4-(4,6-Dichloropyrimidin-2-yl)morpholine

2, 4, 6-Trichloropyrimidine (5) (3.158 g, 17.22 mmol) and acetone (60 mL) were combined and cooledto 0 °C. Morpholine (7) (1.05 eq., 1.576 g, 18.09 mmol) was added and the solution stirred at 0 °C for15 min then warmed to room temperature for another 15 min. The reaction was monitored by TLCanalysis (20percent ethyl acetate in hexanes). The reaction was then concentrated via rotary evaporationand further dried under high vacuum. Product was purified using silica column chromatographywith 20percent ethyl acetate in hexanes as the eluent. 10 (major regioisomer) (3.183 g, 13.6 mmol, 79percent).Elem. anal. for C8H9N3OCl2: C, 41.05 (found 42.27); H, 3.88 (found 4.06). 1H-NMR (300 MHz, CDCl3) δ 6.40 (s, 1H), 3.82–3.70 (m, 4H), 3.65 (m, 4H). HRMS [M]+ calcd. for C8H9N3OCl2, 234.0201; found234.0196. 11 (minor regioisomer) (0.806 g, 3.444 mmol, 20percent). 1H-NMR (300 MHz, chloroform-d) δ 6.56 (s, 1H), 3.85–3.60 (m, 8H). 13C-NMR (101 MHz, chloroform-d) δ 161.75, 160.55, 108.31, 66.59, 44.39.HRMS [M]+ calcd. for C8H9N3OCl2, 234.0201; found 234.0196.A solution of morpholine (22.4 mL, 512.4 mmol, 4.2 eq) in EtOH (100 mL) is added dropwise to a cooled (0°C) solution of 2, 4, 6-trichloropyrimidine (14 mL, 122 mmol, 1 eq) in EtOH (200 mL). The mixture is stirred at rt overnight. The crude mixture is poured onto a saturated solution of NaHSOTo a solution of 2, 4, 6-trichloropyrimidine (14.0 mL, 122 mmol, 1 .0 eq.) in EtOH (150 mL) is added a solution of morpholine (1 1 .2 mL, 256 mmol, 2.1 eq.) and N, N- diisopropylethylamine (44.6 mL, 256 mmol, 2.1 eq.) in EtOH (150 mL) dropwise at 0 °C. The reaction mixture is stirred overnight at room temperature and the solvent is removed under reduced pressure. The crude product is extracted with dichloromethane (3 x 100 mL) and the organic phase is successively washed with saturated aqueous sodium bisulfate (3 x 400 mL). The combined organic layers are dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude mixture is purified by flash column chromatography (Si0To a solution of 2, 4, 6-trichloropyrimidine (14.0 mL, 122 mmol, 1.0 eq.) in EtOH (150 mL) is added a solution of morpholine (11.2 mL, 256 mmol, 2.1 eq.) and N, N- diisopropylethylamine (44.6 mL, 256 mmol, 2.1 eq.) in EtOH (150 mL) dropwise at 0 °C. The reaction mixture is stirred overnight at room temperature and the solvent is removed under reduced pressure. The crude product is extracted with dichloromethane (3 x 100 mL) and the organic phase is successively washed with saturated aqueous sodium bisulfate (3 x 400 mL). The combined organic layers are dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude mixture is purified by flash column chromatography (Si0To a solution of 2, 4, 6-trichioropyrimidine (14.0 mL, 122 mmol, 1.0 eq.) in EtOH (150mL) is added a solution of morpholine (11.2 mL, 256 mmol, 2.1 eq.) and N, Ndiisopropylethylamine (44.6 mL, 256 mmol, 2.1 eq.) in EtOH (150 mL) dropwise at 0 °C. The reaction mixture is stirred overnight at room temperature and the solvent is removed under reduced pressure. The crude product is extracted with dichloromethane (3 x 100 mL) and the organic phase is successively washed with saturated aqueous sodium bisulfate (3 x 400 mL).The combined organic layers are dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude mixture is purified by flash column chromatography (Si02, cyclohexane / ethyl acetate 9:1 to 3:1) to yield 126 (5.02 g, 18percent) and 127 (16.7 g, 59percent), both as colorless solids.4-(4, 6-dichloropyrimidin-2-yl)morpholine (126): ‘H NMR (400 MHz, CDC13): ö 6.56(s, 1 H), 3.78 (m, 4 H) 3.74 (m, 4 H).4-(2, 6-dichloropyrimidin-4-yl)morpholine (127): ‘H NMR (400 MHz, CDC13): ö 6.41 (s, 1 H), 3.78 (m, 4 H), 3.65 (m, 4 H).Reference (6-Chloro-2-morpholin-4-vI-pyrimidm-4-yl)-(2-pyridin-3-yl- ethvD-amine; To a stirred solution of 2, 4, 6-trichloropyrimidine (10 ml; 87 mmol), and DIPEA (16 mL; 92 mmol) in dioxane (60 mL) at 5 °C was added morpholine (8 ml; 91 mmol) over 5 minutes (a white solid separates during addition). The reaction mixture was stirred whilst allowing to warm to r.t. overnight (16 h). Volatiles were removed in vacuo, the resulting residue was redissolved (CH2-bromoethylether (3.65g), potassium carbonate (8.29g), and N, N-dimethylformamide (75mL) were added to 2-amino-4, 6-dichloropyrimidine (2.46g), and the mixture was refluxed for 3 hours while heated. Subsequently, the reaction mixture was diluted with ethyl acetate, was washed with water, and was dried over anhydrous sodium sulfate. The solvent was removed and the resulting residue was purified on a silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 4, 6-dichloro-2-(morpholine-4-yl)pyrimidine (985mg, 28percent). MS(EI)m/z:233(M+) HRMS(EI): Calcd for C8H9Cl2N3O: 233.0123; found:233.0152To a solution of 2, 4, 6-trichloropyrimidine (5.0 mL, 42.6 mmol) in mesitylen (80 mL) at 165° C. was added dropwise a solution of morpholine (4.83 mL, 55.4 mmol) in mesitylen (20 mL) and the suspension was stirred at 165° C. for 30 min. 4-(4, 6-dichloropyrimidin-2-yl)morpholine 0341] A mixture of 2-morpholinopyrimidine-4, 6-diol (30 g, 0.15 mol) and POCl

Molecular Weight:234.08
XLogP3:2.2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:233.0122673
Monoisotopic Mass:233.0122673
Topological Polar Surface Area:38.2
Heavy Atom Count:14
Complexity:179
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes