis of CP-865,569 | The synthesis of zwitterionic CP-865,569 by three different synthetic routes is described. The first two routes differ in the method of introducing the sulfonic acid at the penultimate step: by sulfite displacement of a benzylic chloride and by oxidation of a benzylic thioacetate. The third route is a convergent route ... | 10.1021/op7000386 | 1 |
Scale-Up Syntheses of Two Naturally Occurring Procyanidins: (−)-Epicatechin-(4β,8)-(+)-catechin and (−)-Epicatechin-3-<i>O-</i>galloyl-(4β,8)-(−)-epicatechin-3-<i>O</i>-gallate | A scaleable process for the synthesis of two naturally occurring procyanidins, namely (−)-epicatechin-(4β,8)-(+)-catechin ( 1 ) and (−)-epicatechin-3- O -galloyl-(4β,8)-(−)-epicatechin-3- O -gallate ( 2 ), is described. The key steps were highlighted by improvements for the benzylation of (+)-catechin ( 3 ), stereosele... | 10.1021/op700031n | 0 |
Catalytic, Enantioselective Synthesis of Taranabant, a Novel, Acyclic Cannabinoid-1 Receptor Inverse Agonist for the Treatment of Obesity | Chiral amide 1 (MK-0364, taranabant) is a potent, selective, and orally bioavailable cannabinoid-1 receptor (CB-1R) inverse agonist indicated for the treatment of obesity. An asymmetric synthesis featuring a dynamic kinetic resolution via hydrogenation for the preparation of the bromo alcohol 5 is disclosed. Conversion... | 10.1021/op700026n | 1 |
Synthetic Improvements in the Preparation of Clopidogrel | Synthetic improvements in the preparation of clopidogrel are described. The synthesis was accomplished in four steps or one-pot in above 70% overall yield. The process featured PTC catalyzed alkaline hydrolysis of the key intermediate 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2- c ]pyridin-5(4 H )-yl)acetonitrile and h... | 10.1021/op700025d | 1 |
Synthesis of Tetracyclic Heterocompounds as Selective Estrogen Receptor Modulators. Part 1. Process Development for Scale-up of 2,5,8-Substituted 5,11-Dihydrochromeno[4,3-<i>c</i>]chromene Derivatives | Unsymmetrical benzopyranobenzopyran compounds are novel selective estrogen receptor modulators (SERMs). A reproducible and nonchromatographic process was developed to prepare multihundred gram quantities of 5-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-5,11-dihydrochromeno[4,3- c ]chromene-2,8-diyl-bis(2,2-dimethylpropanoate)... | 10.1021/op700020f | 1 |
Process Development for ABT-472, a Benzimidazole PARP Inhibitor | A nine-step convergent process was developed for the synthesis of ABT-472, a benzimidazole PARP inhibitor. The identity and origin of several impurities were determined, and the process was modified to reduce or eliminate these impurities. A number of safety and control issues were investigated. The original synthesis ... | 10.1021/op7000194 | 1 |
A Microcapillary Flow Disc Reactor for Organic Synthesis | This paper reports proof of concept, development, and trials for a novel plastic microcapillary flow disc (MFD) reactor. The MFD was constructed from a flexible, plastic microcapillary film (MCF), comprising parallel capillary channels with diameters in the range of 80−250 μm. MCFs were wound into spirals and heat trea... | 10.1021/op700015f | 0 |
Practical Synthesis and Molecular Structure of a Potent Broad-Spectrum Antibacterial Isothiazoloquinolone | We report the synthesis of the new 2-sulfonylquinolone ethyl 1-cyclopropyl-6,7-difluoro-2-methanesulfonyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate ( 5 ). Sulfone 5 is a key intermediate used in the optimized synthesis of the isothiazoloquinolone 9-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpyridin-4-yl)-9 H -i... | 10.1021/op700014t | 1 |
Improvement of Process Safety and Efficiency of Grignard Reactions by Real-Time Monitoring | Grignard reactions possess considerable hazard potentials due to the spontaneous heat release during the initiation of these strongly exothermic reactions and the high reactivity of the Grignard compounds. To establish an industrially applicable method for an objective real-time detection of the reaction start-up and f... | 10.1021/op700012g | 0 |
Development of a Preparative-Scale Asymmetric Synthesis of (<i>R</i>)-<i>p</i>-Tolyl Methyl Sulfoxide for Use in a One-Pot Synthesis of a Drug Intermediate Containing a Trifluoromethyl-Substituted Alcohol Functionality | A one-pot process for the synthesis of ( S )-1,1,1-trifluoro-4-(5-fluoro-2-methoxy-phenyl)-4-methyl-2-(( R )-toluene-4-sulfinylmethyl)pentan-2-ol ( 3 ) is described, which was a key intermediate for the preparation of a class of novel glucocorticoid receptor ligands. The chemistry features the preparative-scale synthes... | 10.1021/op700010a | 1 |
An Efficient Synthesis of Dibenzo[<i>c</i>,<i>f</i>]-2,7-naphthyridine Ring System through Design of Experiments | The dibenzo[ c, f ]-2,7-naphthyridine ring system was found to be of biological interest, but had limited synthetic accessibility. The initial compound of interest, 10,11-dimethoxy-4-methyldibenzo[ c, f ]-2,7-naphthyridine-3,6-diamine, was obtained in <25% yield by reacting 4-chloro-6,7-dimethoxy-quinoline-3-carbonitri... | 10.1021/op700009t | 1 |
Process Development for (<i>S,S</i>)-Reboxetine Succinate via a Sharpless Asymmetric Epoxidation | Reboxetine mesylate is a selective norepinephrine uptake inhibitor (NRI) currently marketed as the racemate. The ( S,S )-enantiomer of reboxetine is being evaluated for the treatment of neuropathic pain and a variety of other indications. ( S,S )-Reboxetine has usually been prepared by resolution of the racemate as the... | 10.1021/op700007g | 1 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.