title string | abstract string | doi string | has_route int64 |
|---|---|---|---|
Development of Continuous Anti-Solvent/Cooling Crystallization Process using Cascaded Mixed Suspension, Mixed Product Removal Crystallizers | This paper describes a two-stage mixed-suspension, mixed-product removal (MSMPR) continuous crystallization developed for a pharmaceutical intermediate which uses anti-solvent and cooling to generate supersaturation. The results indicate that the stage in which anti-solvent is added has a significant influence on the f... | 10.1021/op2002886 | 0 |
Evaluation of Competing Process Concepts for the Production of Pure Enantiomers | Various promising concepts exist for improving the performance of productions of pure enantiomers. An efficient approach is developed for the systematic conceptual design of such processes. The proposed three-step procedure aids a fast selection of the optimal process configuration out of many possible candidates and l... | 10.1021/op200285v | 0 |
Efficient Synthesis of Impurity-C of Antimigraine Agent Rizatriptan Benzoate | During the commercial manufacturing of antimigraine drug Rizatriptan benzoate, several impurities are reported to be formed. This present work demonstrates a convergent and short synthesis of the most critical impurity (C) of Rizatriptan, [2-(5-((1H-1,2,4-triazol-1-yl)methyl)-1H-indole-2-yl)- N, N -dimethylethanamine (... | 10.1021/op200284m | 1 |
Large-Scale Synthesis of Singh’s Catalyst in a One-Pot Procedure Starting from Proline | A practical one-pot procedure for the preparation of Singh’s catalyst from either l -/ d -proline or Boc-proline is described. The coupling partner, a chiral amino alcohol, can be prepared and used directly without purification from the corresponding amino acid ester. Moreover, a procedure for tert -butoxycarbonyl (Boc... | 10.1021/op200283q | 0 |
Continuous Preparation of Arylmagnesium Reagents in Flow with Inline IR Monitoring | A newly developed microscale ReactIR flow cell was used as a convenient and versatile inline analytical tool for Grignard formation in continuous flow chemical processing. The LiCl-mediated halogen/Mg exchange reaction was used for the preparation of functionalized arylmagnesium compounds from aryl iodides or bromides.... | 10.1021/op200275d | 0 |
Development of the Large-Scale Preparation of 2-(Methanesulfonyl)benzenesulfonyl Chloride | A practical and scalable process is described for the preparation of 2-(methansulfonyl)benzenesulfonyl chloride, a key building block used in the synthesis of several drug candidates. The material is prepared by an efficient four-step sequence from inexpensive 1,2-dichlorobenzene and methanethiol, and the process has b... | 10.1021/op2002744 | 1 |
Safety of Chemical Processes 11 | ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTSafety of Chemical Processes 11Trevor LairdCite this: Org. Process Res. Dev. 2011, 15, 6, 1406Publication Date (Web):October 17, 2011Publication History Published online17 October 2011Published inissue 18 November 2011https://pubs.acs.org/doi/10.1021/op200273hhttps://doi.or... | 10.1021/op200273h | 0 |
Safe Scale-Up of Processes Containing Hazardous Species in the Headspace with Inline IR | Inline IR has been applied to evaluate the scale-up of processes that potentially generate hazardous diborane, hydrazoic acid, methyl chloride, or acetylene in the headspace of reactors. In addition, a new, simplified approach to calibrate the online IR analyzer for the measurement of hydrazoic acid in the gas phase ha... | 10.1021/op200271b | 0 |
Process Intensification via Reaction Telescoping and a Preliminary Cost Model to Rapidly Establish Value | Process intensification via reaction telescoping has recently been demonstrated in our research laboratories. The improved process is significantly streamlined; 1 intermediate isolation vs 2, 24 workup and purification unit operations vs 49, and a batch cycle time of 116 h vs 177 h are the key improvements realized. A ... | 10.1021/op200270f | 0 |
Design of an Integrated Process of Chromatography, Crystallization and Racemization for the Resolution of 2′,6′-Pipecoloxylidide (PPX) | An integrated process for the chiral separation of the industrially relevant substance 2′,6′-pipecoloxylidide (PPX), an intermediate in the manufacture of a number of anesthetics, was developed. By combining three different techniques, chromatography, crystallization, and racemization, high productivity was achieved. A... | 10.1021/op200268h | 0 |
Holistic Route Selection | New agrochemical, fine chemical, and pharmaceutical products often require the development and selection of economical and effective chemical routes to enable commercial success. Atom economy and reaction step minimization are key drivers for low-cost routes. In addition, capital requirements, process operability and r... | 10.1021/op200264t | 1 |
Allylic Amines as Key Building Blocks in the Synthesis of (<i>E</i>)-Alkene Peptide Isosteres | Nucleophilic imine additions with vinyl organometallics have developed into efficient, high yielding, and robust methodologies to generate structurally diverse allylic amines. We have used the hydrozirconation-transmetalation-imine addition protocol in the synthesis of allylic amine intermediates for peptide bond isost... | 10.1021/op2002613 | 1 |
Practical Convergent Laboratory-Scale Synthesis of a CCR5 Receptor Antagonist | An efficient laboratory-scale synthesis has been developed for the selective CCR5 antagonist 1 . The convergent route has a longest linear sequence of nine steps (15 steps overall), and has overall yields of 18–25%. The route has enabled the preparation of 550 g of 1 . | 10.1021/op200259t | 1 |
Kilogram-Scale Synthesis of an Inhaled Corticosteroid | The development and implementation of a safe and scalable process for the manufacture of corticosteroid PF-4714224 ( 1 ) is described. Initial routes used to synthesise analogues from this series directly from fluocinolone acetonide ( 2 ) were unsuitable for large-scale use. Key aspects of the route are the efficient a... | 10.1021/op200257g | 1 |
Monitoring and Control of a Continuous Grignard Reaction for the Synthesis of an Active Pharmaceutical Ingredient Intermediate Using Inline NIR spectroscopy | Inline near-infrared (NIR) spectroscopy has been used to monitor a continuous synthesis of an active pharmaceutical ingredient (API) intermediate by a Grignard alkylation reaction. The reaction between a ketone substrate and allylmagnesium chloride may form significant impurities with excess feeding of the Grignard rea... | 10.1021/op2002563 | 0 |
Development of Safe One-Pot Synthesis of <i>N</i>-1- and <i>C</i>-2-Substituted Benzimidazole via Reductive Cyclization of <i>o</i>-Nitroarylamine Using Na<sub>2</sub>S<sub>2</sub>O<sub>4</sub> | We report that the reductive cyclization of o -nitroarylamine with aldehyde using sodium dithionite (Na 2 S 2 O 4 ) could be accelerated by addition of H 2 O, which made it possible to control the heat release of the reaction by semibatch-type operation. Safety evaluation was performed using DSC, ARSST, in situ IR anal... | 10.1021/op200251c | 1 |
Multikilogram-Scale Synthesis of a Chiral Cyclopropanol and an Investigation of the Safe Use of Lithium Acetylide–Ethylene Diamine Complex | A six-step route starting from a readily available vinyl boronate was identified to produce an enantioenriched cyclopropanol in an overall 16% yield. Key steps involve the use of lithium acetylide-ethylene diamine complex 5 and an enzymatic resolution of a racemic cyclopropanol acetate. Process safety considerations su... | 10.1021/op2002497 | 1 |
Diarylketone Ketoreductase Screen and Synthesis Demonstration to Access mGlu2 Receptor Potentiators | This communication describes proof of concept for an enantioselective enzyme-based synthesis of diarylmethanol ( S )- 1 to access mGlu2 receptor potentiators. A ketoreductase (KRED) screen was applied to benzophenone 8 to afford chiral diarylmethanol ( S )- 9, which is a useful intermediate for the preparation of chira... | 10.1021/op2002479 | 1 |
Continuous Hydrolysis and Liquid–Liquid Phase Separation of an Active Pharmaceutical Ingredient Intermediate Using a Miniscale Hydrophobic Membrane Separator | Continuous hydrolysis of an active pharmaceutical ingredient intermediate, and subsequent liquid–liquid (L-L) separation of the resulting organic and aqueous phases, have been achieved using a simple PTFE tube reactor connected to a miniscale hydrophobic membrane separator. An alkoxide product, obtained in continuous m... | 10.1021/op200242s | 0 |
Development of a Potential Manufacturing Route to PF-00610355: A Novel Inhaled β<sub>2</sub>-Adrenoreceptor Agonist | The development of a practical, scalable route to PF-00610355 ( 8 ) is described. In this convergent approach, amine 9 is coupled to protected bromohydrin 1 to give the doubly protected intermediate 26 . TBS-Deprotection of 26 affords the benzyl protected penultimate intermediate 25 which is crystallized as the corresp... | 10.1021/op2002408 | 1 |
Intermittent Simulated Moving Bed Processes for Chromatographic Three-Fraction Separation | Simulated moving bed (SMB) chromatography is a well-established technique to resolve racemic mixtures into pure enantiomers. However, the conventional SMB process is restricted to binary separations, and its applicability is therefore limited when impurities are present. In this contribution we address this issue by co... | 10.1021/op200239e | 0 |
Multkilogram Scale-Up of a Reductive Alkylation Route to a Novel PARP Inhibitor | Novel PARP inhibitor 1 is a promising new candidate for treatment of breast and ovarian cancer. A modified synthetic route to 1 has been developed and demonstrated on 7 kg scale. In order to scale up the synthesis to multikilogram scale, several synthetic challenges needed to be overcome. The key issues included signif... | 10.1021/op200238p | 1 |
Catalytic Hydrogenation of Esters. Development of an Efficient Catalyst and Processes for Synthesising (<i>R</i>)-1,2-Propanediol and 2-(<i>l</i>-Menthoxy)ethanol | A ruthenium catalyst for the reduction of esters by hydrogenation has been developed. Processes for the hydrogenation of esters have also been developed for ( R )-1,2-propanediol and 2-( l -menthoxy)ethanol. The catalyst shows good catalytic activity for the hydrogenation of esters in methanol. Methyl lactate was reduc... | 10.1021/op200234j | 0 |
Development of a Scaleable Synthesis of a Geminal Dimethyl Tertiary Amine as an Inhaled Muscarinic Antagonist for the Treatment of COPD | An efficient and scalable process for the synthesis of muscarinic antagonist, PF-3635659 1, is described, illustrating redesign of an analogue-targeted synthesis which contained a scale-limiting rhodium-activated C–H amination step. The final route includes a reproducible modified Bouveault reaction which has not previ... | 10.1021/op200233r | 1 |
A Simplified Process for the Manufacture of Imagabalin Hydrochloride (PD-0332334), an α2δ-Ligand for the Treatment of Generalised Anxiety Disorder | The development of a highly efficient two-step process for the manufacture of the α2δ-ligand imagabalin hydrochloride 1 is described in 50% overall yield from ( R )-3-methylhexanoic acid 2 . Key aspects of this route include the development of a one-pot process for the synthesis of β-enamine ester 7 and its subsequent ... | 10.1021/op2002326 | 1 |
Development and a Practical Synthesis of the JAK2 Inhibitor LY2784544 | The route selection and process research and development of a practical synthesis for JAK2 inhibitor LY2784544 is described. The first-generation synthesis route, similar to that used in discovery for derivatization of a benzylic amine moiety, was 14 overall steps and possessed several steps that required extensive dev... | 10.1021/op200229j | 1 |
An Improved and Impurity-Free Large-Scale Synthesis of Venlafaxine Hydrochloride | An improved and impurity-free synthetic method for large-scale synthesis of venlafaxine hydrochloride was developed using inexpensive reagents. The overall yield obtained from this newly developed process is 55% in a highly pure state with >99.9% purity by HPLC. | 10.1021/op200221y | 1 |
Scalable Synthesis of the Desoxy-biphenomycin B Core | We describe the evolution of a kilogram-scale synthesis of the protected cyclic tripeptide desoxy-biphenomycin B, based on an early discovery route. The retrosynthetic concept included a macrolactamization strategy to build the core ring system of biphenomycin B in combination with a double catalytic asymmetric hydroge... | 10.1021/op200207h | 1 |
Genotoxic Impurities: A Regulatory Toxicology Commentary on Recent Articles in <i>Organic Process Research & Development</i> | Although it has now been over four years since the introduction of the EU guideline on limits of genotoxic impurities, even after various amendments the regulatory guidance is still associated with ambiguity and differing interpretations. In spite of this, it is believed that a critical toxicological analysis can shed ... | 10.1021/op200205b | 0 |
Development of Two Scalable Syntheses of 4-Amino-5-aminomethyl-2-methylpyrimidine: Key Intermediate for Vitamin B<sub>1</sub> | Two scalable processes for the synthesis of 4-amino-5-aminomethyl-2-methylpyrimidine ( 2 ) are described. In the first approach, the less expensive 2-cyanoacetamide was reacted with Vilsmeier reagent to afford enamine 18, followed by the condensation with acetamidine to produce the 4-amino-2-methylpyrimidine-5-carbonit... | 10.1021/op2002003 | 1 |
Process Research Towards a Scalable Synthesis of the Muscarinic M<sub>1</sub> Receptor Subtype Selective Agonist MCD-386 | An efficient process for the M 1 -selective muscarinic agonist MCD-386 has been developed that offers significant advantages over the original synthetic approach. The new process utilizes an improved preparation of a known symmetrical diamine ester, followed by elaboration to a symmetrical 5-substituted tetrahydropyrim... | 10.1021/op2001996 | 1 |
Facile One-Pot Process for Large-Scale Production of Highly Pure Bosentan Monohydrate, an Endothelin Receptor Antagonist | Described is an efficient, economic, and one-pot process for the production of highly pure bosentan ( 1 ), an endothelin receptor antagonist. The synthesis comprises the reaction of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2′-bipyrimidine ( 2 ) with 4- tert -butylbenzenesulfonamide ( 3 ) and ethylene glycol ( 4 ) in acetoni... | 10.1021/op200197z | 1 |
Development of a Suitable Physical Form for a Sphingosine-1-phosphate Receptor Agonist | AMG 369 ( 1 ), a novel S1P 1 agonist, was selected for clinical development for the treatment of multiple sclerosis. Form B of the zwitterionic molecule was initially identified as a potential development form. However, because of the instability of the phase as a function of ambient relative humidity, investigations o... | 10.1021/op200192n | 0 |
Design of Crystallization Processes for the Resolution of Conglomerate-Forming Chiral Compounds Exhibiting Oiling Out | A methodology for the design of cooling crystallization processes for chiral resolution from nonracemic initial solutions is presented. Such processes are encountered when chiral resolution is attained by hybrid processes, where the crystallization step is preceded by a pre-enrichment step accomplished by either asymme... | 10.1021/op200191d | 0 |
Development of an Enabling Route to PF-00610355: A Novel Inhaled β<sub>2</sub>-Adrenoreceptor Agonist | The initial route used to prepare PF-00610355 ( 8 ) for early clinical development is described. Through careful choice of solvent, an efficient, telescoped route to carboxylic acid 23 was developed, affording this late-stage intermediate in 80% yield over 4 steps. Deprotection of 23 to give sodium salt 24a and couplin... | 10.1021/op2001904 | 1 |
Development of a Practical Synthesis of Stearoyl-CoA Desaturase (SCD1) Inhibitor MK-8245 | A practical kilogram scale chromatography-free synthesis of stearoyl-CoA desaturase 1 (SCD1) inhibitor MK-8245 is described. The key features of this sequence include an efficient addition–elimination reaction of a piperidine fragment with a 3-bromoisoxaline followed by an iodine-mediated oxidation to the corresponding... | 10.1021/op200186d | 1 |
Synthesis of a Bicyclic Piperazine from<scp>l</scp>-Aspartic Acid and Application of a Fluoride-Promoted S<sub>N</sub>Ar Coupling | The process development is reported of a pivotal C–N bond formation involving ((7 R,9a S )-octahydro-1 H -pyrido[1,2- a ]pyrazin-7-yl)methanol ( 2 ) undergoing nucleophilic aromatic substitution with 3-chlorobenzo[ d ]isoxazole ( 3 ) to furnish ((7 R,9a S )-2-(benzo[ d ]isoxazol-3-yl)octahydro-1 H -pyrido[1,2- a ]pyraz... | 10.1021/op2001854 | 1 |
Chemical Development of an α2δ Ligand, (3<i>S</i>,5<i>R</i>)-3-(Aminomethyl)-5-methyloctanoic Acid | Three synthetic approaches, suitable for the large scale manufacture of the α2δ-ligand, (3 S,5 R )-3-(aminomethyl)-5-methyloctanoic acid 3, have been evaluated. The selected seven step manufacturing process has then been optimized and used to deliver over 20 kg of API; salient features of the synthesis include the use ... | 10.1021/op2001832 | 1 |
Commercial Synthesis of (<i>S</i>,<i>S</i>)-Reboxetine Succinate: A Journey To Find the Cheapest Commercial Chemistry for Manufacture | The development of a synthetic process for ( S, S )-reboxetine succinate, a candidate for the treatment of fibromylagia, is disclosed from initial scale-up to deliver material for registrational stability testing through to commercial route evaluation and subsequent nomination. This entailed evaluation of several alter... | 10.1021/op200181f | 1 |
Preparative Synthesis via Continuous Flow of 4,4,5,5-Tetramethyl-2-(3-trimethylsilyl-2-propynyl)-1,3,2-dioxaborolane: A General Propargylation Reagent | A scalable process for the preparation of 4,4,5,5-tetramethyl-2-(3-trimethylsilyl-2-propynyl)-1,3,2-dioxaborolane from trimethylsilylpropyne, isopropyl pinacol borate, and n -butyllithium is described. Problems associated with implementing a typical aqueous workup and batch process into production due to borolane “ate”... | 10.1021/op200180t | 1 |
Convergent Asymmetric Synthesis of Two Complex TRPV1 Antagonists | The convergent scale-up synthesis of two complex TRPV1 antagonists to support exploratory toxicology studies is described. Both compounds contain three chiral centers introduced by asymmetric synthesis with chiral control being critical for the success of the project. Preparation of the key cyclopropyl intermediate uti... | 10.1021/op200177b | 1 |
Discovery of a Novel, Efficient, and Scalable Route to Bendamustine Hydrochloride: The API in Treanda | Process Research and Development activities leading to a new and efficient route to bendamustine hydrochloride, 1, the active ingredient in Treanda, a treatment for blood cancers, are disclosed. Two key features of this new process include a one-pot hydrogenation/dehydration sequence to construct the benzimidazole moie... | 10.1021/op200176f | 1 |
Asymmetric Synthesis of LFA-1 Inhibitor BIRT2584 on Metric Ton Scale | The synthesis of LFA-1 inhibitor BIRT2584 on metric-ton scale was accomplished by means of a safe and robust process. Highlights of the process include the asymmetric synthesis of the key advanced intermediate by implementation of Seebach’s self-regeneration of stereocenters principle, and a Ph 3 PCl 2 -induced dehydra... | 10.1021/op200175t | 1 |
Use of an Iridium-Catalyzed Redox-Neutral Alcohol-Amine Coupling on Kilogram Scale for the Synthesis of a GlyT1 Inhibitor | A recent development for the efficient and environmentally friendly synthesis of aliphatic amines is the transition-metal-catalyzed redox-neutral coupling of an alcohol and an amine, generally referred to as a “borrowing hydrogen” reaction. In this work, we describe the first kilogram-scale application of this technolo... | 10.1021/op200174k | 1 |
Development an Efficient Route to the 5-Lipoxygenase Inhibitor PF-04191834 | A convergent six-step process for the synthesis of PF-04191834 ( 1 ), a potent and selective 5-lipoxygenase inhibitor, has been developed and used to deliver over 20 kg of API. The process uses the same bond-forming steps as the initial medicinal chemistry route, including the use of two consecutive Pd-catalyzed Ar–S c... | 10.1021/op200173g | 1 |
Pilot Plant Preparation of <i>tert-</i>Butyl-4-(2-hydroxyethyl)-4-(pyrrolidin-1-yl)-piperidine-1-carboxylate, An Intermediate of Novel Antiarteriosclerotics, Via a Safe, Scalable Reformatsky-Type Reaction | Reported here is a safe, scalable process via a Reformatsky-type reaction of iminium salt ( 4 ) followed by Red-Al reduction giving tert -butyl-4-(2-hydroxyethyl)-4-(pyrrolidin-1-yl)-piperidine-1-carboxylate ( 6 ), an intermediate of novel antiarteriosclerotics ( 1 ). The key points of this safe process are the use of ... | 10.1021/op2001723 | 1 |
Chemical Development of the Casein Kinase I - Epsilon Inhibitor: 3-(3-Fluorophenyl)sulfanyl-1<i>H</i>-pyrrolo[3,2-<i>b</i>]pyridine-2-carboxylic Acid Amide | The development of a scalable process for 3-arylsulfanyl-1 H -pyrrolo[3,2- b ]pyridine-2-carboxylic acid amides ( 1 ), potent casein kinase I inhibitors, is described. The rapid identification of suitable reaction conditions expedited the lab scale synthesis of drug substances for early toxicological evaluations. Furth... | 10.1021/op200171a | 1 |
Process Research on the Asymmetric Hydrogenation of a Benzophenone for Developing the Manufacturing Process of the Squalene Synthase Inhibitor TAK-475 | A practical synthetic method for the synthesis of the chiral benzhydrol 8, which is the key intermediate of the squalene synthase inhibitor TAK-475 ( 1 ), has been developed. The method, via asymmetric hydrogenation of the benzophenone 7, employed Noyori’s ruthenium precatalyst of the type [RuCl 2 (diphosphine)(diamine... | 10.1021/op2001673 | 1 |
A Facile Stereoselective Biocatalytic Route to the Precursor of Woody Acetate | Carbonyl reductase (CRED) technology has been shown to be an important tool for the rapid and efficient preparation of cis- and trans -4- tert -butylcyclohexanol, the precursors to the high volume fragrance ingredients known as Woody Acetate. | 10.1021/op200166a | 0 |
Screening Binary Systems of Chelating Agents Combined with Carbon or Silica Gel Adsorbents: The Development of a Cost-Effective Method to Remove Palladium from Pharmaceutical Intermediates and APIs | The increasing use of palladium catalysts in the synthesis of pharmaceutical intermediates and active pharmaceutical ingredients (APIs) has created the rising need for cost-effective ways to remove the resulting metal contaminants. A simple binary palladium scavenging system was developed using a chelating agent in com... | 10.1021/op2001657 | 0 |
The Development of a Practical Multikilogram Synthesis of the Chiral β-Amino Acid Imagabalin Hydrochloride (PD-0332334) via Asymmetric Hydrogenation | The development and implementation of a robust process for the manufacture of metric ton quantities of the α2δ ligand imagabalin hydrochloride 4 is described. Key aspects of the synthesis include a chromatography-free, two-step telescoped process to prepare a mixture of Z: E -enamides 7 followed by a robust asymmetric ... | 10.1021/op2001639 | 1 |
Practical Aspects of Integrated Operation of Biotransformation and SMB Separation for Fine Chemical Synthesis | Integrated operation of biotransformation and simulated moving bed (SMB) separation is an attractive option for high-yield manufacturing of commercially relevant compounds such as rare sugars and sialic acids from equilibrium-limited isomerase- or aldolase-catalyzed reactions. Here, we present the first lab-scale imple... | 10.1021/op200160e | 0 |
Development of an Improved Immobilized CAL-B for the Enzymatic Resolution of a Key Intermediate to Odanacatib | An immobilized form of Candida antarctica lipase B (CAL-B) has been developed with enhanced stability and activity compared to commercially available preparations. The immobilized CAL-B is more active, and 15 times more stable than the previously used preparation. This permits a continuous dynamic kinetic resolution pr... | 10.1021/op200157c | 0 |
Synthesis of the Hepatitis B Nucleoside Analogue Lagociclovir Valactate | 2′,3′-Dideoxy-3′-fluoro-5- O -[(S)-(+)-2-( l -valyloxy)-propionyl] guanosine (lagociclovir valactate) is a prodrug of 3′-fluoro-2′,3′-dideoxyguanosine with high oral bioavailability in humans and potent activity against hepatitis B virus (HBV). A five-step synthesis of lagocyclovir valactate starting from 2-amino-6-chl... | 10.1021/op200153s | 1 |
Prediction of Agglomerate Type during Scale-Up of a Batch Crystallization Using Computational Fluid Dynamics Models | The impact of hydrodynamics on agglomeration during the crystallization of an active pharmaceutical ingredient (API) was investigated. The type of agglomerate formed was experimentally observed to correlate with agitation level at the laboratory and kilo-lab scales. It was hypothesized that differences in agglomerate t... | 10.1021/op200152u | 0 |
Concise Synthesis of Two β-Adrenergic Blocking Agents in High Stereoselectivity Using the Readily Available Chiral Building Block (2<i>S</i>,2′<i>S</i>,2″<i>S</i>)-Tris-(2,3-epoxypropyl)-isocyanurate | A concise synthesis of ( S )-propranolol and ( S )-metoprolol in high stereoselectivity using the readily available chiral building block (2 S,2′ S,2″ S )-tris-(2,3-epoxypropyl)-isocyanurate (S-TGT) as the key intermediate is described. | 10.1021/op2001518 | 1 |
Work-Up Optimization en Route to an Improved Process To Prepare a Progesterone Receptor Antagonist | When the process to prepare nonsteroidal progesterone receptor antagonist 5 was scaled up, significant problems were encountered, and as a result lower than expected yields were obtained. In particular, the alkylation of pyrazole 2 with chloromethyl methyl sulfide failed to reach completion, and partial degradation of ... | 10.1021/op200145j | 1 |
Route Selection and Process Development for a 5-Piperazinylquinaldine Derivative for the Treatment of Depression and Anxiety | 1-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone, 1, was identified as a potential drug for the treatment of depression and anxiety. Herein is described the work carried out to select the manufacturing route and the process research studies to optimize the key stages of route B. A partic... | 10.1021/op200140v | 1 |
Design and Scale-Up of Diels–Alder Reactions for the Practical Synthesis of 5-Phenylbicyclo[2.2.2]oct-5-en-2-one | Several synthetic pathways towards racemic 5-phenylbicyclo[2.2.2]oct-5-en-2-one 1 have been devised starting with a Diels–Alder reaction of (cyclohexa-1,5-dien-1-yloxy)trimethylsilane and α-acetoxyacrylonitrile, acrylonitrile, or α-chloroacrylonitrile. The first ‘fit-for-purpose’ route relied on α-acetoxyacrylonitrile ... | 10.1021/op200139r | 1 |
Micro Reaction Technology in Organic Synthesis | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewMicro Reaction Technology in Organic SynthesisTrevor LairdCite this: Org. Process Res. Dev. 2011, 15, 4, 947Publication Date (Web):June 6, 2011Publication History Published online6 June 2011Published inissue 15 July 2011https://pubs.acs.org/doi/10.1021/op200137whttps://doi.or... | 10.1021/op200137w | 0 |
Sustainable Process Chemistry | ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTSustainable Process ChemistryRobert Appell, Dinesh Gala, and Yogesh S. Sanghvi*View Author Information Guest Editors and Members of the Editorial Advisory Board[email protected]Cite this: Org. Process Res. Dev. 2011, 15, 4, 898–899Publication Date (Web):June 6, 2011Publicat... | 10.1021/op200135v | 0 |
Process Safety Evaluation of a Tungsten-Catalyzed Hydrogen Peroxide Epoxidation Resulting In a Runaway Laboratory Reaction | An investigation of a runaway chemical reaction in the laboratory highlighted the potential hazards of oxidation chemistry involving hydrogen peroxide in the presence of tungsten catalysts. Under the process conditions, a combination of a high adiabatic temperature rise, an unstable target molecule, and a potentially i... | 10.1021/op200133q | 0 |
Lipase-Catalyzed Monostearin Synthesis under Continuous Flow Conditions | Biodegradable, biocompatible and nontoxic nonionic surfactants are widely used in food, pharmaceutical and industrial applications being commonly produced based on alkaline-catalyzed chemical glycerolysis of natural oil and fats at high temperatures and elevated pressure under nitrogen atmosphere. In this work we have ... | 10.1021/op200132y | 0 |
Fit-for-Purpose Development of the Enabling Route to Crizotinib (PF-02341066) | A robust six-step process for the synthesis of crizotinib, a novel c-Met/ALK inhibitor currently in phase III clinical trials, has been developed and used to deliver over 100 kg of API. The process includes a Mitsunobu reaction, a chemoselective reduction of an arylnitro group, and a Suzuki coupling, all of which requi... | 10.1021/op200131n | 1 |
Large-Scale Synthesis of a Substituted <scp>d</scp>-Phenylalanine Using Asymmetric Hydrogenation | A synthetic route to an N -BOC d -phenylalanine pharmaceutical intermediate suitable for rapid scale-up to 150-kg scale was required. A seven-step route based on asymmetric hydrogenation of an N -acetyl dehydroamino-acid was developed. Starting with terephthalic dialdehyde, monoreduction of one aldehyde group, Erlenmey... | 10.1021/op200129m | 1 |
Process Development of a Potent Glucosylceramide Synthase Inhibitor | An economic, scalable process for the production of glucosylceramide synthase (GCS) inhibitor 7 has been developed. Herein we report a three-step synthesis to aldehyde 4 with high yield and purity that employs the selective cleavage of an endocyclic C–O bond of a THP ether using borane/THF as the key step. This particu... | 10.1021/op2001222 | 1 |
Convergent Synthesis of a 5HT<sub>7</sub>/5HT<sub>2</sub> Dual Antagonist | The development of an efficient and convergent route to 3-(4-fluorophenyl)-2-isopropyl-2,4,5,6,7,8-hexahydropyrazolo[3,4- d ]azepine ( 1 ), a potent 5HT 7 /5HT 2 dual antagonist, is described. Significant features of this route are: (a) a regioselective construction of a tetra-substituted pyrazole 6a by reacting an N -... | 10.1021/op2001194 | 1 |
The Safe Use of Sodium Hydride on Scale: The Process Development of a Chloropyrimidine Displacement | Sodium hydride was found to be the best base for a displacement reaction on a chloropyrimidine. Due to the insolubility of sodium hydride in all solvents and high reactivity with atmospheric moisture, solutions dealing with the associated safety concerns on kilogram scale are described. The use of sodium hydride in pre... | 10.1021/op200114t | 0 |
Multigram Synthesis of Glyceollin I | Scaled-up procedures and preparation of glyceollin I in multigram quantities are described. The synthesis features construction of a cis-fused ring system in high enantiomeric excess after Sharpless asymmetric dihydroxylation of a key intermediate that is initially produced by an intramolecular Wittig reaction to affor... | 10.1021/op200112g | 1 |
Adaptive Process Optimization for Continuous Methylation of Alcohols in Supercritical Carbon Dioxide | A self-optimizing continuous flow reactor has been developed using the Super-Modified Simplex algorithm. This system, coupled with online gas chromatographic analysis enables automated optimization via a feedback control loop without user intervention. This has been applied to the methylation of 1-pentanol in supercrit... | 10.1021/op200109t | 0 |
Enzymatic Desymmetrization Route to Ethyl [3-(2-Amino-2-methylpropyl)phenyl]acetate | An efficient process to ethyl [3-(2-amino-2-methylpropyl)phenyl]acetate 6 has been developed. Key steps include a novel enzymatic desymmetrization of diester 2 and a Ritter reaction between alcohol 4 and chloroacetonitrile, followed by chemoselective deprotection with thiourea. | 10.1021/op200108k | 1 |
The Lactol Route to Fesoterodine: An Amine-Promoted Friedel–Crafts Alkylation on Commercial Scale | We report the discovery and optimization of an amine-promoted Friedel–Crafts alkylation of cinnamaldehyde with 4-hydroxymethyl phenol. This reaction has been used successfully on commercial scale (200 kg) in the context of the manufacture of fesoterodine, a muscarinic antagonist used for the treatment of overactive bla... | 10.1021/op200107g | 1 |
Convergent Kilo-Scale Synthesis of a Potent Renin Inhibitor for the Treatment of Hypertension | Process research and development of a synthetic route towards a novel renin inhibitor ( 1 ) is described. The highly convergent synthetic route provided 1 in 15% yield on multikilogram scale with a longest linear sequence of 11 steps. The use of catalytic hydrogenation features prominently in our design. The proper cho... | 10.1021/op2001063 | 1 |
A Scalable Two-Step Continuous Flow Synthesis of Nabumetone and Related 4-Aryl-2-butanones | Three different continuous flow strategies for the generation of important 4-aryl-2-butanone derivatives including the anti-inflammatory drug nabumetone [4-(6-methoxy-2-naphthalenyl)-2-butanone] and the aroma compounds raspberry ketone [4-(4-hydroxyphenyl)-2-butanone] and its methyl ether [4-(4-methoxyphenyl)-2-butanon... | 10.1021/op2001047 | 1 |
Using the Right Green Yardstick: Why Process Mass Intensity Is Used in the Pharmaceutical Industry To Drive More Sustainable Processes | There have been a many publications and much discussion about green metrics. While many have been proposed, The American Chemical Society Green Chemistry Institute’s Pharmaceutical Roundtable has chosen process mass intensity (PMI) as the key, high-level metric for evaluating and benchmarking progress towards more sust... | 10.1021/op200097d | 0 |
An Efficient, Economical Synthesis of the Novel Anti-tumor Agent CPI-613 | An efficient and practical synthesis of the novel anti-tumor compound 6,8-dithiobenzyl octanoic acid, CPI-613 ( 2 ), was developed and executed on a practical scale. CPI-613 can be made in a single vessel from (±)-lipoic acid ( 1 ) via reductive opening of the disulfide ring followed by benzylation of the sulfhydryls w... | 10.1021/op200091t | 0 |
Scale-Up of Microwave-Assisted Reactions in a Multimode Bench-Top Reactor | An evaluation of a new bench-top microwave batch reactor that uses a single 1 L reaction vessel is presented. Several microwave-assisted organic reactions have been scaled-up, including Newman Kwart and Diels–Alder reactions, Pd-catalyzed cross-couplings, heterocycle synthesis, aromatic substitution, and a Knoevenagel ... | 10.1021/op200090k | 0 |
Practical Gram Scale Asymmetric Catalysis with Boroxinate Brønsted Acids Derived from the VAPOL and VANOL Ligands | Our laboratories have been engaged in utilizing catalysts derived from the VAPOL and VANOL ligands towards the development of efficient asymmetric processes over the last several years. Subsequent to their development, practical scale-up of these methodologies to gram scale has always been deemed necessary to demonstra... | 10.1021/op200087f | 1 |
Enoate Reductase-Mediated Preparation of Methyl (<i>S</i>)-2-Bromobutanoate, a Useful Key Intermediate for the Synthesis of Chiral Active Pharmaceutical Ingredients | Enoate reductases belonging to the Old Yellow Enzyme (OYE) family were employed to develop a biocatalysed approach to methyl ( S )-2-bromobutanoate, a key intermediate for the introduction of a particular stereogenic unit into the molecular skeleton of a certain class of chiral drugs. Methyl ( Z )-2-bromocrotonate affo... | 10.1021/op200086t | 0 |
Biotechnological Development of a Practical Synthesis of Ethyl (<i>S</i>)-2-Ethoxy-3-(<i>p</i>-methoxyphenyl)propanoate (EEHP): Over 100-Fold Productivity Increase from Yeast Whole Cells to Recombinant Isolated Enzymes | The coupling of the enantioselective reduction catalyzed by Old Yellow Enzymes (OYEs), together with the in situ substrate feeding product removal (SFPR) concept, significantly improved the productivity of the g-scale preparation of ethyl ( S )-2-ethoxy-3-( p -methoxyphenyl)propanoate (EEHP), an important precursor of ... | 10.1021/op200085k | 1 |
Development of a Commercial Process for (<i>S</i>)-β-Phenylalanine | The development of a commercial manufacturing route for ( S )-β-phenylalanine 8, a key pharmaceutical building block, is described. The different approaches which were investigated, based on catalytic asymmetric hydrogenation of enamide intermediates and on biocatalysis using acylase and lipase hydrolyses, are compared... | 10.1021/op200084g | 1 |
Design and Scalable Synthesis of New Chiral Selectors. Part 2: Chiral Ionic Liquids Derived from Diaminocyclohexane and Histidine | We disclose the conception and synthesis of new chiral selectors useful for enantioselective liquid–liquid extraction processes (ELLE). We report synthetic methods giving access to substantial amounts of the compounds, at least at the multigram scale. Two series are examined, i.e. ionic liquids based on diaminocyclohex... | 10.1021/op200082a | 1 |
Serendipitous Discovery of a Zidovudine Guanidine Complex: A Superior Process for the Production of Zidovudine | A superior process for the commercial production of zidovudine (AZT) has been developed. It was discovered that an AZT–guanidine complex formed when a crude zidovudine solution was treated with guanidine. This readily precipitated from protic solvents resulting in the exclusion of impurities and permitted the developme... | 10.1021/op2000805 | 1 |
A Simplified Process for the Manufacture of AZD0530, a Potent SRC Kinase Inhibitor | An efficient process for the manufacture of AZD0530 1, a potent SRC kinase inhibitor, has been developed. The key transformation, reaction of monofluoroanilide 7 with alcohol 8, was much simplified between manufacturing campaigns. The development of a robust, efficient, and scalable process for this transformation drew... | 10.1021/op200079g | 1 |
Development of a Fit-for-Purpose Large-Scale Synthesis of an Oral PARP Inhibitor | Compound ( 1 ) a poly(ADP-ribose)polymerase (PARP) inhibitor has been made by a fit-for-purpose large-scale synthesis using either a classical resolution or chiral chromatographic separation. The development and relative merits of each route are discussed, along with operational improvements and extensive safety evalua... | 10.1021/op2000783 | 1 |
The Development of Scalable and Efficient Methods for the Preparation of Dicyclopropylamine HCl Salt | The unique chemical properties of dicyclopropylamine (DCPA) 1 render its synthesis a challenge for process chemists despite its structural simplicity. Chemical instability and high aqueous solubility further complicate the process for DCPA’s preparation, isolation, and purification. In this note we describe the develop... | 10.1021/op2000755 | 1 |
A Reactive Distillation Process To Produce 5-Hydroxy-2-methyl-1,3-dioxane from Mixed Glycerol Acetal Isomers | The four cyclic glycerol acetal isomers can be readily produced via the acid-catalyzed reaction of glycerol with acetaldehyde or a related acetal species. In the presence of the acid catalyst used in acetal formation, the isomers interconvert to form an equilibrated mixture that contains similar quantities of the four ... | 10.1021/op200072x | 0 |
Multijet Oscillating Disc Millireactor: A Novel Approach for Continuous Flow Organic Synthesis | This report discloses proof of concept and experimental results from a project involving design, development, and investigation of a novel approach for flow chemistry and the realization of equipment operating according to this new approach. This device is named multijet oscillating disk (MJOD) reactor and is dedicated... | 10.1021/op2000699 | 0 |
A Large-Scale Synthesis of Potent Glucokinase Activator MK-0941 via Selective <i>O</i>-Arylation and <i>O</i>-Alkylation | An efficient, practical preparation of MK-0941, a potent glucokinase activator, is described. Keys to the success of the synthesis are a highly selective mono- O -arylation of methyl 3,5-dihydroxybenzoate with 2-ethanesulfonyl-5-chloropyridine and the choice of a proper protective group for the subsequent S N 2 O -alky... | 10.1021/op200068c | 1 |
A Safe Two-Step Process for Manufacturing Glycidyl Nitrate from Glycidol Involving Solid–Liquid Phase-Transfer Catalysis | A new and safer two-step process for manufacturing glycidyl nitrate from glycidol is reported. In the first step glycidyl tosylate is obtained by reacting glycidol with p -tosyl chloride in the presence of triethylamine according to any one of the well-known procedures for obtaining tosyl esters described in the litera... | 10.1021/op200066e | 0 |
Development of an Asymmetric Hydrogenation Route to (<i>S</i>)-<i>N</i>-Boc-2,6-dimethyltyrosine | An improved, simpler and potentially more economical route to ( S )- N -Boc-2,6-dimethyltyrosine 1, based on a previously published route, is presented. Key modifications were to prepare the dehydroaminoacid hydrogenation substrate 6 in a one-pot process directly from serine methyl ester and 4-iodo-3,5-dimethylphenyl a... | 10.1021/op200065p | 1 |
Book Review of Pharmaceutical Process Chemistry for Synthesis, Rethinking the Routes to Scale-Up | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Pharmaceutical Process Chemistry for Synthesis, Rethinking the Routes to Scale-UpWill WatsonView Author Information Scientific UpdateCite this: Org. Process Res. Dev. 2011, 15, 3, 727Publication Date (Web):April 1, 2011Publication History Published online1 ... | 10.1021/op200063u | 0 |
Statistical Optimization of Reaction Parameters for the Synthesis of 2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane | An orthogonal array design (OA 32 ) was employed as a statistical optimization method to enhance the performance of the synthesis of 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (HNIW). The current application of the Taguchi method was successful in optimizing the experimental parameters of HNIW synthesis... | 10.1021/op200056j | 0 |
A Versatile Lab to Pilot Scale Continuous Reaction System for Supercritical Fluid Processing | A compact and versatile continuous reaction system for supercritical fluids as mobile phase was realised using commercially available components where possible. All process parameters of particular importance to the specific properties of near- or supercritical fluids such as pressure, temperature, and composition ( p,... | 10.1021/op200053w | 0 |
Synthetic Route Discovery and Introductory Optimization of a Novel Process to Idebenone | An environmentally benign, convenient, high yielding, and cost-effective synthesis leading to idebenone is disclosed. The synthesis includes a bromination process for the preparation of 2-bromo-3,4,5-trimethoxy-1-methylbenzene, a protocol for the Heck cross-coupling reaction using either thermal or microwave heating, o... | 10.1021/op200051v | 1 |
Rhodium-Catalyzed C–H Amination. An Enabling Method for Chemical Synthesis | Reaction methods for selective C-H amination are finding ever-increasing utility for the preparation of nitrogen-derived fine chemicals. This brief account highlights the remarkable versatility of dirhodium-based catalysts for promoting oxidation of aliphatic C-H centers in both intra- and intermolecular reaction proce... | 10.1021/op200046v | 0 |
A Practical Asymmetric Synthesis of Isopropyl (1<i>R</i>,2<i>S</i>)-Dehydrocoronamate | A novel asymmetric synthesis of isopropyl (1 R,2 S )-dehydrocoronamate is described from ( S )-1,2,4-butanetriol as the starting material in 28% overall yield. Highlights of this synthetic route include selective cyclopropanation between chiral cyclic sulfate 5 and diisopropyl malonate ( 8c ), formation of vinylcyclopr... | 10.1021/op200038y | 1 |
A New Process for Synthesis of Apricitabine, 2-(<i>R</i>)-Hydroxymethyl-4-(<i>R</i>)-(cytosin-1′-yl)-1,3-oxathiolane, an Anti-HIV NRTI | Apricitabine is a novel inhibitor of the HIV virus reverse transcriptase polymerase which is currently in clinical development for the treatment of AIDS. A new process for the preparation of apricitabine is presented which requires only three steps from 2-( R )-benzoyloxymethyl-1,3-oxathiolane. The new process produces... | 10.1021/op2000332 | 1 |
An Improved Synthesis of Valsartan | Biphenyltetrazole group, an important component of sartans, is usually formed in excellent yield by the reaction of 4′-alkylbiphenyl-2-carbonitrile with excessive organotin azide. However, it is restricted in industrial scale because of the difficult post-treatment. In this article, an improved synthetic method for val... | 10.1021/op200032b | 1 |
A Practical Synthesis of Biaryls via a Thermal Decarboxylative Pd-Catalyzed Cross-Coupling Reaction Operating at Moderate Temperature | The palladium-catalyzed decarboxylative cross-coupling of aminothiophene carboxylate and 1-bromo-4-chlorobenzene to produce 3-amino-2-(4-chlorophenyl)thiophene ( 2 ) is described. The cross-coupling proceeds under relatively mild conditions using catalytic Pd(0) and TBAB. Through use of a mixed-solvent system of DMF an... | 10.1021/op200030t | 1 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.