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Route design and process development of the small nitrogen heterocycle 2·HCl, a constituent of AZD5718 (1), is described. The novel synthetic sequence to 2.HCl involves a desymmetrizing alkylation ...

Early chemical development studies into the best way of assembling AZD9742, an antibacterial drug candidate, have involved swapping the order of two reductive aminations. The orthogonally functiona...

Micellar reaction conditions, in a predominantly aqueous medium, have been developed for transformations commonly used by synthetic chemists working in the pharmaceutical industry to discover and develop drug candidates. The reactions covered in this review are the Suzuki–Miyaura, Miyaura borylation, Sonogashira coupling, transition-metal-catalysed CAr–N coupling, SNAr, amidation, and nitro reduction. Pharmaceutically relevant examples of these applications will be used to show how micellar conditions can offer advantages in yield, operational ease, amount of waste generated, transition-metal catalyst loading, and safety over the use of organic solvents, irrespective of the setting in which they are used.1 Introduction2 Micelles as Solubilising Agents3 Micelles as Nanoreactors4 Designer Surfactants5 A Critical Evaluation of the Case for Chemistry in Micelles6 Scope of Review7 Suzuki–Miyaura Coupling8 Miyaura Borylation9 Sonogashira Coupling10 Transition-Metal-Catalysed CAr–N Couplings11 SNAr12 Amidation13 Nitro Reduction14 Micellar Sequences15 Summary and Outlook

A wide variety of technology platforms were used to rapidly select a commercial manufacturing route to the inhaled glucocorticoid receptor modulator AZD7594. This collaborative approach to the route design employed idea generation, high-throughput salt formation, solubility and chemical reaction screening, process analytical techniques and factorial experimental design to propose, assess and select the new strategic route within a five-month window. The selected route is currently undergoing further process development and optimisation and will be implemented in future manufacturing campaigns to supply drug substance for ongoing clinical studies and ultimately for the commercially marketed product.

Historically used in stoichiometric hydroalumination chemistry, recent advances have transformed aluminium hydrides into versatile catalysts for the hydroboration of unsaturated multiple bonds. This catalytic ability is founded on the defining reactivity of aluminium hydrides with alkynes and alkenes: 1,2‐hydroalumination of the unsaturated π‐system. This manuscript reports the aluminium hydride catalyzed dehydroborylation of terminal alkynes. A tethered intramolecular amine ligand controls reactivity at the aluminium hydride centre, switching off hydroalumination and instead enabling selective reactions at the alkyne C−H σ‐bond. Chemoselective C−H borylation was observed across a series of aryl‐ and alkyl‐substituted alkynes (21 examples). On the basis of kinetic and density functional theory studies, a mechanism in which C−H borylation proceeds by σ‐bond metathesis between pinacolborane (HBpin) and alkynyl aluminium intermediates is proposed., The aluminium hydride catalyzed dehydroborylation of terminal alkynes is reported. By using a tethered‐intramolecular‐amine Lewis base as a ligand at the aluminium hydride centre the reactivity is controlled. Hydroalumination is switched off and selective reactions at the alkyne C−H σ‐bond are enabled.

The need to define a set of processes for the manufacture of a glucokinase activator called for an evaluation of different strategies to differentiate the hydroxyls of an α-resorcylic acid derivative. While direct functionalization proved possible, it did not allow access to crystalline intermediates that offered control over the rejection of process impurities. The strategy taken forward involved the installation of a benzoyl protecting group using careful control of pH in order to achieve useful levels of selectivity. This allowed the remaining α-resorcylate hydroxyl to be functionalized using a Mitsunobu reaction, with liquid–liquid partitioning being used to separate downstream intermediates of interest away from the redox byproducts of this reaction. Downstream challenges that were overcome in order to deliver a commercially viable means of manufacturing the API included developing an amidation reaction with a poorly reactive aminopyrazine coupling partner.

A selective aziridinium ring-opening was used to etherify an α-aryl-β-amino alcohol with stereochemical retention. This transformation was achieved in a biphasic system to address phenoxide solubility and the formation of a sulfonate ester impurity. The protecting group strategy was directed by a stability study of the activated α-aryl-β-amino alcohol in this system. Process analytical techniques were used to establish reaction understanding, and mixing on large scale was modeled in silico. The process provided a selective and efficient method of preparing the nonsteroidal, inhaled selective glucocorticoid receptor modulator AZD7594.

Commercial route definition for a glucokinase activator called for a re-evaluation of the synthesis and processes used to access multikilogram quantities of a pyrazine building block. The processes developed allowed a literature route to sodium 6-oxo-1H-pyrazine-3-carboxylate to be leveraged. One of these processes consisted of a highly selective decarboxylation that allowed the target building block to be accessed with complete regioselectivity in standard batch processing equipment. The presence of an azetidine ring in the target required the mitigation of impurity liabilities arising from the use of the hydrochloride salt of azetidine as an input material.

In 2007 the members of the ACS Green Chemistry Institute® Pharmaceutical Roundtable assembled a list of key green chemistry research areas to both identify transformations that would benefit from improvements in process greenness and to encourage academic research to this end. The list provided the topics for a review of the literature, published in 2007 in the journal Green Chemistry. As part of the 10th anniversary of the founding of the Roundtable in 2015, the membership revisited the list. This article discusses the selection of the revised list, the updated 10 key green chemistry research areas, 2 solvent themes and the emerging area of medium molecules that resulted from the exercise.

Commercial route definition for a glucokinase activator called for a reevaluation of the synthesis and processes used to access multikilogram quantities of 2-amino-5-methylpyrazine. After consideration of different options, a variation of the Curtius rearrangement used by the medicinal chemistry route was selected for further development. The formation of an acyl azide for the Curtius rearrangement required a process safety control strategy to be put in place. The process developed was used to successfully deliver multikilogram quantities of 2-amino-5-methylpyrazine in an overall yield of 68%, starting from 5-methylpyrazine-2-carboxylic acid.

Enzymes are a catalytic class of proteins that possess high specificity, selectivity and biocompatibility, which makes them ideal for multiple applications in industrial production and biotechnology. However, the use of enzymes in such applications is limited due to their low operational stability and increased cost attributed to difficulty of purification and reuse. Immobilization of enzymes onto nano-sized solid supports has emerged as a potential solution to these shortcomings with a trade-off of a percentage of activity loss upon immobilization. Herein, a comprehensive study of enzyme immobilization techniques with emphasis on active-surface decontamination applications is presented. In Chapter 1, an overview of the potential uses of enzymes and enzyme immobilization techniques is given. Benefits of enzyme-nanosupport conjugates in industrial catalysis, energy production (i.e. biofuels and biofuel cells), biosensing and bioactive coatings are discussed with emphasis on enzyme-based decontamination coatings. It is emphasized that enzyme-based conjugates are capable of increasing enzyme stability at operational conditions used in industrial production of fine chemicals, pharmaceuticals and foods. Also, this Chapter emphasizes the benefits of enzyme immobilization in regard to the development of the next generation of biosensors with enhanced selectivity and specificity or biofuel cells that do not require a membrane, and thus allow miniaturization. Additionally, coatings capable of decontaminating pathogens such as bacteria and spores can be produced through the incorporation of enzyme-nanomaterial conjugates. Finally, the chapter provides new perspectives and future directions in enzyme-based biotechnology. A. Campbell, C. Dong, C. Xiang, N. Q. Wu and C. Z. Dinu, “Enzyme-Based Technologies: Perspectives and Opportunities” Accepted to Green Polymer Chemistry: Biocatalysis and Biomaterials, ACS Symposium Series 2012. In Chapter 2, the impacts of the reactions that take place upon enzyme immobilization at the nanointerface are discussed and the effects of multiple variables present in the immobilization process on enzyme retained activity are identified. These variables include nanosupport characteristics (i.e. physical and chemical properties, rate of curvature), enzyme properties (i.e. surface properties, molecular weight, isoelectric point) and immobilization technique (i.e. chemical or physical binding). Prior to immobilization of the selected enzymes (i.e. soybean peroxidase (SBP), chloroperoxidase (CPO) and glucose oxidase (GOX)) all nanosupports (i.e. single-walled carbon nanotubes (SWCNTs), multi-walled carbon nanotubes (MWCNTs) and graphene oxide nanosheets (GON)) are chemically functionalized under user-controlled conditions through strong acids treatment and characterized in terms of structure and morphology. A comparison of how the characteristics of both the nanosupports used as well as immobilization technique employed affect retained activity in an enzyme specific manner is also presented. A. Campbell,…

The effect of the halogen on the rate of sodium amide induced cyclization of 2-haloprop-2-enylamines to methyleneaziridines is studied. Using DFT calculations and competition experiments, it is shown to proceed faster using iodide-based substrates. A practical route to 1-aryl-2-methyleneaziridines is devised based on these observations and their further rearrangement to cyclopropanimines explored.

The cycloisomerization of enynes catalyzed by Pd(OAc)

The highly regioselective iron-catalyzed formal hydrofunctionalization of styrene derivatives with a diverse range of electrophiles has been developed using a single, operationally simple hydromagnesiation procedure and only commercially available, bench-stable reagents. Using just 0.5 mol % FeCl2·4H2O and N,N,N',N'-tetramethylethylenediamine, hydromagnesiation and electrophilic trapping have been used to form new carbon-carbon bonds (13 examples) and carbon-heteroatom bonds (5 examples) including the products of formal cross-coupling reactions, hydroboration, hydroamination, hydrosilylation, and hydrofluorination.

The development and use of an in situ Raman spectroscopic method for the end-point detection of an etherification reaction, during a pilot plant scale manufacturing campaign, is described. Monitoring the reaction progress and minimising the level remaining of a chloropyrazine starting material at the reaction end-point were important, as the latter impacted a drug substance critical quality attribute (CQA). Furthermore, the etherification reaction required the use of a heterogeneous base (K2CO3), and therefore the time to reach reaction completion could be scale dependent, owing to differences in reactor geometry and mixing characteristics. To provide valuable process understanding about the rate and extent of reaction during scale-up, a quantitative method utilising in situ Raman spectroscopy was developed. A series of laboratory scale reactions were performed to provide the spectroscopic and off-line reference measurements (HPLC) required for calibration model development. A quantitative multivariate ca...

Most recent advances in metallation chemistry have centred on the bulky secondary amide 2,2,6,6-tetramethylpiperidide (TMP) within mixed metal, often ate, compositions. However, the precursor amine TMP(H) is rather expensive so a cheaper substitute would be welcome. Thus this study was aimed towards developing cheaper non-TMP based mixed-metal bases and, as cis-2,6- dimethylpiperidide (cis-DMP) was chosen as the alternative amide, developing cis-DMP zincate chemistry which has received meagre attention compared to that of its methyl-rich counterpart TMP. A new lithium diethylzincate, [(TMEDA)LiZn(cis-DMP)Et] (TMEDA=N,N,N′,N′- tetramethylethylenediamine) has been synthesised by co-complexation of Li(cis-DMP), EtZn and TMEDA, and characterised by NMR (including DOSY) spectroscopy and X-ray crystallography, which revealed a dinuclear contact ion pair arrangement. By using N,N-diisopropylbenzamide as a test aromatic substrate, the deprotonative reactivity of [(TMEDA)LiZn(cis-DMP)Et] has been probed and contrasted with that of the known but previously uninvestigated di-tert-butylzincate, [(TMEDA)LiZn(cis-DMP)tBu]. The former was found to be the superior base (for example, producing the ortho-deuteriated product in respective yields of 78 % and 48 % following D O quenching of zincated benzamide intermediates). An 88 % yield of 2-iodo-N,N-diisopropylbenzamide was obtained on reaction of two equivalents of the diethylzincate with the benzamide followed by iodination. Comparisons are also drawn using 1,1,1,3,3,3-hexamethyldisilazide (HMDS), diisopropylamide and TMP as the amide component in the lithium amide, EtZn and TMEDA system. Under certain conditions, the cis-DMP base system was found to give improved results in comparison to HMDS and diisopropylamide (DA), and comparable results to a TMP system. Two novel complexes isolated from reactions of the di-tert-butylzincate and crystallographically characterised, namely the pre-metallation complex [{(iPr)N(Ph)Ci'O}LiZn(cis-DMP)tBu ] and the post-metallation complex [(TMEDA)Li(cis-DMP){2-[1-C(=O) N(iPr)]CH}Zn(tBu)], shed valuable light on the structures and mechanisms involved in these alkali-metal-mediated zincation reactions. Aspects of these reactions are also modelled by DFT calculations. Amide austerity: Lithium amidozincate bases replacing expensive TMP (2,2,6,6-tetramethylpiperidide) by inexpensive cis-DMP (cis-2,6- dimethylpiperidide) have been synthesised (see scheme) and utilised for the ortho-deprotonation of a benzamide substrate for comparision with their TMP and other common amido analogues.

Die Cyclotryptamine sind eine Familie von Alkaloiden mit sehr unterschiedlichen biologischen Aktivitaten. Die komplexeren Mitglieder dieser Naturstoffklasse sind durch benachbarte quartare Kohlenstoffzentren charakterisiert und wegen der schwierig aufzubauenden, oligomeren Polyindolinstruktur schwer zuganglich. In den letzten Jahren konnten wir eine Reihe von Methoden entwickeln, die einen einfachen Zugang zu Polyindolinen ermoglichen; einige dieser Methoden nutzen Palladiumkatalysatoren zum Aufbau von Kohlenstoff-Kohlenstoff-Bindungen mit beeindruckenden Regio- und Stereoselektivitaten. In diesem Aufsatz schildern wir die Entwicklung eines Repertoires an Synthesemethoden und deren Anwendung in den Totalsynthesen einiger strukturell komplexer Cyclotryptamine. Insbesondere zeigen wir auf, wie es gelingen kann, mithilfe asymmetrischer Katalysen komplexe, hochfunktionalisierte Molekule aufzubauen.

The effect of the halogen on the rate of sodium amide induced cyclization of 2-haloprop-2-enylamines to methyleneaziridines is studied. Using DFT calculations and competition experiments, it is shown to proceed faster using iodide-based substrates. A practical route to 1-aryl-2-methyleneaziridines is devised based on these observations and their further rearrangement to cyclopropanimines explored.

An operationally simple, chemo- and regioselective hydromagnesiation reaction generates benzylic Grignard reagents.

A general thermolysis reaction for the transformation of Group 1 TMP compounds (LiTMP, NaTMP, KTMP) to 1-aza-allylic TTHP derivatives is reported. TMEDA accelerates the reaction and produces the crystalline complexes [(TMEDA)LiTTHP] and [(TMEDA·NaTTHP)2]. Methane elimination during the transformational process was confirmed via TVA coupled to MS.

El programa BTEC es un programa de estudios que permite obtener una cualificación profesional o laboral. Este recurso está preparado para ayudar al alumno en el curso BTEC First, nivel 2, sector profesional arte y diseño y se divide en dos secciones: conocimientos y destrezas; la primera sección comprende cinco unidades y la segunda sección, tres unidades. Incluye actividades de evaluación en cada unidad que cubren todos los criterios de ésta para ofrecer a los estudiantes la oportunidad de practicar sus tareas y profundizar en el conocimiento y la comprensión de la materia. SC Biblioteca de Educación del Ministerio de Educación, Cultura y Deporte; Calle San Agustín, 5 - 3 planta; 28014 Madrid; Tel. +34917748000; biblioteca@mecd.es GBR

Our ability to access the more complex members of the cyclotryptamine family of alkaloids, and to exploit their disparate biological activities, is limited by the synthetic challenge posed by their oligomeric, polyindoline structures. A recurring structural theme within these molecules is the presence of multiple quaternary stereocenters in close proximity to one another. Over the last decade, we have developed a set of transformations that allow rapid access to polyindolines, a number of which exploit the ability of catalytic levels of palladium to orchestrate carbon-carbon bond formation with impressive levels of regio- and stereocontrol. This review tells the story behind the development of this toolbox of synthetic methods, and their validation through the total synthesis of a number of structurally complex cyclotryptamine alkaloids. It also highlights an aspect of asymmetric catalysis that has received little attention, the ability of catalytic asymmetric reactions to selectively elaborate complex, polyfunctional molecules.

(1998). Cover The advance of burnt areas in Central Africa as detected by ERS-1 ATSR-1. International Journal of Remote Sensing: Vol. 19, No. 9, pp. 1635-1637.

The convergent syntheses of the C(1-32) and C(33-46) domains of phorboxazole B are described. An iterative cyclocondensation strategy exploited the Jacobsen hetero-Diels-Alder (HDA) reaction as a platform for the synthesis of both the C(5-9) and C(11-15) tetrahydropyran rings. The use of 2-silyloxydiene coupling partners bearing an increasing resemblance to the phorboxazole skeleton was found to lead to a reduction in diastereoselectivity, however, in the case of the C(11-15) ring. The coupling of aldehyde and 2-silyloxydiene by this route provided a C(1-32) fragment which was elaborated to the macrolide core of phorboxazole B. The synthesis of the C(33-46) domain involved a Nozaki-Kishi coupling of aldehyde 31 and vinyl iodide 39. The syntheses of 31 and 39 were highly diastereoselective: an Evans [Cu(Ph-pybox)](SbF6)2-catalysed Mukaiyama aldol reaction formed the cornerstone of the synthesis of 31 whilst a Nagao-Fujita acetate aldol reaction provided a convenient means of installing the sole stereogenic centre of 39.