Antihormonal agents. Part 2: HPLC of ZK 98734 and its metabolites and ZK 98299

Procedures are described for the reverse phase HPLC analysis of the antihormonal steroid ZK 98734 and two of its metabolites. Conditions are developed for the HPLC of the pure drug substance and for following its pharmacokinetics and metabolism. Analysis conditions are also reported for the antiprogestin ZK 98299.     

Elucidating the Beneficial Effect of Vinylene Carbonate on the Electrochemistry of Antimony Electrodes in Lithium Batteries

Vinylene carbonate (VC) is an effective electrolyte additive for improving electrode performance in lithium‐ion batteries. We confirm its beneficial effects in a nanosized Sb–cellulose fiber composite electrode and examine its mechanism of action by X‐ray photoelectron spectroscopy, the most suitable technique for characterizing active particle surfaces (especially electrode/electrolyte interfaces). Vinylene carbonate clearly increases electrolyte stability (particularly that of LiPF₆) by avoiding the formation of a thick layer of LiF that conceals Sb and prevents its reaction with Li. Decreasing the layer thickness therefore increases the reversibility of the electrochemical reaction and improves capacity retention on cycling. The presence of VC afforded high‐quality Sb 4d and Li 1s photoemissions, fitting of which clearly exposed a previously unreported low‐energy component. We believe that this component is an Li_xSb alloy, which for the first time is identified spectroscopically.     

Structural effects of fluorine substitution in proteins

The consequences of substitution of fluorine for the para hydrogen of a phenylalanine residue in ribonuclease-S were investigated by conformational energy calculations using the AMBER force field. Both the fluorine-containing protein and the corresponding nonfluorinated material were subjected to conformational adjustment through energy minimization and the minimum energy structures so defined were compared. Fluorine substitution leads to small alterations in many atomic positions in the protein, with adjustments at at sites more than 0.5 nm from the fluorine appearing to be somewhat larger than those within the immediate vicinity of the fluorine. Several atoms proximate to the fluorine atom were observed to move toward the fluorine while others in the same vicinity move away. The greater bulk of the fluorine atom and the strongly different electronic properties of fluorine compared to hydrogen thus appear to be insufficient to cause a consistent, unidirectional change in nearest-neighbor interactions upon introduction of a fluorine atom into a protein structure. Virtually all changes in atomic positions that are predicted by these calculations would be barely detectable by a crystallographic study with a resolution of 0.2 nm.     

Replacement of Trimethylamine in Trimethylamine‐trispentafluoroethyl‐borane. Structures of [(C2F5)3BNMe3], [NMe4][(C2F5)3BOH], and K[(C2F5)3BCH2(CO)C6H5]

Trimethylamine‐tris(pentafluoroethyl)borane [(C₂F₅)₃BNMe₃] ( 1 ) reacts at 190 °C with water under displacement of the trimethylamine ligand to yield the hydroxy‐tris(pentafluoroethyl)borate [(C₂F₅)₃BOH]^? ( 2 ). In tributylamine 1 reacts with alkynes HC≡CR to form novel ethynyl‐tris(pentafluoroethyl)borate anions [(C₂F₅)₃BC≡CR]^? – R = C₆H₅ ( 3 ), C₆H₄CH₃ ( 4 ), Si(CH(CH₃)₂)₃ ( 5 ) – in moderate yields. Compound 3 adds water across the triple bond to form the novel anion [(C₂F₅)₃BCH₂(CO)C₆H₅]^? ( 6 ). The structures of [(C₂F₅)₃BNMe₃], [NMe₄][(C₂F₅)₃BOH] and K[(C₂F₅)₃BCH₂(CO)C₆H₅] have been determined by x‐ray crystallography.     

Convenient Method for the Preparation of the 2-Methyl Thiophen-3-yl Magnesium Bromide Lithium Chloride Complex and Its Application to the Synthesis of 3-Substituted 2-Methylthiophenes

Lithium chloride was found to accelerate formation of the Grignard reagent from inactive 3-bromo-2-methylthiophene (1) and commercial magnesium metal. Based on this finding, a convenient and potentially scalable preparation of ethyl 2-methylthiophene-3-carboxylate (3) was achieved. In addition, this process has been found to provide a new, general approach to 3-substituted 2-methylthiophenes.     

The effects of vinylic and allylic fluorine substitution in iso-butylene

Molecular orbital calculations using the 3-21G basis set have been performed for iso-butylene (IB; 2-methyl-1-propene), difluoro-iso-butylene (DFIB; 1,1-difluoro-2-methyl-1-propene), hexafluoro-iso-butylene (HFIB; 3,3,3-trifluoro-2-(trifluoromethyl)-1-propene), and perfluoro-iso-butylene (PFIB; 1,1,3,3,3-pentafluoro-2-(trifluoromethyl)-1-propene). The effects of fluorine substitution were studied by comparison of several calculated quantities of the fluorinated compounds with those of IB. Through an analysis of the computed electron density distributions, it is suggested that a vinylic fluorine acts as a π acceptor, by electron transfer into the C? F bond, and a π repeller, by polarization of the adjacent π electrons. An allylic fluorine acts as a π attractor through electrostatic effects, although in HFIB a minor contribution from hyperconjugation was evident. Finally, electrostatic potentials for the molecules were calculated. These show that fluorine substitution has large effects on the electrostatic potential associated with the π electrons. These effects change the sign of the calculated electrostatic potential in the plane containing the π bond to such an extent that PFIB is quite susceptible to nucleophilic attack.     

Lithium Selective Chromogenic Azocrown Ethers

Novel chromogenic crown ethers having an intraannular azo and phenolic hydroxy subunits have been used as complexing reagents for alkali metal cations. The complex formation was studied by visible spectroscopy and formation constants were calculated. The most pronounced spectral changes were observed for lithium ion.     

On the additivity of basis set effects in some simple fluorine containing systems

The reactions F + H₂ → HF + H, HF → H + F, F → F⁺ + e^? and F + e^? → F^? were used as simple test cases to assess the additivity of basis set effects on reaction energetics computed at the MP4 level. The 6-31G and 6-311G basis sets were augmented with 1, 2, and 3 sets of polarization functions, higher angular momentum polarization functions, and diffuse functions (27 basis sets from 6-31Gd, p) to 6-31 ++ G(3df, 3pd) and likewise for the 6-311G series). For both series substantial nonadditivity was found between diffuse functions on the heavy atom and multiple polarization functions (e.g., 6-31 + G(3d, 3p) vs. 6-31 + G(d, p) and 6-31G(3d, 3p)). For the 6-311G series there is an extra nonadditivity between d functions on hydrogen and multiple polarization functions. Provided that these interactions are taken into account, the remaining basis set effects are additive to within ±0.5 kcal/mol for the reactions considered. Large basis set MP4 calculations can also be estimated to within ±0.5 kcal/mol using MP2 calculations, est. E_MP4(6-31 ++ G(3df, 3pd)) ≈ E_MP4(6-31G(d, p)) + E_MP2(6-31 ++ G(3df, 3pd)) – E_MP2(6-31G(d, p)) or E_MP4(6-31 + G(d, p) + E_MP2(6-31 ++ G(3df, 3pd)) – E_MP2(6-31 + G(d, p)) and likewise for the 6-311G series.     

手性四氢咪唑衍生物的合成及与醛的反应

用含有C2对称轴的手性1，2－二胺同n-Bu3Sn取代的醛类化合物反应，制得了 具有手性辅助基的烯醇化物等价体。再利用金属交换反应将生成的烯醇负离子同醛 类化合物进行缩合反应，制得具有立体选择性的羟基化合物。     

Crystallinity and fluorine substitution effects on the proton conductivity of porous hydroxyapatites

Porous calcium hydroxyapatite (p-HAp) was prepared by wet chemical methods. The poorly crystalline structure and the high surface specific area (235 m²/g) of this hydroxyapatite have effects on the variation of the electrical properties. Good linearity of logarithm of conductivity versus the relative humidity in the range from 19% to 88% (RH) was observed using the complex impedance spectroscopy. The proton conduction was affected by the relative humidity related to H₂O adsorption on the material surfaces. The fluorine substitution in p-HAp also modifies the crystalline and the proton conduction properties.     

The elimination of matrix effects in the determination of fluorine by proton induced prompt gamma-spectrometry

By measuring the yield of prompt gamma-rays, induced by energetic protons, the ratio of the ranges in sample and standard was used in the average cross-section method to determine fluorine. By spiking the sample with known amounts of a lithium compound, a nonanalyte element (absent from the sample), the appropriate ranges in the samples were determined by measuring the prompt gamma-rays induced in the non-analyte spike. Fluorine was determined in ores and ivory and the method was tested by analyzing the standard reference materials SRM 91, SRM 120c and SRM 694.     

Reagent concentration effects in the REM resin solid phase synthesis of tertiary amines

The use of reagent concentration has resulted in increased rates for all stages of the REM resin synthesis of tertiary amines. These increases in rate translate into faster reaction times, higher yields and lower reagent consumption. Of the methods examined, the most successful was the use of perfluorous solvents, either alone or with a small amount of organic co-solvent.     

The solid complex Zn(CF3)Br·2DMF as an alternative reagent for the preparation of both, trifluoromethyl and pentafluoroethyl copper, CuCF3 and CuC2F5

Trifluoromethylcopper and pentafluoroethylcopper are prepared conveniently via the reaction of the solid complex Zn(CF₃)Br·2DMF with copper(I) bromide in N,N-dimethylformamide. The reactions of both copper species with 2,4-dinitrochlorobenzene, 4-iodonitrobenzene, 4-nitrobenzyl iodide, 4-bromobenzoic acid ethyl ester, 4-iodobenzoic acid ethyl ester, 2-iodopyridine and 2-iodopyrimidine have been studied. The structure of 2,4-dinitrotrifluoromethylbenzene has been elucidated.     

Toxic fluorine compounds containing the C---F link—XI Lability of the fluorine atom in 2-fluoroethanol

It has been shown that 2-fluoroethanol, often described as a chemically unreactive compound, will react with a number of nucleophilic reagents.     

Quantitative data on the effects of alkyl substituents and Li-O and Li-N chelation on the stability of secondary alpha-oxy-organolithium compounds

A DeltaG(eq) stability scale of secondary alpha-oxy-organolithium compounds was established from measurements of tin-lithium exchange equilibria in THF, and the quantitative effects of substituents at the anionic center on carbanion stability are presented. A new lead-lithium exchange equilibrium reaction was also investigated and shown to be a very useful alternative for the determination of the relative stability of the more sterically hindered organolithium compounds. Alkyl groups adversely affect the stability of organolithium compounds when attached to the carbon bearing the negative charge, but the extent of this effect is highly dependent on the nature of the rest of the substituents attached to the anionic center. Quantitative data on the stabilization imparted to organolithium compounds by Li-O and Li-N chelation have been determined for a variety of systems. The formation of four- and five-membered chelate rings leads to a considerable stabilization of the organolithium compound, while chelation through the formation of six-membered rings affords no extra stabilization to this type of organometallics. Multinuclear NMR experiments carried out on several alpha-oxy-organolithium compounds to determine their aggregation state are supportive of these species being monomers in THF solution.     

Ordering the relative power of electrophilic fluorinating,trifluoromethylating, and trifluoromethylthiolating reagents: A summary of recent efforts

Electrophilic fluorination and fluoroalkylation are one of the most promising and efficient strategies in the synthesis of organofluorine compounds. The rapid progress of this field has been made possible by the emergence of a wide variety of power-variable, readily prepared, and easy-to-handle electrophilic fluorinating and fluoroalkylating reagents. Understanding the relative power of these reagents is thus vital for their use in synthetic transformations. This digest will outline some recent efforts to quantitatively ordering the relative power of electrophilic fluorinating, trifluoromethylating, and trifluoromethylthiolating reagents.