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With hydrogenchloride; sodium nitrite; In water; at 0 - 20℃; for 1.5h;
To a solution 2-amino-4-methoxy-6-methylpyrimidine (5 g, 35.97 mmol) in aqueous concentrated HCl (50 ml) was added NaNO2 (2.97 g, 43.16 mmol) in water(5 ml) slowly drop by drop over a period 30 min at 0oC and then the reaction mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was quenched with 10 N sodium hydroxide solution then insoluble material was, filtered and filtrate was partitioned between brine and AcOEt and the aqueous layer was extracted with AcOEt. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a brown oil. The crude compound which upon purification by flash chromatography using (silica-gel: 100-200 mesh, AcOEt -petroleum ether; 10:90→ 15:85) gave 600 mg (yield 8%) of a white solid corresponding to 2-chloro-4-methoxy-6- methylpyrimidine.
With sodium nitrite; In hydrogenchloride; water;
EXAMPLE 6 2-Chloro-4-methyl-6-methoxypyrimidine A solution of 25.4 g of 2-amino-4-methyl-6-methoxypyrimidine in 150 ml concentrated hydrochloric acid was cooled to ca. 0 C. and treated with a solution of 25.3 g of sodium nitrite in 50 ml water, added over a period of 30-40 minutes. The thick orange reaction mixture was stirred at room temperature for 4-5 hours and then adjusted to pH 10 by addition of 12.5N sodium hydroxide solution. The precipitate was filtered and extracted thoroughly with approximately 600 ml of hot ether. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give 7.2 g of 2-chloro-4-methyl-6-methoxypyrimidine as a white, crystalline solid, m.p. 36-38 C. NMR(CDCl3): δ 6.5 (1H, s, heterocyclic H); 4.0 (3H, s, --OCH3); 2.4 (3H, s, --CH3).
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