ethyl 2-phenylpyrimidine-5-carboxylate

In a round bottomed flask under argon atmosphere were successively added anhydrous ethanol(5 mL), sodium metal (0.426 g, 18.5 mmol), benzamidine hydrochloride (2.90 g, 18.5 mmol)and diethyl 2-(ethoxymethylene)malonate (4.0 g, 18.5 mmol). The reaction mixture was stirredat room temperature for 9 h, and then poured into ice. The precipitate was filtered, washedwith coldwater and recrystallized in EtOH-MeOH-CHCl3 (1:1:1) (45 mL), giving the ethyl4-hydroxy-2-phenylpyrimidine-5-carboxylate (8) as a white crystalline solid in 50percent yield. Thederivative 8 (1.2 g, 4.91 mmol) and POCl3 (9.8 g, 63.9 mmol) were refluxed at 100oC for 1 h. Theexcess of POCl3 was removed under vacuum, ice was added on the resulting solid into the reactionflask, followed by filtration and washing with cold water. The chloride compound 9, obtained as awhite amorphous solid in 98percent yield, was successively dehalogenated with zinc powder (0.176 g, 2.69 mmol, 4 equiv) in anhydrous THF (2 mL). The reaction mixture was stirred at 60 °C for 1 h, andthen 5 drops of acetic acid were added to the reaction vessel. After stirring at 60 °C for 23 h, thereaction mixture was cooled to room temperature, followed by addition of CH2Cl2 (3 mL), filtrationand evaporation of solvent. Purification by silica gel column chromatography (n-hexane-EtOAc 0.6percent)afforded the title compound as a white crystalline solid in 50percent yield.General procedure: To a solution of and halide in the indicated solvent is added boronic acid or ester, carbonate base, and palladium catalyst at room temperature. After stirring at 100 °C overnight, the mixture is cooled and concentrated.Following Procedure B using ii (500 mg, 2.67 mrnol). dioxane (10 mL), phenylboronic acid (650 mg, 5.36 mmoi), potassium carbonate (1.85 g. 13.4 mmol), and Pd(dppf)C12 (50 mg), then purified by silica gel column chromatography (EA:PE = 1:100 to 1:50) to give 20 as a white solid (400 mg, 65percent yield). (MS: M+Hi 229.1)Example 32 In a round bottomed flask under argon atmosphere were successively added anhydrous ethanol(5 mL), sodium metal (0.426 g, 18.5 mmol), benzamidine hydrochloride (2.90 g, 18.5 mmol)and diethyl 2-(ethoxymethylene)malonate (4.0 g, 18.5 mmol). The reaction mixture was stirredat room temperature for 9 h, and then poured into ice. The precipitate was filtered, washedwith coldwater and recrystallized in EtOH-MeOH-CHCl3 (1:1:1) (45 mL), giving the ethyl4-hydroxy-2-phenylpyrimidine-5-carboxylate (8) as a white crystalline solid in 50percent yield. Thederivative 8 (1.2 g, 4.91 mmol) and POCl3 (9.8 g, 63.9 mmol) were refluxed at 100oC for 1 h. Theexcess of POCl3 was removed under vacuum, ice was added on the resulting solid into the reactionflask, followed by filtration and washing with cold water. The chloride compound 9, obtained as awhite amorphous solid in 98percent yield, was successively dehalogenated with zinc powder (0.176 g, 2.69 mmol, 4 equiv) in anhydrous THF (2 mL). The reaction mixture was stirred at 60 °C for 1 h, andthen 5 drops of acetic acid were added to the reaction vessel. After stirring at 60 °C for 23 h, thereaction mixture was cooled to room temperature, followed by addition of CH2Cl2 (3 mL), filtrationand evaporation of solvent. Purification by silica gel column chromatography (n-hexane-EtOAc 0.6percent)afforded the title compound as a white crystalline solid in 50percent yield.General procedure: To a solution of and halide in the indicated solvent is added boronic acid or ester, carbonate base, and palladium catalyst at room temperature. After stirring at 100 °C overnight, the mixture is cooled and concentrated.Following Procedure B using ii (500 mg, 2.67 mrnol). dioxane (10 mL), phenylboronic acid (650 mg, 5.36 mmoi), potassium carbonate (1.85 g. 13.4 mmol), and Pd(dppf)C12 (50 mg), then purified by silica gel column chromatography (EA:PE = 1:100 to 1:50) to give 20 as a white solid (400 mg, 65percent yield). (MS: M+Hi 229.1)Example 32 Example 32 2-PHENYLPYRIMIDINE-5-CARBONYL CHLORIDE A solution of ethyl 3-N, N-dimethylamino-2-formylacrylate (4.0 g, 23 mmol) (Arnold, Coll. Czech. Chem. Commun. 26:3051, 1961), benzamidine hydrochloride (4.0 g, 26 mmol) and sodium (0.65 g, 28 mmol) in EtOH (40 mL) was heated at reflux for 1 h. The solution was filtered and concentrated and the residue partitioned between EtOAc and dilute HCl (10%). The organic layer was dried (Na2 SO4), and concentrated to give ethyl 2-phenylpyrimidine-5-carboxylate (4.0 g, 75% yield); m.p. >220 C. (dec.).General procedure: To a solution of and halide in the indicated solvent is added boronic acid or ester, carbonate base, and palladium catalyst at room temperature. After stirring at 100 C overnight, the mixture is cooled and concentrated.Following Procedure B using ii (500 mg, 2.67 mrnol). dioxane (10 mL), phenylboronic acid (650 mg, 5.36 mmoi), potassium carbonate (1.85 g. 13.4 mmol), and Pd(dppf)C12 (50 mg), then purified by silica gel column chromatography (EA:PE = 1:100 to 1:50) to give 20 as a white solid (400 mg, 65% yield). (MS: M+Hi 229.1)K2CO3 (2.1 g, 15.4 mmol) was added to a mixture of benzamidine hydrochloride hydrate (1.55 g, 10.0 mmol) and 14 (1.0 g, 7.7 mmol) in DMF at ambient temperature. The solution was heated at 100 °C for 4 h. After confirming that the reaction was complete by using TLC analysis, the solution was cooled to room temperature and water (15 mL) is added. The reaction mixture was extracted with EtOAc and brine. The organic phase was dried over Na2SO4 overnight and the solvent was removed under vacuum. The crude product was purified by silica gel column chromatography to give the target product 2g. 1H NMR (600 MHz, DMSO-d6) delta 9.31 (s, 2H), 8.49-8.44 (m, 2H), 7.59 (ddd, J = 15.9, 7.7, 3.6 Hz, 3H), 4.40 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H).To a solution of

Molecular Weight:228.25
XLogP3:2.1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:4
Exact Mass:228.089877630
Monoisotopic Mass:228.089877630
Topological Polar Surface Area:52.1
Heavy Atom Count:17
Complexity:244
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes