4-Chloro-5,6,7,8-tetrahydro-7-(phenylmethyl)pyrido[3,4-d]pyrimidine

To 69A (3.00 g, 12.4 mmol) in toluene (40 mL) at room temperature was added phosphorus oxychloride (2.28 g, 14.9 mmol) followed by Hunig's base (1.28 g, 9.92 mmol) and the reaction was heated to 100°C for 30 minutes then cooled to rt. The resulting mixture was quenched with 200 mL of saturated aqueous sodium bicarbonate solution and 200 mL of crushed ice. After stirring at room temperature for lh, the mixture was then extracted with dichloromethane (100 mL x 4). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give 3.32 g of 69B (-100percent) as a dark brown oil that was used directly without any further purification. HPLC Ret. Time: 0.95 min. MH+ (m/z) 260.To a mixture of 7-benzyl-5, 6, 7, 8-tetrahydropyrido[3, 4-d]pyrimidin-4(3H)-one4.83 g, 20.0 mmol) in toluene (80 mL) at 25 °C was added N, N-diisopropylethylamine (3.4 5 8 mL, 20.0 mmol), followed by phosphorous oxychloride (2.24 mL, 24.0 mmol). The reaction mixture was heatedat reflux for 2 h. After cooling to room temperature, the mixture was diluted with water and ethyl acetate. The aqueous phase was adjusted to ~pH 7 employing saturated aqueous sodium bicarbonate solution. The phases were separated. The organic phase was washed with water and brine, dried over anhyd. sodium sulfate, filtered and concentrated. The residue was dissolved in 1-chlorobutane, and the resulting mixture was filtered. The filtrate was concentrated under vacuum to provide 7-benzyl-4-chloro-5, 6, 7, 8-tetrahydropyrido[3, 4-d]pyrimidine (4.75 g, 91percent) as an orange-red oil; LC/MS: m/z 260.10 (M + H)Part B: To a mixture of 7-benzyl-5, 6, 7, 8-tetrahydropyrido[3, 4- d]pyrimidin-4(3H)-one 4.83 g, 20.0 mmol) in toluene (80 mL) at 25 B. 7-Benzyl-4-chloro-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidine [00228] 7-Benzyl-5, 6, 7, 8-tetrahydro-3H-pyrido [3, 4-d] pyrimidin-4-one (9.4g, 39mmol) was dissolved in anhydrous 1, 2-dichloroethane and stirred under N2 (g) atmosphere. To the mixture was added POC13 (29mL, 312mmol), followed by N, N-dimethyl aniline (4.75g, 39mmol). The mixture was refluxed for 2 h and the solvents were removed under vacuum to give a red residue. The residue was dissolved in 20 mL of ethyl acetate and 20ml of water was added. The solution was neutralized with ice and solid NaHC03. After neutralization, ethyl acetate was added and the orgarhC layer'was washed with water ana Dnne. ine organic layer was dried over Na2SO4 and the solvents were removed under vacuum. The resulting red residue was purified using a gradient of ethyl acetate: hexane (0-100percent) to give the desired compound as yellow crystals (3.8g, 38percent).A RBF (250 mL) equipped with a reflux condenser was charged with 35.3 g of 7-benzyl-5, 6, 7, 8-tetrahydro-3H-pyrido[3, 4-d]pyiimidin-4-one HCl followed by the addition OfPOClGeneral procedure: To the solution of 6-benzyl-4-chloro-5, 6, 7, 8-tetrahydropyrido[4, 3-d]pyrimidine (1.5 g, 5.8 mmol) and 2-fluoro-4-(methylsulfonyl)aniline(1.3 g, 6.9 mmol) in 1, 4-dioxane (30 mL) was added Pd2(dba)3 (1.1 g, 1.2 mmol), X-Phos (0.57 g, 1.2 mmol) and Cs2CO3 (0.81 g, 2.5 mmol)under nitrogen atmosphere. The reaction was heated to reflux overnight.After cooled down to room temperature the mixture was dilutedwith EtOAc (60 mL) and washed with brine. The organic layer wasdried over MgSO4, filtered and evaporated. The residue was purified bycolumn chromatography (petroleum ether: EtOAc=1: 1) to afford thedesired product as a yellow solid (2.0 g, 83%).

Molecular Weight:259.73
XLogP3:2.6
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:259.0876252
Monoisotopic Mass:259.0876252
Topological Polar Surface Area:29
Heavy Atom Count:18
Complexity:268
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes