SYNTHESIS OF POTENTIAL ANTICANCER AGENTS
463tion was complete the ice-salt-bath was removed and the reaction mixture was stirred for 1-4 hr. a t room temperature.The thermometer was replaced by a condenser and a solution of 7.0 g. (0.3 g. atom) of sodium in 70 ml. of absolute methanol (dried over magnesium methoxide) was added dropwise a t such a rate as to maintain gentle reflux. After the addition was complete the reflux was maintained by external heating to complete the reaction. The reaction was considered complete when a test portion of the reaction mixture gave a negative test with acidified starch-iodide paper (70 min.). The reaction mixture was cooled, and the precipitated sodium chloride was removed by filtration and washed three times with small portions of dry benzene. The filtrate was poured cautiously into a separatory funnel containing 150 ml. of 2 N hydrochloric acid solution.a4 The aqueous portion was separated and the benzene layer was extracted three times with 50-ml. portions of 2 N hydrochloric acid solution. The combined acid extracts were washed twice with 50-ml. portions of ether (which were discarded).The aqueous solution was evaporated to Cyness in a rotating evaporator a t a temperature below 40 . The residue was extracted (under reflux) with 200-ml. and 150-ml. portions of isopropyl alcohol to which 1.0 ml. of concentrated hydrochloric acid per 100 ml. of alcohol had been added.36The precipitate which formed upon cooling the extracts separately was removed by filtration and washed with dry ether. The filtrates were either evaporated under reduced pressure to approximately half of their original volumes or were diluted with equal volumes of ether. Either treatment yielded a second crop of crystals (also washed with ether). The total yield of phenacylamine hydrochloride was 13.4 g.(7870), m.p. 186.6' dec.The principal variations necessary in the preparations of the other amino ketone hydrochlorides were as follows. In the preparation of p-nitrophenacylamine hydrochloride the addition of the sodium methoxide solution was carried out kn an ice-water-bath to maintain the temperature below 10 .Even so the color of the solution changed from yellow to green to brown as the addition progressed. After the addition was complete the mixture was stirred a t room tempera-(34) The reverse order of addition may lead to the formation of the self condensation products of the a-amino ketone.(35) Inasmuch as sodium chloride is very nearly insoluble in hot isopropyl alcohol, the latter is the solvent of choice for such extractions. For less soluble amino ketone hydrochlorides, ethyl or methyl alcohols could be used, but the products may have been contaminated with traces of sodium chloride. ture until a negative test was obtained with starch-iodide paper (2 hours) or, less desirably, heated on the steam-bath (60 min.). The times required to obtain a negative test with starch-iodide paper for the other preparations are listed in Table I as reaction times. In the preparation of 2-amino cyclopentanone the aque...
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