No abstract

octa-3,5-diene (5) was prepared by treating ira«5-2-benzoyl-3phenylaziridine with cinnamaldehyde in an ethanolic solution saturated with ammonia. Treatment of 5 with sodium methoxide gave a high yield of fra/ij-2-styryl-4,6-diphenyl-l,2-dihydropyrimidine (6). Ultraviolet irradiation of 5 has been found to afford four products whose structures are identified as 1,4,8-triphenyl-2,5-diazaocta-1,3,5,7-tetraene (13), ?ro/zs-2-styryl-3,6-diphenyldihydropyrazine ( 14), rra«5-2-styryl-3,6-diphenylpyrazine (15), and 3,6-diphenyl-5,6-dihydrobenzo[/]quinoxaline ( 16). The formation of 16 from 5 was resolved into a sequence of four discrete reactions involving ring opening to 13, thermal electrocyclization, photooxidation, and photocyclization.

We have developed a novel approach for using near infrared (NIR) spectroscopy; this is to create and apply calibration models "on-the-fly". We define a process to create, validate, implement and approve a disposable library for discriminating between active and placebo pharmaceutical dosage forms packaged for clinical studies. This approach is based on two concepts; one germane to the particular needs and requirements of the pharmaceutical industry and the second based on an observation of the proposed experimental parameters. The first is that validation, in the general sense, implies control over a method. The second is that each clinical trial is a unique event, consisting of a finite or closed population of samples. The essence of the idea behind our process is to use disposable libraries, that is, libraries of NIR spectra created for one-time use and then archived. The justification for this approach is that the population of samples used both to create the library and subsequently to be identified using that library consists of a finite set of samples. This paper describes the rationale of this approach, discusses in detail the requirements for suitable protocols for using this method of verifying the dosages used in clinical trials, and describes the application of this approach on two separate clinical trials. Many other examples exist in the authors' laboratory. We also provide formatted templates that can be used to document and report NIR analytical results for discriminating between drug product and placebo dosage forms packaged in patient kits for clinical studies. The use of these templates, carefully designed to ensure regulatory requirements for validation are met, makes the implementation of the technique both rapid and compliant with regulatory requirements.

The synthesis and base-induced reactions of 2,3,5,7-tetraphenyl-l,4-diazabicyclo[4.1.0]hept-4-enes are described. These compounds are prepared from the reaction of meso-and rac -stilbenediamine with 1,3-diphenyl-2.3-dibromo-l-propanone. The assignment of stereochemistry about the ring system was made on the basis of the NMR spectra of the various structural isomers. The l,4-diazabicyclo[4.1.0]hept-4-ene ring system was found to undergo an interesting set of reactions on treatment with base. The particular product formed was found to depend on both the initial stereochemistry of the ring system as well as on the experimental conditions used. The exo,exo isomer 4 gave l-benzyl-2,3,5-triphenyldihydropyrazine (10) on treatment with potassium tert-butoxide. The other possible isomeric diazabicycloheptenes gave triphenylpyrazine when benzene was used as a solvent.When the reaction was carried out in tert-butyl alcohol, 2-benzyl-3,5,6-triphenylpyrazine (7), 2,3,5,7-tetraphenyl-1.4-diazacyclohepta-l,3,5-triene (13), and 2,4,5,7-tetraphenyl-3,6-diazabicyclo[3.2.0]hepta-3,6-diene were isolated as the major products. The mechanistic pathways involved in the base-induced reactions are discussed.

The detection, isolation, and identification of the impurities in the technical grade of the insecticide thiofanox are described. A 13C NMR method was employed to detect impurities at about the 0.1% level or greater. The 13C spectrum of very high signal-to-noise ratio of an impurity concentrate was used to guide subsequent separation and identification work. The sensitivity and reliability of this approach are discussed. Preparative and semipreparative high performance liquid chromatography was employed to isolate 39 nonvolatile components. These were identified on the basis of spectral data and by comparisons with authentic samples which were synthesized when necessary. Some stereochemical assignments are made on the basis of NMR chemical shifts. An additional 30 volatile components were isolated and identified by vacuum distillation and gas chromatography/ mass spectrometry.