Trifluoromethoxy Group Research Articles

Metabolism, Pharmacokinetics, and Excretion of the Substance P Receptor Antagonist CP-122,721 in Humans: Structural Characterization of the Novel Major Circulating Metabolite 5-Trifluoromethoxy Salicylic Acid by High-Performance Liquid Chromatography-Tandem Mass Spectrometry and NMR Spectroscopy

The metabolism, pharmacokinetics, and excretion of a potent and selective substance P receptor antagonist, CP-122,721 [(+)-(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzylamino)-2-phenylpiperidine], have been studied in six healthy male human subjects [four extensive metabolizers (EMs) and two poor metabolizers (PMs) of CYP2D6) following oral administration of a single 30-mg dose of [14C]CP-122,721. Approximately 84% of the administered radioactivity was recovered from the urine and feces of the subjects over a period of 312 h. Approximately 80% of the dose for EM subjects was recovered within 48 h. PM subjects, however, excreted only about 45% of the dose in 48 h and required the full 312 h to achieve nearly 80% recovery. Absorption of CP-122,721 was rapid in both extensive and poor metabolizers, as indicated by the rapid appearance of radioactivity in serum. The serum concentrations of total radioactivity were always much greater than those of unchanged drug indicating early formation of metabolites. The average CP-122,721 t1/2 was 6.7 h and 45.0 h for EM and PM subjects, respectively. The serum concentrations of CP-122,721 reached a peak of 7.4 and 69.8 ng/ml for extensive and poor metabolizers, respectively. The major metabolic pathways of CP-122,721 were due to O-demethylation, aromatic hydroxylation, and indirect glucuronidation. The minor metabolic pathways included aliphatic oxidation at the piperidine moiety, O-dealkylation of the trifluoromethoxy group, N-dealkylation, and oxidative deamination. In addition to the major human circulating metabolite 5-trifluoromethoxy salicylic acid (TFMSA), all other circulating metabolites of CP-122,721 were glucuronide conjugates of oxidized metabolites. TFMSA was identified using high pressure liquid chromatography/tandem mass spectrometry and NMR and mechanisms were proposed for its formation. There are no known circulating active metabolites of CP-122,721.

Synthesis and mesomorphic properties of tolane‐based liquid crystals with a fluorinated polar end group

Three series of tolane‐based liquid crystalline compounds with a fluorinated polar end group have been synthesized. Their phase transition temperatures were measured by texture observation in a polarizing microscope and confirmed by DSC. The all‐fluorinated trifluoromethyl and trifluoromethoxy group have a tendency to promote the smectic A phase, but the difluoromethoxy group has the tendency to promote a wide nematic phase.

Experimental determination of the conformational free energies (A values) of fluorinated substituents in cyclohexane by dynamic 19F NMR spectroscopy. Part 2. Extension to fluoromethyl, difluoromethyl, pentafluoroethyl, trifluoromethylthio and trifluoromethoxy groups

The synthesis of monosubstituted and 1,4-substituted cyclohexanes bearing one of the title groups is described. The conformational analysis of these compounds was studied by 19F NMR spectroscopy at various temperatures. Chemical shifts for each conformer above the coalescence temperature were obtained by binomial regression from low temperature values, allowing the high precision determination of the equilibrium constants, and the corresponding thermodynamic parameters (ΔG°, ΔH°, ΔS°) of the fluorinated substituents. For A values (−ΔG°298K), the following averaged data were obtained: 1.59 (CFH2), 1.85 (CF2H), 2.67 (C2F5), 0.79 (OCF3) and 1.18 (SCF3) [in kcal mol−1].

Acidity of Substituted Benzenes − An Ab Initio Study of the Influence of Methoxy, Trifluoromethyl and Trifluoromethoxy Groups by a Novel Trichotomy Formula

AbstractThe acidities of mono‐ and polysubstituted benzenes incorporating one, two, or three OCH3, OCF3, or CF3 groups were investigated by use of reliable ab initio theoretical models. The calculated deprotonation energies are in very good agreement with available experimental data, although these are unfortunately sparse. A recently developed novel trichotomy formula proved useful for interpretation of predicted variation in acidity in the monosubstituted compounds. In particular, the long‐range final state effect in OCF3 and CF3 derivatives is confirmed. It is reflected in the stabilization of the lone‐pair electrons formed upon deprotonation at the meta and para positions. The theoretically established long‐range influence of OCF3 and CF3 substituents is in accordance with empirical knowledge obtained by experimental chemical reactivity studies. The acidities of multiply substituted benzenes exhibit additivity properties based on the ISA (independent substituent approximation) model established earlier. It is conclusively shown that the combination of the additivity rule and the trichotomy formula offers a powerful tool for interpretation of the acidity of polysubstituted benzenes and of other multiply substituted aromatics, thus shedding new light on this very old and important problem. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Trends in the Torsional Potentials of Methoxy and Trifluoromethoxy Groups: An ab Initio and Density Functional Study on the Structure of para-Substituted Pyridines and Pyridinium Cations

The structures and the torsional potentials around the aryl-O bond of 4-methoxypyridine, 4-trifluoromethoxypyridine, 4-methoxypyridinium cation, and 4-trifluoromethoxypyridinium cation were studied systematically with the aid of large-scale ab initio calculations performed at the Møller−Plesset second-order level and with a density functional method. In all compounds, the most stable conformer corresponds to the structure in which the methoxy or the trifluoromethoxy group is in an eclipsed conformation, oxygen and carbon atoms coplanar with the pyridine ring. The highest barrier to rotation, about 9.0 kcal mol-1, is predicted for 4-methoxypyridinium cation at an orthogonal conformation with a torsional angle of 90°. The lowest torsional barrier, less than 1 kcal mol-1, is obtained for 4-trifluoromethoxypyridine. The systematic variations of the calculated torsional potentials of these compounds are compared to those recently computed for methoxy- and trifluoromethoxybenzene and for their para-deprotonated anions. The trends in the energy differences between eclipsed and orthogonal conformations are correlated with concomitant changes of some of the optimized geometrical parameters in this series. Particularly suited are the two carbon−oxygen distances forming the ether linkage, and even more so their difference. The simple and astonishingly regular structural and energetic trends in this series can be rationalized by the assumption of a systematic decrease of the conjugation of the arene with the methoxy and trifluoromethoxy groups upon going from the 4-methoxypyridinium cation to the para-deprotonated trifluoroanisole anion.

The Trifluoromethoxy Group: A Long-Range Electron-Withdrawing Substituent

The Trifluoromethoxy Group: A Long-Range Electron-Withdrawing Substituent

The trifluoromethoxy group: a long-range electron-withdrawing substituent.

Judged by its capacity to promote a hydrogen/metal permutation at an ortho position, the trifluoromethoxy group is superior to both the methoxy and trifluoromethyl groups. Moreover, like CF(3) and unlike OCH(3), OCF(3) exerts a long-range effect that still considerably lowers the basicity of arylmetal compounds when located in a more remote meta or even para position. As a consequence, 4-(trifluoromethoxy)anisole is deprotonated by sec-butyllithium mainly, and by tert-butyllithium exclusively, at a position adjacent to the OCH(3) group rather than next to the strongly electron-withdrawing CF(3)O group. 1,3-Benzodioxole undergoes ortho lithiation only six times faster than anisole, whereas 2,2-difluoro-1,3-benzodioxole reacts about 5000 times faster, as evidenced by competition experiments. The structure and distance dependence of substituent effects can be rationalized by assuming superposing sigma- and pi-polarizing interactions.

Carbon‐14 labeling of a trifluoromethoxy group: synthesis of a substance P antagonist

AbstractSynthesis of a carbon‐14 labeled trifluoromethoxy group has been accomplished using the stepwise oxidative fluorination–desulfurization of a readily prepared [14C]xanthate (5). This novel labeling procedure allowed a rapid synthesis of substance P antagonist candidate 1 that avoided potentially more complex ring‐labeling procedures. Similar procedures have been used to prepare C‐14 labeled trifluoromethyl and trifluoromethylamine groups. Copyright © 2001 John Wiley & Sons, Ltd.

ChemInform Abstract: A Facile Synthesis of Novel Liquid Crystalline Materials Having a Trifluoromethoxy Group and Their Electro‐Optical Properties.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A Facile Synthesis of Novel Liquid Crystalline Materials Having a Trifluoromethoxy Group and Their Electro-Optical Properties

Abstract Novel liquid crystals (LCs) containing a trifluoromethoxy group connected to a cyclohexane mesogen or to an alkyl tail were prepared through an oxidative desulfurization-fluorination reaction of the corresponding dithiocarbonates. They were compared with LCs containing a methoxy group with respect to phase transition behavior and physical and electro-optical properties. Most of the CF3O-substituted LCs exhibited in a wide range of temperatures LC phases depending on the type of a mesogenic structure. LCs with a trifluoromethoxycyclohexane mesogen were shown to be thermally more stable than the LCs with a trifluoromethoxybenzene mesogen. LCs having a trifluoromethoxyalkyl tail show physical and electro-optical properties favorable to materials for not only TN-LCDs but TFT-addressed TN-LCDs. Furthermore, 3-β-CF3O-substituted cholestane was shown to be a potential chiral dopant for TFT-addressed TN-LCDs.

Synthesis and QSAR of Herbicidal 3-Pyrazolyl α,α,α-Trifluorotolyl Ethers

Pyrazole nitrophenyl ethers (PPEs) were recently identified as a novel class of chemistry exerting herbicidal effects by inhibition of protoporphyrinogen IX oxidase. This area of chemistry has been extended to include herbicidal pyrazolyl fluorotolyl ethers. In these compounds, a trifluoromethyl group substitutes for the 4‘-nitro group found in the original herbicides and in “classical” nitrodiphenyl ether hebicides. Fluoroanisole pyrazole ethers, in which a trifluoromethoxy group replaces the nitro group of diphenyl ether herbicides, are also described. The shift from 4‘-nitro to 4‘-trifluoromethyl substitution, which is conservative in terms of electrostatics, produced a novel class of herbicide with substantial pre-emergent activity on narrowleaf weed species. Quantitative structure/activity relationships obtained with respect to substitution on the pyrazole ring and at the 3‘-position of the fluorotolyl moiety can be summarized effectively by comparative molecular field analysis. In general, 5-methanesulfonyl fluorotoluidide ethers were found to be most active. Keywords: Herbicide; protoporphyrinogen oxidase; structure/activity; QSAR; pyrazole phenyl ether; comparative molecular field analysis; CoMFA

Etude conformationnelle du complexe η 6-(4-(trifluorométhoxy)aniline)tricarbonylchrome

Conformational study of η 6-(4-(trifluoromethoxy)aniline)tricarbonylchromium shows in the solid state that the trifluoromethoxy group is nearly perpendicular to the arene ring (CF 3CO = 117°) and that the amino group is eclipsed by a chromium carbonyl bond, conformation which is also found in solution.

Aromatic substituent chemical shifts and J(CF) coupling constants in fluoro‐substituted benzenes

AbstractAromatic substituent chemical shifts are reported for the difluoromethylthio, trifluoromethoxy, pentadecafluoroheptyl and fluosulfonyl groups. Long‐range coupling to the ortho and para carbons is observed in all cases except the trifluoromethoxy group.

A study of the infrared spectra of aryl trifluoromethyl ethers

1. The infrared spectra of seven aryl trifluoromethyl ethers have been obtained and the attribution of the trifluoromethoxy group absorption is discussed. The intense 1262±5 cm−1 (υCarom), 1178±10 cm−1 (νC-F), 1222±4 cm−1 (νc-f), and 925 cm−1 bands can be used in analysis for determining the presence of an OCF3 group in the benzene ring. 2. The shifts in the frequencies of theC-F valence vibrations show that transmission of the electron effects of the para substituent on the C-F bond via the ring-heteroatom system diminishes in the order-S->-O->-SO2-.

F19 Chemical Shifts of the Sulfur Pentafluoride, Trifluoromethoxy, Trifluoromethylthio and Trifluoromethylsulfonyl Groups in Aromatic Compounds

<b>F¹⁹ Chemical Shifts of the Sulfur Pentafluoride, Trifluoromethoxy, Trifluoromethylthio and Trifluoromethylsulfonyl Groups in Aromatic Compounds</b>