Organic Process Development

Library of Congress Cataloging-in-Publication Data is available for this publication. ISBN 978-0-8330-4757-1 iii The Army believes that it needs the new joint cargo aircraft, the C-27J Spartan, to transport mission critical, time sensitive (MCTS) cargo and passengers to the brigade combat teams and supporting forces conducting full-spectrum operations. This issue is relevant in today's wars in Iraq and Afghanistan and in future counterinsurgencies where ground forces are widely dispersed across long resupply distances, as well as in stability operations overseas and support to civil authorities at home. Two related questions arise: Is the C-27J Spartan a reasonable replacement for the C-23 Sherpa that is being used today in Iraq to deliver MCTS cargo and passengers? Are there ways to improve the resupply routes and the air tasking procedures that are currently being used by the Army to provide direct support to the field commanders? In April 2009, after the research phase of our study was completed, the Secretary of Defense decided to place the Air Force in charge of the C-27J Joint Cargo Aircraft (JCA) program and reduce the number of aircraft procured from 78 to 38. In speaking to reporters, Pentagon Comptroller Robert Hale explained that "what we're looking for in transferring to the Air Force is to exploit some synergy between the C-130s, particularly the C-130s the Air Force has, and the JCA." This programmatic change does not alter the findings of our study. Irrespective of whether the Air Force or the Army owns and operates the C-27J aircraft, the Army needs to have access to a responsive airlift system that can deliver MCTS cargo to the forward operating forces. This requires an air scheduling system that incorporates rapid approval procedures and does not lead to excessive aircraft holds and procedural delays.

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Introduction There has recently been much interest in the development of high performance semiconductor optical amplifier (SOA) based switches for computing and other optical networking applications as they offer high on-off switching ratios and provide inherent optical gain. Demonstrations have been made both for switches based on discrete components1 and also partially populated integrated solutions2. To date however monolithic crosspoint devices have been formed with port counts of 4x4, and recently 1x8 port splitters made by active passive integration in quantum well ...

Solution chemistry is carried out in solvents, that is in liquids under the conditions of application, which can exert a considerable influence on the properties of the dissolved solute species. A short historical overview on the influence of solvents on chemical processes (equilibria, reaction rates) and physical processes (absorption spectra, crystallization) is presented. The term "solvent polarity" is discussed, and a solvatochromic parameter for its empirical determination is mentioned. A classification of solvents according to their chemical bonds is given, with special attention to supercritical fluids, fluorous solvents, and room temperature ionic liquids as promising new reaction media.

Organic Solvent Nanofiltration (OSN) technology is a membrane process for molecular separation in harsh organic media. However, despite having well-documented potential applications, development hurdles have hindered the widespread uptake of OSN technology. One of the most promising areas of application is as an iterative synthesis platform, for instance for oligonucleotides or peptides, where a thorough purification step is required after each synthesis cycle, preferably in the same working solvent. In this work, we report a process development study for liquid-phase oligonucleotide synthesis (LPOS) using OSN technology. Oligonucleotide (oligo) based drugs are being advanced as a new generation of therapeutics functioning at the protein expression level. Currently, over one hundred oligo based drugs are undergoing clinical trials, suggesting that it will soon be necessary to produce oligos at a scale of metric tons per year. However, there are as yet no synthesis platforms that can manufacture oligos at >10 kg batch-scale. With the process developed here, we have successfully carried out 8 iterative cycles of chain extension and synthesized 5-mer and 9-mer 2'-O-methyl oligoribonucleotide phosphorothioates, all in liquid phase media. This paper discusses the key challenges, both anticipated and unexpected, faced during development of this process, and suggests solutions to reduce the development period. An economic analysis has been carried out, highlighting the potential competitiveness of the LPOS-OSN process, and the necessity for a solvent recovery unit.

Ultrasound-assisted crystallization is a promising process for the production of crystals within a size distribution width. Towards the direction of attaining high-quality crystals, this article proposes and assesses a theoretical feedback control scheme that can be applied in a continuous tubular crystallizer. In this crystallizer, the antisolvent crystallization of aspirin (pharmaceutical ingredient), in water (antisolvent), and ethanol (solvent) takes place under ultrasound. Initially, a dynamic model is developed and includes the aspirin's concentration variations while also taking into account temperature modifications in the inlet. After model validation, a PI control scheme is finely tuned, implemented theoretically and critically assessed at the i) the trajectory control of the crystal length (average size), ii) the alleviation of suddenly emerged disturbances (e.g., solvent flow rate, inlet temperature), and iii) combination of worst-case operating scenarios. As was identified, the proposed controller can offer a practical platform that can be readily applied to different scales and geometries in continuous tubular crystallizers operating with ultrasound. During all simulations, the produced crystals maintained a high-quality.

Miniaturization is a tactic employed in many technologies to accelerate discovery and enable new applications such as systems-level evaluation. The miniaturization of chemical synthesis to the limits of chemoanalytical and bioanalytical limits of detection could accelerate drug discovery by increasing the amount of experimental data collected per milligram of material consumed. Here we demonstrate the miniaturization of popular reactions used in drug discovery such as reductive amination, N-alkylation, N-Boc deprotection and Suzuki coupling for utilization in 1.2 μL reaction droplets. Reaction methods were evolved to perform in high boiling solvents at room temperature, enabling the diversification of precious starting materials, such as the complex natural product staurosporine.

The rate constant for the reaction of methyl 2,4-dichloro-3,5-dinitrobenzoate (1) with different piperidine concentrations have been measured spectrophotometrically in nine pure solvents, viz. methanol, ethanol, n-propanol, isopropanol, t-butyl alcohol, acetonitrile, dimethysulphoxide, dioxane and benzene at different temperatures to study the effect of the solvents. The kinetic results postulate three solvation models: (a) alkanol extensively solvating the amine and weakening the intramolecular hydrogen bonding in the intermediate; (b) the non-polar solvents enhance the intramolecular hydrogen bonding in the intermediate increasing the nucleophilicity of amine; (c) the dipolar aprotic solvents solvate the amine and timely solvating the intermediate by intermolecular hydrogen bond. The solvent parameters have been correlated with the rate constant for the reaction through linear free energy relationships. The adequacy of the multi-parametric scales as appropriate approaches to describe the solvent features in microscopic environments has also been analyzed.

Tetrabutylammonium decatungstate (TBADT) has emerged as an efficient and versatile photocatalyst for hydrogen atom transfer (HAT) processes that enables the cleavage of both activated and unactivated aliphatic C-H bonds. Using a recently developed oscillatory millistructured continuous-flow photoreactor, investigations of a decatungstate-catalyzed C(sp 3 )-H alkylation protocol were carried out, and the results are presented here. The performance of the reactor was evaluated in correlation to several chemical and process parameters, including residence time, light intensity, catalyst loading, and substrate/reagent concentration. In comparison with previously reported batch and flow protocols, conditions were found that led to considerably higher productivity, achieving a throughput up to 36.7 mmol/h with a residence time of only 7.5 min.

The development of a continuous-flow sequence for the synthesis of an important drug candidate precursor is reported. Abediterol is a β 2 -adrenoceptor agonist that has undergone phase IIa clinical trials for the treatment of respiratory disease. A flow sequence is developed for the preparation of the lipophilic amine tail portion of abediterol. The sequence comprises of a phase-transfer-catalyzed liquid/liquid O-alkylation, a rhodium-catalyzed hydroformylation, and a ruthenium-catalyzed reductive amination. The reactions were optimized separately within continuous-flow environments to identify important parameter effects. The strongly basic O-alkylation operates with greater than 90% conversion within a 23 min residence time. The hydroformylation uses 1 mol % Rh(acac)(CO) 2 (acac = acetylacetone) as a catalyst and 6 mol % Xantphos as a ligand with 1.1 equiv of hydrogen and carbon monoxide. The optimized O-alkylation and hydroformylation telescoped flow process was successfully operated over 6 h. The protocol is shown to be high yielding for the desired linear aldehyde (75% gas chromatography yield, ∼2.5 g/h). The sequence requires a solvent switch prior to the reductive amination. The final step is a high-pressure (40 bar) and high-temperature (150 °C) Ru-catalyzed reductive amination using ammonia and hydrogen to afford the amine tail. The solution yield for the formation of the amine tail was 78%. The yield of the reductive amination with an unoptimized isolation was 50%, resulting in an overall isolated yield for the three-step sequence of 38%. This compares favorably against the batch yield of 26% using a different synthetic route.

Introduction: ASCO is actively developing CancerLinQ (CLQ), a rapid learning system for oncology care. The purpose of this study was to explore providers’ opinions and concerns related to implementation of CLQ, including ethical issues. Methods: Twenty key informant oncologists were recruited for individual in-depth interviews through ASCO contacts, purposively selected to represent a wide variety of cancer specialties as well as different levels of familiarity with CLQ (familiar v unfamiliar). Qualitative data analysis was completed by a three-member team using an inductive narrative approach. Themes were examined by participants familiar and unfamiliar with CLQ, and quotations exemplifying each theme are provided. Results: Participants’ opinions centered on three main themes: (1) general attitudes regarding learning health care systems, (2) optimal approach to patient consent, and (3) appropriateness of data use. There was clear support for the use of big data in clinical decision...

A palladium-catalyzed asymmetric three-component synthesis of α-arylglycine derivatives starting from glyoxylic acid, sulfonamides and arylboronic acids is reported. This novel, operationally simple method offers access to the α-arylglycine scaffold in good yields and enantioselectivities. The utilization of a tailored catalyst system enables the enantioselective synthesis of the desired αarylglycines despite a fast racemic background reaction. The obtained products can be directly employed as building blocks in peptide synthesis.

A palladium-catalyzed asymmetric three-component synthesis of α-arylglycine derivatives starting from glyoxylic acid, sulfonamides and arylboronic acids is reported. This novel, operationally simple method offers access to the α-arylglycine scaffold in good yields and enantioselectivities. The utilization of α tailored catalyst system enables the enantioselective synthesis of the desired α-arylglycines despite a fast racemic background reaction. The obtained products can be directly employed as building blocks in peptide synthesis.

Herein, we disclose the use of polysulfide anions as visible light photoredox catalysts for aryl cross-coupling reactions. The reaction design enables single-electron-reduction of aryl halides upon photo-excitation of tetrasulfide dianions (S42–). The resulting aryl radicals are engaged in (hetero)biaryl cross-coupling, borylation, and hydrogenation in a redox catalytic regime involving S4•–/S42– and S3•–/S32– redox couples.

An efficient scalable synthesis for dronedarone hydrochloride (2) via Friedel-Craft acylation of 2-(-2-butyl-1benzofuran-5-yl)-1H-isoindole-1,3(2H)dione ( ) with 4-(3-chloropropoxy) benzoic acid (13) in good yield and high purity has been developed by using Eaton's reagent instead of hazardous and toxic metal halide catalyst like AlCl 3 or SnCl 4 .

During process optimization of Escitalopram oxalate novel impurities, 6 and 7 were observed, which were isolated and characterized, and the proposed structure was confirmed by chemical synthesis. Investigation of the cause of impurities formation improved the yield and purity of the drug product during the bulk API synthesis.

An efficient scalable synthesis for dronedarone hydrochloride (2) via Friedel-Craft acylation of 2-(-2-butyl-1benzofuran-5-yl)-1H-isoindole-1,3(2H)dione ( ) with 4-(3-chloropropoxy) benzoic acid (13) in good yield and high purity has been developed by using Eaton's reagent instead of hazardous and toxic metal halide catalyst like AlCl 3 or SnCl 4 .

Classical experimental designs have been used as configurations of choice at GlaxoSmithKline within Chemical Development in establishing robust products and processes while achieving other goals such as reduction of cost, waste, process investigation times and most importantly improved quality. Occasionally, as in this paper, these first intent designs have been proved to be unworkable through irregularly shaped experimental regions induced through chemistry constraints. To achieve optimum efficiency, a fit for purpose computer-aided D-Optimal Design in considering the reduction of cyclic imides to amines has been investigated here, proving to be an invaluable additional tool in applying the appropriate design at the relevant time. In addition, partial least squares (PLS) analyses has been explored with a view of simultaneously modelling the responses whilst primarily identifying those factors having the largest impact across the responses of interest (quantity of reducing agent and solvent, temperature, and time). This combined with process analytical technology (PAT) through online IR monitoring has facilitated part of this cyclic process of investigations using scientific and business judgment.

we report a 5-step synthesis of 2-cyano-5-formyl-4-methyl-1H-indole through sequential functionalization of readily available 4-methyl-1H-indole. Cyano and aldehyde functionalities are regio-selectively installed at 2 and 5 position, respectively. The sequence is concise and high-yielding, amenable for kilogram scale production.

2-Aminoquinazolin-4-one based efficient organocatalytic eco-friendly reductive amination approach was developed for the mono N-alkylation of anilines using hydrosilane as a reducing agent. This practically easy and sustainable approach works under neat reaction conditions and utilizes non-toxic environmentally benign acetic acid as a dehydrating agent. The developed protocol have several advantages such as broad substrate scope, wide functional group tolerance, short reaction time and absence of metal catalyst in the reaction.

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In the problem of cracking of composite structures of several sorts, the pullout problem has frequently been solved. In some previous papers by the authors, curvilinear fibers reinforcing concrete mainly during its curing process have been studied. It was shown that the fibers of Dramix type proved to have a higher local bearing capacity than the straight fibers. The problem was solved in 3D on a unit cell assuming a periodicity of fiber placing. The linear behavior of concrete was taken into account and the pullout test was simulated by the finite element method. In this paper the optimal slope of fibers is sought. Using similar computations as those which were carried out in the above-mentioned papers, the optimum conditions have been added. They obey the typical Mohr-Coulomb law along the fiber-concrete interfacial zones and the compressive strength in the concrete cannot be exceeded at any point. The study is carried out on different unit cells, i.e. different positioning of fibers is considered. A different fiber ratio is also considered to show the mechanical behavior and to limit analysis of the composite aggregate.

Shape optimization of fibers based on the highest bearing capacity of composite aggregate on a unit cell is studied using Inverse variational principles. They have been applied mostly in connection with finite elements. It appears now that boundary elements are much more efficient. On the other hand, it is necessary to find an appropriate function, which describes boundary density of potential energy and at the same time variational bounds or homogenization of the composite have to be carried out. If one starts with homogenization, a mathematical formulation has to prove that a solution exists and is unique. The latter problem seems not to be as simple as it first seems. Additional constraints must be introduced to ensure the uniqueness of the solution. If bounds are sought, we start with extended Hashin-Shtrikman principles. A study is carried out for different relations of fibers and matrices. Keynotes: optimization, Inverse variational principles, classical composites.

The conversion of saturated fatty acids to high value chiral hydroxy-acids and lactones poses a number of synthetic challenges: the activation of unreactive C-H bonds and the need for regio-and stereoselectivity. Here we report the first example of a wild type cytochrome P450 monooxygenase (CYP116B46 from Tepidiphilus thermophilus) capable of enantio-and regioselective C5 hydroxylation of decanoic acid 1 to (S)-5hydroxydecanoic acid 2. Subsequent lactonization yielded (S)-δdecalactone 3, a high value fragrance compound, with > 90 % ee. Docking studies provide a rationale for the high regio-and enantioselectivity of the reaction.

We report a method for mild and atom-efficient synthesis of ketazines via nickel-catalyzed intermolecular hydroamination of internal alkynes with NH2-hydrazones. This alkyne hydrohydrazonation process is promoted by [Ni(cod)2] as a Ni(0) precatalyst and IPr as a N-heterocyclic carbene (NHC) ligand. A stoichiometric reaction between in situ generated [Ni(IPr)2] and benzophenone hydrazone (Ph2C=NNH2) led to the isolation of IPr-coordinated and hydroxo-bridged dinuclear Ni(II) hydrazonato complex [(IPr)Ni(HNN=CPh2)(2-OH)]2 that displayed high activity as a hydrohydrazonation pre-catalyst. We propose a catalytic cycle involving CN bond formation via alkyne insertion into the NiN linkage of Ni(II) hydrazonato intermediates.

A convenient and highly efficient synthesis of indenamines has been developed via rutheniumcatalyzed [3+2] carbocyclization under very mild conditions. A catalyst system of Ru(II) π-allyl precursor and N-heterocyclic carbene (NHC) ligand promotes facile coupling between aromatic N-H ketimines with internal alkynes at mild temperatures, without added oxidants or other metal salts, and in non-polar solvents. A proposed mechanism involves imine-directed activation of aromatic C-H bond, alkyne insertion, and carbocyclization by intramolecular imine insertion into Ru-alkenyl linkages.

Two possible ways of crystallite downsizing of cocarboxylase hydrochloride namely mechanical milling and precipitation under high supersaturation conditions were studied as well as their influence on the drying parameters of the produced powders. It was found that both methods allowed shortening drying times of powders. However, precipitation from highly supersaturated solutions was found to have a more significant effect on cocarboxylase hydrochloride drying in comparison with the milling as the crystallites produced by the former method have smaller sizes (b 10 μm) without additional disintegration and contain much less inclusions of mother liquor. Obtaining solutions with high supersaturation degrees was achieved due to application of microwave irradiation at the evaporation stage that provided uniform gradientless heating of cocarboxylase aqueous solutions. The results of this work can be applied for producing other fine-crystalline substances and materials when particle sizes play a key role in the manufacture of products with the desired qualitative characteristics.

Raman spectroscopy was used to characterize hydrogenation reactions involving single-step and two-step processes. The Raman technique was shown to be well-suited for endpoint determination as well as process optimization. In this investigation, hydrogenation of cyclohexene to produce cyclohexane was used as a model system. Conditions were varied to determine the effect of catalyst loading, solvent ratios, and reactant concentrations. Four catalysts were evaluated. The kinetic profiles of each reaction process were determined for each of the catalysts. In one case, a side reaction leading to an intermediate was observed for the hydrogenation reaction when run under hydrogen-starved conditions. After these cyclohexene hydrogenations were characterized, Raman spectroscopy was applied to the conversion of carvone to tetrahydrocarvone and the hydrogenation of 2-(4-hydroxyphenyl) propionate. Raman was used to characterize the kinetics of these reactions and was also used to prove that two-step hydrogenation mechanisms occurred in each. Raman was shown to be useful for process understanding, process optimization, process monitoring, and endpoint determination. Accomplishment of these goals leads to better process controls upon transfer of the procedure to a process environment. This ultimately leads, in turn, to the mitigation of risk of making out-of-specification product in manufacturing.

Article Recommendations M any industrial chemical incidents happen around the world every year, causing fatalities, property damage, and disrupted supply chains. For example, the Tianjiayi Chemical explosion in Jiangsu, China, on March 21, 2019, at a plant producing chemical intermediates caused 78 fatalities, 76 severe injuries, 640 hospitalizations, and an estimated direct economic loss of $300 million. 1 An explosion at AB Specialty Silicones in Waukegan, Illinois, on May 3, 2019, killed four workers. 2 More recently, on July 27, 2021, an explosion at the Chempark complex in Leverkusen, Germany, caused seven fatalities and left 31 injured. 3 While these were local events, process safety incidents like these can have international consequences. For example, the Tianjiayi explosion caused disruptions for many global chemical and pharmaceutical companies who were buyers of the company's products. Systematically studying process safety performance and learning from the past is an effective way to prevent such incidents. 5 But improving process safety does not mean we need to wait to learn when the next explosion, death, or injury occurs. Instead, research that contributes to preventing process safety incidents from ever occurring is regularly published in several journals, including Organic Process Research & Development (OPR&D), ACS Chemical Health & Safety (ACS CHAS), and the Journal of Loss Prevention in the Process Industries (JLPPI). These three journals have now pooled their efforts to publish a joint Virtual Special Issue, "Process Safety from Bench to Pilot to Plant." This unique collaboration between American Chemical Society and Elsevier journals highlights work that merges natural, social, management, and engineering sciences. The scope and audience of each journal can be found online. Briefly, OPR&D publishes research on industrial process chemistry to enable safe, environmentally benign, and ultimately economical manufacturing of organic compounds in larger quantities. ACS CHAS publishes work on current and emerging technical, human, and organizational factors affecting chemical risk management, safety information, regulatory updates, effective chemical hygiene practices, safety training, and hazard assessment tools. JLPPI publishes on technical, human, and organizational process safety measures to prevent and mitigate process-related injuries and damage arising from fire, explosion, and toxic release during the use, storage, manufacture, handling, and transportation of hazardous materials. Process safety starts with students, as they are the foundation Biographies ACS Chemical Health & Safety pubs.acs.org/acschas

Article Recommendations M any industrial chemical incidents happen around the world every year, causing fatalities, property damage, and disrupted supply chains. For example, the Tianjiayi Chemical explosion in Jiangsu, China, on March 21, 2019, at a plant producing chemical intermediates caused 78 fatalities, 76 severe injuries, 640 hospitalizations, and an estimated direct economic loss of $300 million. 1 An explosion at AB Specialty Silicones in Waukegan, Illinois, on May 3, 2019, killed four workers. 2 More recently, on July 27, 2021, an explosion at the Chempark complex in Leverkusen, Germany, caused seven fatalities and left 31 injured. 3 While these were local events, process safety incidents like these can have international consequences. For example, the Tianjiayi explosion caused disruptions for many global chemical and pharmaceutical companies who were buyers of the company's products. Systematically studying process safety performance and learning from the past is an effective way to prevent such incidents. 5 But improving process safety does not mean we need to wait to learn when the next explosion, death, or injury occurs. Instead, research that contributes to preventing process safety incidents from ever occurring is regularly published in several journals, including Organic Process Research & Development (OPR&D), ACS Chemical Health & Safety (ACS CHAS), and the Journal of Loss Prevention in the Process Industries (JLPPI). These three journals have now pooled their efforts to publish a joint Virtual Special Issue, "Process Safety from Bench to Pilot to Plant." This unique collaboration between American Chemical Society and Elsevier journals highlights work that merges natural, social, management, and engineering sciences. The scope and audience of each journal can be found online. Briefly, OPR&D publishes research on industrial process chemistry to enable safe, environmentally benign, and ultimately economical manufacturing of organic compounds in larger quantities. ACS CHAS publishes work on current and emerging technical, human, and organizational factors affecting chemical risk management, safety information, regulatory updates, effective chemical hygiene practices, safety training, and hazard assessment tools. JLPPI publishes on technical, human, and organizational process safety measures to prevent and mitigate process-related injuries and damage arising from fire, explosion, and toxic release during the use, storage, manufacture, handling, and transportation of hazardous materials. Process safety starts with students, as they are the foundation

Since ionic liquids (ILs), salts with a melting point below 100 °C, have unique physicochemical properties, they have been spotlighted as novel alternatives to organic solvents. However, studies relating to polymorph control using IL as solvent have not yet been performed due to the numerous (10 18 ) available IL types with unknown effects on the control of polymorphic transformation, and the extremely high unit price compared with conventional organic solvents. Presently, the pharmaceutical industry highly prefers the high soluble form-I polymorph among several polymorphs of the active pharmaceutical ingredients (APIs), clopidogrel bisulfate (CLP). However, as form-I polymorphs are metastable crystals, their phase transformation to stable form-II crystals occurs only within 5 min in the organic solvent. Therefore, the present study was performed in order to control the phenomenon that induces the rapid phase transformation from form-I to form-II. Ethanol was used as solvent, ILs including 1-allyl-3-ethylimidazolium tetrafluoroborate (AEImBF 4 ), 1-butyl-2,3dimethylimidazolium tetrafluoroborate (BDMImBF 4 ), and 1,3-diallylimidazolium tetrafluoroborate (AAImBF 4 ) were used as antisolvents, and drowning-out crystallization was the method applied. Among three ILs used in this experiment, only AEImBF 4 could induce crystals precipitation. Therefore, AEImBF 4 was used as antisolvent for further studies. The thermodynamic factor, the temperature, was set in the range of 25 to 50 °C; then the phase transformation phenomenon from form-I to form-II under temperature variation was studied. In order to illustrate the quantitative analysis of the polymorphic transformation under the new IL solvent, the nucleation and mass transfer equations were used.

Washing is a key step in pharmaceutical isolation to remove the unwanted crystallization solvent (mother liquor) from the Active Pharmaceutical Ingredient (API) filter cake. The mother liquor is typically replaced with a miscible solvent in which the API has lower solubility, to prevent any product loss, and lower boiling point to allow for easy removal during drying. However, precipitation of API and the associated impurities of synthesis in the mother liquor may occur during washing and can affect the purity of the isolated product. In addition, formation of crystal bridges in the cake leads to agglomeration, which affects the particle size distribution and powder flow properties.1 An anti-solvent screening methodology is developed to quantitatively analyse the propensity for precipitation of paracetamol and its impurities during the washing process. Aim of this work was to validate the notion that the precipitation of API and its impurities occurs during the washing process. This...

Washing is a key step in pharmaceutical isolation to remove the unwanted crystallization solvent (mother liquor) from the active pharmaceutical ingredient (API) filter cake. This study looks at strategies for optimal wash solvent selection, which minimizes the dissolution of API product crystals while preventing the precipitation of product or impurities. Selection of wash solvents to avoid both these phenomena can be challenging but is essential to maintain the yield, purity, and particle characteristics throughout the isolation process. An anti-solvent screening methodology has been developed to quantitatively evaluate the propensity for precipitation of APIs and their impurities of synthesis during washing. This is illustrated using paracetamol (PCM) and two typical impurities of synthesis during the washing process. The solubility of PCM in different binary wash solutions was measured to provide a basis for wash solvent selection. A map of wash solution composition boundaries for precipitation for the systems investigated was developed to depict where anti-solvent phenomena will take place. For some crystallization and wash solvent combinations investigated, as much as 90% of the dissolved PCM and over 10% of impurities present in the PCM saturated mother liquor were found to precipitate out. Such levels of uncontrolled crystallization during washing in a pharmaceutical isolation process can have a drastic effect on the final product purity. Precipitation of both the product and impurities from the mother liquor can be avoided by using a solvent in which the API has a solubility similar to that in the mother liquor; for example, the use of acetonitrile as a wash solvent does not result in precipitation of either the PCM API or its impurities. However, the high solubility of PCM in acetonitrile would result in noticeable dissolution of API during washing and would lead to agglomeration during the subsequent drying step. Contrarily, the use of n-heptane as a wash solvent for a PCM crystal slurry resulted in the highest amount of precipitation among the solvent pairs evaluated. This can be mitigated by designing a multi-stage washing strategy where wash solutions of differing wash solvent concentrations are used to minimize step changes in solubility when the mother liquor and the wash solvent come into contact.

This report is the first published record of the presence of heartwood rot fungal diseases in Indian sandalwood in Australia. It attempts to identify and quantify the possible impact of such diseases on sandalwood aromatic heartwood and oil production.

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 amidoxime moiety by aqueous hydroxylamine, its cyclization into the corresponding oxadiazole by treatment with dialkyl carbonates and the following hydrolysis of the ester and transformation into the medoxomil ester. Several so far undocumented side-products were identified and some of them were synthesized and duly characterized as potential impurities. Formation and control of critical possible impurities is described. addition to this therapeutic class, a prodrug form of azilsartan (1) azilsartan medoxomil (2), was approved in 2011 and marketed under the trade name Edarbi (Figure ).

All five possible 1-aryl-1methylethylhydroperoxides derived from naphthalene and anthracene were synthesized and their thermal decomposition in GC-MS conditions was investigated to explain the unusual inhibition effect of 1-(1-naphthyl)-1methylethylhydroperoxide on the liquid-phase oxidation of isopropylarenes. 2-(1-Aryloxy)propenes were identified as the main decomposition products of 1-(1-naphthyl)-1-methylethylhydroperoxide and 1-(1-anthryl)-1-methylethylhydroperoxide. The relatively unstable 2-aryloxypropenes have thus far never been described as thermal decomposition products of 1-aryl-1-methylethylhydroperoxides. The plausible mechanism of the formation of 2-(1-aryloxy)propenes was proposed on the basis of AM-1 calculations of the possible rearrangement paths of the alkoxy radicals derived from the investigated hydroperoxides. The mechanism explains the inhibition effect of 1-(1naphthyl)-1-methylethylhydroperoxide on the oxidation of isopropylarenes.

The process development and the kilogram-scale synthesis of Beclabuvir BMS-791325 (1) is described. The convergent synthesis features the use of asymmetric catalysis to generate a chiral cyclopropane fragment and coupling with an indole fragment via an alkylation. Subsequent palladium catalyzed intramolecular direct arylation efficiently builds the central 7-membered ring. The target was prepared in 12 linear steps with 5 isolations in an overall yield of 8 %.

A series of Cu or Ni monometallic and Cu-Ni bimetallic catalysts supported on γ-Al 2 O 3 were synthesized by incipient wetness impregnation method. X-ray diffraction results exhibited the formation of bimetallic Cu-Ni phase in the reduced Cu-Ni(1:1)/γ-Al 2 O 3 catalyst. Among the catalyst examined for hydrogenolysis of glycerol, bimetallic catalysts exhibited higher catalytic activity than monometallic catalysts due to synergetic effect of Cu-Ni bimetal. Cu-Ni(1:1)/γ-Al 2 O 3 catalyst displayed a maximum glycerol conversion of 71.6% with 92.8% selectivity to 1,2-propanediol at 210 °C and 4.5 MPa hydrogen pressure. The superior performance of Cu-Ni(1:1)/γ-Al 2 O 3 catalyst was attributed to the formation of bimetallic Cu-Ni phase, high active metal surface area, small Cu-Ni particle size, and high acidic strength of the catalyst. Stability and reusability of Cu-Ni(1:1)/γ-Al 2 O 3 catalyst was performed and detailed characterization results of fresh and used catalysts suggested that bimetallic Cu-Ni phase remained stable after reuses.

An efficient aluminum-catalyzed selective hydroboration of alkenes and alkynylsilanes is reported. A wide variety of alkenes and alkynylsilanes bearing various functional groups and heterocyclic substituents were converted to boronic ester products in good yields with high selectivity. Mechanistically, density functional theory calculations favored a mechanism involving the insertion of the double bond into the Al-H species followed by C-Al/B-H metathesis.

An optimized, convergent, safe synthesis of LAF389 (9), an anticancer agent analogous to bengamide B, is described. Starting from r-D-glucoheptonic (D-glycero-D-gulo-heptonic acid) γ-lactone (10), the lactone 15 was constructed in five steps. Major improvements were made in the preparation of the aldehyde precursor 14 and subsequent olefination to yield 15 via a modified Julia protocol. This olefination was significantly improved by using TMSCl as an additive. The second fragment of the drug substance, E-caprolactam 7, was obtained in two one-pot operations from (5R)-5-hydroxy-L-lysine (1). Finally, opening 15 with 7 using sodium 2-ethyl hexanoate (Na-EH) gave 8, which on deprotection yielded LAF389.