Improved Process for the Synthesis of 3-(3-Trifluoromethylphenyl)propanal for More Sustainable Production of Cinacalcet HCl

Cinacalcet (I), sold as hydrochloride salt, is a calcimimetic drug which has been approved for the treatment of secondary hyperparathyroidism in patients with chronic renal disease and for the treatment of hypercalcemia in patients with parathyroid carcinoma. Here, an improved method for the synthesis of 3-(3-trifluoromethylphenyl)propanal (II), a key intermediate for the preparation of I, is described. The protocol required a Mizoroki–Heck cross-coupling reaction between 1-bromo- 3-(trifluoromethyl)benzene and acroleine diethyl acetal, catalyzed by Pd(OAc)2 in the presence of nBu4NOAc (tetrabutylammonium acetate), followed by the hydrogenation reaction of the crude mixture of products in a cascade process. Palladium species, at the end of the reaction, were efficiently recovered as Pd/Al2O3. The procedure was developed under conventional heating conditions as well as under microwave-assisted conditions. The obtained mixture of 1-(3,3-diethoxypropyl)-3- (trifluoromethyl)benzene (III), impure for ethyl 3-(3-trifluoromethylphenyl) propanoate (IV), was finally treated, under mild conditions, with potassium diisobutyl-tert-butoxyaluminum hydride (PDBBA) to obtain after hydrolysis 3-(3-trifluoromethylphenyl)propanal (II), in an excellent overall yield and very high purity. Microwave conditions permitted a reduction in reaction times without affecting selectivity and yield. The final API was obtained through reductive amination of (II) with (R)-(+)-1-(1-naphthyl)ethylamine (V) using a catalyst prepared by us with a very low content of precious metal

MODERNIZATION OF LINE FOR ARRANGING OF PRODUCTS IN NEW CENTRAL STORE

Diplomsko delo zajema opis posodobitve naprave za komunikacijo vozičkov v novem centralnem skladišču NAVIS v družbi Gorenje d.d. V prvem delu diplomske naloge sem predstavil odvoz gotovih izdelkov iz proizvodnih linij preko razvrščanja, navedel razloge za njeno posodobitev, hkrati pa predstavil komponente, ki so uporabljene za komuniciranje vozičkov, kot je močnostni tirni ojačevalnik (PWB) in opisal zakaj ga potrebujemo. V drugem delu sem predstavil novo stanje naprave in programske rešitve krmilnika ter rešitve za izvedbo Profineta.Thesis work involves the modernization of line for arranging of products in new central store \u27\u27HZA\u27\u27 in Gorenje d.d. In the first part of the thesis I presented the removal of finished products from production lines over the classification, the reasons for its modernization modernization but also introduced the components that are used for communication trucks, such as power rail booster (PWB) and describe why we need it. In the second part I presented a new state of the device controller and software solutions and solutions for the implementation of Profinet

SAFETY ENGINEERING INTEGRATION IN INDUSTRIAL AUTOMATION

Magistrsko delo zajema predstavitev varnostne tehnike v industrijski avtomatizaciji. Razložili smo, kako pravilno upoštevati varno načrtovanje stroja, katerega želimo prenesti na trg in z njim varno upravljati, in kaj vse moramo upoštevati pri sami izgradnji. Za lažjo razlago smo izbrali primer projekta robotske celice v podjetju Gorenje d.d..This master thesis covers the presentation of safety technology in industrial automation. We explained the proper way to safely design a machine, which we want to transfer to the market and operate it safely, and everything that should be considered in the construction. For a better understanding this was explained on an example of robotic cells project in Gorenje d.d

Detection of Printed Circuit Board Defects with Photometric Stereo and Convolutional Neural Networks

The research work of this article was performed at the Polymer Competence Center Leoben GmbH (PCCL, Austria) within the framework of the COMET program of the Federal Ministry for Transport, Innovation and Technology and the Federal Ministry of Digital and Economic Affairs with contributions by AT&S (Austria Technologie & Systemtechnik AG). The PCCL is funded by the Austrian Government and the State Governments of Styria, Lower Austria, and Upper Austria

Regioselective Hydrolysis and Transesterification of Dimethyl 3‑Benzamidophthalates Assisted by a Neighboring Amide Group

An efficient, highly regioselective hydrolysis and transesterification of dimethyl 3-benzamidophthalates into the corresponding carboxylic acid monoesters and mixed esters (including <i>tert</i>-butyl esters) under basic conditions is presented. The selectivity is governed by the neighboring 3-benzamido moiety’s participation and by the nature of the solvent. In alcohols the reaction occurred exclusively at the <i>ortho</i>-position to the benzamido functionality, in pyridine or acetonitrile at both ester groups. An insight into the mechanistic pathway was obtained from a ¹H NMR study in perdeuteromethanol

En Route to 2‑(Cyclobuten-1-yl)-3-(trifluoromethyl)‑1<i>H</i>‑indole

A six-step synthetic route from 4-chloro-2-methylaniline to 5-chloro-2-(cyclobut-1-en-1-yl)-3-(trifluoromethyl)-1<i>H</i>-indole (<b>1</b>) has been reported. Compound <b>1a</b> is a key impurity of reverse transcriptase inhibitor efavirenz, an important anti-HIV/AIDS drug. Synthetic challenges, dead ends, and detours are discussed

A Way to Avoid Using Precious Metals: The Application of High-Surface Activated Carbon for the Synthesis of Isoindoles via the Diels–Alder Reaction of 2<i>H</i>-Pyran-2-ones

The application of activated carbon (Darco KB) for the acceleration and direction of the transformation of various 2<i>H</i>-pyran-2-ones with <i>N</i>-substituted maleimides toward isoindole derivatives through the reaction sequence cycloaddition/elimination/dehydrogenation is described. In this reaction, the catalyst mainly influences the dehydrogenation step, which is essential to avoid the formation of bicyclo[2.2.2]­octenes as the other possible products. We found that the combination of Darco KB, as the metal-free catalyst, and decalin, as the solvent in a closed vessel, represents the most successful conditions. A comparison of the effect of various dehydrogenation catalysts and reaction conditions is also presented. In addition, we have proven that the aromatization occurs via a hydrogen transfer from the cyclohexadiene intermediate to the maleimide derivative (therefore producing succinimides). This transfer is facilitated by the active surface of the heterogeneous carbon-based catalyst

Enhancement of Astroglial Aerobic Glycolysis by Extracellular Lactate-Mediated Increase in cAMP

Besides being a neuronal fuel, L-lactate is also a signal in the brain. Whether extracellular L-lactate affects brain metabolism, in particular astrocytes, abundant neuroglial cells, which produce L-lactate in aerobic glycolysis, is unclear. Recent studies suggested that astrocytes express low levels of the L-lactate GPR81 receptor (EC50 ≈ 5 mM) that is in fat cells part of an autocrine loop, in which the Gi-protein mediates reduction of cytosolic cyclic adenosine monophosphate (cAMP). To study whether a similar signaling loop is present in astrocytes, affecting aerobic glycolysis, we measured the cytosolic levels of cAMP, D-glucose and L-lactate in single astrocytes using fluorescence resonance energy transfer (FRET)-based nanosensors. In contrast to the situation in fat cells, stimulation by extracellular L-lactate and the selective GPR81 agonists, 3-chloro-5-hydroxybenzoic acid (3Cl-5OH-BA) or 4-methyl-N-(5-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-4-(2-thienyl)-1,3-thiazol-2-yl)cyclohexanecarboxamide (Compound 2), like adrenergic stimulation, elevated intracellular cAMP and L-lactate in astrocytes, which was reduced by the inhibition of adenylate cyclase. Surprisingly, 3Cl-5OH-BA and Compound 2 increased cytosolic cAMP also in GPR81-knock out astrocytes, indicating that the effect is GPR81-independent and mediated by a novel, yet unidentified, excitatory L-lactate receptor-like mechanism in astrocytes that enhances aerobic glycolysis and L-lactate production via a positive feedback mechanism