Honors Cup Synthetic Proposal Section: 250 Group Members: Garrett Coyan, Amanda Kupstas, Tracy Lent, Ruchika Vij Title: Synthesizing 1-[4-(Acridin-9-ylamino) phenyl] ethanone Introduction: Acridines with different substituents have the potential to have properties with many medical uses(8,9,10). Here, we are synthesizing a precursor to a cell antiinflammatory drug. With different substituents, the molecule can have different properties, ranging from antiseptic to anti-tumor capabilities. The particular synthetic product produced by this procedure, 1-[4-(Acridin-9-ylamino) phenyl] ethanone, is a very effective inhibitor in DNA that can serve to block protein synthesis in damaged (perhaps cancerous) cells. In this procedure, we use a large variety of different laborotory techniques including vacuum nitrogenous atmosphere distillation, separatory funnel extraction, and crystallization. These reactions provide a forerunner to anti-inflammatory agents with no considerable cytotoxicity that can prove useful against mast cells (cells involved in inflammatory diseases). Our particular product shows anti-inflammatory reactions in current research (8,9). Overall synthetic reaction scheme: ClOHONHHCuO, K2CO3DMF, 2 hr refluxNHOHO(Goldberg Reaction)1)2)NHOHO2 POCl3, 3 HCLNCl3)NCl2 BuOH1-(4-aminophenyl)-ethanoneNNHCH3O33O-chlorobenzoic acid (1)aniline (2)N-phenylanthranilic (3)(3) 9-chloroacridine (4)1-[4-(Acridin-9-ylamino)phenyl] ethanone (5)(4)Step 1 Synthetic transformation 1: ClOHONHHCu, K2CO32 hr refluxNHOHOGoldberg ReactionDMF(1)(2)(3) Experimental 1 O-chlorobenzoic acid (1)(1.91 g./0.011 mol), aniline (2)(2.07g./0.0223 mol), copper powder (0.05g.) and anhydrous potassium carbonate (0.551g./ 0.0056 mol) are refluxed in DMF (10 mL) under nitrogen atmosphere for 2 hours. The mixture is slowly added to to HCl (1:1) solution (30 mL) while shaking/stirring. The solution is left to stand overnight. Solid (3) is filtered and washed, extracted with boiling water and crystallized from absolute ethanol. Modifications/Discussion: This is a customized experimental step that is arrived upon from a gathering information from the literature (1,2,3). The literature suggests that the Goldberg reaction can be carried out in water (3) or DMF, with DMF giving the better yields and shorter reaction times (1,2). The nitrogenous atmosphere is suggested in some of the literature (1), but not in others, so the researchers are guessing on the safe side. The yield below provides for ample extra material for characterization and because of the varying reports in the literature. The 80% is merely and average for the values seen across the board, and the technique described above lends itself to such a yield as seen in the literature (1). Expected yield: 80 % 1.90 g Safety, disposal and green issues 1: O-chlorobenzoic acid is an irritant, keep away from eyes. Aniline is toxic, keep under the hood; also, if released outside, it is an environmental hazard. Copper powder is flammable, keep it under the hood and away from any open flames. Aqueous potassium hydroxide is corrosive, keep away from eyes. Diethyl ether is extremely flammable and harmful if ingested. Hydrochloric acid is also corrosive, keep away from eyes. Absolute ethanol is flammable, keep under the hood and away from open flames. The solvent DMF is toxic.Step 2 Synthetic transformation 2: NHOHO2 POCl3, 3 HCLNCl(3)(4) Experimental 2 Place (1.3 g./ 0.0061 mol.) N-phenylanthranilic acid (3) and (7.03g./0.0459 mol.) phosphorus oxychloride in a round bottom flask. Heat slowly in a water bath at 85-90 C. After 15 min. remove from heat, expect a vigorous, violent reaction. If the reaction becomes too violent, it is best to place mixture in a cold water-bath for a moment. After 5-10 min. (boiling subsides) immerse flask in an oil bath. Then raise the temperature to 135-140 C and maintain under reflux for 2 hrs. Remove the excess phosphorus oxychloride by distilling form an oil bath at 140-150 C under a vacuum of about 50mm. (9-chloroacridine is readily hydrolyzed in neutral and acid solutions; hence it must not be exposed to the air after removal of the phosphorus oxychloride and before treatment with ammonia.) After cooling, pour mixture into a well-stirred mixture of 5.21 ml concentrated ammonia solution, 13 g. ice, and 5.21 g. chloroform. Rinse the flask with the chloroform-ammonia mixture. Allow 30 min. for the solid to dissolve completely. Extract aqueous layer with additional chloroform. Dry the chloroform extracts over 2.5 g. calcium chloride, and filter. Remove the solvent by distillation. Dry the product at 70 C for 20 min. This reaction yields crude 9-chloroacridine (4) with an m.p. of 117-118 C. Modifications/Discussion: This process is mainly derived from an alternative procedure found in the literature (4). This particular procedure uses chloroform to speed up the reaction to an acceptable rate and to avoid the necessary filtrations associated with the normal synthetic method (5). The nitrogenous atmosphere need not be added until the phosphorus chloride is removed, and the vacuum filtration will require the nitrogen atmosphere (a creative apparatus, yet completely within the realm of Chemistry 216H). The procedure found in the main article of interest (4) tells that a crude product is formed, which is the reason for the higher than 100% yield. This is perfectly fine, and should not affect the rest of the synthesis significantly. Expected yield: 101.97 % 1.32 g Note: percentage reflects crude product Safety, disposal and green issues 2: Safety: N-phenylanthranilic acid is an irritant, keep away from eyes. Phosphorus oxychloride is very toxic and is corrosive. Ammonia is toxic and dangerous to the environment; do not inhale directly. Chloroform is harmful, do not ingest. Calcium chloride is an irritant. The product 9-chloroacridine is a severe irritant.Step 3 Synthetic transformation 3: NCl2 BuOH1-(4-aminophenyl)-ethanoneNNHCH3O(4)(5) Experimental 3 1-[4-(Acridin-9-ylamino)phenyl]ethanone : 4-Aminoacetophenone (0.6758 g./0.005 mol. )is refluxed with 9-chloroacridine (4)(0.577g./ 0.0027 mol.) in 2-butanol (26.7 mL) for three hours. The mixture is allowed to cool to room temperature and is then poured into ice water (50 mL). When a precipitate forms, filter off via suction, wash the precipitate with water, and crystallize using MeOH to yield
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