4,6-Dichloro-5-pyrimidinecarbaldehyde

White to off-white solid

4-[6-Amino-5-(methoxyimino-methyl)-pyrimidin-4-yl]-piperazine-l-carboxylic acid (4-isopropoxy-phenyl)-amidea. 4, 6-Dichloro-pyrimidine-5-carbaldehyde; A mixture of DMF (3.2 mL) and POClA mixture of DMF (3.2 mL) and POClA mixture of DMF (3.2 mL) and POClb. Amixture of DMF (3.2 mL, 41.34mmol) and POClA 250mL three-necked flask was added POCl30 mL of phosphorylchloride (POClTo DMF (64 niL) at ODMF (5.50 mL, 71.34 mmol) was slowly added dropwise under ice-coolingPOCl3 (17.00 mL, 185.71 mmol), Stirring reaction 1h, Remove the ice bath, 4, 6-dihydroxypyrimidine (4.00 g, 35.68 mmol) was added, Temperature reflux 3h, Cooled to room temperature, Poured into ice water, Dichloromethane extraction, Concentrated under reduced pressure, Petroleum ether-ethyl acetate (P: E = 4: 1 (V: V)), 4.74 g of a yellow solid, Yield 75.4percentExample 1-Synthesis of 4, 6-dichloropyrimidine-5-carbaldehyde 1 The DMF 30ml of dimethylformamide and 80ml of phosphorus oxychloride were mixed and stirred at 0 30 minutes, Was added 4, 6-dihydroxypyrimidine and 20.0g (0.18mol). Heated to 120 , refluxed for 5 hours. Concentrated under reduced pressureTo dryness, the residue was poured into ice water, extracted three times with ethyl acetate, the combined organic phases, the organic phase was driedAnd concentrated to give a yellow solid 23.1g, yield 72.7percent.(1) Weigh POCl3 (4 eq) into the reaction flask, and under nitrogen protection, cool to about 0°C. Add DMF (1.85 eq) to the feed solution. When adding, control the temperature at 08°C, add it. Feed solution 0 ~ 10 °C, stirring 1h, To the solution was added 4, 6-dihydroxypyrimidine. After the addition was completed, the mixture was naturally warmed to room temperature and stirred for 1 hour. Then, the mixture was warmed to reflux and stirred for 2 hours. The mixture was cooled and stirred overnight.The feed solution was evaporated under reduced pressure to remove excess POCl3, the residue was slowly added to ice water, the product was extracted with ethyl acetate (2 volumes *3), the organic phases were combined, washed with water (2 volumes) and washed with saturated sodium bicarbonate solution (2 The volume of) was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 4, 6-dichloropyrimidine-5-carboxaldehyde (yield: 70percent), which was used directly in the next reaction.Intermediate 16: 4, 6-Dichloro-pyrimidine-5-carbaldehyde; Phosphorous oxychloride (249 mL, 671 mmol) was added slowly to dimethylformamide (75 mL) with continuous stirring at 0° C. under nitrogen. After the addition was complete, was added 4, 6-dihydroxypyrimidine (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 50.0 g, 446 mmol) and stirred at room temperature for 2 hours followed by refluxing (135° C.) for 3 hours. The reaction mixture was cooled to room temperature, poured into chilled water with stirring and extracted with diethyl ether (3.x.200 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give 4, 6-dichloro-pyrimidine-5-carbaldehyde (54.0 g, 68percent) as a white solid, which was used for the next step without further purification. 4, 6-Dichloropyrimidine-5-carbaldehyde (26) [0168] In a 5 L 4-neck flask equipped with a mechanical stirrer, an addition funnel, a condenser, a thermocouple, and a NDimethylformamide (31.82 mL, 413 mmol) was added dropwise to phosphorus oxychloride (100 mL, 1.07 mol) at OTo cooled (0° C.) phosphorus oxychloride (20.0 mL, 215 mmol, 4.8 equiv.) was added DMF (6.4 mL, 83 mmol, 1.9 equiv) dropwise over 3 min. The reaction mixture was stirred for fifteen min and the ice bath was removed. 4, 6-Dihydroxypyrimidine (5.0 g, 44.6 mmol, 1.0 equiv.) was added and the reaction mixture was heated to 130° C. and stirred for 3.5 hr. The mixture was cooled to RT and concentrated. Ice was slowly added to the dark brown residue, followed by 600 mL of ice water. The aqueous mixture was extracted with diethyl ether (5.x.100 mL), and the organic extracts were washed with aqueous saturated NaHCO(Ref: A. Gomtsyan, S. Didomenico, C-H. Lee, M. A. Matulenko, K. Kim, E. A. Kowaluk, C. T. Wismer, J. Mikusa, H. Yu, K. Kohlhass, M. F. Jarvis, S. S. Bhagwat; J. Med. Chem., 2002, 45, 3639-3648.) A mixture of DMF (32 mL) and POClDMF (7 mL) was added dropwise to POC13 (22 mL) keeping the internal temperature below 30 °C. 4, [6-DIHYDROXYPYRIMIDINE] [(5. 0] g) was added maintaining the temperature below [30 °C.] The reaction mixture was stirred for 20 minutes and then heated to reflux for 4 hours. Excess POC13 was removed by evaporation and the resulting viscous mixture was poured into a stirred ice solution. The product was extracted with diethyl ether (6 x 50 mL). The combined organics were concentrated in vacuo and then purified by flash chromatography on silica eluting with hexane: EtOAc (7: 1 to 2: 1) to afford the title compound as [A] white crystalline solid (4.42 g, 56percent); [1H] NMR [(CDC13)] 8 8. 89 (s, 1H), 10.46 (s, 1H).4, 6-Dichloro-5-pyrimidinecarbaldehyde; A mixture of DMF (64 mL) and POClPreparation 95-A; 4.6-Dichloropyrimidine-5-carbaldehvde; Charge DMF (8.9 mL, 1.3eq) in a round bottom flask and cool to 04, 6-Dichloro-pyrimidine-5-carbaldehyde : DMF (7 mL, 0.09 mol) was added to POC13 (21 mL, 0.23 mol) at 0°C. The reaction mixture was stirred at room temperature for 0.5 h. 4, 6-Dihydroxy-pyrimidine-5-carbaldehyde (5 g, 0.045 mol) was added in small portions. The reaction mixture was heated to 90°C for 6 h and cooled to room temperature. A large excess of crushed ice was added to the reaction mixture very slowly under ice-bath. The mixture was extracted with CH2C12. The combined organic layers were washed with water, brine, and dried over NA2S04. After concentration, the residue was purified by column chromatography (20percent EtOAc/ hexane) to yield the title compound (4 g, 50percent). 1H NMR (400 MHz, CDC13) 8 8.91 (1H, s), 7.87 (1H, s). LRMS (M+H) + M/Z 177.DMF (7 mL, 0.09 mol) was added to POCl3 (21 mL, 0.23 mol) at 0° C. The reaction mixture was stirred at room temperature for 0.5 h. 4, 6-Dihydroxy-pyrimidine-5-carbaldehyde (5 g, 0.045 mol) was added in small portions. The reaction mixture was heated to 90° C. for 6 h and cooled to room temperature. A large excess of crushed ice was added to the reaction mixture very slowly under ice-bath. The mixture was extracted with CH2Cl2. The combined organic layers were washed with water, brine, and dried over Na2SO4. After concentration, the residue was purified by column chromatography (20percent EtOAc/hexane) to yield the title compound (4 g, 50percent). 1H NMR (400 MHz, CDCl3) δ 8.91 (1H, s), 7.87 (1H, s). LRMS (M+H)+ m/z 177.A mixture of phosphorus oxychloride (20ML, 0. 22 mol) and N, -DIMETHYLFORMAMIDE (6.4 mL) was stirred at 0°C for 1 hour. 4, 6-Dichloropyrimidine (5.00 g, 44.6 mmol) was added to the reaction mixture, which was then stirred for 3 hours at 120°C. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with ice-water and extracted with ether. The separated organic phase was washed with saturated sodium hydrogen carbonate solution and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residual solid was triturated with hexane to give 4, 6-dichloro- pyrimidine-5-carbaldehyde (4.73 g, 60percent).

Molecular Weight:176.99
XLogP3:1.6
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:175.9544181
Monoisotopic Mass:175.9544181
Topological Polar Surface Area:42.8
Heavy Atom Count:10
Complexity:123
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes