2,4-Dichloro-5-cyanopyrimidine

General procedure: A suspension of 5-nitrouracil (10 g, 63 mmol) in POCl3 (100 mL) was refluxed for 5 h in the presence of N, N-dimethylaniline (10 mL), cooled to room temperature and poured on to crushed ice with vigorous stirring. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent was evaporated under reduce pressure. The residue was purified by chromatography on silica gel (hexane/ethyl acetate; 1/1; v/v) to give the desired 2, 4-dichloro-5-nitropyrimidine. LCMS: ret. time: 23.26 min.; purity: 95percent; 1H NMR (CDCl3): delta 9.16 (1H, s).To a solution of compound 11b (500 mg, 2.46 mmol) in i-PrOH (5 mL) was added DIEA (635 mg, 4.91 mmol) and compound 85a (470 mg, 2.70 mmol). The resulting mixture was stirred at 80C for 1 hr. The mixture was poured into water (20 mL) and extracted with EtOAc (100 mL 3). The combined organic layers were dried over Na 2SO 4, filtered and concentrated in vacuum to give the crude product, which was purified by prep-HPLC [column Boston Green ODS 150*30 5um, condition 65%B (A, water/0.1%TFA, B: CH 3CN) ; Flow rate: 25 ml/min]. The pH of the fractions were adjusted to 7-8 with sat. NaHCO 3 and extracted with EtOAc (20 mL 3). The combined organic layers were washed with brine (50 mL), dried over Na 2SO 4, filtered and concentrated in vacuum to give desired compound 85b (280 mg, 33% yield) and its regioisomer. LCMS: R t = 3.661 in 10-80AB_7.0 min_220&254 chromatography (Xtimate C18 2.1*30mm), MS (ESI) m/z= 322.8 [M+H-18] +. 1H NMR (400MHz, DMSO-d 6) delta 11.22 (br s, 1H), 8.82 (s, 1H), 8.23 (d, J=7.2 Hz, 1H), 7.44 (d, J=11.2 Hz, 1H), 6.63 (br s, 1H), 1.53 (s, 6H).To a flask were added 2, 4-dichloropyrimidine-5-carbonitrile (1-a) (3.0 g, 17.24 mmol) , (R) -tert-butyl 2-methylpiperazine-1-carboxylate (12-a) (3.3 g, 16.5 mmol) , DMF (100 ml) and DIEA (8 ml, 46 mmol) . The mixture was stirred at RT for 2 h. To the resulting mixture were added EtOAc and water, and the organic phase was separated and concentrated in vacuo to afford tert-butyl (R) -4- (4-chloro-5-cyanopyrimidin-2-yl) -2-methylpiperazine-1-carboxylate, (15-a) which was used in next step without further purification. MS (ESI) Calc'd for C15H21ClN5O2[M+1]+, 338; found, 338.To a solution of 2, 4-dichloropyrimidine-5-carbonitrile (1-a) (0.5 g, 2.9 mmol) in EtOH (5 ml) was added 1- (3-fluorophenyl) piperazine (9-c) (0.52 g, 2.9 mmol) and TEA (0.29 g, 2.9 mmol) at 0 and then the resulting mixture was stirred for 2 h at 0 the reaction mixture was then concentrated in vacuo, and the residue was purified by column chromatography (silica gel, eluting 0-10%MeOH in DCM) to afford 2-chloro-4- (4- (3-fluorophenyl) piperazin-1-yl) pyrimidine-5-carbonitrile (9-d) . MS (ESI) Calc'd for (C15H14ClFN5) [M+H]+, 318, found, 318.To a solution of 2, 4-dichloropyrimidine-5-carbonitrile (1-a) (600 mg, 3.5 mmol) in THF (14 mL) were sequentially added TEA (698 mg, 6.90 mmol) and tert-butyl 2, 2-dimethylpiperazine-1-carboxylate (8-a) (739 mg, 3.45 mmol) drop wise at -10 with stirring. The resulting solution was stirred at -10 for 30 min. The solution was then concentrated in vacuo. The crude residue was purified by reverse-phase preparative flash column chromatography (eluting with 25-60%acetonitrile in water) to afford tert-butyl 4- (2-chloro-5-cyanopyrimidin-4-yl) -2, 2-dimethylpiperazine-1-carboxylate (8-b) . MS (ESI) Calc'd for (C16H23ClN5O2) [M+H]+, 352, found, 352.

Molecular Weight:173.98
XLogP3:1.8
Hydrogen Bond Acceptor Count:3
Exact Mass:172.9547524
Monoisotopic Mass:172.9547524
Topological Polar Surface Area:49.6
Heavy Atom Count:10
Complexity:164
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes