4,6-Dichloro-2-methyl-5-nitropyrimidine

This nitropyrimidine (205 mg, 1.2 mmol) was dissolved in phosphoryl chloride (1 ml) and diethylaniline (0.3 ml, 1.9 mmol) was added thereto, and the mixture was stirred for 1 hour at 100° C. and for 1 hour at 120° C. The reaction solution was added to ice and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (eluent-hexane:ethyl acetate=20:1) to obtain 194 mg (yield 77percent) of 4, 6-dichloro-2-methyl-5-nitropyrimidine as a colorless needle crystal.(b) [00859] This nitropyrimidine (205 mg, 1.2 mmol) was dissolved in phosphoryl chloride (1 ml) and diethylaniline (0.3 ml, 1.9 mmol) was added thereto, and the mixture was stirred for 1 hour at 100 C. and for 1 hour at 120 C. The reaction solution was added to ice and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (eluent-hexane:ethyl acetate=20:1) to obtain 194 mg (yield 77%) of 4, 6-dichloro-2-methyl-5-nitropyrimidine as a colorless needle crystal.Part B: The product of Part A was added portionwise to phosphorous oxychloride (400 mL) under a nitrogen atmosphere followed by dropwise addition of N, N-diethylaniline (80 mL). The reaction mixture was refluxed for 21/2 h with stirring, cooled to room temperature, poured over ice (2.0 Kg) and stirred for 1 hr. The aqueous layer was extracted with diethyl ether (4*500 mL) and the extracts combined. The combined extracts were washed with brine (500 mL), dried over anhydrous magnesium sulfate, filtered and stripped down to afford 4, 6-dichloro-2-methyl-5-nitropyrimidine as a yellow solid (68.8 g) which has an unpleasant odor.Part B The product of Part A was added portionwise to phosphorous oxychloride (400 mL) under a nitrogen atmosphere followed by dropwise addition of N, N-diethylaniline (80 mL). The reaction mixture was refluxed for 21/2 h with stirring, cooled to room temperature, poured over ice (2.0 Kg) and stirred for 1 hr. The aqueous layer was extracted with diethyl ether (4*500 mL) and the extracts combined. The combined extracts were washed with brine (500 mL), dried over anhydrous magnesium sulfate, filtered and stripped down to afford 4, 6-dichloro-2-methyl-5-nitropyrimidine as a yellow solid (68.8 g) which has an unpleasant odor.Reference Example 178 4, 6-Dichloro-2-methyl-5-nitropyrimidine To 4, 6-dihydroxy-2-methyl-5-nitropyrimidine were added phosphoryl chloride (160 mL) and N, N-diethylaniline (49.4 mL), and the reaction vessel was equipped with a reflux condenser, and the mixture was stirred at 110C for 1.5 hours. The reaction mixture was cooled to room temperature, and poured into ice, and the resulting mixture was stirred at room temperature until the ice melted. To the mixture was added diethyl ether, and the mixture was stirred at the same temperature for 10 minutes. The insoluble material was removed by filtration, and the organic layer of the filtrate was separated. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 20/1 - 9/1) to give the title compound (24.7 g).(a) 4-((6S, 2R)-2, 6-Dimethylpiperidyl)-6-chloro-2-methyl-5-nitropyrimidine. To a solution of 4, 6-dichloro-2-methyl-5-nitro pyrimidine (Example 76 (b)) (2.44 g, 11.78 mmol, 1.0 eq) and triethylamine (Aldrich Chemical Company, 2.38 g, 23.56 mmol, 2.0 eq) in THF (12 mL) was added a solution of cis-2, 6-dimethylpiperidine (Aldrich Chemical Company, 1.59 g, 11.78 mmol, 1.0 eq) in THF (12 mL) slowly. The final reaction mixture was stirred at room temperature for 3 days. After the removal of solvent in vacuo, the crude material was purified by flash chromatography on silica gel with 0-10% EtOAc/hexanes as eluant to afford the title compound (2.80 g, 84%) as a brown solid. 1H NMR (CDCl3, 500 MHz): d 1.29 (d, 6, J=7.0), 1.56 (m, 1), 1.60-1.63 (m, 2), 1.73 (m, 2), 1.84-1.90 (m, 1), 2.50 (s, 3), 4.42 (m, 2). MS m/z: 285 (M+H), m/z: 283 (M-H).

Molecular Weight:208.00
XLogP3:2.4
Hydrogen Bond Acceptor Count:4
Exact Mass:206.9602317
Monoisotopic Mass:206.9602317
Topological Polar Surface Area:71.6
Heavy Atom Count:12
Complexity:174
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes