Novel polycyclic heterocycles. XIV. 1,2-Dihydro-4-(trifluoromethyl)-3H-8H-quino[1,8-ab][4,1]benzoxazepin-3-one and its derivatives

Procedures for the isolation of 1,2-dihydro-4-(trifluoromethyl)-3H,8H-quino[1,8-ab][4,1]-benzoxazepine, 3 , from reaction mixtures containing 3 as the minor component, and the isomer, 1,2-dihydro-11-(trifluoromethyl)-3H,7H-quino[8,1-cd][1,5]benzoxazepin-3-one, 2 , as the major component, are described. The reactivity of 3 toward hydroxylamine and aromatic aldehydes has been investigated and the preparation of derivatives with those reactants is described.     

Novel polycyclic heterocycles. VII. Synthesis of tetracyclic ketones and derivatives from tricyclic 5,11-dihydrodibenz[b,e][1,4] oxazepines

Michael addition of 5,11-dihydrodibenz[b,e][1,4]oxazepines to acrylonitrile gave 5,11-di-hydrodibenz[b,e][1,4]oxazepine-5-propionitriles, which were converted to the corresponding methyl 5-propionates. Mild alkaline hydrolysis of these esters furnished the key intermediates, the 5,11-dihydrodibenz[b,e] [1,4]oxazepine-5-propionic acids. In the preferred procedure, these propionic acids were cyclized to the tetracyclic ketones in yields of 60-90%, by the action of one equivalent of trifluoroacetic anhydride in benzene. When ring C was involved in cylcization, 1,2-dihydro-3H,7H-quino[8,1-cd][1,5]benzoxazepin-3-ones were obtained, and when ring A was involved, 1,2-dihydro-3H,8H-quino[1,8-ab] [4,1]benzoxazepin-3-ones were formed. With 1c , both modes of cyclization were observed. In an alternative procedure that gave lower yields, the propionic acids were first converted to the corresponding acid chlorides, and these were cyclized by means of anhydrous stannic chloride; as anticipated, the products by this method were identical with those obtained via the trifluoroacetic anhydride method. Several reactions of these tetra-cylcic ketones, e.g., their ease of oxime formation, and dehydrogenation to the α,β-unsaturated ketones, are described. The α,β-unsaturated ketones do not form oximes. The structures assigned to the ketones are based on interpretations of their pmr, uv, and ir spectra. These assignments were confirmed by an X-ray analysis of a single crystal of one representative ketone, 2b ; the X-ray study was also useful in indicating the thermodynamically preferred conformation of 2b . The structures of all the other compounds followed from similar spectral interpretations. The mass spectra of a few compounds are also discussed.     

Ultra-performance liquid chromatographic determination of manufacturing intermediates and subsidiary colors in D&C Red No. 34 and its lakes

An ultra-performance liquid chromatography (UPLC) method was developed to determine the manufacturing intermediates and subsidiary colors in the monosulfo monoazo color additive D&C Red No. 34 and its lakes. This method is currently used for batch certification of the color additives by the U.S. Food and Drug Administration to ensure that each lot meets published specifications for coloring drugs and cosmetics. The new UPLC method has replaced an HPLC method for determining the intermediates and a TLC method for determining the subsidiary colors. The intermediates are 2-amino-1-naphthalenesulfonic acid (Tobias acid) and 3-hydroxy-2-naphthalenecarboxylic acid (3-hydroxy-2-naphthoic acid). Subsidiary colors are positional isomers of the major dye component or related compounds containing lower numbers of substituent groups. The analytes are identified by comparison of their UPLC retention times and UV or visible absorption spectra with those of standards. Validation studies showed that peak area calibrations for the analytes were generally linear (R > 0.999), and recoveries were 98-103%. The LODs were 0.002-0.02%, and the RSDs at the specification levels were 0.7-2.2%. Survey analyses of 12 samples of certified D&C Red No. 34 straight colors and lakes from six domestic and foreign manufacturers yielded results for the intermediates by UPLC and HPLC that were consistent within experimental error. The UPLC analyses yielded results for the subsidiary colors that were consistently lower than results previously obtained by TLC, which we attribute to limitations of the TLC method. The new UPLC method provides sharper peaks, better peak separation, and faster analysis times than the formerly used HPLC method and is more accurate, much faster, and much less labor-intensive than the formerly used TLC method.     

Direct method for determination of Sudan I in FD&C Yellow No. 6 and D&C Orange No. 4 by reversed-phase liquid chromatography

A reversed-phase liquid chromatographic method was developed to determine parts-per-million and higher levels of Sudan 1, 1-(phenylazo)-2-naphthalenol, in the disulfo monoazo color additive FD&C Yellow No. 6 and in a related monosulfo monoazo color additive, D&C Orange No. 4. Sudan I, the corresponding unsulfonated monoazo dye, is a known impurity in these color additives. The color additives are dissolved in water and methanol, and the filtered solutions are directly chromatographed, without extraction or concentration, by using gradient elution at 0.25 mL/min. Calibrations from peak areas at 485 nm were linear. At a 99% confidence level, the limits of determination were 0.008 microg Sudan I/mL (0.4 ppm) in FD&C Yellow No. 6 and 0.011 microg Sudan I/mL (0.00011%) in D&C Orange No. 4. The confidence intervals were 0.202 +/- 0.002 microg Sudan I/mL (10.1 +/- 0.1 ppm) near the specification level for Sudan I in FD&C Yellow No. 6 and 20.0 +/- 0.2 microg Sudan I/mL (0.200 +/- 0.002%) near the highest concentration of Sudan I found in D&C Orange No. 4. A survey was conducted to determine Sudan I in 28 samples of FD&C Yellow No. 6 from 17 international manufacturers over 3 years, and in a pharmacology-tested sample. These samples were found to contain undetected levels (16 samples), 0.5-9.7 ppm Sudan I (0.01-0.194 microg Sudan I/mL in analyzed solutions; 11 samples including the pharmacology sample), and > or =10 ppm Sudan I (> or = 0.2 microg Sudan I/mL; 2 samples). Analyses of 21 samples of D&C Orange No. 4 from 8 international manufacturers over 4 years found Sudan I at undetected levels (8 samples), 0.0005 to < 0.005% Sudan I (0.05 to < 0.5 microg Sudan I/mL in analyzed solutions; 3 samples, including a pharmacology batch), 0.005 to <0.05% Sudan I (0.5 to <5 microg Sudan I/mL; 9 samples), and 0.18% Sudan I (18 microg Sudan I/mL; 1 sample).     

Electrostatic interactions in molecular dynamics simulation of a three-dimensional system with periodicity in one direction

The Mellin transform and Poisson summation formula are used to derive an expression for the Coulomb interaction energy of a three-dimensional system with periodicity in one direction. Initially, calculations are performed for interactions characterized by any inverse power and, using the analytical continuation of the energy function, one obtains the final expression for the interaction energy of charges. We consider also a special case when two different charges are located on a line parallel to the periodicity direction. The energy and force expressions are identical to those obtained from the Lekner summation which is simply a sum over reciprocal lattice terms. The convergence behaviour of the Lekner summation is compared with that based on the Ewald type approach.     

Summation methods of Coulomb interactions in computer simulations of a system with one—dimensional periodic boundary conditions

The Ewald-type method, its modified version and the Lekner-type method for summing Coulomb interactions in a system periodic along one direction are presented and compared. Advantages and disadvantages of these methods are discussed, and the methods are tested in molecular dynamics simulations of acetone molecules confined to cylindrical silica pores.