29-Sep-21 News Chemistry Milestones Of C4H6O5

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2-AROYLHEXANONES IN THE SYNTHESIS OF AZOLES

2-Aroylcyclohexanones, obtained from piperidinocyclohexene, react with hydrazine, hydroxylamine, and o-phenylenediamine to give the corresponding derivatives of bicyclic heterocycles – indazole, 2,1-benzisoxazole, and 2-spiro-cyclohexylbenzimidazole. The structure of a derivative of benzyloxazole has been determined by X-ray crystallography.

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Reference:
Benzisoxazole – Wikipedia,
,Benzisoxazole – an overview | ScienceDirect Topics

9/18/21 News New explortion of C4H6O5

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THE STRUCTURE OF NEW CIS AND TRANS 3′-PHENYL-3′,3A’,4′,5′,6′,7A’-HEXAHYDRO-2,1-BENZISOXAZOLE-7A’-SPIRO-2-(3-PHENYLAZIRIDINE)

The reaction of dibenzalcyclohexanone with hydroxylamine hydrochloride afforded three compounds 1-3 including the aziridine 3 showing a 3′,3a’-trans configuration. Now we report on the isolation of a new aziridine 4, possessing a 3′,3a’-cis configuration. Its structure was deduced by 2D nmr and single crystal X-ray diffraction studies.

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Reference:
Benzisoxazole – Wikipedia,
,Benzisoxazole – an overview | ScienceDirect Topics

09/18/21 News Extracurricular laboratory: Discover of C4H6O5

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Death following an intramuscular injection of paliperidone: A case report

Paliperidone (9-hydroxyrisperidone), the primary active metabolite of risperidone, is a benzisoxazole derivative of the second-generation antipsychotics. Paliperidone patmitate or PP (the patmitate ester of paliperidone) is available as a once-daily oral tablet, a once-monthly injection or PP1M, and a 3-monthly injection or PP3M (marketed under the name of Trevicta (R) in the European Union). Despite the recent availability of PP3M, several cases of intoxication have been reported worldwide, including lethal cases. However, in Europe, no case of fatal poising has been reported to date. A 33-year-old man was found dead in his room at his parents’ home. His only medical background was a history of schizophrenia. The external examination was without any particularity except a runny nose of brownish liquid with an alcoholic smell. Given the context and the tack of evidence of a third party intervention, an autopsy was not considered necessary. Toxicological analysis of right femoral blood highlighted the presence of paliperidone (240 mu g/ L) only. The risk associated with the use of PP3M formulation is still imperfectly evaluated and several cases of intoxication have been reported worldwide, including fatal cases. In this case, paliperidone poisoning appears to be the highly likely cause of death. In fact, the blood concentration of paliperidone is high, twice the toxicity threshold used in therapeutic monitoring, and no other substances have been identified. This case highlights: the necessity to always evaluate the benefit-risk balance when prescribing this sustained-release form of paliperidone and the difficulties in interpreting paliperidone concentration in forensic cases. (C) 2019 Societe Francaise de Toxicologie Analytique. Published by Elsevier Masson SAS. All rights reserved.

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Reference:
Benzisoxazole – Wikipedia,
,Benzisoxazole – an overview | ScienceDirect Topics

9/16 News Decrypt The Mystery Of C4H6O5

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APPLICATION OF HYPHENATED LC/NMR AND LC/MS TECHNIQUES IN RAPID IDENTIFICATION OF IN-VITRO AND IN-VIVO METABOLITES OF ILOPERIDONE

Iloperidone, 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone, is currently undergoing clinical trials as a potential antipsychotic agent. Iloperidone was found to be extensively metabolized to a number of metabolites by rats, dogs, and humans, LC/MS/MS was used to characterize and identify metabolites of iloperidone present in complex biological mixtures obtained from all three species. Identification of some of the unknown metabolites in rat bile was achieved successfully by combination of LC/NMR and LC/MS with a minimum amount of sample cleanup. The utility of coupling a semipreparative HPLC to LC/MS instrument for further characterization of collected metabolites was demonstrated. It was shown that iloperidone was metabolized by O-dealkylation processes to yield 6-fluoro-3-[1-[3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole and 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-hydroxyphenyl]ethanone. Oxidative N-dealkylation led to the formation of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole and a secondary metabolite, 3-[(4-acetyl-2-methoxy)phenoxy]propionic acid. Iloperidone was reduced to produce 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-alpha-methylbenzenemethanol as the major metabolite in humans and rats. Hydroxylation of iloperidone produced 1-[4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-hydroxy-5-methoxyphenyl]ethanone and 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]-3-methoxyphenyl]propoxy]-2-hydroxyethanone, the later of which was found to be the principal metabolite in dogs. The identities of all these metabolites were established by comparing the LC/MS retention times and mass spectral data with synthetic standards.

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Reference:
Benzisoxazole – Wikipedia,
,Benzisoxazole – an overview | ScienceDirect Topics

6 Sep 2021 News Our Top Choice Compound: C4H6O5

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6-Methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole is a high affinity (K-i = 8.2 nM) reversible inhibitor of acetylcholinesterase (AChE). The carbon-11 labeled form was prepared in high (>97%) radiochemical purity and with specific activities of 37 +/- 20 GBq/mu mol at end of synthesis, by the alkylation of the desmethyl precursor with [C-11]methyl trifluoromethanesulfonate in N,N dimethylformamide at room temperature. In vivo studies in mice demonstrated good blood brain permeability but essentially uniform regional brain distribution. Thus, despite in vitro and in vivo activity as an AChE inhibitor, 6-[C-11]methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole does not appear to be a good candidate for in vivo imaging studies of AChE in the mammalian brain. NUCL MED BIOL 26;1: 99-103, 1999. (C) 1999 Elsevier Science Inc.

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Benzisoxazole – Wikipedia,
,Benzisoxazole – an overview | ScienceDirect Topics

Sep 2021 News A new application about C4H6O5

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The catalytic antibody 21D8 efficiently catalyzes the decarboxylation of a substituted 3-carboxybenzisoxazole-a simple, unimolecular reaction that is not susceptible to general acid/base catalysis but that is highly sensitive to the microenvironment. The transition-state structure of this decarboxylation reaction has been probed by measuring the carbon kinetic isotope effect for the uncatalyzed decarboxylation in water and for the dioxane-accelerated and antibody-catalyzed reactions. The isotope effect for the decarboxylation of 5-nitro-3-carboxybenzisoxazole is k12/k13 = 1.046 in aqueous buffer at 20-degrees-C and 1.048 for the antibody-catalyzed reaction. With increasing dioxane in the reaction medium, the rate of the spontaneous decarboxylation increases by almost four orders of magnitude, whereas the isotope effect displays only a slight, progressive decrease to k12/k13 = 1.043 in 100% dioxane. Together, these results indicate that the structure of the transition state undergoes very little change in spite of > 10(4)-fold increases in the rate of the reaction caused by solvation of the substrate by organic solvents or the low dielectric environment of the antibody active site.

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,Benzisoxazole – an overview | ScienceDirect Topics

02/9/2021 News Interesting scientific research on C4H6O5

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The acid/base-catalysed Kemp elimination of 5-nitro-benzisoxazole forming 2-cyano-4-nitrophenol has long served as a design platform of enzymes with non-natural reactions, providing new mechanistic insights in protein science. Here we describe an alternative concept based on redox catalysis by P450-BM3, leading to the same Kemp product via a fundamentally different mechanism. QM/MM computations show that it involves coordination of the substrate’s N-atom to haem-Fe(II) with electron transfer and concomitant N-O heterolysis liberating an intermediate having a nitrogen radical moiety Fe(III)-N-center dot and a phenoxyl anion. Product formation occurs by bond rotation and H-transfer. Two rationally chosen point mutations cause a notable increase in activity. The results shed light on the prevailing mechanistic uncertainties in human P450-catalysed metabolism of the immunomodulatory drug leflunomide, which likewise undergoes redox-mediated Kemp elimination by P450-BM3. Other isoxazole-based pharmaceuticals are probably also metabolized by a redox mechanism. Our work provides a basis for designing future artificial enzymes.

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Reference:
Benzisoxazole – Wikipedia,
,Benzisoxazole – an overview | ScienceDirect Topics

A new application about C4H6O5

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OPLS-AA force field parameters have been developed and validated for use in the simulation of 68 unique combinations of room temperature ionic liquids featuring 1-alkyl-3-methylimidazolium [RMIM] (R = Me, Et, Bu, Hex, Oct), N-alkylpyridinium [RPyr], and choline cations, along with Cl-, PF6-, BF4-, NO3-, AlCl4-, Al2Cl7-, TfO-, saccharinate, and acesulfamate anions. The new parameters were fit to conformational profiles from gas-phase ab initio calculations at the LMP2/cc-pVTZ(-f)//HF/6-31 G(d) theory level and compared to experimental condensed-phase structural and thermodynamic data. Monte Carlo simulations of the ionic liquids, gave relative deviations from experimental densities of ca. 1-3% at 25 degrees C for most combinations and also yielded close agreement over a temperature range of 5 to 90 degrees C. Predicted heats of vaporization compared well with available experimental data and estimates. Transferability of the new parameters to multiple alkyl side-chain lengths for [RMIM] and [RPyr] was determined to give excellent agreement with charges and torsion potentials developed specific to desired alkyl lengths in 35 separate ionic liquid simulations. As further validation of the newly developed parameters, the Kemp elimination reaction of benzisoxazole via piperidine was computed in 1-butyl-3-methylimidazolium hexafluorophosphate [BMIM][PF6] using mixed quantum and molecular mechanics (QM/MM) simulations and was found to give close agreement with the experimental free energy of activation.

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Reference:
Benzisoxazole – Wikipedia,
,Benzisoxazole – an overview | ScienceDirect Topics

What Kind of Chemistry Facts Are We Going to Learn About (R)-2-Hydroxysuccinic acid

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The developed method was employed in the synthesis of medicinally important compounds and intermediates in the organic synthesis. Herein we report a variety of novel N-chloro derivatives of benzisoxazole, benzimidazoles and several other N-chloro derivatives using 1.2 equivalents of calcium hypochlorite. The process does not require any additives like acids or bases and produced moderate to excellent yields of desired products under mild conditions.

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Benzisoxazole – Wikipedia,
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Polystyrene latexes with quaternary ammonium ion-exchange sites catalyze the decarboxylation of 6-nitrobenzisoxazole-3-carboxylate in aqueous dispersions. A catalytic rate constant of 2.1 X 10(4) times the rate constant in water was achieved in particles containing 24 mol % of poly((styrylmethyl)tri-n-butylammonium chloride) repeat units. This is the largest rate enhancement reported at 25 degrees-C for decarboxylation of 6-nitrobenzisoxazole-3-carboxylate in any colloidal or polymeric medium. The decarboxylation kinetics fit both the enzyme model of micellar catalysis and an ion-exchange model. Added electrolyte decreases the rate of decarboxylation but increases the intrinsic catalytic rate constants in the more highly swollen latexes. The fraction of (styrylmethyl)trimethylammonium ion repeat units in the polymers has little effect on the rate of decarboxylation. The catalytic activity of the poly((styrylmethyl)trailkylammonium) ions in the latex increases in the order of in lipophilicity: Me < Et < Pr < Bu. The 200-350-nm diameter monodisperse colloidal particles with varied functional group content were prepared by emulsion copolymerization of styrene, (styrylmethyl)trimethylammonium chloride, divinylbenzene, and (chloromethyl)styrene followed by reactions with trialkylamines to form the anion-exchange sites. I am very proud of our efforts over the past few months and hope to 636-61-3 help many people in the next few years. Recommanded Product: (R)-2-Hydroxysuccinic acid.

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Benzisoxazole – Wikipedia,
,Benzisoxazole – an overview | ScienceDirect Topics