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With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 16h;
53.3 Step 3: 5-Chloro-2- (4-fluorophenoxy) -4-methylpyridine-3- carbonitrile
To a mixture of 2 , 5-dichloro-4-methylpyridine-3- carbonitrile (1.3 g, 6.95 mmol) and 4-fluorophenol (0.85 g, 7.64 mmol) in N, N-dimethylformamide (15 mL) was added potassium carbonate (1.9 g, 13.9 mmol). The reaction mixture was heated at 80°C for 16 hours, cooled to room temperature, and poured into an ice cold water to obtain precipitate. The precipitate was collected by filtration, and dried to give the title compound as a white solid (1.2 g, 67%). MS(ESI)m/z: 262.8 (M+l); 1H MR CDC13: δ 2.6 (s, 3H) , 7.07-7.15 (m, 4H) , 8.17 (s, 1H)
With phosphorus pentachloride; trichlorophosphate for 1h; Reflux;
53.2 Step 2: 2 , 5-Dichloro-4-methylpyridine-3-carbonitrile
A mixture of 5-chloro-2-hydroxy-4-methylpyridine-3- carbonitrile (2.0 g, 11.9 mmol), phosphoryl chloride (3.33 mL, 35.71 mmol) and phosphorus pentachloride (0.74 g, 3.57 mmol) was refluxed for 1 hour. The reaction mixture was cooled to room temperature and then concentrated to dryness. The obtained residue was diluted with aqueous sodium bicarbonate solution. The precipitate thus obtained was collected by filtration, and dried to give the title compound as an off- white solid (1.8 g, 81%). MS(ESI)m/z: 186.9 [M(35C1)+1], 188.9 [M(37C1)+1] ; XH NMR CDC13: δ 2.8 (s, 3H) , 8.48 (s, 1H)
72%
With trichlorophosphate at 120℃; for 12h;
9.1 Step 1. Preparation of 2,5-dichloro-4-methylnicotinonitrile
A solution of 5-chloro-2-hydroxy-4-methylpyridine-3-carbonitrile (500 mg, 3.0 mmol) in POCh (3 mL) was stirred for 12 h at 120 °C. Ice water was then added the mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and the residue was purified using silica gel chromatography (eluent: 9% EtOAc in PE) to afford 400 mg (72% yield) of the title compound as a yellow solid.
Multi-step reaction with 2 steps
1.1: potassium carbonate / N,N-dimethyl-formamide / 16 h / 80 °C
2.1: N,N-dimethyl-formamide / 12 h / Reflux
2.2: 2 h / 50 °C
Multi-step reaction with 3 steps
1.1: potassium carbonate / N,N-dimethyl-formamide / 16 h / 80 °C
2.1: N,N-dimethyl-formamide / 12 h / Reflux
2.2: 2 h / 50 °C
3.1: trichlorophosphate / 1 h / 130 °C
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