TERT-BUTYL 2,4-DICHLORO-5,6-DIHYDROPYRIDO[3,4-D]PYRIMIDINE-7(8H)-CARBOXYLATE

To a 0 °C solution of the intermediate 4 (270 mg, 1.33 mmol) in DCM (30 mL) were added (Boc)To a solution of benzyl (2S)-2-(cyanomethyl)piperazine-l-carboxylate (646 mg, 2.49 mmol, 1.00 eq, trifluoroacetic acid salt) and Diisopropylethylamine (1.29 g, 9.96 mmol, 4.00 eq) in dimethylsulfoxide (20 mL) was added tert-butyl 2, 4-dichloro-5, 6-dihydropyrido[3, 4- d]pyrimidine-7(8H)-carboxylate (758 mg, 2.49 mmol, 1.00 eq) in one portion. The resulted solution was stirred at 50 C for 9 hours. The reaction solution was diluted with ethyl acetate (200 mL) and water (100 mL). The organic layer was separated and collected, washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a yellow liquid. The yellow liquid was purified by column chromatography (silicon dioxide, Petroleum ether/Ethyl acetate = 10/1 to 1/1) to obtained tert- butyl 4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl) piperazin-l-yl]-2-chloro-6, 8-dihydro-5H- pyrido[3, 4-d]pyrimidine-7-carboxylate (1.10 g, 2.09 mmol, 84% yield) as yellow liquid. LC/MS (ESI) m/z 527.1 [M+l] +; 1H-NMR (400MHz, CDCL) d 7.46 - 7.32 (m, 5H), 5.26 - 5.14 (m, 2H), 4.67 (d, 7=17.6 Hz, 2H), 4.51 - 4.42 (m, 1H), 4.21 - 4.05 (m, 2H), 3.93 - 3.75 (m, 2H), 3.40 (d, 7=10.8 Hz, 2H), 3.12 (dt, 7=3.2, 12.4 Hz, 1H), 2.97 - 2.51 (m, 3H), 1.61 (s, 2H), 1.50 (s, 9H).Compound 183a was prepared from tert-butyl 2, 4-dichloro-5, 6-dihydropyrido[3, 4- d]pyrimidine-7(8H)-carboxylate (182a) (1.0 g, 3.29 mmol) in 2-Propanol (15 mL) using DIPEA (2.3 mL, 13.15 mmol) and 1-(3, 4, 5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (0.98 g, 3.95 mmol). This gave after workup and purification by flash column chromatography [silica gel, (12 g) eluting with DMA-80 in DCM (0 to 80%)] fert-butyl 2-chloro-4-((l-(3, 4, 5- trimethoxyphenyl)-lH-imidazol-4-yl)amino)-5, 6-dihydropyrido[3, 4-d]pyrimidine-7(8H)- carboxylate (183a) (0.87 g, 51 % yield) as a buff solid; NMR (300 MHz, DMSO-^e) delta 9.65 (s, 1H, D20 exchangeable), 8.16 (d, J = 1.5 Hz, 1H), 7.78 (d, J = 1.6 Hz, 1H), 6.90 (s, 2H), 4.35 (s, 2H), 3.87 (s, 6H), 3.69 (s, 3H), 3.61 (t, J = 5.8 Hz, 2H), 2.69 - 2.60 (m, 2H), 1.43 (s, 9H).

Molecular Weight:304.17
XLogP3:2.9
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:303.0541321
Monoisotopic Mass:303.0541321
Topological Polar Surface Area:55.3
Heavy Atom Count:19
Complexity:348
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes