title string | abstract string | doi string | has_route int64 |
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Development and Scale-Up of an Optimized Route to the Peptide Boronic Acid, CEP-18770 | CEP-18770 is an unstable peptide boronic acid and an amorphous solid, making it a challenging synthetic target. Process R&D led to a new process that avoided chromatography through crystalline intermediates, increased atom and volume efficiency, provided a chromophore, and gave higher yields and purity. A stable, cryst... | 10.1021/op400010u | 1 |
Special Feature Sections of <i>Organic Process Research & Development</i> in 2013 and 2014 | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTSpecial Feature Sections of Organic Process Research & Development in 2013 and 2014Trevor LairdCite this: Org. Process Res. Dev. 2013, 17, 2, 159Publication Date (Web):January 30, 2013Publication History Published online30 January 2013Published inissue 15 February 2013https://p... | 10.1021/op400009x | 0 |
An Improved and Efficient Process for the Production of Dronedarone Hydrochloride, an Antiarrhythmia Drug | An improved, high-yielding, and efficient process for the production of dronedarone hydrochloride (1), a class III antiarrhythmia drug for the prevention of cardiac arrhythmias such as atrial fibrillation (AF) is described. The developed process avoids isolation of unstable intermediates at several stages by telescopin... | 10.1021/op400008e | 1 |
Synthesis of Donepezil Hydrochloride via Chemoselective Hydrogenation | ADVERTISEMENT RETURN TO ISSUEPREVRetractionNEXTSynthesis of Donepezil Hydrochloride via Chemoselective HydrogenationAjay Singh Rawat*, Sachin Pande, Nilay Bhatt, Raju Kharatkar, Chandrakant Belwal, and Anand VardhanCite this: Org. Process Res. Dev. 2013, 17, 12, 1617Publication Date (Web):April 9, 2013Publication Histo... | 10.1021/op400007p | 1 |
Development of a Scalable Synthesis of a Pyridinyl-3-azabicyclononene, a Novel Nicotinic Partial Agonist | The process research and development of two syntheses of a novel nicotinic partial agonist, TC-8817 ( (+)-5 ), are described. The original Medicinal Chemistry route had multiple flaws, making it unsuitable for further development. A second approach was explored which was more amenable to optimization. The key steps wer... | 10.1021/op400002r | 1 |
A Fast and Effective Hydrogenation Process of Protected Pentasaccharide: A Key Step in the Synthesis of Fondaparinux Sodium | An improved method for the simultaneous removal of O -benzyl and N -carboxybenzyl groups as well as reducing azide groups to amines in protected heparin-like pentasaccharides, a key process in fondaparinux sodium synthesis, is reported. Under catalytic transfer hydrogenation conditions, using readily available and inex... | 10.1021/op300367c | 1 |
A Novel Scalable Process to the GSK3β Inhibitor AZD8926 Based on a Heterocyclic Ziegler Coupling | Development of a new, safe, and scalable route to the GSK3β inhibitor, AZD8926, is presented. In brief, the process constitutes of (i) a synthesis of 1-(pyran-4-yl)-2-trifluoromethyl-imidazole, 14; (ii) a Ziegler-type coupling of lithiated 14 with commercially available 2-chloro-5-fluoropyrimidine via 1,2-addition over... | 10.1021/op300365e | 1 |
On the Fischer Indole Synthesis of 7-Ethyltryptophol—Mechanistic and Process Intensification Studies under Continuous Flow Conditions | 7-Ethyltryptophol, a key intermediate in the synthesis of the anti-inflammatory agent etodolac, was produced by Fischer indole synthesis of 2-ethylphenylhydrazine and 2,3-dihydrofuran under continuous flow conditions. The reaction generates several undesired byproducts and therefore product yields could not be improved... | 10.1021/op300363s | 0 |
Integration of Process Analytical Technology Tools in Pilot-Plant Setups for the Real-Time Monitoring of Crystallizations and Phase Transitions | In this study it was demonstrated that the usage of an access unit connected to a pump-around loop cycle is a good solution for the integration of various online analytical measurement techniques in pilot-plant or industrial-scale reactors without time and cost intensive modifications of the existing setup. As a model ... | 10.1021/op300359p | 0 |
Safety/Hazard Indices: Completion of a Unified Suite of Metrics for the Assessment of “Greenness” for Chemical Reactions and Synthesis Plans | An overall Safety/Hazard Index (SHI) is introduced and defined in the same way as the previously described benign index (BI) covering various environmental impacts. Following the same themes and symbolism usage found in the Workplace Hazardous Materials Information System (WHMIS) and National Fire Protection Associatio... | 10.1021/op300352w | 1 |
Development of a Scalable Synthesis of Oxadiazole Based S1P<sub>1</sub> Receptor Agonists | A robust and scalable synthesis was developed for the preparation of oxadiazole based S1P 1 inhibitors. A new method for the separation of triphenylphosphine oxide from reaction products and an improved method for the synthesis of oxadiazoles in the presence of DBU were incorporated into the process to achieve its scal... | 10.1021/op300345v | 1 |
Development of an Alternate Synthesis for a Key JAK2 Inhibitor Intermediate via Sequential C–H Bond Functionalization | The development of an alternative synthetic route to a functionalized imidazopyridazine which strategically streamlines the synthesis and avoids a number of problematic reagents is described. Key to the success of this alternative route is the use of two C–H functionalization reactions: a Pd-catalyzed direct benzylatio... | 10.1021/op300344m | 1 |
One-Pot Racemization Process of 1-Phenyl-1,2,3,4-tetrahydroisoquinoline: A Key Intermediate for the Antimuscarinic Agent Solifenacin | ( S )-(+)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline, which is the key intermediate in preparing the urinary antispasmodic drug solifenacin, was racemized in quantitative yield by a simple one-pot procedure through N-chlorination with trichloroisocyanuric acid, conversion of the N -chloroamine into the imine hydrochloride... | 10.1021/op300343q | 1 |
Optimization of the Manufacturing Route to PF-610355 (2): Synthesis of the API | PF-610355 is a novel inhaled β-2 adrenoreceptor agonist. Process development of the final intermediate and the API are discussed with emphasis on the control of physical properties and subsequent isolations. This includes development of a constant volume distillation and evaluation of Nutsche filtration, agitated filte... | 10.1021/op300342y | 1 |
Optimization of the Manufacturing Route to PF-610355 (1): Synthesis of Intermediate <b>5</b> | Tertiary carbinamine 5 is an isolated intermediate in the synthesis of a novel, inhaled β-2 adrenoreceptor agonist PF-610355 . Process development for the key amide-formation and Ritter reactions, together with reaction understanding studies are discussed in context of the synthesis of 5 . The optimized process employe... | 10.1021/op300341n | 0 |
Practical and Efficient Large-Scale Preparation of Dimethyldioxirane | An improved procedure for large-scale and also commercially viable preparation of dimethyldioxirane (DMDO), a common and widely used oxidation agent in organic synthesis, was developed using a conventional laboratory plant. All reaction parameters were optimized, and the stability of a freshly prepared solution of DMDO... | 10.1021/op300338q | 0 |
Commercial Scale Process of Galanthamine Hydrobromide Involving Luche Reduction: Galanthamine Process Involving Regioselective 1,2-Reduction of α,β-Unsaturated Ketone | Effect of lanthanide chloride in the Luche regioselective 1,2-reduction of 1-bromo-11-formyl-nornarwedine ( 5 ) was studied. Thus, 1-bromo-11-formyl-nornarwedine ( 5 ) is reduced with sodium borohydride in the presence of lanthanide chloride to yield 1-bromo-11-formyl-galanthamine isomers ( 6 ), which is a key intermed... | 10.1021/op300337y | 1 |
Development of a Robust and Sustainable Process for Nucleoside Formation | A practical and robust process for the synthesis of an Isatoribine pro-drug was demonstrated. The process relies on a streamlined glycosylation carried out in xylene and an effective regioselective enzymatic hydrolysis that can be run in a semicontinuous way. Analysis of the process mass intensity established the high ... | 10.1021/op300335d | 1 |
Chemical and Process Safety | ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTChemical and Process SafetyTrevor LairdCite this: Org. Process Res. Dev. 2012, 16, 12, 1979Publication Date (Web):November 30, 2012Publication History Published online30 November 2012Published inissue 21 December 2012https://pubs.acs.org/doi/10.1021/op3003322https://doi.org... | 10.1021/op3003322 | 0 |
Synthesis of a Sodium–Hydrogen Exchange Type 1 Inhibitor: An Efficient Cu-Catalyzed Conjugated Addition of a Grignard Reagent to an Acetyl Pyridinium Salt | A facile and economical five-step process for the synthesis of a sodium–hydrogen exchange type I inhibitor (NHE-1) was developed from readily available starting materials in 43% overall yield. Key transformations included a highly efficient copper-catalyzed conjugate addition of 2-trifluoromethylphenyl Grignard reagent... | 10.1021/op300331b | 1 |
Development of a Practical Synthesis of a TORC1/2 Inhibitor: A Scalable Application of Memory of Chirality | Progression toward a scalable synthesis of TORC1/2 inhibitor bulk drug, culminating in the first GMP manufacturing campaign, is described. Process research and development was needed to obtain the prerequisite stereocenter in high enantiomeric excess for kilogram-scale production. Through route selection, a six-linear ... | 10.1021/op300330f | 1 |
A Practical and Scalable Manufacturing Process for an Antifungal Agent, Nikkomycin Z | A scalable and reliable manufacturing process for Nikkomycin Z HCl on a 170 g scale has been developed and optimized. The process is characterized by a 2.3 g/L fermentation yield, 79% purification yield, and >98% relative purity of the final product. This method is suitable for further scale up and cGMP production. The... | 10.1021/op3003294 | 0 |
How To Use the Lasentec FBRM Probe on Manufacturing Scale | A Lasentec FBRM probe was installed in a 450-L production unit and deployed to monitor the final three stages of the manufacturing process. Each step features a different type of crystallization: reactive, pH switch and cooling. In total over 100 batches were monitored. The probe detected ‘oiling out’ and seeding with ... | 10.1021/op300326b | 1 |
Application of Continuous Flow Micromixing Reactor Technology for Synthesis of Benzimidazole Drugs | Synthesis of pharmaceutically active compounds by employing continuous flow micromixing reactor technology is an interesting research area. In this article we describe the synthesis of benzimidazole core drugs, such as lansoprazole ( 1a ), pantaprazole ( 1b ), and rabeprazole ( 1c ) by using a continuous flow micromixi... | 10.1021/op300325f | 1 |
Development of a Scalable Route to a Dual NK-1/Serotonin Receptor Antagonist | The evolution of a process for the preparation of a new heterocyclic dual NK1/serotonin receptor antagonist is described. The final synthesis features a telescoped sequence in which an iron(III)-catalyzed Grignard coupling is followed by a benzylic chlorination utilizing trichlorocyanuric acid to construct an unsymmetr... | 10.1021/op300323k | 1 |
Synthesis of a Spiroindolinone Pyrrolidinecarboxamide MDM2 Antagonist | A practical synthesis of a spiroindolinone pyrrolidinecarboxamide MDM2 antagonist 2 is reported. Cycloaddition of dipolarophile 3 with imine 30 afforded a complex mixture of diastereomers that were isomerized to the desired stereoisomer 31 by heating the mixture in the presence of DBU. After hydrolysis, the resulting p... | 10.1021/op3003213 | 1 |
Biodiesel Synthesis Evaluated by Using Real-Time ATR-FTIR | Real-time attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) was used as an analytical method capable of providing quantitative data regarding the yield of biodiesel synthesis. 1 H NMR was used as a reference technique to check the consistency of the data obtained by ATR-FTIR. The evaluatio... | 10.1021/op300318k | 0 |
Industrial Scale-Up of Enantioselective Hydrogenation for the Asymmetric Synthesis of Rivastigmine | Two efficient processes for the synthesis of rivastigmine, one of the most potent drugs for the treatment of mild-to-moderate dementia of the type presenting in Alzheimer’s disease, has been developed. Of particular note is the processes used for the asymmetric hydrogenation by applying the highly efficient chiral spir... | 10.1021/op3003147 | 1 |
Process Development of a Potent Neuroprotector Agent: Collismycin A | An efficient synthetic process for the natural product of marine origin, collismycin type A, a potent neuroprotector agent, has been developed. This new synthetic route avoids chromatographic steps, implies an improvement cost, and provides easy access to large scale. | 10.1021/op3003129 | 1 |
Selection of an Enantioselective Process for the Preparation of a CGRP Receptor Inhibitor | ( R )- N- (3-(7-Methyl-1 H -indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazine-1-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide ( 1 ) is a potent calcitonin gene-related peptide (CGRP) receptor antagonist. We have developed a convergent, stereoselective, and economical synthesis of ... | 10.1021/op3003097 | 1 |
Practical Synthesis of PGI<sub>2</sub> Agonist: Resolution–Inversion–Recycle Approach of Its Chiral Intermediate | Practical synthesis of ((2 R )-5-benzyloxy-2-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methanol ( ( R )-7b ), a key chiral intermediate for the synthesis of the novel PGI 2 agonist, ( R )-[6-[(diphenylcarbamoyloxy)methyl]-6-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yloxy]acetic acid ( 1 ), was achieved via optical resolution ... | 10.1021/op3003085 | 1 |
An Efficient Large-Scale Synthesis of a Naphthylacetic Acid CRTH2 Receptor Antagonist | An efficient and practical synthesis of a naphthylacetic acid CRTH2 receptor antagonist is reported. Michael addition of ethyl t -butyl malonate to an allenoate afforded a triester, which was selectively hydrolyzed and decarboxylated to give a benzylidenepentanedioic acid monoester. Treatment of this compound with pota... | 10.1021/op300306c | 1 |
An Efficient Process for the Large-Scale Synthesis of a 2,3,6-Trisubstituted Indole | The efficient synthesis of a key trisubstituted indole intermediate 1 is described. The synthetic route required the use of an aryl Grignard reagent which was not commercially available, and the large-scale formation of this fragment and the thermal evaluation for this step is presented. The key step in the sequence wa... | 10.1021/op300303p | 1 |
Process Research on a Phenoxybutyric Acid LTB4 Receptor Antagonist. Efficient Kilogram-Scale Synthesis of a 3,5-Bisarylphenol Core | An improved, kilogram-scale synthesis of a LTB4 receptor antagonist is reported. The title compound was prepared in four linear steps (seven steps total) and 54% overall yield. The 3,5-bisarylphenol core was obtained in nearly quantitative yield by the condensation of 1-benzotriazol-1-ylpropan-2-one with a chalcone. Al... | 10.1021/op300302s | 1 |
Development of a Multigram Synthesis of URB937, a Peripherally Restricted FAAH Inhibitor | A new synthetic approach to URB937 was developed starting from the inexpensive and widely available 4-benzyloxyphenol. A reproducible four-step procedure, requiring no chromatographic purifications, was optimized that allowed the preparation of 100 g of URB937 in 45% overall yield. | 10.1021/op300301u | 1 |
Rapid Analysis of Residual Palladium in Pharmaceutical Development Using a Catalysis-Based Fluorometric Method | Measurement of residual metals in pharmaceutical intermediates is routinely performed using inductively coupled plasma-optical emission spectroscopy (ICP-OES) or inductively coupled plasma-mass spectrometry (ICP-MS). However, these techniques suffer from drawbacks that limit their utility in pharmaceutical process deve... | 10.1021/op3003008 | 0 |
A Practical Synthesis of a PI3K Inhibitor under Noncryogenic Conditions via Functionalization of a Lithium Triarylmagnesiate Intermediate | We report a practical synthesis of PI3K inhibitor GDC-0941 . The synthesis was achieved using a convergent approach starting from a thienopyrimidine intermediate through a sequence of formylation and reductive amination followed by Suzuki-Miyaura cross-coupling. Metalation of the thienopyrimidine intermediate involving... | 10.1021/op3002992 | 1 |
Development of Related HCV Protease Inhibitors: Macrocyclization of Two Highly Functionalized Dienyl-ureas via Ring-Closing Metathesis | A novel assembly of two structurally related 14-membered ring macrocyclic hepatitis C virus protease inhibitors is presented. Key to their successful construction was an ultimate ring-closing metathesis step on the respective highly functionalized dienyl-ureas. In the case of IDX316, this procedure significantly outper... | 10.1021/op300296t | 1 |
Efficient Large-Scale Synthesis of a 2,4,5-Triarylimidazoline MDM2 Antagonist | An improved, kilogram-scale synthesis of a triarylimidazoline MDM2 antagonist is reported. The nicotinic acid component was prepared in three steps from ethyl 2-dimethylaminomethylene-3-oxo-butyrate. The coupling of the nicotinic acid with the meso -diamine selectively produced the monoamide which was cyclized in the p... | 10.1021/op300294g | 1 |
Development of Synthetic Routes, via a Tropinone Intermediate, to a Long-Acting Muscarinic Antagonist for the Treatment of Respiratory Disease | This contribution describes the development of two synthetic routes to an investigational muscarinic antagonist for the treatment of chronic obstructive pulmonary disease. The first route used a starting material which was in plentiful supply within the GSK network and was used to make material for early clinical trial... | 10.1021/op3002933 | 0 |
Complexity-Based Metric for Process Mass Intensity in the Pharmaceutical Industry | Process mass intensity (PMI) is a key metric for evaluating the sustainability of a manufacturing process. Within Eli Lilly and Co. (Lilly), a process based on the molecular complexity and the projected market demand has been adopted to set PMI targets for prospective drugs. This strategy is described. PMIs for relevan... | 10.1021/op3002917 | 0 |
Optimization of Reaction Parameters for the Synthesis of Chromium Methionine Complex Using Response Surface Methodology | This study deals with a new and better protocol to prepare chromium methionine using aqueous ethanol solution as the reaction medium. Response surface methodology (RSM) coupled with Box-Behnken design was employed to model and optimize the operational parameters of this protocol. The ethanol content of aqueous ethanol,... | 10.1021/op3002905 | 0 |
Scalable Synthesis of a Cis-Substituted Cyclobutyl-Benzothiazole Pyridazinone: Process Development of an Efficient Copper Catalyzed C–N Cross-Coupling Reaction | A scalable process for the preparation of 2-(2-( cis -3-(piperidin-1-yl)cyclobutyl)benzothiazol-6-yl)pyridazin-3(2H)-one in multi-kilogram amounts and in high purity has been developed. The key features of this synthesis are the copper-catalyzed C–N cross-coupling reaction and the development of a highly diastereoselec... | 10.1021/op3002883 | 1 |
Improved Process for Azilsartan Medoxomil: A New Angiotensin Receptor Blocker | An improved process for the active pharmaceutical ingredient of a new angiotensin II AT 1 receptor antagonist, azilsartan medoxomil, has been developed. The results include reinvestigation of the described process as well as its novel modifications. This new process includes transformation of the CN group into amidoxim... | 10.1021/op3002867 | 1 |
The Large-Scale Synthesis of (<i>S</i>)-<i>N</i>-Boc-bis(4-fluorophenyl)alanine | The synthesis of ( S )- N -Boc-bis(4-fluorophenyl)alanine, an intermediate in the synthesis of denagliptin, is described from the synthesis of a 12 g proof of principle sample to a >900 kg cGMP manufacturing campaign. The chiral centre was established by the asymmetric hydrogenation of the sterically crowded precursor,... | 10.1021/op3002855 | 0 |
The Development of Practical Synthetic Routes to a CB<sub>2</sub> Agonist: Efficient Construction of a Densely Substituted Purine Core | An efficient and scalable process for the preparation of a purine-based CB 2 agonist was developed. The production route to the requisite purine core relies on N -acylation and sequential substitution of a 5-amino-4,6-dichloropyrimidine with two amine building blocks followed by a cyclocondensation reaction. The chemis... | 10.1021/op300278c | 1 |
Applications of Transition Metal Catalysis in Drug Discovery and Development | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTApplications of Transition Metal Catalysis in Drug Discovery and DevelopmentTrevor LairdCite this: Org. Process Res. Dev. 2012, 16, 11, 1874Publication Date (Web):October 18, 2012Publication History Published online18 October 2012Published inissue 16 November 2012https://... | 10.1021/op300277x | 0 |
Evaluation of Different Process Concepts for the Indirect Hydration of Cyclohexene to Cyclohexanol | An indirect hydration process route for the production of cyclohexanol was proposed by Steyer et al., which uses formic acid as a reactive entrainer ( Steyer, F.; Freund, H.; Sundmacher, K. Ind. Eng. Chem. Res. 2008, 47, 9581−9587; Steyer, F.; Sundmacher, K. Ind. Eng. Chem. Res. 2007, 46, 1099–1104). This route overcom... | 10.1021/op300276e | 0 |
Continuous Flow Synthesis of <i>n</i>-Alkyl Chlorides in a High-Temperature Microreactor Environment | Applying continuous flow processing in a high-temperature/high-pressure regime, n -alkyl chlorides can be prepared in high yields and selectivity by direct uncatalyzed chlorodehydroxylation of the corresponding n -alcohols with 30% aqueous hydrochloric acid. Optimum conditions for the preparation of n -butyl and n -hex... | 10.1021/op300273u | 0 |
A Robust Process for an mGluR5 Negative Allosteric Modulator: Difluoromethylation and Sonogashira Coupling on Large Scale | The development of the potent and selective mGluR5 negative allosteric modulator (NAM) 1 is described. Key features in the process, which has been implemented on a multikilogram scale, include a high-temperature difluoromethylation reaction, a Sonogashira coupling, and careful control of residual Pd and Cu in the final... | 10.1021/op3002728 | 1 |
A Concise Synthesis of a Tetrahydropyrazolopyrazine Building Block | A concise synthesis of a tetrahydropyrazolopyrazine building block is described. 5-Methyl-4,5,6,7-tetrahydropyrazolo[1,5- a ]pyrazin-2-ylamine was prepared in three steps and 80% yield from 5-nitro-2 H -pyrazole-3-carboxylic acid. This compound was then coupled with 4-bromo-6-chloro-2-methyl-2 H -pyridazin-3-one in the... | 10.1021/op300270r | 1 |
Convergent Kilogram-Scale Synthesis of Dual Orexin Receptor Antagonist | MK-6096 is an orexin receptor antagonist in clinical trials for the treatment of insomnia. Herein we describe its first kilogram-scale synthesis. Chirality on the α-methylpiperidine core was introduced in a biocatalytic transamination using a three-enzyme system with excellent enantioselectivity (>99% ee). Low diastere... | 10.1021/op3002678 | 1 |
Heart-Cutting Two-Dimensional Ultrahigh-Pressure Liquid Chromatography for Process Development: Asymmetric Reaction Monitoring | This contribution presents the first application of two-dimensional, ultrahigh-pressure liquid chromatography (2D-UHPLC) for monitoring asymmetric reactions in process development. Several asymmetric transformations were studied to illustrate the operation of the instrument and evaluate the performance of 2D-UHPLC. Two... | 10.1021/op300266j | 0 |
Scale-up of Azide Chemistry: A Case Study | We report research and development conducted to enable the safe implementation of a highly enantioselective palladium-catalyzed desymmetrization of a meso – bis -ester using trimethylsilylazide (TMSN 3 ) as the nucleophile. This work is used as a case example to discuss safe practices when considering the use of azide ... | 10.1021/op3002646 | 0 |
Synthesis of the Pleuromutilin Antibiotic SB-268091: A New Practical and Efficient Synthesis of Quinuclidine-4-thiol | A synthesis of the pleuromutilin antibiotic SB-268091 is described which includes a new and improved route to the quinuclidine-4-thiol ligand. This chemistry has been run on multikilo scale and involved a reductive double debenzylation using sodium in liquid ammonia. Alternative conditions have been developed to prepar... | 10.1021/op300263w | 1 |
Process Development and Scale-Up of an Hsp90 Inhibitor | A scalable process for the manufacture of a Hsp90 inhibitor was developed and optimized. Key features in the seven-step process include a selective S N Ar reaction followed by an Ullmann-type coupling of indazolone to an aryl halide. This improved process afforded 65% yield over two critical steps compared to 25% follo... | 10.1021/op300262z | 1 |
A New and Improved Process for <i>N</i>-(4-Chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide | A new and improved synthetic route to N -(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide ( 1 ) is described on a kilogram scale. The key step is the basic cyclization of o -[(2-cyanovinyl)amino]benzoate ( 14 ) in t BuONa/ t BuOH system to give the 3-cyano-4-hydroxyquinoline ( 7 ). The final product 1 is obtained with... | 10.1021/op300260m | 1 |
Improved One-Pot Synthesis of Citalopram Diol and Its Conversion to Citalopram | An improved process is developed for the preparation of citalopram diol, 2 which involves two consecutive Grignard reactions in situ followed by an efficient and simple workup process with improved overall yield. Process development efforts for conversion of 2 into citalopram, 1, and a control strategy for impurities a... | 10.1021/op3002596 | 1 |
Development and Practical Synthesis of a Triple Reuptake Inhibitor, (1<i>R</i>,2<i>S</i>)-SIPI 5357 | A new chromatography-free synthetic route to triple reuptake inhibitor (1 R,2 S )-SIPI 5357 was developed and demonstrated on a 300-g scale. The key feature of this route is an asymmetric induction reaction, where the (2 S,3 S )-aminoketone 6 was highly stereoselectively reduced to (1 R,2 S,3 S )-amino alcohol 7 . Afte... | 10.1021/op300258w | 1 |
Development of a Selective Friedel–Crafts Alkylation Surrogate: Safe Operating Conditions through Mechanistic Understanding | This article describes a selective one-pot, Friedel–Crafts acylation/ketone reduction protocol, effectively a surrogate for the Friedel–Crafts alkylation reaction with a primary alkyl halide. A potentially dangerous failure mode was identified, resulting in the uncontrolled evolution of hydrogen. A series of mechanisti... | 10.1021/op300257z | 1 |
A Practical Synthesis of a <i>cis</i>-4,5-Bis(4-chlorophenyl)imidazoline Intermediate for Nutlin Analogues | A practical synthesis of cis -4,5-bis(4-chlorophenyl)imidazoline, a key intermediate for Nutlin analogues, is reported. The title compound was prepared in 81–88% yield by boric acid catalyzed direct condensation of meso -bis(4-chlorophenyl)ethane-1,2-diamine with a benzoic acid. The process was successfully scaled up i... | 10.1021/op300254q | 0 |
Development of a Practical Synthesis of a Functionalized Pyrrolo[2,1-f][1,2,4]triazine Nucleus | Functionalized pyrrolotriazine 1b is a key heterocyclic building block in the synthesis of BMS-690514, a potent anticancer agent. Described herein are our development activities that led to the efficient preparation of 1b on a large scale. The key transformations include a selective C-alkylation of an oxalacetate salt ... | 10.1021/op300252n | 1 |
Asymmetric Synthesis of a Glucagon Receptor Antagonist via Friedel–Crafts Alkylation of Indole with Chiral α-Phenyl Benzyl Cation | Development of a practical asymmetric synthesis of a glucagon receptor antagonist drug candidate for the treatment of type 2 diabetes is described. The antagonist consists of a 1,1,2,2-tetrasubstituted ethane core substituted with a propyl and three aryl groups including a fluoro-indole. The key steps to construct the ... | 10.1021/op300249q | 1 |
Application of Flow Photochemical Bromination in the Synthesis of a 5-Bromomethylpyrimidine Precursor of Rosuvastatin: Improvement of Productivity and Product Purity | In this report we present a flow photochemical bromination of a 5-methyl-substituted pyrimidine precursor of rosuvastatin. The study demonstrated that the reaction productivity can be increased markedly with a flow-mode approach compared to a batch-mode synthesis. Indeed, reaction times can be significantly shortened f... | 10.1021/op300248y | 0 |
Development of a Process for the Preparation of Chloromethyl Chlorosulfate | A new and efficient synthesis of chloromethyl chlorosulfate (CMCS) from chloroiodomethane and chlorosulfonic acid is described. This process leverages a chlorosulfonic acid-mediated iodide oxidation to drive the equilibrating displacement process to full conversion. The resulting iodine byproduct is further oxidized an... | 10.1021/op300246d | 0 |
Development and Characterization of a Cocrystal as a Viable Solid Form for an Active Pharmaceutical Ingredient | A phosphoric acid cocrystal of a drug substance candidate at Boehringer Ingelheim was identified from the standard salt form screen and was characterized and shown to have desirable physicochemical properties, stability characteristics, and improved solubility and bioavailability compared to those of the free form. The... | 10.1021/op300239h | 0 |
Development of a Practical and Scalable Synthesis of a Potent p38 Mitogen-Activated Protein Kinase Inhibitor | Process research and development of a practical and scalable synthetic method toward a potent inhibitor of p38 mitogen-activated protein kinase 1 is described. The medicinal chemistry synthetic method had several issues in scale-up synthesis. In contrast, the synthetic method described here does not require purificatio... | 10.1021/op300237b | 1 |
Development of a Scalable Strategy for the Synthesis of PI3Kδ Inhibitors: Selective and Efficient Functionalization of Purine Derivatives | The first-generation development route used to prepare the PI3Kδ inhibitor GNE-293 ( 3 ) for early toxicology studies is described. Through the use of a metal-free S N Ar reaction in place of a Pd-catalyzed C–N coupling, the synthesis was both simplified and made more reproducible in preparation for scale-up by reducin... | 10.1021/op300235t | 1 |
Demonstration of a Scalable One-Pot Synthesis of Fmoc-<i>O</i>-Benzylphospho-<scp>l</scp>-serine | A cost-effective one-pot synthesis of Fmoc- O -benzylphospho- l -serine, an amino acid commonly used in the synthesis of phosphorylated peptides, has been developed. Two methods for executing this synthesis are described, and both have been scaled to provide kilogram quantities of the title compound in ∼50% isolated yi... | 10.1021/op300233g | 0 |
Science of Synthesis Workbench Edition: Water in Organic Synthesis | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTScience of Synthesis Workbench Edition: Water in Organic SynthesisTrevor LairdCite this: Org. Process Res. Dev. 2012, 16, 9, 1571Publication Date (Web):September 4, 2012Publication History Published online4 September 2012Published inissue 21 September 2012https://pubs.acs... | 10.1021/op300231a | 0 |
Process Development, Impurity Control, and Production of a Novel Tubulin Inhibitor | Process development and production of a novel tubulin inhibitor are described. The desired API was obtained through selective iodination of the 12′ position of vinblastine and subsequent thiomethylation. Most of the impurities were identified, and process parameters were adjusted to control such impurities. The optimiz... | 10.1021/op3002307 | 0 |
A Scalable Synthesis of CE-157119 HCl Salt, an SRI/5-HT<sub>2A</sub> Antagonist | A scalable synthesis of CE-157119 HCl salt ( 1 ), an SRI/5-HT 2A antagonist, was developed via the regioselective S N Ar etherification between a phenol and an N -methylamide. This early development route shortened the original 5-step synthesis to three steps, eliminated all chromatography and increased the overall yie... | 10.1021/op3002273 | 1 |
The Development of a Scalable, Chemoselective Nitro Reduction | We have demonstrated a scalable chemoselective reduction of a nitro functional group in the presence of an aryl imine using (NH 4 ) 2 S/EtOH or hydrogenation (Sponge Nickel) to afford the corresponding amino-imines in moderate to excellent yields. Other reducible groups such as aryl halides, styryl olefins, and ether l... | 10.1021/op3002239 | 0 |
An Approach to Control Strategies for Sulfonate Ester Formation in Pharmaceutical Manufacturing Based on Recent Scientific Understanding | The issue of sulfonate ester formation is one that has been of significant concern to regulatory authorities since the start of the millennia. These concerns, focused primarily on the risk of ester formation where sulfonic acid salts are formed in alcoholic solvents, has led to the need for specific analysis for such s... | 10.1021/op300216x | 0 |
Efficient Purification of an Active Pharmaceutical Ingredient via Cocrystallization: From Thermodynamics to Scale-Up | Cocrystallization as a purification step was the only way to isolate an active pharmaceutical ingredient with acceptable chemical and physical specifications. The process design controlling chemical quality and polymorphism issues is described, from the thermodynamics of cocrystal formation and cleavage, to microscale ... | 10.1021/op300214p | 0 |
A Facile Total Synthesis for Large-Scale Production of Imatinib Base | An efficient, economic process has been developed for the production of imatinib with 99.99% purity and 50% overall yield from four steps. Formation and control of all possible impurities is described. The synthesis comprises the condensation of N -(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine with 4-(4-me... | 10.1021/op300212u | 1 |
Demonstration on Pilot-Plant Scale of the Utility of 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD) as a Catalyst in the Efficient Amidation of an Unactivated Methyl Ester | The utility of 1,5,7-triazabicyclo[4.4.0]dec-5-ene as a reagent to facilitate efficient amide formation by reaction of an amine with an unactivated ester was demonstrated on pilot-plant scale as a key step in the synthesis of an H-PGDS inhibitor. | 10.1021/op300210j | 0 |
Telescoped Flow Process for the Syntheses of <i>N</i>-Aryl Pyrazoles | N -Aryl pyrazoles were prepared from anilines in a three step telescoped approach. An aniline was diazotized to give the diazonium fluoroborate, followed by reduction with tin(II) chloride to give the corresponding hydrazine, which in turn reacted with a ketoenamine to give the N -aryl pyrazole. The deprotection of the... | 10.1021/op300209p | 1 |
Practical Process Research and Development - A Guide For Organic Chemists | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTPractical Process Research and Development - A Guide For Organic ChemistsWill WatsonView Author Information Scientific Update, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, United Kingdom[email protected]Cite this: Org. Process Res. Dev. 2012, 16, 9, 1569Pu... | 10.1021/op300207u | 0 |
A Novel Integrated Bioprocess for Efficient Production of (<i>R</i>)-(−)<i>-</i>Mandelic Acid with Immobilized <i>Alcaligenes faecalis</i> ZJUTB10 | An integrated bioprocess for the enantioselective hydrolysis of mandelonitrile to ( R )-(−)-mandelic acid (R-MA) with immobilized Alcaligenes faecalis ZJUTB10 cells was constructed. Production of A. faecalis ZJUTB10 nitrilase in a pilot-scale fermenter (700 L) with high activity was achieved after optimizing cultivatio... | 10.1021/op3001993 | 0 |
Process Research and Kilogram Synthesis of an Investigational, Potent MEK Inhibitor | TAK-733 ( 1 ) is an investigational, novel MEK kinase inhibitor that bears a 6-fluoropyridopyrimidone core. Process research of 1 was conducted, and an efficient, scalable route was developed. The key intermediate, a multisubstituted fluoropyridone, was formed in one pot via a three-step cascade reaction: condensation ... | 10.1021/op300198a | 1 |
Multikilogram Synthesis of a Hepatoselective Glucokinase Activator | This work describes the process development and manufacture of early-stage clinical supplies of a hepatoselective glucokinase activator, a potential therapy for type 2 diabetes mellitus. Critical issues centered on challenges associated with the synthesis of intermediates and API bearing a particularly racemization-pro... | 10.1021/op300194c | 1 |
An Improved and Scalable Process for the Synthesis of 5-Azacytidine: An Antineoplastic Drug | An improved, practical, and scalable process for the manufacture of antineoplastic drug, 5-azacytidine ( 1 ), is described. A thorough understanding of the reaction parameters and stability of the reaction intermediates led us to the development of a robust process. The challenges in the isolation and systematic approa... | 10.1021/op300192e | 1 |
Lewis Acid-Catalyzed Synthesis of 4-Aminopyrimidines: A Scalable Industrial Process | Pyrimidine synthesis starting from acrylonitrile has been known since the 1960s. The new Lewis acid-catalyzed condensation reaction allows the synthesis of 4-aminopyrimidines starting from the easily accessible chemical acrylonitrile without the need for carcinogenic chemicals and costly derivatization in up to 90% yie... | 10.1021/op300190s | 1 |
The Manufacture of a Homochiral 4-Silyloxycyclopentenone Intermediate for the Synthesis of Prostaglandin Analogues | A process is described for the synthesis of kilogram quantities of homochiral 4-silyloxycyclopentenone ( R )- 1, a key intermediate useful for the synthesis of a plurality of prostaglandin analogue drugs. Cyclopentenone ( R )- 1 was synthesized in 14 isolated steps from furfural. Key steps in the synthesis include a Wi... | 10.1021/op300188x | 1 |
Process Optimization of Aldol-Type Reaction by Process Understanding Using in Situ IR | A high-yield robust LHMDS-mediated aldol-type reaction of benzyl maltol ( 2 ) and benzaldehyde ( 3 ) was developed using in situ IR to overcome the problems of low yield and yield fluctuation of the pilot synthesis. In situ IR studies indicated that unexpected side reactions of LHMDS and 3 reduced the yield of the aldo... | 10.1021/op300186p | 1 |
Identification and Development of an Efficient Route to SB-649915 | The discovery and development of an efficient manufacturing route to the SSRI-5-HT1A receptor antagonist 6-[(1-{2-[(2-methyl-5-quinolinyl)oxy]ethyl}-4-piperidinyl)methyl]-2 H -1,4-benzoxazin-3(4 H )-one (SB-649915) 1 is described. The existing route to 1 involved coupling quinoline 6 with piperidine 5 and was considere... | 10.1021/op300185s | 1 |
Development of a Practical Synthesis of a p38 Kinase Inhibitor via a Safe and Robust Amination | The development of a practical synthesis for a p38 kinase inhibitor is described. The key advances include an improved route to the key intermediate, a substituted pyrrole, and a subsequent animation utilizing O -(4-nitrobenzoyl)hydroxylamine, which provides a safe, scalable, and robust amination method. The new protoc... | 10.1021/op300181r | 1 |
An Efficient, Commercially Viable, and Safe Process for Preparation of Losartan Potassium, an Angiotensin II Receptor Antagonist | An efficient, commercially viable and safe process for the preparation of losartan potassium, an antihypertensive drug substance, with an overall yield of 55.5% and ∼99.9% purity (including five chemical reactions and two recrystallizations) and meeting all other regulatory requirements is described. Formation and cont... | 10.1021/op300179u | 1 |
Use of Footnotes and References in <i>Org. Process Res. Dev.</i> Papers | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTUse of Footnotes and References in Org. Process Res. Dev. PapersTrevor LairdCite this: Org. Process Res. Dev. 2012, 16, 8, 1319Publication Date (Web):July 25, 2012Publication History Published online25 July 2012Published inissue 17 August 2012https://pubs.acs.org/doi/10.1021/op... | 10.1021/op3001756 | 0 |
Selection and Scale-Up Evaluation of an Alternative Route to (−)-(3<i>R</i>,4<i>R</i>)-1-Benzyl-4-(benzylamino)piperidin-3-ol | An efficient, scalable synthesis of (−)-(3 R,4 R )-1-benzyl-4-(benzylamino)piperidin-3-ol ( 4 ) is described. Reduction of the pyridinium salt prepared from pyridine and benzyl chloride generated the corresponding tetrahydropyridine derivative. A two-stage epoxidation, followed by ring-opening of the epoxide with BnNH ... | 10.1021/op300174w | 1 |
Development of Scalable Manufacturing Routes to AZD1981. Application of the Semmler–Wolff Aromatisation for Synthesis of the Indole-4-amide Core | A safe and efficient synthesis of AZD1981 is described in which the indole 4-amide core is formed by a Semmler–Wolff aromatisation of a cyclohexenone oxime fused to a pyrrole ring. The substrate was obtained via Paal–Knorr pyrrole synthesis, followed by incorporation of the key 3-arylthio substituent by reaction with 4... | 10.1021/op300173z | 1 |
Scale-Up Synthesis of Antidepressant Drug Vilazodone | A scale-up synthesis of antidepressant drug vilazodone was accomplished in five steps. Friedel–Crafts acylation of 1-tosyl-1 H -indole-5-carbonitrile with 4-chlorobutyryl chloride, selective deoxygenation in NaBH 4 /CF 3 COOH system coupled with ethyl 5-(piperazin-1-yl)-benzofuran-2-carboxylate hydrochloride, one-step ... | 10.1021/op300171m | 1 |
Development of a Scalable Route to the SMO Receptor Antagonist SEN794 | A practical and scalable route to the SMO receptor antagonist SEN794 1 is described herein. A new and efficient access to the key intermediate 7 via the Kröhnke reaction was developed, significantly simplifying the synthesis and reducing costs. The optimized route consists of six chemical steps plus a palladium scaveng... | 10.1021/op300170q | 1 |
Continuous-Flow Preparation and Use of β-Chloro Enals Using the Vilsmeier Reagent | The Vilsmeier reagent is used in the preparation of a wide variety of heterocycles, such as pyrazoles, via formation of β-chloroacrolein intermediates. However, use of this extremely reactive reagent on large scale requires special precautions to avoid potentially dangerous exotherms. This article describes the safe pr... | 10.1021/op300168z | 0 |
Noncryogenic Preparation of Functionalized Arylboronic Esters through a Magnesium–Iodine Exchange with in Situ Quench | International audience | 10.1021/op300166m | 0 |
Discovery and Development of an Efficient Process to Atovaquone | The discovery and development of an efficient and more sustainable manufacturing route to the anti-pneumocystic agent atovaquone (2-((1 R,4 R )-4-(4-chlorophenyl)cyclohexyl)-3-hydroxynaphthalene-1,4-dione) 1 is described. The existing commercial route to atovaquone delivers a poor yield of product and uses expensive re... | 10.1021/op300165q | 1 |
A Novel Method for the Large Scale Synthesis of Cinacalcet Hydrochloride Using Iron Catalyzed C–C Coupling | A novel synthetic route for commercial preparation of cinacalcet hydrochloride ( 1 ), a calcimimetic agent and calcium-sensing receptor antagonist, is described. Our synthetic approach involves the preparation of cinacalcet using C–C bond formation catalyzed by iron acetylacetonate/NMP complex with aryl Grignard reagen... | 10.1021/op300164y | 1 |
A Scalable Synthesis of a Hydroxamic Acid LpxC Inhibitor | A short and scalable synthesis of chiral hydroxamic acid 1, a LpxC inhibitor, is described. This work discloses a novel diastereoselective addition of 2-nitropropane-generated lithium salt to tert -butanesulfinimine. Moreover, the impurity profiles of reactions giving oily products and practical means of purifying thes... | 10.1021/op300163n | 1 |
Optimization of Reductive Debenzylation of Hexabenzylhexaazaisowurtzitane (the Key Step for Synthesis of HNIW) Using Response Surface Methodology | Reductive debenzylation of hexabenzylhexaazaisowurtzitane (HBIW) was carried out using palladium hydroxide deposited on activated carbon catalyst. The catalyst has been characterized using a nitrogen adsorption/desorption isotherm, a hydrogen isotherm, scanning electron microscopy (SEM), and transmission electron micro... | 10.1021/op300162d | 0 |
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