title string | abstract string | doi string | has_route int64 |
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Coupling Polymorphism/Solvatomorphism and Physical Stability Evaluation with Early Salt Synthesis Optimization of an Investigational Drug | The need for effective solid-form screening approaches, especially designed for the early discovery phases, is well recognized within the pharmaceutical industry. Here we report on the early polymorphism and solvatomorphism evaluation of a new drug candidate for selective α 2C -adrenoceptor antagonists ORM10921·HCl. Th... | 10.1021/op200026f | 0 |
Synthesis, Chromatographic Purification, and Isolation of Epothilone–Folic Acid Conjugate BMS-753493 | We describe the synthesis, chromatographic purification, and isolation of the epothilone–folic acid conjugate BMS-753493, an investigational new drug candidate for the treatment of cancer. The main challenges for process development were the instability of BMS-753493 in aqueous solution, the design and optimization of ... | 10.1021/op200023g | 0 |
Continuous Flow Processing of Slurries: Evaluation of an Agitated Cell Reactor | A general method for the continuous processing of suspensions and particulates is reported. A commercially available agitating cell reactor which uses a transverse mixing motion to maintain solids in suspension has been successfully applied to a salt-forming reaction. The flow device delivered 208 g of N -iodomorpholin... | 10.1021/op2000223 | 0 |
Development of a Practical Synthesis of Toll-like Receptor Agonist PF-4171455: 4-Amino-1-benzyl-6-trifluoromethyl-1,3-dihydroimidazo [4,5-<i>c</i>] pyridin-2-one | The development and implementation of a scalable process for the manufacture of the Toll-like receptor (TLR7) agonist PF-4171455 ( 1 ) is described. Initial routes used to synthesise 1 in milligram quantities were unsuitable for large-scale synthesis to provide bulk material. As part of the transfer between Medicinal C... | 10.1021/op200021a | 1 |
An Efficient Process for the Manufacture of Carmegliptin | A short and high-yielding synthesis of carmegliptin ( 1 ) suitable for large-scale production is reported. The tricyclic core was assembled efficiently by a decarboxylative Mannich addition−Mannich cyclization sequence. Subsequent crystallization-induced dynamic resolution of enamine 7 using ( S, S )-dibenzoyltartaric ... | 10.1021/op2000207 | 1 |
Development of a Scalable Synthesis of (<i>S</i>)-3-Fluoromethyl-γ-butyrolactone, Building Block for Carmegliptin’s Lactam Moiety | Several new routes are reported for the synthesis of ( S )-3-fluoromethyl-γ-butyrolactone. An asymmetric hydrogenation-based synthesis was chosen as the enabling route to produce the lactone on a 10-kg scale. A superior stereoselective route starting from ( S )- tert -butyl glycidyl ether which afforded the desired lac... | 10.1021/op200019k | 1 |
Industrial Application of the Forster Reaction: Novel One-Pot Synthesis of Cinacalcet Hydrochloride, a Calcimimetic Agent | Described is a new, practical, and one-pot process, based on the Forster reaction, for the synthesis of cinacalcet hydrochloride ( 1 ), a calcimimetic agent and calcium-sensing receptor antagonist. The synthesis comprises the condensation of (1 R )-(+)-1-naphthylethyl amine ( 2 ) with benzaldehyde ( 3 ) followed by rea... | 10.1021/op200016a | 1 |
Book Review: Process Analytical Technology: Spectroscopic Tools and Implementation Strategies for the Chemical and Pharmaceutical Industries | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review: Process Analytical Technology: Spectroscopic Tools and Implementation Strategies for the Chemical and Pharmaceutical IndustriesTrevor LairdCite this: Org. Process Res. Dev. 2011, 15, 2, 480Publication Date (Web):February 11, 2011Publication History Published ... | 10.1021/op2000139 | 0 |
Book Review of Manufacturing of Pharmaceutical Proteins: From Technology to Economy | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Manufacturing of Pharmaceutical Proteins: From Technology to EconomyTrevor LairdCite this: Org. Process Res. Dev. 2011, 15, 2, 479Publication Date (Web):February 8, 2011Publication History Published online8 February 2011Published inissue 18 March 2011https:... | 10.1021/op200012c | 0 |
Fast, Economic, and Green Synthesis of <i>N</i>-Formylated Benzotriazoles | Formylation is an integral part of organic, medicinal, and biological chemistry both in industrial and academic set-ups. A reflection of this importance is the number of approaches and reagents that have been developed to achieve it. We have developed a fast, efficient, and environmentally friendly procedure for the sy... | 10.1021/op200011x | 0 |
Optimization of the Neutralization Process for Cesium Catalyst Removal after Polyol Production | The aim of this study was the optimization of the neutralization process to remove the catalyst cesium hydroxide from crude polyether polyols. Sulfuric acid was chosen as the neutralization agent. First of all, the water content in the neutralization agent solution was optimized. An optimum particle size was obtained f... | 10.1021/op200010e | 0 |
Development of a Fully Telescoped Synthesis of the S1P1 Agonist GSK1842799 | The development of a fully telescoped synthesis of the potent and selective S1P1 agonist GSK1842799 is described. Key features in the synthesis, which has been implemented on a multikilogram scale, include a nucleophilic aromatic substitution to install a lipophilic 1-octyloxy chain, introduction of a chiral quaternary... | 10.1021/op2000095 | 1 |
Noncryogenic Preparation of Functionalized Arylboronic Esters through a Magnesium−Iodine Exchange with in Situ Quench | Various functionalized aryl boronic esters derived from hexylene glycol and pinacol were prepared in excellent yields according to a simple, safe procedure. The metal−halogen exchange reaction between i PrMgCl·LiCl and aryl iodides is performed at 0 °C in the presence of a cyclic borate ester (MPBO i Pr or PinBO i Pr);... | 10.1021/op2000089 | 0 |
Mitsunobu Inversion of a Secondary Alcohol with Diphenylphosphoryl azide. Application to the Enantioselective Multikilogram Synthesis of a HCV Polymerase Inhibitor | The development of a practical synthesis of the hepatitis C virus polymerase inhibitor 1 was necessary to support preclinical safety and human clinical studies. Significant challenges face the process chemist in developing a route to 1 that is amenable to multikilogram operation. In particular, an efficient constructio... | 10.1021/op200002u | 1 |
Application of Chemoselective Pancreatin Powder-Catalyzed Deacetylation Reaction in the Synthesis of Key Statin Side Chain Intermediate (4<i>R</i>,6<i>S</i>)-4-(<i>tert</i>-Butyldimethylsilyloxy)-6-(hydroxymethyl)tetrahydropyran-2-one | A chemoselective biocatalytic procedure for the synthesis of (4 R,6 S )-4-( tert -butyldimethylsilyloxy)-6-(hydroxymethyl)tetrahydro-2 H -pyran-2-one, a key lactonized statin side chain intermediate, from its acetate precursor is described. The presented method is based on the pancreatin powder-catalyzed cleavage of th... | 10.1021/op100341m | 0 |
Fast Scale-Up Using Microreactors: Pyrrole Synthesis from Micro to Production Scale | A flow chemistry method for the synthesis of pyrroles was developed. The method was optimized in 0.13 to 7 μL microreactors in continuous flow, reaching yields of nearly 100%. Subsequently, the method was scaled up in continuous flow using a 9.6-mL internal volume, glass, microstructured flow reactor, leading to produc... | 10.1021/op100338z | 0 |
Reactor Kinetics Studies via Process Raman Spectroscopy, Multivariate Chemometrics, and Kinetics Modeling | The deployment of in situ analytics for monitoring chemical reactions in process chemistry development and scale-up is facilitated by advanced instrumentation such as Raman spectrometry. Furthermore, greater process understanding can be engendered by coupling in situ Raman data with multivariate chemometrics analyses a... | 10.1021/op100337v | 0 |
A Safe and Efficient Synthetic Route to a 2,5-Dimethyl-1-aryl-1<i>H</i>-imidazole Intermediate | An optimized route to an iodo-imidazole intermediate in the synthesis of 4-ethynyl-2,5-dimethyl-1-aryl-1 H -imidazoles ( 6 ) was devised. Important data for the optimization work was obtained by carrying out a DOE study to gain understanding of the parameters that affect the key intramolecular cyclization to build the ... | 10.1021/op100335q | 1 |
The Art of Process Chemistry | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTThe Art of Process ChemistryTrevor LairdCite this: Org. Process Res. Dev. 2011, 15, 2, 476Publication Date (Web):December 30, 2010Publication History Published online30 December 2010Published inissue 18 March 2011https://pubs.acs.org/doi/10.1021/op100332dhttps://doi.org/1... | 10.1021/op100332d | 0 |
<i>N</i>-Amination of Indoles on Pilot-Plant Scale via Simultaneous and Proportional Metering of Reagents | The N -amination of indoles on large scale, utilizing a portable Coriolis mass flow metering and pumping system that provides precise dispensing of two reagent streams simultaneously and proportionally, is described. | 10.1021/op100330h | 0 |
Key Green Engineering Research Areas for Sustainable Manufacturing: A Perspective from Pharmaceutical and Fine Chemicals Manufacturers | In 2005, the American Chemical Society (ACS) Green Chemistry Institute (GCI) and global pharmaceutical companies established the ACS GCI Pharmaceutical Roundtable to encourage the integration of green chemistry and engineering into the pharmaceutical industry. The Roundtable developed a list of key research areas in gr... | 10.1021/op100327d | 0 |
Process Development for a Key Synthetic Intermediate of LY2140023, a Clinical Candidate for the Treatment of Schizophrenia | To fuel clinical development of the experimental CNS medicine LY2140023, we developed a scalable route for the multistep synthesis of a pivotal synthetic intermediate. The core of the conformationally restricted glutamic acid-based amino acid analogue was built via a Rh-catalyzed cyclopropanation of thiophene. Regiosel... | 10.1021/op100325h | 1 |
New Procedure for the Preparation of (<i>Z</i>)-2-(5-Amino-1,2,4-thiadiazole-3-yl)-2-trityloxyiminoacetic Acid | A novel and efficient procedure has been developed for the preparation of the C-7 side chain of ceftobiprole, ( Z )-2-(5-amino-1,2,4-thiadiazole-3-yl)-2-trityloxyiminoacetic acid ( 2 ) from malononitrile ( 9 ) in a total yield of 19%. The key intermediate N -(3-(2-acetamido-2-oxoethyl)-1,2,4-thiadiazol-5-yl)benzamide (... | 10.1021/op100323b | 1 |
The Preparation of Desflurane by the Vapor-Phase Fluorination of Isoflurane | There are several known processes for manufacturing the commercially important anaesthetic desflurane (CF 3 CHFOCHF 2 ) by the catalyzed reaction of commercially available isoflurane (CF 3 CHClOCHF 2 ) with hydrogen fluoride. The present available methods have the disadvantage of high catalyst usage, with consequent en... | 10.1021/op100318b | 1 |
Development of Safe, Scalable Nitric Acid Oxidation Using a Catalytic Amount of NaNO<sub>2</sub> for 3-Bromo-2,2-bis(bromomethyl)propanoic Acid: An Intermediate of S-013420 | A safe, scalable process was developed for nitric acid oxidation of 3-bromo-2,2-bis(bromomethyl)propan-1-ol ( 2 ) to give 3-bromo-2,2-bis(bromomethyl)propanoic acid ( 3 ), an intermediate in the synthesis of S-013420 ( 1 ). The key points are the use of a catalytic amount of NaNO 2 and addition of the starting material... | 10.1021/op1003133 | 0 |
Stereoselective Synthesis of Monoamine Reuptake Inhibitor NS9544 Acetate | (−)-3-(2-Benzothienyl)-8- H -8-azabicyclo[3,2,1]oct-2-ene acetate, NS9544 acetate, is a candidate drug intended to treat pain and other CNS disorders. In the synthetic route tropinone was enantioselective deprotonated with a chiral lithium amide derived from [ R -( R *, R *)]-bis(α-methylbenzyl)amine hydrochloride. The... | 10.1021/op1003117 | 1 |
Enzyme and Process Development for Production of Nicotinamide | Through screening a library of nitrile hydratases developed in-house, NHT-120 was selected to catalyze the hydration of 3-cyanopyridine for production of nicotinamide. After reaction optimization, a fed-batch method was used to alleviate the substrate inhibition. Under this approach, 200 g/L of 3-cyanopyridine could be... | 10.1021/op100309g | 0 |
A Continuous Kilogram-Scale Process for the Manufacture of 7-Ethyltryptophol | An expeditious and multikilogram-scale process for the synthesis of 7-ethyltryptophol via a continuous flow reactor from 2-ethylphenylhydrazine and 4-hydroxybutyraldehyde in higher and high yield was described. The main steps in this synthesis involved not only the generation of the hydrazone intermediate in situ but a... | 10.1021/op1003083 | 1 |
Development of a Scalable Synthesis of a GPR40 Receptor Agonist | Early process development and salt selection for AMG 837, a novel GPR40 receptor agonist, is described. The synthetic route to AMG 837 involved the convergent synthesis and coupling of two key fragments, ( S )-3-(4-hydroxyphenyl)hex-4-ynoic acid ( 1 ) and 3-(bromomethyl)-4′-(trifluoromethyl)biphenyl ( 2 ). The chiral β... | 10.1021/op1003055 | 1 |
Toxicological Assessment of 2-Methyltetrahydrofuran and Cyclopentyl Methyl Ether in Support of Their Use in Pharmaceutical Chemical Process Development | Herein we document our evaluation of the oral toxicity of MeTHF and CPME as determined in three month repeat-dose toxicity studies in rats as well as a battery of tests conducted under Good Laboratory Practice (GLP) to assess induction of micronuclei, microbial mutagenicity, and chromosomal aberrations. Based on the st... | 10.1021/op100303c | 0 |
Complementary Syntheses of <i>N</i>,<i>O</i>-Protected-(<i>S</i>)-2-methylserine on a Multikilogram Scale | Two complementary and scalable approaches have been used to manufacture multikilogram quantities of N, O -protected-( S )-2-methylserine. The first approach uses a diastereomeric salt resolution of 2-methylserine methyl ester as the (1 S )-(+)-camphorsulfonate salt, and was used to rapidly access 15 kg of ( S )-3- tert... | 10.1021/op100299d | 1 |
Scale-Up Synthesis of a TRPV1 Antagonist Featuring a Facile Thiazolo[5,4-<i>d</i>]pyrimidine Formation | An efficient and practical synthesis of a TRPV1 inhibitor bearing a thiazolo[5,4- d ]pyrimidine core was developed. The initial synthesis was modified to facilitate acylation of 5-aminopyrimidine and subsequent thiazole formation. The synthesis features an efficient two-pot, five-step process for the construction of th... | 10.1021/op1002984 | 1 |
Process Development of the PDE4 Inhibitor K-34 | A short and practical synthesis of the PDE4 inhibitor K-34 ( 1 ) was developed. This synthesis was achieved in four steps and with a 58% overall yield. The unique spiro acetal was created with exceptionally high yield by utilizing the neighbor carboxylic acid assistance. This synthesis also features efficient ketone co... | 10.1021/op100291g | 1 |
A General, One-Step Synthesis of Substituted Indazoles using a Flow Reactor | Flow chemistry is a rapidly emerging technology within the pharmaceutical industry, both within medicinal and development chemistry groups. The advantages of flow chemistry, increased safety, improved reproducibility, enhanced scalability, are readily apparent, and we aimed to exploit this technology in order to provid... | 10.1021/op100288t | 1 |
Development of Scalable Syntheses of Selective PI3K inhibitors | On the basis of a more practical and scalable route to an iodothiophene, an efficient and reliable synthesis has been developed for three selective PI3K inhibitors. From this advanced intermediate, the three title compounds were each prepared in five additional steps. Key learnings also include: high throughput experim... | 10.1021/op100286g | 1 |
The First Large-Scale Synthesis of MK-4305: A Dual Orexin Receptor Antagonist for the Treatment of Sleep Disorder | A new synthetic route to drug candidate 1, a potent and selective dual orexin antagonist for the treatment of sleep disorders, has been developed. The key acyclic precursor 10 was prepared in a one-step process in 75% isolated yield from commercially available starting materials using novel chemistry to synthesize 2-su... | 10.1021/op1002853 | 1 |
Practical Large-Scale Preparation of (±)-2-<i>exo</i>-Norbornyl Carboxylic Acid and Its Improved Isolation As the Sodium Salt | A practical, robust, and high-yielding three-step−one-pot procedure for the diastereoselective synthesis of (±)-2- exo -norbornyl carboxylic acid starting from norbornylene has been found and demonstrated on multikilogram scale, setting a new benchmark for low-pressure hydroformylation of cyclic, bridged olefins. The n... | 10.1021/op100284a | 0 |
Preparation of 4-Allylisoindoline via a Kumada Coupling with Allylmagnesium Chloride | A practical, cost-effective Kumada coupling for the preparation of 4-allylisoindoline has been developed. The first catalyst screen for this reaction with allylmagnesium reagents is described. The challenges associated with product isomerization have been minimized by a thorough understanding of the reaction parameters... | 10.1021/op1002837 | 0 |
Current Practices of Process Validation for Drug Substances and Intermediates | Process validation includes laboratory optimization, pilot-plant introduction, and process implementation on manufacturing scale, as well as monitoring batches after implementation and continuously improving the manufacturing processes. There are many opportunities to change and optimize operations. The background info... | 10.1021/op1002825 | 0 |
Development of a Safe and Practical <i>N-</i>Oxidation Procedure Using <i>m</i>-CPBA in Acetic Acid | A safe and practical procedure for the N -oxidation of pyrazolopyridine 4 using meta -chloroperbenzoic acid ( m -CPBA) in acetic acid is described. Key safety experiments are outlined which have led to the development and implementation of this reaction on 28-kg scale in 98% isolated yield. | 10.1021/op100280c | 0 |
Asymmetric Synthesis of (<i>S</i>)-3-Amino-4-methoxy-butan-1-ol by Way of Reductive Amination | A new synthesis of ( S )-3-amino-4-methoxy-butan-1-ol is reported. The synthesis is based on the preparation of the primary, nonprotected enamine of the commercially available β-keto ester methyl 4-methoxy-3-oxo-butanoate and asymmetric catalytic enamine hydrogenation using a Ru-MeOBIPHEP catalyst. Alternatively, the p... | 10.1021/op1002775 | 1 |
The Development of a Robust Process for a CRF<sub>1</sub> Receptor Antagonist | A scalable and robust process was developed for the preparation of pexacerfont ( 2 ), a pyrazolotriazine corticotropin-releasing factor receptor 1 antagonist (CRF 1 ). The formation of the core hydroxypyrazolotriazine moiety was achieved through two consecutive cyclizations of a semicarbazide, employing reaction condit... | 10.1021/op100270u | 1 |
Development of an Early Enabling Synthesis for PF-03052334-02: A Novel Hepatoselective HMG-CoA Reductase Inhibitor | Early process development work toward a promising pyrazole-based HMG-CoA reductase inhibitor is described. PF-03052334-02 ( 1 ) was prepared in 14 synthetic steps with a 21% overall yield, highlighted by a modified three-step hydroxypyrazole formation in which the yield was improved from 37% to 73%, a Suzuki/ozonolysis... | 10.1021/op100268e | 1 |
A Robust Three-Step Telescoped Synthesis of Electron- Deficient Amide Substituted Arylboronic Acids | A robust three-step telescoped process for the preparation of electron-deficient amide-substituted arylboronic acids from readily available bromobenzoic acids has been developed. An EDC-HOBT-promoted amide formation of a bromobenzoic acid was followed by subjection of the product stream to a palladium-mediated cross-co... | 10.1021/op100267p | 1 |
A Scalable Oxidation for the Final Stage of Synthesis of Cathepsin K Inhibitor SB-462795 | In developing the manufacturing route for the cathepsin K inhibitor SB-462795, the oxidation of a secondary alcohol for the final chemical stage is described. Prospective conditions were limited by several factors, particularly general safety concerns of oxidation reactions, the requirement to control impurities and tr... | 10.1021/op100266s | 0 |
Dialkyl Sulfide Stabilisation in a Catalytic Dicuprate 1,6-Dienone Addition Process | The catalytic dicuprate addition of 1,9-dibromononane to a sterol 1,6-dienone is strongly enhanced by the presence of dimethylsulfide. Dimethylsulfide appears to have an important stabilising effect on the active organo-dicuprate species formed by reaction of Cu(I)Cl with di(bromomagnesio)nonane. In the absence of dime... | 10.1021/op1002648 | 0 |
Scalable Synthesis of Cyclotriphenolene | Hyperpolarized xenon magnetic resonance imaging ( 129 Xe MRI) is becoming a powerful imaging method that requires cage molecules to encapsulate xenon. Cyclotriphenolene 1 is a key compound for the synthesis of cryptophane cages. A scalable procedure for the synthesis of cyclotriphenolene 1 was developed by which 40 g o... | 10.1021/op100260w | 0 |
Development of the Route of Manufacture of an Oral H<sub>1</sub>−H<sub>3</sub> Antagonist | A new route to an H 1 −H 3 antagonist was developed to address scalability and environmental and cost of goods issues associated with the initial route. | 10.1021/op1002598 | 1 |
The Combination of Hydroformylation and Biocatalysis for the Large-Scale Synthesis of (<i>S</i>)-Allysine Ethylene Acetal | The compound, ( S )-2-amino-5-[1,3]dioxolan-2-yl-pentanoic acid [( S )-allysine ethylene acetal], is a key intermediate in a number of angiotension-I converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitors currently in clinical trials. Through a combination of our hydroformylation and biocatalysis technologi... | 10.1021/op100258j | 1 |
Development of a Second-Generation, Highly Efficient Manufacturing Route for the HIV Integrase Inhibitor Raltegravir Potassium | A manufacturing route for the synthesis of raltegravir potassium 1 was developed via a thermal rearrangement of amidoxime DMAD adducts 6 to construct the key, highly functionalized hydroxypyrimidinone core 7 . Utilizing this route 1 was prepared in nine linear chemical steps with 22% overall yield. A second-generation ... | 10.1021/op100257r | 1 |
Kinetic and Scale-Up Investigations of Epoxide Aminolysis in Microreactors at High Temperatures and Pressures | A continuous-flow microreactor is applied for a kinetic study of a model β-amino alcohol formation by epoxide aminolysis. A large number of experiments are performed in a short time with minimal reagent consumption. The kinetics of formation of secondary aminolysis between starting epoxide and product are decoupled fro... | 10.1021/op100252m | 0 |
Second-Generation Process Research Towards Eletriptan: A Fischer Indole Approach | The development of a second-generation process for the synthesis of eletriptan via a Fischer indole cyclisation is described. The finalised process offers several potential advantages over the current route of manufacture including cost, throughput, and safety. | 10.1021/op100251q | 1 |
The Development of Continuous Process for Alkene Ozonolysis Based on Combined in Situ FTIR, Calorimetry, and Computational Chemistry | Two continuous apparatuses were designed that are capable of safely scaling the highly energetic ozonolysis reaction to multikilogram scale where flow chemistry allowed excellent temperature control and minimized the inventory of the highly unstable ozonide intermediate. First, a continuous stirred tank reactor was dev... | 10.1021/op100249z | 1 |
Development of an Optimized Process for the Preparation of 1-Benzylazetidin-3-ol: An Industrially Important Intermediate for Substituted Azetidine | A thoroughly optimized and robust process for the synthesis of 1-benzylazetidin-3-ol has been emphasized. 1-Benzylazetidin-3-ol has been utilized as a starting material in the commercial synthesis of azetidin-3-ol hydrochloride. Synthesis of azetidin-3-ol hydrochloride involves the usage of very low cost and commercial... | 10.1021/op100247m | 1 |
Solvent-Free and Safe Process for the Quantitative Production of Phosgene from Triphosgene by Deactivated Imino-Based Catalysts | Phosgene is quantitatively formed from solid triphosgene in a solvent-free and safe process without any reaction heat, catalyzed by planar N-heterocycles with deactivated imino functions. The rate of phosgene generation is adjustable to the rate of phosgene consumption in the subsequent phosgenation reaction by thermal... | 10.1021/op100239n | 0 |
Convenient and Practical One-Pot Synthesis of 4-Chloropyrimidines via a Novel Chloroimidate Annulation | Reaction of aromatic or heteroaromatic 2-acyl(amino)nitriles with phosphorus pentachloride triggers a novel chloroimidate cyclization, leading directly to the corresponding annullated 4-chloropyrimidines in good to excellent yields. The reaction lends itself to the telescoped one-pot construction of 4-functionalized py... | 10.1021/op1002352 | 0 |
Development of a New Practical Synthesis of a 5-HT<sub>2C</sub> Receptor Agonist | A new practical synthesis of a 5-HT 2C receptor agonist has been developed and implemented on multikilogram scale. The key step, the selective epoxide opening in the glycidyl tosylate with the aryl Grignard reagent, allowed the incorporation of this commercially available chiral C 3 synthon into the molecule and elabor... | 10.1021/op100233f | 1 |
Book Review of Asymmetric Catalysis on Industrial Scale: Challenges, Approaches and Solutions | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewBook Review of Asymmetric Catalysis on Industrial Scale: Challenges, Approaches and SolutionsTrevor LairdCite this: Org. Process Res. Dev. 2010, 14, 6, 1521Publication Date (Web):October 1, 2010Publication History Received24 August 2010Published online1 October 2010Published ... | 10.1021/op100232t | 0 |
Practical Access to Metallo Thiophenes: Regioselective Synthesis of 2,4-Disubstituted Thiophenes | This report describes a protocol for functionalization of thiophenes, utilizing a regioselective magnesiation mediated by commercial Grignard reagents and catalytic 2,2,6,6-tetramethylpiperidine. This metalation provides practical access to metallo thiophenes, avoiding cryogenic conditions, prolonged reaction times, an... | 10.1021/op100226k | 1 |
Kilogram Synthesis of a Second-Generation LFA-1/ICAM Inhibitor | The process development and the kilogram-scale synthesis of BMS-688521 ( 1 ) are described. The synthesis features a highly efficient telescoped sequence which utilizes previously described spirocyclic hydantoin ( 4b ) to produce the final intermediate via an SN AR reaction. A final deprotection step affords BMS-688521... | 10.1021/op100225g | 1 |
In-Process Monitoring and Control of Supersaturation in Seeded Batch Cooling Crystallisation of <scp>l</scp>-Glutamic Acid: From Laboratory to Industrial Pilot Plant | A measurement-based closed-loop control system using in-process ATR-FTIR spectroscopy coupled with a multivariate chemometric PLS calibration model is developed, validated, and applied to the monitoring and control of supersaturation in a 250- L industrial pilot-plant crystalliser. Supersaturation control experiments a... | 10.1021/op100223a | 0 |
A Kilolaboratory Preparation of the CNRS Chiral Auxiliary | An improved preparation at kilolaboratory scale of the CNRS chiral auxiliary is presented. | 10.1021/op1002227 | 0 |
Green Progression for Synthesis of Regioselective β-Amino Alcohols and Chemoselective Alkylated Indoles | Solid acid catalysts based on zirconia materials were investigated for the first time as catalysts for regioselective organic synthesis under environmentally benign and mild conditions. The novel TiO 2 −ZrO 2 mixed oxide catalyst led to two distinct products by the formation of an N−C bond (β-amino alcohols) and a C−C ... | 10.1021/op1002177 | 0 |
Guidelines and Cost Analysis for Catalyst Production in Biocatalytic Processes | Biocatalysis is an emerging area of technology, and to date few reports have documented the economics of such processes. As it is a relatively new technology, many processes do not immediately fulfill the economic requirements for commercial operation. Hence, early-stage economic assessment could be a powerful tool to ... | 10.1021/op1002165 | 0 |
Multienzyme-Catalyzed Processes: Next-Generation Biocatalysis | Biocatalysis has been attracting increasing interest in recent years. Nevertheless, most studies concerning biocatalysis have been carried out using single enzymes (soluble or immobilized). Currently, multiple enzyme mixtures are attractive for the production of many compounds at an industrial level. In this review, a ... | 10.1021/op1002159 | 0 |
Book Report of Cinchona Alkaloids in Synthesis and Catalysis: Ligands, Immobilization and Organocatalysis | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewBook Report of Cinchona Alkaloids in Synthesis and Catalysis: Ligands, Immobilization and OrganocatalysisCite this: Org. Process Res. Dev. 2010, 14, 5, 1274Publication Date (Web):August 16, 2010Publication History Received2 August 2010Published online16 August 2010Published i... | 10.1021/op100213x | 0 |
An Efficient and Scalable Synthesis of the Spirocyclic Glycine Transporter Inhibitor GSK2137305 | An efficient and scalable synthesis of a glycine transporter inhibitor is presented. The key steps in the synthetic sequence are the formation of a spirocyclic imidazolidinone from an α-amino nitrile and a cyclic ketone and an arylation of 4-methyl imidazole under ‘ligandless’ Ullmann coupling conditions. | 10.1021/op100210s | 1 |
Application of Quality by Design Principles for the Definition of a Robust Crystallization Process for Casopitant Mesylate | GlaxoSmithKline (GSK) has identified casopitant as a potent NK 1 antagonist. It was selected for its potential activities on a number of therapeutic targets such as inflammatory bowel disease, overactive bladder, CNS disorders and others. The mesylate salt of casopitant was selected for full development using a quality... | 10.1021/op100209c | 0 |
An Integrated Chemo-enzymatic Route for Preparation of β-Thymidine, a Key Intermediate in the Preparation of Antiretrovirals | A chemo-enzymatic method for production of β-thymidine, an intermediate in the synthesis of antiretrovirals, is described. Guanosine and thymine were converted by means of enzymatic transglycosylation to yield 5-methyluridine (5-MU), which was reproducibly synthesised at a 10−20-L scale in 85% yield at a final product ... | 10.1021/op100208x | 0 |
Development of a Practical Synthesis of a Pyrazolopyridinone-Based p38 MAP Kinase Inhibitor | A practical synthesis of the pyrazolopyridinone-based p38 MAP kinase inhibitor ( 4 ) was required for an ongoing program. The synthesis of a key pyrazolopyridinone building block was refined and optimized to provide kilogram quantities of 10 without chromatography or extractive workups. An efficient building-block stra... | 10.1021/op100205s | 1 |
Development of a Suitable Salt Form for a GPR40 Receptor Agonist | AMG 837 ( 1 ) is a novel GPR40 agonist selected for clinical development for the treatment of type 2 diabetes. A lysine salt was initially identified as a development form. However, due to the poor crystallinity and severe hygroscopicity of this form, investigations on the free acid form of the drug substance and salt ... | 10.1021/op100204u | 0 |
Development of a Practical and Efficient Synthesis of Chloromethyl 2-Ethoxy-2-methylpropanoate | An efficient synthesis of chloromethyl 2-ethoxy-2-methylpropanoate from 2-bromoisobutyric acid is reported. Four developments were key to this route: (i) a mild, base-mediated ethanolysis of a tertiary alkyl bromide, (ii) a sodium bisulfite purge of 2-methylacrylic acid, (iii) preparation of a thiomethyl ester via a fo... | 10.1021/op1002038 | 1 |
Variable Microwave Effects in the Synthesis of Ureidopyrimidinones: the Role of Heterogeneity | Microwave-irradiated and conventionally heated nucleophilic additions of various C-6 substituted isocytosines (methyl, ethyl, isopropyl, and phenyl) to (di)isocyanates have been compared. As compared to conventional heating, the heterogeneous reaction mixtures showed higher reaction rates on using microwave heating. Va... | 10.1021/op100202j | 0 |
Initial Scale-Up and Process Improvements for the Preparation of a Lead Antibacterial Macrolone Compound | Macrolones are a novel class of potent antimicrobial agents that consist of a macrolide scaffold to which a quinolone unit is tethered by various linkers to the 4′′- O -position of the cladinose sugar. In this paper is described a modified 13-step route to a lead compound in the series. Critical reaction steps in the m... | 10.1021/op100199t | 1 |
Dexmethylphenidate: An Efficient Process for the Racemization of Unwanted (2<i>S</i>,2′<i>S</i>or<i>l</i>-<i>threo</i>)-α-Phenyl-α-(2-piperidyl)acetamide | (2 R,2′ R )- d - threo -α-Phenyl-α-(2-piperidyl)acetamide ( 3 ), an advanced intermediate for dexmethylphenidate hydrochloride synthesis, is prepared by the resolution of dl - threo -α-phenyl-α-(2-piperidyl)acetamide ( 2 ) with dibenzoyl- d -tartaric acid in isopropanol with % yield and 99% ee. Although this process is... | 10.1021/op100197g | 0 |
Scale-Up of a Chemo-Biocatalytic Route to (2<i>R</i>,4<i>R</i>)- and (2<i>S</i>,4<i>S</i>)-Monatin | Monatin, a natural sweetener, refers to a collection of four isomers of 2-((1 H -indol-3-yl)methyl)-4-amino-2-hydroxypentanedioic acid. A chemo-biocatalytic approach to kilogram quantities of enantiopure 2 S,4 S -monatin and 2 R,4 R -monatin from indole is described. Key steps in the process include a (2 + 3) cycloaddi... | 10.1021/op1001947 | 1 |
Scaleable Preparation of Sensitive Functionalized Aromatics and Heteroaromatics via Directed Metalation Using tmpZnCl·LiCl | A range of functional aryl and heteroaryl zinc reagents were prepared in THF via directed zincation using the previously reported amide base tmpZnCl·LiCl. These metalation reactions were carried out on 50 mmol scale. Diverse sensitive functional groups such as a nitro group, an aldehyde, an ester, and a nitrile are tol... | 10.1021/op1001935 | 0 |
Selective Hydrogenolysis of Glycerol to 1,2-Propanediol: Comparison of Batch and Continuous Process Operations | The screening of copper chromite catalysts with various promoters such as Al, Zn, and Ba for glycerol hydrogenolysis to 1,2-propanediol (1,2-PDO) in a batch reaction showed that Cu−Cr (Ba) catalyst gave the highest conversion of 34% and selectivity of 84% to 1,2-PDO. In a continuous operation (23 g catalyst bed) the sa... | 10.1021/op1001897 | 0 |
Development of a Novel Catalytic Distillation Process for Cyclohexanol Production: Mini Plant Experiments and Complementary Process Simulations | A new, two-step process concept for the production of cyclohexanol by indirect hydration of cyclohexene using formic acid as a reactive entrainer is suggested, and its principle technical feasibility is demonstrated. The first step of this process is based on an ester formation reaction of cyclohexene with formic acid.... | 10.1021/op1001879 | 0 |
Discovery and Development of an Efficient, Scalable, and Robust Route to the Novel CENP-E Inhibitor GSK923295A | The discovery and development of an efficient manufacturing route to the CENP-E inhibitor 3-chloro- N -{(1 S )-2-[( N, N -dimethylglycyl)amino]-1-[(4-{8-[(1 S )-1-hydroxyethyl]imidazo[1,2- a ]pyridin-2-yl}phenyl)methyl]ethyl}−4-[(1-methylethyl)oxy]benzamide (GSK923295A) is described. The existing route to GSK923295A wa... | 10.1021/op100186c | 1 |
A Switchable Oxidation Process Leading to Two Various Versatile Pharmaceutical Intermediates | An efficient high-yielding and environmentally benign switchable oxidation process that can selectively produce two different versatile synthetic intermediates is disclosed. One of the two intermediates, 2,3-dimethoxy-5-methylcyclohexa-2,5-diene-1,4-dione (coenzyme Q 0 ), is obtained by means of a telescoped two-step s... | 10.1021/op100185x | 0 |
Robust Synthesis of Methyl 5-Chloro-4-fluoro-1<i>H</i>-indole-2-carboxylate: A Key Intermediate in the Preparation of an HIV NNRTI Candidate | A synthetic preparation of methyl 5-chloro-4-fluoro-1 H -indole-2-carboxylate, a key intermediate towards phosphoindole inhibitors of HIV non-nucleoside reverse transcriptase, is described. The five-step synthesis involved Boc protection of the commercially available 4-chloro-3-fluoroaniline and regioselective iodinati... | 10.1021/op1001808 | 1 |
Convenient Method for Synthesis of <i>N</i>-Protected α-Amino Epoxides: Key Intermediates for HIV Protease Inhibitors | A convenient method for synthesis of 2 R,3 S and 2 S,3 S N -Boc phenylalanine epoxides using readily available allylamine is described. Previous methods employed multistep synthetic routes from l -phenyl alanine that include use of m -chloroperbenzoic acid ( m- CPBA) and a chromatographic method for purification of the... | 10.1021/op100174j | 1 |
Optimization of a Hydrogenation Process using Real-Time Mid-IR, Heat Flow and Gas Uptake Measurements | This paper describes using real-time mid-IR, heat flow, and gas uptake data to optimize the hydrogenation of a nitroaromatic to an aniline that had been difficult to control during a previous campaign in the pilot plant. A bimetallic Pt/V catalyst was identified that eliminated the buildup of reaction intermediates and... | 10.1021/op100169j | 0 |
An Efficient Scalable Route for the Synthesis of Enantiomerically Pure <i>tert</i>-Butyl-(1<i>R</i>,4<i>S</i>,6<i>R</i>)-4-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate | An efficient scalable route to synthesize the enantiomerically pure tert -butyl-(1 R,4 S,6 R )-4-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate is described. Compared to the original routes, significant improvements were made by using an innovative approach starting from commercially available chiral lactone.... | 10.1021/op100164v | 1 |
Development of an Efficient and Practical Route for the Multikilogram Manufacture of the SRC Kinase Inhibitor AZD0530 | In a previous publication ( Org. Process Res. Dev. 2010, 14, DOI: 10.1021/op100161y ) we described the process research and development of a manufacturing route for the potent SRC kinase inhibitor AZD0530. While the route was successfully used to manufacture 4.5 kg of AZD0530 difumarate, it was still relatively long, u... | 10.1021/op100163m | 1 |
Process Research and Development for the Kilogram Manufacture of the SRC Kinase Inhibitor AZD0530 | Process research and development of a synthetic route towards a novel SRC kinase inhibitor is described. The Medicinal Chemistry route was very long and suffered from extensive use of chlorinated solvents and chromatography. A number of steps in the Medicinal Chemistry route were also unattractive for large-scale use f... | 10.1021/op100161y | 1 |
Process Development and Pilot-Plant Synthesis of (2-Chlorophenyl)[2-(phenylsulfonyl)pyridin-3-yl]methanone | Routes to (2-chlorophenyl)[2-(phenylsulfonyl)pyridin-3-yl]methanone, 1, an intermediate in the manufacture of NK1-II inhibitor LY686017 are described which produce 1 in >75% yield and 95% purity. A highly selective telescoped ortho lithation/condensation/oxidation process was developed and successfully scaled to the cl... | 10.1021/op100157q | 0 |
Enzymatic Preparation of an (<i>S</i>)-Amino Acid from a Racemic Amino Acid | The ( S )-amino acid, ( S )-2-amino-3-(6- o -tolylpyridin-3-yl)propanoic acid ( 3 ), is a key intermediate needed for synthesis of an antidiabetic drug candidate. Three enzymatic routes to 3 were explored. ( S )-Amino acid 3 could be prepared in 73% isolated yield with 99.9% ee from racemic amino acid 1 using ( R )-ami... | 10.1021/op1001534 | 0 |
Development of an Efficient Synthesis of Two CRF Antagonists for the Treatment of Neurological Disorders | BMS-764459 ( 1 ) and BMS-763534 ( 2 ) are CRF1 antagonists for the treatment of neurological disorders such as depression and anxiety. An efficient synthesis of 1 and 2 is described, which features an efficient palladium-catalyzed cyanation of a 5-chloropyrazinone where zinc acetate suppresses dehalogenation. This synt... | 10.1021/op1001512 | 1 |
Development of Drug Substances as Mixture of Polymorphs: Studies to Control Form 3 in Casopitant Mesylate | Polymorphism is characterized as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice and this can impact the physical properties of a drug substance. In this paper the studies carried out on casopitant m... | 10.1021/op100150b | 0 |
Identification of a Manufacturing Route of Novel CRF-1 Antagonists Containing a 2,3-Dihydro-1<i>H</i>-pyrrolo[2,3-<i>b</i>]pyridine Moiety | A case study on the synthesis of novel CRF-1 antagonists containing the 2,3-dihydro-1 H -pyrrolo[2,3- b ]pyridine moiety is presented. The development of ever more efficient synthetic routes allowed the progression of three candidates at the same time. A manufacturing route was identified and successfully demonstrated ... | 10.1021/op100147h | 1 |
The Synthesis of Two Potent β-3 Adrenergic Receptor Agonists | This contribution describes the initial preparation of two potent β-3 receptor agonists 1 and 2 . Subsequent scale up of these two compounds was required for further evaluation and proceeded via a common key amine intermediate 24 . Synthesis of this key intermediate by way of a Ritter reaction was a vital step in the s... | 10.1021/op1001462 | 1 |
An Optimized Process to 10-Bromo-1-decanol | A multivariate design and optimization study for the synthesis of the bromoalkanol 10-bromo-1-decanol using decane-1,10-diol as substrate is reported. The bromination process was supported by the phase transfer catalyst tetrabutylammonium bromide with aqueous HBr (48%) as the brominating reagent. The optimized batch pr... | 10.1021/op100143t | 0 |
Investigation into the Formation of the Genotoxic Impurity Ethyl Besylate in the Final Step Manufacturing Process of UK-369,003-26, a Novel PDE5 Inhibitor | Sulfonate esters have a demonstrated potential for genotoxicity, and therefore their potential presence at trace levels in active pharmaceutical ingredients (APIs) has recently raised concerns [ Mesylate Ester Type Impurities Contained in Medicinal Products; Swissmedic Department for Control of the Medicinal Products M... | 10.1021/op100141g | 1 |
Organic Solvent Nanofiltration: A New Paradigm in Peptide Synthesis | Solid-phase synthesis is the dominant paradigm for peptide synthesis, used ubiquitously from discovery to production scale. However, the solid-phase approach produces coupling steps that may not be quantitative, introducing errors in amino acid sequences. It also entails an excess of reagents to overcome mass transfer ... | 10.1021/op1001403 | 0 |
Development of a New Synthesis for the Large-Scale Preparation of Triple Reuptake Inhibitor (−)-GSK1360707 | The triple reuptake inhibitor, GSK1360707, was synthesized via an efficient, scalable route, which features a vinyl triflate Suzuki coupling followed by a single-step, double alkylative cyclopropanation with a dihalomethane. Also, a mechanistic understanding of the Suzuki reaction (as it relates to the control of a pol... | 10.1021/op100139f | 1 |
Practical Synthesis of (1<i>s</i>,4<i>s</i>)-4-(Methylamino)-1′<i>H</i>-spiro[cyclohexane-1,3′-furo[3,4-<i>c</i>]pyridin]-1′-one | A practical and scalable process for the preparation of (1 s,4 s )-4-(methylamino)-1′ H -spiro[cyclohexane-1,3′-furo[3,4- c ]pyridin]-1′-one 2a, a highly functionalized and potentially useful building block for pharmaceutical research is described. The material is prepared via an efficient two-step sequence from readil... | 10.1021/op100138t | 0 |
Review of U.S. Patents in the Field of Organic Process Development Published During February and March 2010 | ADVERTISEMENT RETURN TO ISSUEPREVHighlights From Pate...Highlights From PatentsNEXTReview of U.S. Patents in the Field of Organic Process Development Published During February and March 2010Keith TurnerView Author Information Kappa Tau Consulting, 12 The Avenue, Fairfield, Stockton-on-Tees, TS19 7EY, U.K. E-mail: [emai... | 10.1021/op100134a | 0 |
Process Improvements for the Manufacture of Tenofovir Disoproxil Fumarate at Commercial Scale | The three-step manufacturing process used in the synthesis of tenofovir disoproxil fumarate ( 1 ) was studied and optimized, leading to a more productive and robust process. The yield was improved from about 13% overall to 24%. Key process improvements identified included implementation of a telescoped process for the ... | 10.1021/op1001337 | 1 |
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