Phenylpropynal-hexacarbonylcobalt complex, prepared from 3-phenylpropynal with octacarbonylcobalt, afforded on treatment with the seven-membered ketene trimethylsilyl acetal the syn-aldol product in a highly stereoselective manner. Similar exposure of the above complex to the six-and five-membered ketene trimethylsilyl acetal gave the corresponding syn-aldol products predominantly. The aldol reaction of the cobalt complexes derived from 3-trimethylsilyl-and 3-butyl-propynal with those cyclic ketene silyl acetals proceeded syn-selectively to provide the syn-aldol products. The preferential formation of the syn-over the anti-isomers was also achieved in the reaction of the cobalt complexed 3-trimethylsilylpropynal with acyclic ketene trimethylsilyl acetals, derived from methyl or tert-butyl propionate. In contrast, uncomplexed 3-phenyl-, 3-trimethylsilyl-and 3butylpropynal furnished the corresponding aldol products nonselectively or anti-isomers predominantly depending on the structure of the starting ketene trimethylsilyl acetal.Paper 1/03005A

An essential part of the pharmaceutical development of new drugs is the quantitative determination of their chemical reactivity under conditions that are relevant to the way they are manufactured, stored, and used. The goals of preformulation stability studies are two-fold. First, it is important to obtain detailed kinetic information under a variety of environmental conditions so that the storage shelf life of a new drug can be estimated. Second, the mechanism of degradation must be determined so that the formulation can be scientifically designed to maximize the stability of the active ingredient in the drug product. Due to the generally higher reactivity of drugs in solution as opposed to the solid phase, preformulation studies are particularly important for compounds that will be formulated as aqueous solutions.The relatively low reactivity of many substances makes it necessary to conduct high temperature stability studies and extrapolate the results to room temperature. This procedure, however, may be prone to gross inaccuracies under circumstances where the observed reactivity is the sum of several reaction steps such as oxidation reactions.1) Also, extrapolation of high temperature data will lead to errors if there is a change in the reaction mechanism over the temperature range of interest. Thus, a detailed analysis of kinetic, mechanistic, and product data are needed to obtain reliable predictions of room temperature stability for many pharmaceuticals. In this paper, we present the results of preformulation stability studies with [5S-[5a,6b,7a Fig. 1), a potent and specific non-peptidyl antagonist for the endothelin receptor.2) Kinetic and product studies in aqueous solution indicate that J-104,132 is prone to an acid-catalyzed epimerization reaction, and we present a mechanism that involves a novel enamine intermediate. Studies of the reaction as a function of pH and temperature are presented and analyzed in terms of forward and reverse rate constants for epimerization. Finally, the accelerated stability data are used to derive the room temperature reactivity of the drug in a probe intravenous formulation, and these predictions are compared to long-term data obtained at 25°C. ExperimentalMaterials All solvents were obtained from Fisher Scientific (Pittsburgh, PA, U.S.A.) and were HPLC grade or equivalent. Reagents were obtained from Fisher Scientific and were certified ACS grade. Laboratory samples of J-104,132 were obtained from Banyu Pharmaceutical Co. Ltd. (Menuma, Japan); the samples were greater than 99% pure as judged by reverse phase HPLC and were used without further purification.Kinetic Procedures Solutions used for kinetic studies consisted of the drug (5.0 mg/ml) and mannitol (42 mg/ml, used to provide physiologically isotonic media) dissolved in a 0.010 M buffer. The buffers used were sodium citrate/hydrochloric acid (pH 6.5 and 7.5) and tris/hydrochloric acid (pH 8.5). Measurement of pH was accomplished with a Fisher Accumet Model 15 pH meter.The kinetic runs were all performed in essentia...

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Pentandion (I) reagiert mit Formaldehyd (II) in Gegenwart katalytischer Mengen Piperidin zu den Kondensationsprodukten (III) und (IV).