title string | abstract string | doi string | has_route int64 |
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Living Anionic Polymerization in Continuous Flow: Facilitated Synthesis of High-Molecular Weight Poly(2-vinylpyridine) and Polystyrene | We describe the living anionic polymerization of 2-vinylpyridine (2VP) and styrene (S) in continuous flow, comparing two micromixing devices with different mixing principles. The use of a continuous flow setup reduces the experimental effort for living anionic polymerizations significantly, compared to a conventional b... | 10.1021/op500149t | 0 |
Asymmetric Hydrogenation of 3,5-Bistrifluoromethyl Acetophenone in Pilot Scale with Industrially Viable Ru/Diphosphine–Benzimidazole Complexes | A novel efficient asymmetric hydrogenation (AH) process was developed for the preparation of ( R )-1-(3,5-bis(trifluoromethyl)phenyl)ethanol ( 3 ), using a catalyst Ru/(4 R,5 R )-(+)-4,5-bis(diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxoane-( R, R -Diop)-2 R -(α-methylmethanamine)-4,7-dimethyl-1 H -benzo[ d ]imidazole... | 10.1021/op500148k | 1 |
A Greener Approach for the Large-Scale Synthesis of 1,4,5-Trisubstituted Pyrazole, AZD8329 | The development of a convenient, safe and scalable process for AZD8329 manufacturing is reported here. Synthesis was achieved in a two-step telescopic process with an excellent overall yield of 75%. In the first step enamine ( 6 ) was synthesized with 90% yield through three chemical transformations. In the next step A... | 10.1021/op5001463 | 1 |
Isothermal Suspension Conversion as a Route to Cocrystal Production: One-Pot Scalable Synthesis | Isothermal suspension conversion is presented as a suitable method for the manufacture of pure cocrystal products once the ternary phase diagram (TPD) for the cocrystal system in the desired solvent is available. One:one and 3:2 cocrystals of p -toluenesulphonamide/triphenylphosphine oxide were produced in acetonitrile... | 10.1021/op500145a | 0 |
Sequential Nitration/Hydrogenation Protocol for the Synthesis of Triaminophloroglucinol: Safe Generation and Use of an Explosive Intermediate under Continuous-Flow Conditions | A continuous-flow process for the synthesis of triaminophloroglucinol has been developed. The synthetic procedure is based on a sequential nitration/reduction protocol which uses phloroglucinol as an inexpensive substrate. During the initial exothermic nitration step employing a combination of ammonium nitrate and sulf... | 10.1021/op5001435 | 1 |
A Scalable Synthesis of (<i>R</i>,<i>R</i>)-2,6-Dimethyldihydro-2<i>H</i>-pyran-4(3<i>H</i>)-one | A scalable synthesis of ( R, R )-2,6-dimethyldihydro-2 H -pyran-4(3 H )-one is reported. Key to this strategy is the Ti(O i Pr) 4 -catalyzed Kulinkovich cyclopropanation of silyl protected ( R )-ethyl 3-hydroxybutanoate, and subsequent oxidative fragmentation of the cyclopropanol. The resulting vinyl ketone intermediat... | 10.1021/op500135x | 1 |
A One-Pot Asymmetric Synthesis of a <i>N</i>-Acylated 4,5-Dihydropyrazole, A Key Intermediate of Thrombin Inhibitor AZD8165 | A short, chromatography-free, and scalable synthetic route to thrombin inhibitor 1, the active metabolite of the propionic ester prodrug AZD8165, has been developed. The key synthetic step involved cycloaddition of TMS–diazomethane and ethyl acrylate to give an intermediate racemic dihydropyrazole which was reacted wit... | 10.1021/op500134e | 1 |
Multikilogram Scale Organolithiation Chemistry for the Manufacture of Liquid Crystal Intermediates | This paper describes the kilogram-scale regioselective synthesis of various fluorinated arylboronic acids, aryl iodides, aryl acids, aryl aldehydes, and cyclohexenyl-substituted aryls in good to high yields via in situ fluorine-directed ortho-lithiation of fluorinated aryls and their subsequent reactions in a one-pot m... | 10.1021/op500133p | 0 |
Application of In Situ Raman Spectroscopy To Facilitate Use of Hydrogen Peroxide on Kilogram Scale | The safe implementation of a hydrogen-peroxide-mediated oxidation of a poorly reactive sulfide to the corresponding sulfone is described. A three-tiered approach incorporating process understanding, safety studies, and real time PAT (in situ Raman spectroscopy) was leveraged to ensure safe operation. Further investigat... | 10.1021/op500132s | 0 |
Synthesis of Ionic Liquids Equipped with 2-Methoxyethoxymethyl/Methoxymethyl Groups Using a Simple Microreactor System | A simple microreactor system has been utilized for the continuous flow synthesis of novel ionic liquids having a (2-methoxyethoxy)methyl or methoxymethyl substituent. Conversion rates of N -bases and tributylphosphine in the microreactor system are faster than those in the batch system because of less diffusion distanc... | 10.1021/op500131u | 0 |
Scale-Up of a Recombinant Pig Liver Esterase-Catalyzed Desymmetrization of Dimethyl Cyclohex-4-ene-<i>cis</i>-1,2-dicarboxylate | A recombinant isoenzyme of pig liver esterase was used for the highly enantioselective desymmetrization of dimethyl cyclohex-4-ene- cis -1,2-dicarboxylate. The selected recombinant esterase showed a significant advantage in enantioselectivity over the commonly used esterase from the mammalian source. The process was sc... | 10.1021/op500129e | 0 |
An Atom-Efficient Route to Ethyl 3-(difluoromethyl)-1-methyl-1<i>H</i>-pyrazole-4-carboxylate (DFMMP)—A Key Building Block for a Novel Fungicide Family | A growing number of fluorine-containing active ingredients in the pharmaceutical and agrochemical industries inevitably raises the demand for new fluorinated building blocks. Their availability is mainly constricted by suitable chemistry and available bulk fluorine containing starting materials. Because of the high cos... | 10.1021/op500128p | 1 |
The Institute of Process Research and Development at the University of Leeds | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTThe Institute of Process Research and Development at the University of LeedsTrevor LairdCite this: Org. Process Res. Dev. 2014, 18, 5, 561Publication Date (Web):May 16, 2014Publication History Published online16 May 2014Published inissue 16 May 2014https://pubs.acs.org/doi/10.1... | 10.1021/op500124j | 0 |
Improved Synthesis of Fluticasone Propionate | A novel process for the preparation of fluticasone propionate ( 1 ), a corticosteroid, is reported. In this paper, compound 2 was used as starting material to prepare 6 by using NaClO or NaBrO which was much cheaper than H 5 IO 6 as an oxidizing agent. Furthermore, toxic, expensive, and pollutive BrCH 2 F was replaced ... | 10.1021/op5001226 | 1 |
PhenoFluor: Practical Synthesis, New Formulation, and Deoxyfluorination of Heteroaromatics | We report a practical synthesis method of the reagent PhenoFluor on decagram scale, provide a new formulation of PhenoFluor as a toluene solution, which should decrease challenges associated with the moisture sensitivity of the reagent, and expand the substrate scope of deoxyfluorination with PhenoFluor to heteroaromat... | 10.1021/op500121w | 1 |
Multigram Laboratory Scale Synthesis of α-Trifluoromethoxy Carbonyl Compounds | α-trifluoromethoxy carbonyl compounds are valuable building blocks for the synthesis of various trifluoromethoxylated compounds. The best way to easily obtain them is the direct trifluoromethoxylation with the CF 3 O – anion, generated in situ from trifluoromethyl triflate. However, the necessary autogenous pressure ge... | 10.1021/op500118r | 0 |
Development of a Total Telescoped Synthesis of a Renin Inhibitor Containing 3,4,5-Substituted Piperidine with Sterically Hindered Amide Bonds | A telescoped synthesis for the manufacturing of a renin inhibitor containing 3,4,5-substituted piperidine with sterically hindered amide bonds via a five-step synthetic route is described. Highlights of this scalable synthesis include: (1) the byproduct-controlled amidation protocol using Ghosez’s reagent in the presen... | 10.1021/op500116w | 1 |
Synthesis of Fluorinated and Nonfluorinated Tebufenpyrad Analogues for the Study of Anti-angiogenesis MOA | High Resolution Image Download MS PowerPoint Slide In this contribution we report the synthesis of fluorinated and nonfluorinated tebufenpyrad analogues to explore potential druglike properties through the phenotypic screening as part of the Lilly Open Innovation Drug Discovery (OIDD) program. | 10.1021/op500114v | 1 |
Continuous Process for Production of CuCF<sub>3</sub> via Direct Cupration of Fluoroform | The first continuous flow process has been developed for the synthesis of a superior trifluoromethylating reagent, “ligandless” CuCF 3, from fluoroform, by far the best CF 3 source in terms of availability, cost, and atom economy. Optimization of the residence time and feed rates for CHF 3 (gas), the cuprating reagent ... | 10.1021/op500109v | 0 |
Exploiting the Differential Reactivities of Halogen Atoms: Development of a Scalable Route to IKK2 Inhibitor AZD3264 | An efficient and scalable synthesis of AZD3264 is described in which the differential reactivities of various halogen atoms have been employed. The process involves five linear chemical steps with three isolated stages starting from commercially available fragments. | 10.1021/op500105n | 1 |
Industrial Process Scale-Up | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewIndustrial Process Scale-UpTrevor LairdCite this: Org. Process Res. Dev. 2014, 18, 4, 560Publication Date (Web):April 2, 2014Publication History Published online2 April 2014Published inissue 18 April 2014https://doi.org/10.1021/op5001034Copyright © 2014 American Chemical Soci... | 10.1021/op5001034 | 1 |
A New Synthesis and Process Development of Bis(fluoroalkyl)pyrazoles As Novel Agrophores | The synthesis of 3,5-bis(fluoroalkyl)-pyrazoles as novel agrophores is described. Commercially available fluoroacetoacetates are treated with BF 3 -activated TFEDMA affording in a straightforward one-pot sequence pyrazole carboxylates in good yields and with excellent regioselectivity. The carboxylate intermediates hav... | 10.1021/op500102h | 1 |
Multivariate Optimization of a Cyclopropanation, the Key Step in the Synthesis of 3,3,4,4-Tetraethoxybut-1-yne | 3,3,4,4-Tetraethoxybut-1-yne (TEB) is a versatile synthon that can be produced in a four-step synthesis. The third step of the synthesis is a cycloproanation, which has been thoroughly investigated and optimized by means of statistical experimental design and multivariate modeling. At the outset, an exhaustively pre-ex... | 10.1021/op5001012 | 1 |
Process Development and Control with Recent New FBRM, PVM, and IR | Process analytical technologies (PATs) have played an important role in process development and optimization throughout the pharmaceutical industry. Recent new PATs, including in-process video microscopy (PVM), a new generation of focused-beam reflectance measurement (FBRM), miniature process IR spectroscopy, and a flo... | 10.1021/op5000978 | 0 |
Facile Production Scale Synthesis of (<i>S</i>)-Taniguchi Lactone: A Precious Building-Block | A cost-efficient and facile synthesis of ( S )-4-vinyldihydrofuran-2( 3H )-one ( ( S ) -1 ), better known as ( S )-Taniguchi lactone, is described. Racemic Taniguchi lactone rac -1 was ring-opened with ( S )-1-benzylmethylamine providing a diastereomeric mixture of hydroxyl-amides. The desired diastereomer ( S,S ) -2 w... | 10.1021/op500096j | 1 |
Optimization and Scale-up of a Bioreduction Process for Preparation of Ethyl (<i>S</i>)-4-Chloro-3-hydroxybutanoate | Ethyl 4-chloro-3-oxobutanoate (COBE) was asymmetrically reduced with Escherichia coli cells expressing a reductase (ScCR) from Streptomyces coelicolor to afford enantiopure ethyl ( S )-4-chloro-3-hydroxybutanoate [( S )-CHBE], which is an important precursor for preparing the drug atorvastatin. The substrate load was f... | 10.1021/op500088w | 0 |
An Integrated Process Analytical Technology (PAT) Approach for Process Dynamics-Related Measurement Error Evaluation and Process Design Space Development of a Pharmaceutical Powder Blending Bed | In this work, a model pharmaceutical powder blending system consisting of ibuprofen (drug), MCC, and lactose anhydrous was monitored in real-time via inline near-infrared (NIR) spectroscopy for dual purposes: (1) to examine the effects of formulation variables (drug and MCC contents) and a process variable (impeller ro... | 10.1021/op500085m | 0 |
Identification, Synthesis, and Strategy for the Reduction of Potential Impurities Observed in Dabigatran Etexilate Mesylate Processes | Synthetic impurities that are present in dabigatran etexilate mesylate were studied, and possible pathways by which these impurities are formed during the manufacturing process were examined. The impurities were monitored by high-performance liquid chromatography, and their structures were determined by mass spectromet... | 10.1021/op500084q | 1 |
An Improved Process for the Preparation of Highly Pure Solifenacin Succinate via Resolution through Diastereomeric Crystallisation | An improved process for the preparation of solifenacin succinate ( 1 ) involving resolution through diastereomeric crystallization is described. (1 S )-IQL derivative ( 5 ) is esterified to form (1 S )-ethoxycarbonyl IQL derivative ( 6 ) which is condensed with ( RS )-3-quinuclidinol ( 7 ) to form a solifenacin diaster... | 10.1021/op500083y | 1 |
A Challenging Synthesis of the Highly Functionalized Echinocandin ASP9726: A Successor of Micafungin | Here, we describe a practical, scalable, and challenging synthesis of the highly functionalized novel echinocandin ASP9726 ( 1 ) starting from the natural product FR901379 ( 3 ), which is a starting material of micafungin ( 2 ). The synthesis includes transformations that address significant synthetic challenges due to... | 10.1021/op500078y | 0 |
A Green and Facile Approach for Synthesis of Nitro Heteroaromatics in Water | A convenient and green method for the oxidation of nitrogen-rich heterocyclic amines to nitro-substituted heteroaromatics using potassium peroxymonosulfate (2KHSO 5 ·KHSO 4 ·K 2 SO 4, Oxone) in water was developed. This method has several advantages over previous methods: operational simplicity, safety, inexpensive rea... | 10.1021/op5000754 | 0 |
Continuous Flow Synthesis of Thieno[2,3-<i>c</i>]isoquinolin-5(4<i>H</i>)-one Scaffold: A Valuable Source of PARP-1 Inhibitors | An efficient multistep method for the continuous flow synthesis of thieno[2,3- c ]isoquinolin-5(4 H )-one-A (TIQ-A), an important pharmacological tool and building block for PARP-1 inhibitors, has been developed. The synthesis involves a Suzuki coupling reaction to generate 3-phenylthiophene-2-carboxylic acid which is ... | 10.1021/op500074h | 1 |
Multikilogram-Scale Production of Cycloartenol Triterpenoid Glycosides as Synthetic Intermediates for a γ-Secretase Modulator | The process development and production of two cycloartenol triterpenoid glycosides on a multikilogram scale are described. The two compounds were used as key intermediates for the synthesis of a γ-secretase modulator and a novel potential therapeutic agent for Alzheimer’s disease (SPI-1865). This practical and efficien... | 10.1021/op5000732 | 0 |
Optimization of a Kilogram-Scale Synthesis of a Potent Cycloartenol Triterpenoid-Derived γ-Secretase Modulator | This work describes the demonstration of a kilogram-scale synthesis of a γ-secretase modulator from a plant-sterol-derived starting material. Key to developing a synthetic route capable of delivering a kilogram of the target compound was the development of a four-reaction telescope process and a selective O-alkylation ... | 10.1021/op500072b | 1 |
Amidation and N-Boc Deprotection Process Improvement for the Preparation of 5-(1-Piperazinyl)benzofuran-2-carboxamide, a Key Intermediate of Vilazodone | An improved process for the preparation of 5-(1-piperazinyl)benzofuran-2-carboxamide, a key intermediate used in the synthesis of antidepressant drug vilazodone is reported. | 10.1021/op500070t | 1 |
Development of Efficient Processes for the Preparation of Di-<i>tert</i>-butyl Potassium Phosphate and Di-<i>tert</i>-butyl (Chloromethyl) Phosphate | A new and efficient process to prepare di- tert -butyl (chloromethyl) phosphate, a key compound in the formation of many phosphon-oxymethyl pro-drugs, from chloromethyl chlorosulfate (CMCS) and di- tert -butyl potassium phosphate (DTBPP) is described. To develop a process to this important compound with overall efficie... | 10.1021/op500066f | 1 |
Synthesis and Process Optimization of Boceprevir: A Protease Inhibitor Drug | Efforts toward the synthesis and process optimization of boceprevir 1 are described. Boceprevir synthesis was optimized by telescoping the first three steps and last two steps of the five-step process. Optimization of oxidation, which is one of the critical steps in the total synthesis, is discussed. A control strategy... | 10.1021/op500065t | 1 |
Scale-up of Microwave Assisted Flow Synthesis by Transient Processing through Monomode Cavities in Series | A new scale-up concept for microwave assisted flow processing is presented where modular scale-up is achieved by implementing microwave cavities in series. The scale-up concept is demonstrated for case studies of a packed-bed reactor and a wall-coated tubular reactor. With known kinetics and reaction temperature, a pac... | 10.1021/op500064k | 0 |
Development of a Safe, Scalable Process for the Preparation of an Oxaisoxazolidinone | This report describes the development and scale up of the synthesis of oxaisoxazolidinone 1, a significant synthon in the synthesis of the MRSA development compound AZD5847. Studies were carried out to ensure a short-term, risk based preparation of 9 on a 5 L scale with a solid isolation procedure and a safe, long-term... | 10.1021/op500063g | 1 |
Process Chemistry Awards | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTProcess Chemistry AwardsWill WatsonView Author Information Scientific Update, Maycroft Place, Stone Cross Mayfield, East Sussex TN20 6EW, United KingdomE-mail: [email protected]Cite this: Org. Process Res. Dev. 2014, 18, 3, 359Publication Date (Web):February 26, 2014Publication... | 10.1021/op500058g | 0 |
An Integrated Process Analytical Technology (PAT) Approach for Pharmaceutical Crystallization Process Understanding to Ensure Product Quality and Safety: FDA Scientist’s Perspective | In this review, a brief overview of the current regulatory science framework pertinent to pharmaceutical crystallization and process characterization is made first. The FDA’s scientific research on pharmaceutical crystallization process understanding and product characterization is then illustrated via several aspects:... | 10.1021/op500056a | 0 |
Commercial Synthesis of Cefprozil: Development and Control of Process Impurity | A process impurity, ethoxycarbonylcefprozil ( 9 ), formed in the synthesis of cefprozil ( 1 ) was controlled with addition of a catalytic amount of methanesulfonic acid. | 10.1021/op5000545 | 1 |
Enantioselective Synthesis of a Highly Substituted Tetrahydrofluorene Derivative as a Potent and Selective Estrogen Receptor Beta Agonist | The development and execution of a practical asymmetric synthesis of the estrogen receptor beta selective agonist (8 R,10a S )-6-(trifluoromethyl)-8,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5- d ][1,2,3]triazol-7(3 H )-one is described. The optimized route features a key chiral auxiliary-mediated dialkyl... | 10.1021/op5000489 | 1 |
Improved Procedure for Preparation of Abiraterone Acetate | An improved procedure for the preparation of abiraterone acetate is described. The present process highlights reduced reaction time, isolation with acid–base treatment without involving column chromatography, multiple crystallization and is amenable to large-scale synthesis. | 10.1021/op500044p | 1 |
Synthesis of a Nucleoside Phosphoramidate Prodrug Inhibitor of HCV NS5B Polymerase: Phenylboronate as a Transient Protecting Group | A synthetic process for 2′- C -methylcytidine-5′-[2-[(3-hydroxy-2,2-dimethyl-1-oxopropyl)thio]ethyl- N -benzylphosphoramidate], a nucleotide prodrug inhibitor of hepatitis C virus NS5B polymerase, is described. The route developed was demonstrated on 100 g scale and featured the key application of phenylboronic acid as... | 10.1021/op500042u | 1 |
Stereoselective Lithiation and Carboxylation of Boc-Protected Bicyclopyrrolidine: Synthesis of a Key Building Block for HCV Protease Inhibitor Telaprevir | A stereoselective process for the manufacture of bicyclopyrrolidine 7 to 2 has been developed. The process utilizes a stereoselective lithiation/carboxylation sequence. The achiral diamine ligand DPBP induces excellent diastereocontrol, and resolution with ( S )-THNA provides the corresponding salt of 8 in high er and ... | 10.1021/op500040j | 0 |
A Scalable One-Pot Process for the Synthesis of Florfenicol Phosphodiester | A practical and scalable one-pot process for the preparation of florfenicol phosphodiester ( 3 ), a new water-soluble prodrug of florfenicol ( 1 ), has been developed by adopting the phosphorylating system of POCl 3 /pyridine/CH 3 CN. The yield of 3 was 80.72%, and its HPLC purity reached as high as 99.20%, while the c... | 10.1021/op500038s | 1 |
Unnecessary Development of Highly Sensitive Assays for Potentially Mutagenic Impurities (PMIs) | ADVERTISEMENT RETURN TO ISSUEPREVLetter to the EditorNEXTUnnecessary Development of Highly Sensitive Assays for Potentially Mutagenic Impurities (PMIs)David J. SnodinView Author Information Xiphora Biopharma Consulting, United Kingdom[email protected]Cite this: Org. Process Res. Dev. 2014, 18, 3, 360–361Publication Dat... | 10.1021/op5000368 | 0 |
Real-Time Process Analytical Technology Assurance for Flow Synthesis of Oligonucleotides | A feasibility study has been conducted using Process Analytical Technology (PAT) monitoring and chemometric modeling techniques to mitigate risks identified for the solid-phase synthesis of a model oligonucleotide compound in a flow reactor manifold. This paper will discuss three of the key risks identified for this au... | 10.1021/op500035j | 0 |
A Single-Pot Synthesis of Atovaquone: An Antiparasitic Drug of Choice | The present article relates to a practical, economically viable, and validated at industrial scale, single-pot synthetic route for preparation of atovaquone, one of the most versatile antiparasitic drugs of choice used for the prophylaxis and treatment of diseases such as pneumocystis, toxoplasmosis, babesiosis, coccid... | 10.1021/op500032w | 1 |
Development of a Robust Process for the Preparation of High-Quality Dicyclopropylamine Hydrochloride | A short and efficient process for the preparation of high-quality dicyclopropylamine HCl salt is described. An oxygen-mediated Chan–Lam coupling of N -cyclopropyl 4-nitrobenzenesulfonamide with cyclopropylboronic acid was followed by an optimized p -nosyl deprotection with 1-decanethiol, providing the title compound in... | 10.1021/op500031z | 1 |
Exploratory Process Development and Kilogram-Scale Synthesis of a Novel Oxazolidinone Antibacterial Candidate | A concise, environmentally benign, and cost-effective route was developed for the large-scale preparation of 1, a novel oxazolidinone antibacterial candidate. The key intermediate 2-(1-(2-fluoro-4-nitrophenyl)-1 H -pyrazol-4-yl)pyridine 7 was prepared with high purity by mild deamination of the regioisomeric mixture 21... | 10.1021/op500030v | 1 |
Development of a Hydrogenative Reductive Amination for the Synthesis of Evacetrapib: Unexpected Benefits of Water | For the synthesis of cholesteryl ester transfer protein (CETP) inhibitor evacetrapib, a hydrogenative reductive amination was chosen to join the substituted cyclohexyl subunit to the benzazepine core. The addition of water, which suppressed undesired epimerization without affecting the rate of product formation, was ke... | 10.1021/op500025v | 1 |
Development of a Biocatalytic Process to Prepare (<i>S</i>)-<i>N</i>-Boc-3-hydroxypiperidine | ( S )- N -Boc-3-hydroxypiperidine ( S -NBHP) is a useful synthon for the synthesis of pharmaceutical intermediates including ibrutinib, the API of the newly approved drug Imbruvica, for the treatment of lymphoma. To our knowledge, there are no published biotransformation methods scalable to prepare S -NBHP. We report h... | 10.1021/op500022y | 0 |
Synthesis of 2,6,8,12-Tetraacetyl-2,4,6,8,10,12-hexaazaisowurtzitane (TAIW) from 2,6,8,12-Tetraacetyl-4,10-dibenzyl-2,4,6,8,10,12-hexaazaisowurtzitane (TADBIW) by Catalytic Hydrogenolysis Using a Continuous Flow Process | Synthesis of 2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazaisowurtzitane (TAIW) by catalytic hydrogenolysis of 2,6,8,12-tetraacetyl-4,10-dibenzyl-2,4,6,8,10,12-hexaazaisowurtzitane (TADBIW), a key step for the synthesis of 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (HNIW), has been first implemented under c... | 10.1021/op500020d | 0 |
Model Driven Process Design and Development for a Continuous Process | This paper presents a case study where kinetic models were used to drive process development of an amination reaction in a continuous process. The kinetic model was first used to optimize the process by minimizing impurity formation. Then, the kinetic parameters were put into a two-in-series CSTR (continuous stirred ta... | 10.1021/op500016n | 0 |
Improved Operation of Concentration Control for Antisolvent Crystallization Processes | Concentration control (C-control) strategy for semibatch antisolvent crystallization processes has been recently developed with the aid of new sensors that measure in situ process variables. This control strategy gives better robustness over the traditional flow control in the presence of process variations. However, t... | 10.1021/op5000144 | 0 |
Synthesis of an ORL-1 Receptor Antagonist via a Radical Bromination and Deoxyfluorination to Afford a <i>gem</i>-Difluorospirocycle | The development of a synthesis of an ORL-1 receptor antagonist is described. The key process improvements in the synthetic sequence include a multikilogram bromination process and the development of a convergent coupling strategy. The process improvements resulted in the production of the active pharmaceutical ingredie... | 10.1021/op5000094 | 1 |
Large-Scale Crystallization of a Pure Metastable Polymorph by Reaction Coupling | A maximum of more than 40 g of acetaminophen Form II crystals with a yield of 65 mol % is made reproducibly in a 500 mL reactor by coupling the acetylation of p -aminophenol with the neutralization of acetic acid before the crystallization of acetaminophen Form II crystals. This novel working principle involves a sudde... | 10.1021/op500003k | 0 |
The Use of PAT and Off-line Methods for Monitoring of Roller Compacted Ribbon and Granule Properties with a View to Continuous Processing | Real-time process monitoring using process analytical technology (PAT) tools can augment process understanding, enable improved process control, and hence facilitate the production of high-quality pharmaceutical products. While beneficial for batch processes, the availability of PAT tools to monitor continuous processe... | 10.1021/op5000013 | 0 |
Transition Metal-Catalyzed Couplings in Process Chemistry: Case Studies from the Pharmaceutical Industry | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewTransition Metal-Catalyzed Couplings in Process Chemistry: Case Studies from the Pharmaceutical IndustryWill WatsonView Author Information Scientific Update, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, United KingdomE-mail: [email protected]Cite this: Org. Pr... | 10.1021/op400369y | 0 |
A Practical and Economical High-Yielding, Six-Step Sequence Synthesis of a Flavone: Application to the Multigram-Scale Synthesis of Ladanein | Herein we report a short and economic synthesis of the antiviral flavonoid lead ladanein ( 1 ). Ladanein is obtained from 2,6-dimethoxyquinone ( 11 ) in six steps with 51% overall yield. After a high-yielding reductive acetylation and Fries rearrangement, the flavone skeleton is built by means of a Baker–Venkataraman r... | 10.1021/op4003642 | 1 |
Single-Frequency Ultrasonic Crystallization Monitoring (UCM): Innovative Technique for In-Line Analyzing of Industrial Crystallization Processes | The development, principles, and application of the single-frequency, ultrasonic crystallization monitoring (UCM) technique is discussed. It is shown that the three most important process parameters to control industrial crystallization processes (mean crystal size, suspension density, and liquid concentration) can be ... | 10.1021/op400362f | 0 |
Industry Perspectives on Process Analytical Technology: Tools and Applications in API Development | High Resolution Image Download MS PowerPoint Slide The IQ Consortium reports on the current state of process analytical technology (PAT) for active pharmaceutical ingredient (API) development in branded pharmaceutical companies. The article uses an API process workflow (process steps from raw material identification th... | 10.1021/op400358b | 0 |
A Novel Process for Antimalarial Drug Pyronaridine Tetraphosphate | A novel process for preparation of pyronaridine tetraphosphate, an antimalarial drug substance, is reported. The overall yields are 54% and >99.8% (including five chemical steps). Formation and control of possible impurities are also described. | 10.1021/op400357f | 1 |
Scalable Synthesis of a Nonracemic α-Arylpropionic Acid via Ketene Desymmetrization for a Glucokinase Activator | Process research and development for a synthesis of the chiral carboxylic acid ( R )-2 as a key intermediate of the glucokinase activator ( R )-1 is described. The construction of the stereocenter at the α-carbon is a key point for the synthesis of ( R )-2 . The proposed process utilizes desymmetrization of a ketene in... | 10.1021/op400354g | 1 |
An Improved Synthesis of Nomegestrol Acetate | Oral contraceptives (OCs) are synthetic steroids, or progestins, which are structurally related to testosterone or to progesterone. Many progestins have been synthesized and approved for OCs, hormonal replacement therapy (HRT), or the treatment of some gynecological disorders. Nomegestrol acetate (NOMAc) is a newly app... | 10.1021/op4003533 | 1 |
Combining Metabolic Pathway Design and Retrosynthetic Planning for the Design of a Novel Semisynthetic Manufacturing Scheme for Paclitaxel | Using the example of paclitaxel, this paper expounds how retrosynthetic analysis can be combined with metabolic pathway design to devise novel semisynthetic schemes for manufacturing natural products. The analytical framework presented herein leverages the latest developments in chem- and bioinformatics, metabolic engi... | 10.1021/op4003505 | 1 |
Development of a Practical, Biocatalytic Reduction for the Manufacture of (<i>S</i>)-Licarbazepine Using an Evolved Ketoreductase | This contribution describes the development of a ketoreductase enzyme over four rounds of directed evolution and the associated process development that enabled a practical, scalable process to ( S )-licarbazepine (eslicarbazepine). | 10.1021/op4003483 | 0 |
A Scalable Route to an Unusual 3,3-Dimethyl-2,3-dihydrobenzofuran Ring System Present in an HCV Drug Candidate | A scalable synthesis of a key intermediate used for the preparation of an HCV inhibitor containing an unusual dimethyldihydrobenzofuran ring is described. A key element for the successful completion of the synthesis was the correct ordering of a sequence of bromination, chlorination, and methylation to provide optimize... | 10.1021/op4003467 | 1 |
Process Intensification of the Suzuki–Miyaura Reaction over Sol–Gel Entrapped Catalyst Silia<i>Cat</i> DPP-Pd Under Conditions of Continuous Flow | We report the newly developed conditions for the process intensification of the Suzuki–Miyaura reaction under flow over sol–gel entrapped Silia Cat DPP-Pd catalyst with the aim of practical applications. Considerably more concentrated solutions (0.5–1.0 M) are applied, and flow rate is increased up to the practically r... | 10.1021/op4003449 | 0 |
Processing of <i>o</i>-Halobenzoates by Toluene Dioxygenase. The Role of the Alkoxy Functionality in the Regioselectivity of the Enzymatic Dihydroxylation Reaction | In order to investigate the relationship between the size of a substituent on the aromatic substrate and its directing effect on the dihydroxylation, a series of 2-halobenzoates was synthesized and subjected to metabolism by toluene dioxygenase in preparative-scale fermentation cultures of Escherichia coli JM109 (pDTG6... | 10.1021/op400343c | 0 |
Process Intensification: Engineering for Efficiency, Sustainability and Flexibility | ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTProcess Intensification: Engineering for Efficiency, Sustainability and FlexibilityTrevor LairdCite this: Org. Process Res. Dev. 2014, 18, 1, 276Publication Date (Web):December 13, 2013Publication History Published online13 December 2013Published inissue 17 January 2014ht... | 10.1021/op400341e | 0 |
Development and Scale-Up of Cocrystals Using Resonant Acoustic Mixing | In the present work resonance acoustic mixing was applied to afford a practical and environmentally friendly approach to produce and scale up cocrystals. Scale-up options for producing cocrystals are limited. Solution-phase cocrystallizations, although amenable to scale-up in stirred tanks, may be limited due to multip... | 10.1021/op4003399 | 0 |
Multiscale Multiblock Batch Monitoring: Sensor and Process Drift and Degradation | A multiblock multiscale multiway principal component analysis (MSPCA) modeling approach is presented for multivariate statistical process performance monitoring of batch processes. Process measurements, representing the cumulative effect of many underlying process phenomena, are decomposed into scales using wavelet tra... | 10.1021/op400337x | 0 |
Improved and Efficient Process for the Production of Highly Pure Iloperidone: A Psychotropic Agent | The present work describes an improved and highly efficient process for the synthesis of iloperidone ( 1 ), an antipsychotic agent, which is free from potential impurities. The synthesis comprises N -alkylation of 1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone ( 4 ) with 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hyd... | 10.1021/op400335p | 1 |
Practical Synthesis of A Macrocyclic HCV Protease Inhibitor: A High-Yielding Macrolactam Formation | A practical synthesis of a macrocyclic HCV protease inhibitor, MK-1220, is described. The key features are a new synthesis of the trisubstituted isoquinoline, Sonogashira fragment coupling, and a high-yielding, 18-membered macrolactam formation. | 10.1021/op400331j | 1 |
Process Development for Scale-Up of a Novel 3,5-Substituted Thiazolidine-2,4-dione Compound as a Potent Inhibitor for Estrogen-Related Receptor 1 | The development of a reproducible process for multihundred gram production of ( Z )-5-((1-(4-chloro-2-(trifluoromethyl)benzyl)-1 H -indazol-5-yl)methylene)-3-((3 R,4 R )-3-fluoro-1-methylpiperidin-4-yl)thiazolidine-2,4-dione ( 26 ), a potent and selective inhibitor of estrogen-related receptor 1 (ERR1), is described. T... | 10.1021/op400325r | 1 |
Route Design and Development of a MET Kinase Inhibitor: A Copper-Catalyzed Preparation of an <i>N</i>1<i>-</i>Methylindazole | The synthesis of a MET kinase inhibitor in an overall yield of 22% was achieved over eight steps starting with 3-hydroxybenzaldehyde, an improvement from the initial 12-step process with a 5.4% yield. Highlights of the process chemistry design and development are a Cu-catalyzed cyclization to form an important N 1-meth... | 10.1021/op400317z | 1 |
Special Feature Section on Safety of Chemical Processes | ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTSpecial Feature Section on Safety of Chemical ProcessesTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 12, 1572Publication Date (Web):November 19, 2013Publication History Published online19 November 2013Published inissue 20 December 2013https://pubs.acs.org/doi/10.1... | 10.1021/op400316v | 0 |
An Efficient, Scalable Process for Benzphetamine Hydrochloride | Commercial manufacturing of benzphetamine hydrochloride along with its impurity profiling is disclosed. Deoxygenation of pseudoephedrine is reported with ∼100% retention by shielding the amine group as its tert -butyl carbamate, which is very straightforward to eliminate at the end. Four unknown process-related impurit... | 10.1021/op400313y | 1 |
Influence of Cofactor Regeneration Strategies on Preparative-Scale, Asymmetric Carbonyl Reductions by Engineered <i>Escherichia coli</i> | High Resolution Image Download MS PowerPoint Slide This study was designed to determine whether whole cells or crude enzyme extracts are more effective for preparative-scale ketone reductions by dehydrogenases as well as learning which cofactor regeneration scheme is most effective. Based on results from three represen... | 10.1021/op400312n | 0 |
Sad Times for Process Chemistry | ADVERTISEMENT RETURN TO ISSUEEditorialNEXTSad Times for Process ChemistryTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 12, 1463Publication Date (Web):November 15, 2013Publication History Published online15 November 2013Published inissue 20 December 2013https://pubs.acs.org/doi/10.1021/op400311dhttps://doi.org... | 10.1021/op400311d | 0 |
Transaminases Applied to the Synthesis of High Added-Value Enantiopure Amines | Critical parameters affecting the stereoselective amination of (hetero)aromatic ketones using transaminases have been studied, such as temperature, pH, substrate concentration, cosolvent, and source and percentage of amino donor, to further optimize the production of enantiopure amines using both ( S )- and ( R )-selec... | 10.1021/op4003104 | 0 |
An Improved Process for the Preparation of (+)-3-Methoxy-<i>N</i>-formylmorphinan | Two major steps, N -formylation of (−)-octabase and cyclization of the N -formylated product, involved in synthesis of (+)-3-methoxy- N -formylmorphinan, a key intermediate for production of dextromethorphan (DXM), have been improved to achieve higher yields in shorter time with fewer effluents. Methods of analysis of ... | 10.1021/op400309q | 1 |
Application of Kinetic Modeling and Competitive Solvent Hydrolysis in the Development of a Highly Selective Hydrolysis of a Nitrile to an Amide | A combination of mechanism-guided experimentation and kinetic modeling was used to develop a mild, selective, and robust hydroxide-promoted process for conversion of a nitrile to an amide using a substoichiometric amount of aqueous sodium hydroxide in a mixed water and N -methyl-2-pyrrolidone solvent system. The new pr... | 10.1021/op4003054 | 0 |
Process Development and Multikilogram-Scale Synthesis of a TRPV1 Antagonist | The process development and multikilogram preparation of a TRPV1 antagonist, 1, is described. Pyrido[2,3- b ]pyrazine 1 was prepared in a convergent manner by the coupling of two key fragments, glyoxal 2 and diamine 3 . Glyoxal 2 was synthesized in six chemical steps in 20% overall yield, the key step being a challengi... | 10.1021/op400304h | 1 |
Biphasic Catalysis with Disaccharide Phosphorylases: Chemoenzymatic Synthesis of α-<scp>d</scp>-Glucosides Using Sucrose Phosphorylase | Thanks to its broad acceptor specificity, sucrose phosphorylase (SP) has been exploited for the transfer of glucose to a wide variety of acceptor molecules. Unfortunately, the low affinity ( K m > 1 M) of SP towards these acceptors typically urges the addition of cosolvents, which often either fail to dissolve sufficie... | 10.1021/op400302b | 0 |
Commercial Manufacturing of Propofol: Simplifying the Isolation Process and Control on Related Substances | A commercially viable manufacturing process for propofol ( 1 ) is described. The process avoids acid–base neutralization events during isolation of intermediate, 2,6-di-isopropylbenzoic acid ( 3 ) and crude propofol, and thus simplifies the synthesis on industrial scale to a considerable extent. Syntheses of five impur... | 10.1021/op400300t | 1 |
Chromatography- and Lyophilization-Free Synthesis of a Peptide-Linker Conjugate | An optimized and scalable process to manufacture peptide–linker conjugate 1 is reported that avoids the chromatographic purification and lyophilization that are typically required for the isolation of this type of compound. An operationally simple protocol has been developed that couples the peptide to the linker in DM... | 10.1021/op4002998 | 0 |
An Efficient Catalytic Asymmetric Synthesis of a β<sup>2</sup>-Amino Acid on Multikilogram Scale | We describe herein a scalable catalytic asymmetric hydrogenation process for the multikilogram-scale production of a β 2 -amino acid. A short and efficient synthesis of the starting unsaturated N -Boc-protected β 2 -enamide was developed followed by extensive catalysis screening and optimization studies that identified... | 10.1021/op4002966 | 1 |
Development of a Multi-Step Synthesis and Workup Sequence for an Integrated, Continuous Manufacturing Process of a Pharmaceutical | The development and operation of the synthesis and workup steps of a fully integrated, continuous manufacturing plant for synthesizing aliskiren, a small molecule pharmaceutical, are presented. The plant started with advanced intermediates, two synthetic steps away from the final active pharmaceutical ingredient, and e... | 10.1021/op400294z | 1 |
Evaluation and Development of Practical Routes to an Enantiomerically Pure <i>C</i><sub>2</sub>-Symmetric Diamine Building Block | Several routes to an enantiomerically pure C 2 -symmetric diamine were evaluated and modified to scalable methods. A Zn/Me 3 SiCl-mediated reductive coupling of an imine was found to be superior to the other methods investigated, allowing us to safely prepare the enantiomerically pure diamine also on a large scale. One... | 10.1021/op400292m | 1 |
Development of an Early-Phase Bulk Enabling Route to Sodium-Dependent Glucose Cotransporter 2 Inhibitor Ertugliflozin | The development and optimization of a scalable synthesis of sodium-dependent glucose cotransporter 2 inhibitor, ertugliflozin, for the treatment of type-2 diabetes is described. Highlights of the chemistry are a concise, four-step synthesis of a structurally complex API from known intermediate 4 via persilylation–selec... | 10.1021/op400289z | 1 |
Development of a Multi-Kilogram-Scale Synthesis of AZD1283: A Selective and Reversible Antagonist of the P2Y<sub>12</sub> Receptor | Ethyl 6-chloro-5-cyano-2-methylnicotinate ( 4 ) was coupled with 4-piperidinecarboxylic acid (isonipecotic acid) in 81% yield to pyridine acid 10 . An amide coupling between 10 and benzylsulfonamide ( 6 ) afforded AZD1283 ( 1 ) in 79% yield using CDI as coupling reagent. The synthesis has been developed and scaled up t... | 10.1021/op400288v | 1 |
PAT Application in the Expedited Development of a Three-Step, One-Stage Synthesis of the Dipeptide Intermediate of HCV Protease Inhibitor Faldaprevir | A concise scalable synthesis of a chiral dipeptide acid, key substructure of the HCV protease inhibitor faldaprevir, has been developed. A green process with an E-factor of 9.2 was achieved utilizing process analytical technology (PAT) to allow effective processing of multiple-steps in a one-stage operation. Mixed anhy... | 10.1021/op400285y | 1 |
Development of a Scalable Synthesis of a Vascular Endothelial Growth Factor Receptor-2 Kinase Inhibitor: Efficient Construction of a 6-Etherified [1,2,4]Triazolo[1,5-<i>a</i>]pyridine-2-amine Core | A practical and scalable synthesis of the vascular endothelial growth factor receptor-2 (VEGFR-2) kinase inhibitor 1 has been developed. The key features of the process development include facile preparation of the key raw material 3-amino-4-fluorophenol, chemoselective nucleophilic aromatic substitution of 5-chloro-2-... | 10.1021/op4002824 | 1 |
Commercial Route Research and Development for SGLT2 Inhibitor Candidate Ertugliflozin | A practical synthesis of SGLT2 inhibitor candidate ertugliflozin ( 1 ) has been developed for potential commercial application. The highly telescoped process involves only three intermediate isolations over a 12-step sequence. The dioxa-bicyclo[3.2.1]octane motif is prepared from commercially available 2,3,4,6-tetra- O... | 10.1021/op4002802 | 1 |
Controlling the Exothermicity of <i>O</i>-Arylation by Evaporative Cooling during the Process Development of Fluoxetine Hydrochloride | This study illustrates the optimization of the O -arylation step of fluoxetine hydrochloride ( 1 ) synthesis. In the entire process, this is the most critical step that dictates the yield and quality of the product. The highlight of the process is the concept of evaporative cooling that was employed in manipulating the... | 10.1021/op400279n | 1 |
Evaluation of Several Routes to Advanced Pregabalin Intermediates: Synthesis and Enantioselective Enzymatic Reduction Using Ene-Reductases | This publication describes the evaluation of four synthetic routes to the advanced pregabalin (Lyrica) intermediate 7 . Asymmetric reduction of ( E )- 7 with an ene-reductase (OPR1 from Lycopersicon esculentum ) gave a saturated cyanoester intermediate 5 with the desired S stereocenter in >99% ee. OPR1 also catalyzed t... | 10.1021/op4002774 | 1 |
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