4-(2-CHLORO-4-PYRIMIDINYL)MORPHOLINE

To a cooled (0° C.) suspension of 2, 4-dichloropyrimidine (20)(1.0 g, 6.7 mmol) in ethanol (20 ml), which was stirred under an inert atmosphere, was added triethylamine (1.4 ml, 10.1 mmol) and then morpholine (0.59 ml, 6.7 mmol). The mixture was maintained at this temperature for 3 hours whereupon it was concentrated in vacuo, diluted with NaOH (20 ml, 1M) and extracted with EtOAc (3.x.20 ml). The organic extracts were combined, dried (NaGeneral procedure: To a solution of absolute ethanol (5 mL) and dichlorodiazine (3.36 mmol) in a 50mL round-bottom flaskwas added triethylamine (5.03 mmol), followed by the amine (5.03 mmol). The mixture was stirred either under reflux of ethanol (for dichloropyridazine and for dichloropyrazine) or at room temperature (for dichloropyrimidines). The reaction was monitored by GC. Once the starting dichlorodiazinewas completely consumed, the mixture was poured into a saturated NH4Cl solution (20 mL), then extracted with CH2Cl2 (320 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under vacuum. The crude solid was triturated in petroleum ether, filtered through a Buchner to afford the pure product.A solution of 2, 4-dichloropyrimidine (1.00 g, 6.71 mmol) and morpholine (0.59 mL, 6.81 mmol) in THF (25 mL) was charged with triethylamine (1 , 4 mL, 10.0 mmol) at 0 °C. The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was evaporated to dryness, the residue was taken up in CHGeneral procedure: To a stirred solution of 2, 4-dichloropyrimidine in EtOH was added a solution of the corresponding amine (1.2 equiv) in EtOH. After stirring for 12 h at the same temperature, the reaction mixture was concentrated in vacuo. The residue was quenched with H2O and then extracted with EtOAc. The combined organic layers were dried over MgSO4 and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel.A stirred solution of 2, 4-dichloropyrimidine (5.00g, 36.5mmol) and diisopropylethylamine (14.0ml, 80.4mmol) in EtOH (60ml) at 0°C was treated with morpholine (3.18ml, 36.5mmol) and allowed to warm to ambient temperature overnight. The solution was poured into brine and extracted with DCM. The organics were dried (MgS0[0108] A stirred solution of 2, 4-dichloropyrimidine (5.00g, 36.5mmol) and diisopropylethylamine (14.0ml, 80.4mmol)in EtOH (60ml) at 0°C was treated with morpholine (3.18ml, 36.5mmol) and allowed to warm to ambient temperatureovernight. The solution was poured into brine and extracted with DCM. The organics were dried (MgSO4), filtered andevaporated. The residue was purified by column chromatography (SiO2, 5percent EtOH in DCM) to afford the title compoundIVc as a white solid (1.3g, 36percent). 1H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J = 6.2 Hz, 1H), 6.83 (d, J = 6.2 Hz, 1H), 3.72- 3.49 (m, 8H).A solution of 2, 4-dichloropyrimidine (0.500g, 3.36mmol) and N, N-diisopropylethylamine (0.818mL, 4.70mmol) in isopropanol (5mL) was stirred at 0°C. Morpholine (0.319mL, 3.69mmol) was added dropwise and the solution continued to stir at 0°C for 30min, and then room temperature for 12h. The reaction mixture was concentrated under reduced pressure and then partitioned between ethyl acetate and water. The organic layer was extracted three times, washed with brine, dried over sodium sulfate, and concentrated to dryness. The products were purified by silica column chromatography in hexanes and ethyl acetate to afford 4-(4-chloropyrimidin-2-yl)morpholine and 4-(2-chloropyrimidin-4-yl)morpholine in 7percent and 92percent yields, respectively. (0058) 4-(4-chloropyrimidin-2-yl)morpholine (15). (White solid, Yield: 7percent).

Molecular Weight:199.64
XLogP3:1.2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:199.0512396
Monoisotopic Mass:199.0512396
Topological Polar Surface Area:38.2
Heavy Atom Count:13
Complexity:164
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes