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Stage #1: With trimethylaluminum; ammonium chloride In toluene at 0 - 80℃; Inert atmosphere Stage #2: With hydrogenchloride In methanol; diethyl ether; chloroform; toluene at 20℃; for 16 h;
Ammonium chloride (2.9 g, 54 mmol) was suspended in 20 mL of anhydrous toluene, stirred under argon, and cooled to 0° C. To this suspension was added 25 ml (50 mmol) of a 2M solution of trimethylaluminum in toluene. The reaction was allowed to warm to room temperature and stirring was continued until the evolution of methane ceased (1 hour). Then, 3.46 mL (30 mmol) of benzyl cyanide in 10 mL of anhydrous toluene was added and the reaction was heated to 80° C. for 18 hours. The reaction was then cooled to room temperature and slowly poured into a slurry of 15 g of silica gel in 50 mL of chloroform and stirred for 5 minutes. The silica was filtered and washed with methanol. The filtrate and washings were combined and reduced to a volume of 15 mL and refiltered. Then, 18 mL (54 mmol) of a 3N solution of methanolic HCl was added to the filtrate followed by 400 mL of diethyl ether. After 16 hours of stirring at room temperature, a white precipitate formed was subsequently filtered. This crude solid was then added to 150 mL of a 4:1 mixture of isopropanol-acetone and stirred for an additional 16 hours at room temperature. Undissolved ammonium chloride was then removed by filtration and the filtrate reduced to 15 mL. After the addition of 300 mL of diethyl ether the mixture was stirred for 1 hour. The white precipitate was then filtered and dried to yield 3.7 g (72percent) of the objective compound as the hydrochloride salt. MS: (ESI, Pos) m/z 157.9 (M+23) 1H NMR (500 MHz, DMSO-d6): δ (ppm) 9.06 (br.d, 3H), 7.49 (d, 2H), 7.36 (t, 2H), 7.31 (t, 1H), 3.74 (s, 2H).
72%
Stage #1: With trimethylaluminum; ammonium chloride In toluene at 80℃; for 18 h; Inert atmosphere Stage #2: With hydrogenchloride In methanol; diethyl ether; toluene at 20℃; for 16 h; Inert atmosphere
Example 3a 2-Phenylacetamidine (3a)-Ammonium chloride (2.9 g, 54 mmol) was suspended in 20 mL of anhydrous toluene, stirred under argon, and cooled to 0° C. To this suspension was added 25 ml (50 mmol) of a 2M solution of trimethylaluminum in toluene. The reaction was allowed to warm to room temperature and stirring continued until the evolution of methane ceased (1 hour). Then, 3.46 mL (30 mmol) of benzyl cyanide in 10 mL of anhydrous toluene was added and the reaction was heated to 80° C. for 18 hours. The reaction was then cooled to room temperature and slowly poured into a slurry of 15 g of silica gel in 50 mL of chloroform and stirred for 5 minutes. The silica was filtered and washed with methanol. The filtrate and washings were combined and reduced to a volume of 15 mL and refiltered. Then, 18 mL (54 mmol) of a 3N solution of methanolic HCl was added to the filtrate followed by 400 mL of diethyl ether. After 16 hours of stirring at room temperature, a white precipitate formed and was subsequently filtered. This crude solid was then added to 150 mL of a 4:1 mixture of isopropanol-acetone and stirred for an additional 16 hours at room temperature. Undissolved ammonium chloride was then removed by filtration and the filtrate reduced to 15 mL, and 300 mL of diethyl ether was added and the mixture stirred for 1 hour. The white precipitate was then filtered and dried to yield 3.7 g (72percent) of the objective compound as the hydrochloride salt. MS: (ESI, Pos) m/z 157.9 (M+23) 1H NMR (500 MHz, DMSO-d6): δ (ppm) 9.06 (br.d, 3H), 7.49 (d, 2H), 7.36 (t, 2H), 7.31 (t, 1H), 3.74 (s, 2H).
With sodium methylate; In methanol; at 20℃; for 16h;
To a solution of 1-benzyI 4-ethyl 5-oxoazepane-1 ,4-dicarboxyIate (4.5 g, 14 rnmol) in MeOH (30 ml) was added benzyl amidine hydrochloride (3.1g, 18 mmol} and MaOMe (2.3 g, 42 mmol). The resulting solution was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and residue partitioned between sat. NH4CI (aq) and ethyl The combined organic layers were combined, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with ethyl actate/pentane (1 ;3 to 1:1). The relevant fraction were combined and concentrated in vacuo to afford the title compound as a colourless oil (31 mgs, 41% yield). '. The organic layer was dried over magnesium sulfate and concentrated in vacuo to yield the crude piperidone, which was further purified by trituration with diethyl ether (x2) 89%;1H NMR (400 MHz1 CDCI3) delta: 2.86 (m, 2H), 2.95 (m, 2H), 3.62 (m, 2H)1 3.67 (m, 2H)S 3.91 (s, 2H), 5.19 (s, 2H)1 7.25-7.40 (m, 10H). LRMS APCI m/z 390 [MH]+
Stage #1: 2-phenylacetamidine hydrochloride With sodium ethanolate In ethanol at 20℃; for 0.0833333h;
Stage #2: diethyl malonate In ethanol Reflux;
Stage #3: With hydrogenchloride In water
5a
Sodium metal (168 mg, 7.3 mmol) was dissolved in 8 mL of anhydrous ethanol. To this was added 500 mg (2.93 mmol) of 2-phenylacetimidamide hydrochloride 3a and the reaction was allowed to stir at room temperature for 5 minutes. Diethyl malonate (2.9 mmol) was then added and the reaction was heated to reflux overnight. The reaction was then cooled to room temperature and filtered. The solid was washed several times with absolute ethanol. The filtrate and washings were combined and diluted with 2 volumes of water and acidified with 5N HCl to a pH of 2 and the product precipitated. The mixture was chilled and then filtered. The solid was washed several times with diethyl ether and then dried to yield 262 mg (44%) of a peach colored solid. MS: (ESI, Neg) m/z 200.8 (M-1) 1H NMR (500 MHz, DMSO-d6): δ (ppm) 11.80 (br.s, 2H), 7.32 (m, 4H), 7.25 (m, 1H), 5.09 (s, 1H), 3.80 (s, 2H).
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