Multigram Quantities Research Articles

Improved Synthesis of Anxiolytic, Anticonvulsant and Antinociceptive α2/α3-GABA(A)ergic Receptor Subtype Selective Ligands as Promising Agents to Treat Anxiety, Epilepsy, as well as Neuropathic Pain.

An improved synthesis of the anxiolytic, anticonvulsant and antinociceptive compounds: Hz-166, and its bioisosteres 1,2,4-oxadiazole (MP-III-080) and 1,3-oxazole (KRM-II-81) were executed in higher yields and with more facile purification methods (crystallization, etc.) in multigram quantities without column chromatography. In the synthesis of KRM-II-81, an alternative procedure was employed using the selective reducing reagent, potassium diisobutyl-t-butoxy aluminum hydride (PDBBA), to prepare the desired C(3)-aldehyde in the absence of [N(5)-C(6)] imine reduction in good yield on 20 gram scale.

Synthesis of Enantiomerically Pure 6-Substituted-Piperazine-2-Acetic Acid Esters as Intermediates for Library Production.

The piperazine heterocycle is broadly exploited in FDA-approved drugs and biologically active compounds, but its chemical diversity is usually limited to ring nitrogen substitutions, leaving the four carbon atoms underutilized. Using an efficient four-step synthesis, chiral amino acids were transformed into 6-substituted piperazine-2-acetic acid esters as diastereomeric mixtures whose cis and trans products could be chromatographically separated. From six amino acids (both antipodes), a complete matrix of 24 monoprotected chiral 2,6-disubstituted piperazines was obtained, each as a single absolute stereoisomer in multigram quantities. These diverse and versatile piperazines can be functionalized on either nitrogen atom, allowing them to be used as scaffolds for parallel library synthesis or intermediates for the production of novel piperazine compounds.

PET‐RAFT as a facile strategy for preparing functional lipid–polymer conjugates

ABSTRACTFrom readily available starting materials, we report a facile synthesis of lipid–polymer conjugates (LPCs). Easy access to multigram quantities of a dialkyl lipid chain transfer agent allows a range of LPCs to be prepared bearing well‐defined hydrophilic polymer head‐groups, controlled molecular weights and low dispersity by photoelectron transfer RAFT polymerization (PET‐RAFT). As dictated by the lipid packing parameters, the resulting LPCs were suitable for solution‐phase self‐assembly, both independently and in combination with naturally occurring phospholipids, affording micelles, smaller vesicle‐like structures, or stabilized large unilamellar vesicles. Notably, co‐assembly of LPCs and phospholipids bearing mutually orthogonal fluorophores showed negligible phase separation/aggregation. To demonstrate the versatility of these LPCs, the RAFT chain‐end was removed, affording thiol‐terminated LPCs that could be used for the manipulation and stabilization of gold nanoparticle assemblies. Facile access to structurally diverse LPC building blocks enables a variety of biotechnology and biomedical applications, including drug‐delivery, cell engineering, and 3D‐printed biomaterials. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 1259–1268

A multi-gram-scale stereoselective synthesis of Z-endoxifen

Z-Endoxifen is widely regarded as the most active metabolite of tamoxifen, and has recently demonstrated a 26.3% clinical benefit in a phase I clinical trial to treat metastatic breast cancer after the failure of standard endocrine therapy. Future pharmacological and pre-clinical studies of Z-endoxifen would benefit from reliable and efficient synthetic access to the drug. Here, we describe a short and efficient, stereoselective synthesis of Z-endoxifen capable of delivering multi-gram (37 g) quantities of the drug in >97% purity with a Z/E ratio >99% after trituration.

Microwave-induced calcium(II) chloride-catalyzed Paal–Knorr pyrrole synthesis: a safe, expeditious, and sustainable protocol

Among various alkali (Na, K) and alkaline-earth (Ca, Mg, Sr, Ba) chlorides, calcium(II) chloride was found to be a cost-effective Lewis acid catalyst for solvent-free synthesis of pyrroles from primary aromatic and aliphatic amines under open-vessel focused microwave irradiation. The salient features of this environmentally benign method are high to quantitative conversion, short reaction time, safe and clean reaction profile, possibility of scale-up to multigram quantities, and use of a low-cost, widely available, nontoxic catalyst.

An Artemisia-derived natural product-based fluorescent probe for the bitter taste receptor hTAS2R38

The discovery of taste receptors hTAS2Rs expression in extra oral tissue, especially in the gastrointestinal tract and in the respiratory system, has endowed bitter receptors of functionalities that exceed the simple perception of taste and flavour. In particular, stimulation of hTAS2Rs by bitter agents in the airway smooth muscle triggers bronchodilation of possible pharmacological relevance. To study the receptor localization in pulmonary smooth muscle cells and to investigate their biological response to hTAS2R38 activation, we have developed a fluorescent probe for hTAS2R38 starting from the sesquiterpene lactone costunolide, available in multigram amounts from Artemisia umbelliformis Lam. The N-methylanthranilate-containing probe demonstrated a very low cytotoxicity compared to the natural product toward human airway smooth muscle cells and epithelial bronchial cells, but fully retained its binding to hTAS2R38, making it possible the fluorescent detection of cells expressing this bitter receptor.

Selective Base-free Transfer Hydrogenation of α,β-Unsaturated Carbonyl Compounds using iPrOH or EtOH as Hydrogen Source.

Commercially available Ru-MACHOTM -BH is an active catalyst for the hydrogenation of several functional groups and for the dehydrogenation of alcohols. Herein, we report on the new application of this catalyst to the base-free transfer hydrogenation of carbonyl compounds. Ru-MACHOTM -BH proved to be highly active and selective in this transformation, even with α,β-unsaturated carbonyl compounds as substrates. The corresponding aliphatic, aromatic and allylic alcohols were obtained in excellent yields with catalyst loadings as low as 0.1-0.5 mol % at mild temperatures after very short reaction times. This protocol tolerates iPrOH and EtOH as hydrogen sources. Additionally, scale up to multi-gram amounts was performed without any loss of activity or selectivity. An outer-sphere mechanism has been proposed and the computed kinetics and thermodynamics of crotonaldehyde and 1-phenyl-but-2-en-one are in perfect agreement with the experiment.

Synthesis of N- doped graphene nanosheets and its composite with urea choline chloride ionic liquid as a novel electrode for supercapacitor

Reduced graphene oxide (RGO) and graphene oxide (GO) nanosheets are synthesized via one pot electrochemical method using graphite rode in super saturated urea choline chloride and water. GO and ionic liquid are annealed using thermal method to obtain NRGO. Microstructure measurements present that most nitrogen doped on the edge of the surfaces of nanosheets. X-ray photoelectron spectroscopy revealed that nitrogen is grafted to the basal plane of graphene, with about 6.2 atom % nitrogen coverage. Nitrogen-doped RGO is evaluated as a supercapacitor electrode. The NRGO in ionic liquid has an exceptionally high capacitance of 383 F g−1 in 6 M of KOH and two-electrode configuration at current density of 1Ag-1. In comparison, an analogous NRGO and RGO bear low capacitance of 321 and 196 F g−1, demonstrating the importance of ionic liquid in the charge storage process. The method is easily scaled from milligram to multigram quantities of N-doped RGO and ionic liquid.

Practical synthesis of functionalized terminal alkynes, 3,3,3-triethoxypropyne and ketal protected prop-2-ynones

ABSTRACTPractical and economical synthesis of synthetically valuable 3,3,3-triethoxypropyne, ketal protected phenyl and methyl substituents prop-2-ynones is described. Bromination and subsequent 18-crown-6 catalyzed elimination of triethylorthoacrylate and ketal protected terminal alkenes with methyl and phenyl substituent which are inturn readily available from triethylorthopropionate, 3-chlorobutan-2-one and propiophenone afforded multigram quantities (>10 g) of corresponding functionalized terminal alkynes. Exploration of the synthetic utility of these alkynes is also demonstrated by the acetylenic substitution of the phenylalaninol derived 1,2-cyclic sulfamidate to deliver chiral alkynylated amines.

Preparation of Pillar[5]arene-Based [2]Rotaxanes by a Stopper-Exchange Strategy.

A pillar[5]arene-containing rotaxane building block bearing exchangeable stoppers has been prepared in multigram scale quantities with high yields from the reaction of 2,4-dinitrophenol (DNP) with the inclusion complex resulting from the association of dodecanedioyl chloride with 1,4-diethoxypillar[5]arene. Stopper exchange reactions have been achieved by treatment of the resulting DNP diester with various amines through an addition-elimination mechanism preventing the unthreading of the axle component during the reaction and thus preserving the [2]rotaxane structures. The resulting diamide [2]rotaxane derivatives have thus been obtained in good to excellent yields. Importantly, [2]rotaxanes difficult or impossible to prepare by direct introduction of the two stoppers in a single synthetic step are now easily available.

A Scalable Route for the Regio- and Enantioselective Preparation of a Tetrazole Prodrug: Application to the Multi-Gram-Scale Synthesis of a PCSK9 Inhibitor

The synthesis of multigram quantities of small molecule PCSK9 inhibitor (R,S)-3 is described. The route features a safe, multikilogram method to prepare 5-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2H-tetrazole (10). A three-component dynamic kinetic resolution between tetrazole 10, acetaldehyde, and isobutyric anhydride was catalyzed by a chiral DMAP catalyst to afford enantiomerically enriched hemiaminal ester (S)-12 on multikilogram scale. Magnesiation, transmetalation, and Negishi coupling provided access to Boc-intermediate (R,S)-13, which was deprotected to provide (R,S)-3 in multigram quantities.

Discovery, Semisynthesis, Antiparasitic and Cytotoxic Evaluation of 14-Membered Resorcylic Acid Lactones and Their Derivatives

Ten antifouling 14-membered resorcylic acid lactones 1–10 were isolated previously with low or trace natural abundance from the zoanthid-derived Cochliobolus lunatus fungus. Further optimization of fermentation conditions led to the isolation of two major natural compounds 7 and 8 with multi-gram quantities. By one or two steps, we semisynthesized the six trace natural compounds 1–6 and a series of derivatives 11–27 of compounds 7 and 8 with high yields (65–95%). Compounds 11–13 showed strong antiplasmodial activity against Plasmodium falciparum with IC50 values of 1.84, 8.36, and 6.95 μM, respectively. Very importantly, 11 and 12 were non-toxic with very safety and high therapeutic indices (CC50/IC50 > 180), and thus representing potential promising leads for antiplasmodial drug discovery. Furthermore, 11 was the only compound showed obvious antileishmanial activity against Leishmania donovani with an IC50 value of 9.22 μM. Compounds 11 and 12 showed the values of IC50 at 11.9 and 17.2 μM against neglected Chagas’ disease causing Trypanosoma cruzi, respectively.

Mechanically Activated Solvent-Free Assembly of Ultrasmall Bi2S3 Nanoparticles: A Novel, Simple, and Sustainable Means To Access Chalcogenide Nanoparticles

Nanosized Bi2S3 particles are one of the most promising nanomaterials for biomedical imaging, due to a unique combination of low toxicity and the high electron count of bismuth. However, the study and use of nano-sized Bi2S3 have been prevented by major synthetic challenges, including sensitivity to air and harsh solvothermal conditions. Herein, we describe a novel and surprisingly simple pathway, based on solid-state bottom-up self-assembly, to access the elusive Bi2S3 nanoparticles functionalized with surface ligands that allow dispersion in either organic or aqueous media. This one-pot, room-temperature synthesis utilizes mechanical activation in the solid state, either by milling or even manual grinding, to induce the spontaneous assembly of monodisperse 2 nm diameter nanoparticles applicable for CT imaging in physiological media. This solvent-free methodology utilizes readily available precursors to provide unprecedented one-step access to monodisperse nano-Bi2S3 in multigram amounts, including polye...

A Short and Scalable Synthesis of Orthogonally Protected Bis(aminomethyl)malonic Acid: Access to Bioactive Macrocyclic Peptides

A short and scalable process for the preparation of multi-gram quantities of orthogonally protected bis(aminomethyl)malonic acid in good yield from readily available starting material is described. These orthogonally protected amino acids are important building blocks to make peptides based drugs, glycoconjugates, and in the total synthesis of peptide natural products. The newly developed route has only six steps with an overall yield of 27%, which involves nucleophilic attack of a malonate on an imide as one of the key steps.

Development of an Enzymatic Process for the Production of (R)-2-Butyl-2-ethyloxirane

An epoxide resolution process was rapidly developed that allowed access to multigram scale quantities of (R)-2-butyl-2-ethyloxirane 2 at greater than 300 g/L reaction concentration using an easy-to-handle and store lyophilized powder of epoxide hydrolase from Agromyces mediolanus. The enzyme was successfully fermented on a 35 L scale and stability increased by downstream processing. Halohydrin dehalogenases also gave highly enantioselective resolution but were shown to favor hydrolysis of the (R)-2 epoxide, whereas epoxide hydrolase from Aspergillus niger instead provided (R)-7 via an unoptimized, enantioconvergent process.

Abstract 140: Discovery and biological evaluation of PQR530, a highly potent dual pan-PI3K/mTORC1/2 inhibitor

Abstract The PI3K/AKT/mTOR signaling pathway plays a fundamental role in cell proliferation, growth and survival and aberrant activation of this signaling pathway has been shown to drive the progression of malignant tumors.[1] Drugs targeting the pathway at multiple points, such as dual PI3K/mTOR inhibitors appear to have the broadest activity profile to address cancer therapeutic strategies and are currently being explored in numerous clinical studies. Recently, we presented PQR309, a novel, brain-penetrant pan-PI3K/mTOR inhibitor, which entered phase II clinical trials in 2016.[2] Here, we report the lead optimization of PQR530, a potent and brain-penetrant follow-up compound as pan-PI3K/mTORC1/2 inhibitor. The development of a follow-up compound concentrated on the improvement of both, the potency and the selectivity for all targeted kinases, namely the class IA PI3K isoforms as well as mTOR. We present a detailed ligand-based structure-activity relationship study which was obtained by systematic modifications of the hinge region as well as the affinity binding substituents. This study led to the identification of PQR530, a dual pan-PI3K/mTORC1/2 inhibitor showing excellent activities in cellular assays as well as in PI3Kα and mTOR enzymatic binding assays. In A2058 melanoma cells PQR530 inhibited protein kinase B (PKB, pSer473) and ribosomal protein S6 (pS6, pSer235/236) phosphorylation with IC50 values of 0.07 µM. PQR530 showed excellent selectivity over a wide panel of kinases, as well as excellent selectivity versus unrelated receptor enzymes and ion channels. Moreover, PQR530 displayed potency in a panel of 44 cancer cell lines (NTRC OncolinesTM) to prevent cancer cell growth (mean value for GI50 of 426 nM). Oral application of PQR530 to mice resulted in a dose-proportional PK and demonstrated good oral bioavailability and excellent brain penetration.[3] An optimized, robust synthetic route allowed rapid access to multi-gram quantities of PQR530 for pre-clinical development in only 4 steps. In conclusion, PQR530 inhibits all PI3K isoforms and the mammalian target of rapamycin (mTOR) complexes C1/2 potently and selectively, and shows anti-tumor effects in vitro and in vivo. [1] M. P. Wymann, M. Zvelebil, M. Laffargue (2003). Phosphoinositide 3-kinase signalling – which way to target? Trends Pharmacol Sci.; 24, 366-376. [2] V. Cmiljanovic et. al. “PQR309: Structure-Based Design, Synthesis and Biological Evaluation of a Novel, Selective, Dual Pan-PI3K/mTOR Inhibitor” presented at AACR Annual Meeting 2015, April 18-22, Philadelphia, Pennsylvania, USA. [3] P. Hillmann et al. “Pharmacological Characterization of the Selective, Orally Bioavailable, Potent Dual PI3K/mTORC1/2 Inhibitor PQR530” abstract submitted for AACR Annual Meeting 2017, April 1-5, Washington, D. C., USA. Citation Format: Denise Rageot, Florent Beaufils, Anna Melone, Alexander M. Sele, Thomas Bohnacker, Marc Lang, Jürgen Mestan, Petra Hillmann, Paul Hebeisen, Doriano Fabbro, Matthias P. Wymann. Discovery and biological evaluation of PQR530, a highly potent dual pan-PI3K/mTORC1/2 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 140. doi:10.1158/1538-7445.AM2017-140

Optimised synthesis and characterisation of 1-adamantyltrimethylphosphonium iodide

A synthetic route to multigram quantities of 1-adamantyltrimethylphosphonium iodide is reported. The synthesis starts from the commercially available precursor 1-adamantyl bromide and was optimised with respect to yield and ease of purification. The title compound is of interest to zeolite chemists as a potent organic structure-directing agent. Full spectroscopic characterisation data of all isolated intermediates and single crystal X-ray diffraction data of AdP(O)Cl2, [AdPMe2H]I and [AdPMe3]I (Ad=1-adamantyl) are reported.

Kirkendall Growth of Hollow Mn3O4 Nanoparticles upon Galvanic Reaction of MnO with Cu2+ and Evaluation as Anode for Lithium-Ion Batteries

We report the formation of high surface area hollow Mn3O4 nanoparticles that form as a result of the galvanic reaction of Cu2+ with MnO nanocrystals concomitant with a nanoscale Kirkendall effect. The MnO nanocrystals were prepared according to the ultralarge scale synthesis reported by Hyeon, which allowed the preparation of hollow Mn3O4 in multigram quantities. Ex-situ analyses with transmission electron microscopy and powder X-ray diffraction show the morphology and phase stability of the hollow particles correlate with DSC-TGA data and show collapse of the hollow particles at temperatures greater than 200 °C. Electrodes fabricated from hollow Mn3O4 exhibited excellent initial Li ion storage capability (initial discharge capacity = 1324 mAh/g) but poor cycling performance (97% loss of discharge capacity after 10th cycle), whereas Mn3O4-MWCNT electrodes exhibited good reversibility and discharge capacity of 760 mAh/g after 100 cycles.

Hydroheteroarylation of Unactivated Alkenes Using N-Methoxyheteroarenium Salts.

We report the first reductive coupling of unactivated alkenes with N-methoxy pyridazinium, imidazolium, quinolinium, and isoquinolinium salts under hydrogen atom transfer (HAT) conditions, and an expanded scope for the coupling of alkenes with N-methoxy pyridinium salts. N-Methoxy pyridazinium, imidazolium, quinolinium, and isoquinolinium salts are accessible in 1-2 steps from the commercial arenes or arene N-oxides (25-99%). N-Methoxy imidazolium salts are accessible in three steps from commercial amines (50-85%). In total 36 discrete methoxyheteroarenium salts bearing electron-donating, electron-withdrawing, alkyl, aryl, halogen, and haloalkyl substituents were prepared (several in multigram quantities) and coupled with 38 different alkenes. The transformations proceed under neutral conditions at ambient temperature, provide monoalkylation products exclusively, and form a single alkene addition regioisomer. Preparatively useful and complementary site selectivities in the addition of secondary and tertiary radicals to pyidinium salts are documented: harder secondary radicals favor C-2 addition (2->10:1), while softer tertiary radicals favor bond formation to C-4 (4.7->29:1). A diene possessing a 1,2-disubstituted and 2,2-disubstituted alkene undergoes hydropyridylation at the latter exclusively (61%) suggesting useful site selectivities can be obtained in polyene substrates. The methoxypyridinium salts can also be employed in dehydrogenative arylation, borono-Minisci, and tandem arylation processes. Mechanistic studies support the involvement of a radical process.

A New Class of Low‐Loading Catalysts for Highly Enantioselective, Metal‐Free Imine Reduction of Wide General Applicability

AbstractA new class of chiral Lewis bases for the enantioselective HSiCl3‐mediated reduction of imines was developed. Through extensive catalyst structure optimization, an extremely active species was identified that was able to promote the reduction of a large variety of functionalized substrates in high yields with enantioselectivities typically above 90 % with catalyst loadings as low as 0.1–1 mol %. The simple experimental procedure, the low cost of the reagents, the mild reaction conditions, and the straightforward isolation of the product make the methodology attractive for large‐scale applications. Its synthetic potentiality was demonstrated by the preparation of advanced intermediates of important active pharmaceutical ingredients used in the treatment of Alzheimer's and Parkinson's diseases, hyperparathyroidism, neuropathic pains, and neurological disorders. The reaction was also successfully performed in flow reactors, which thus demonstrated the possibility to realize in continuo processes to yield multigram quantities of product.