4-METHOXYPYRIDINE-2-CARBONITRILE

Synthesis of 4-methoxypicolinonitrile [0321] To a stirred solution of 4-methoxypyridine 1 -oxide (5 g, 40.00 mmol) in CHTo a stirred solution of 4-methoxypyridine 1-oxide (5 g, 40.00 mmol) in CHSynthesis of 4-methoxypicolinonitrile Example 2.30: (4-methoxypyridin-2-yl)methanamine; [0268] To a stirring mixture of 1.2 g (9.67 mmol) of 4-methoxypyridine-N-oxide in 18 mL Of CH[Referential Example 15]; 4-Methoxypyridine-2-carbonitrile; In an argon atmosphere, triethylamine (17.8 mL) was added to 4-methoxypyridine-N-oxide (8.0 g) in acetonitrile (160 mL) at room temperature. Trimethylsilyl cyanide (24.1 mL) was added dropwise to the mixture, followed by stirring for 20 minutes. Subsequently, the mixture was stirred at 95°C for 14 hours, and then cooled in air. The solvent was evaporated under reduced pressure. The residue was partitioned between saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate. The organic layer was dried over sodium hydrogensulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane - ethyl acetate), to thereby give the title compound as a solid substance (1.57 g, 18percent).1H-NMR(400MHz, CDCl3)δ: 3.91(3H, s), 7.00-7.02(1H, m), 7 . 22 (1H, d, J=2 . 4Hz) , 8.51 (1H, d, J=6.0Hz) . MS (EI)m/z: 134 (M+) .To a solution of 4-methoxypyridine-N-oxide (4.6 g) in acetonitrile (100 mL) were added, at room temperature, trimethylsilyl cyanide (5.88 mL) and N, N-dimethylcarbamoyl chloride (4.74 g), and the mixture was stirred under a nitrogen stream at 70°C for 5 hr. 2-Cyano-4-methoxypyridine 153 [0310] To a solution of 4-methoxypyridine-N-oxide hydrate (1.25 g, 10 mmol) in DCM (mL) were added molecular sieves (4 A, 3 g, 300 mg/mmol) and the mixture was stirred overnight. The resulting suspension was then cooled at 0 °C and trimethylsilyl cyanide (1.6 mL, 12 mmol) and N, N- dimethyl carbamoyl chloride (1 mL, 10.5 mmol) were added successively. The reaction mixture was stirred at room temperature overnight. Finally, the mixture was filtered over celite and the filtrate was diluted with dichloromethane (80 mL) and an aqueous solution of potassium carbonate (1 M, 70 mL). The mixture was extracted at pH 10-12 with dichloromethane (3 x 80 mL). The combined organic phase was dried by filtration over anhydrous magnesium sulfate, and the filtrate was concentrated to afford 1.2 g of crude product. Separation by column chromatography using hexanes: acetone (95: 05 to 70: 30, 5 percent gradient) gave 1.023 g (76 percent yield) of cyanopyridine 18 as a white solid; 1H NMR (acetone d6) 8 : 4. 01 (s, 3H, OCHs), 7. 27 (dd, 1H, J= 5.8 2.6 Hz), 7.55 (d, 1H, J= 2.6 Hz), 8. 54 (d, 1H, J = 5. 8 Hz).To a mixture of 4-methoxypiridine-N-oxide (5.00 g, 38.6 mmol) and trimethylsilyl cyanide (4.84 g, 46.3 mmol) in dichloromethane (60 ml) cooled to 0° C. was added dropwise N, N-dimethylcarbamoyl chloride (3.8 ml, 40.5 mmol). PREPARATION 249 (A) Compound 100 (1, 202 g, 8, 68 mmol, 1.0 eq) was added to the cooled (0 C) solution of sodium methoxide (0, 5 16 g, 9, 55 mmol, 1.1 eq) in methanol (20 mL). The reaction mixture was stirred at room temperature for 2h to give 101, then cooled to 0 C. Compound 16 (1, 364 g, 8, 68 mmol, 1.0 eq) and sodium methoxide (0, 5 16 g, 9, 55 mmol, 1.1 eq) were added to the resulting mixture at 0 C. The reaction mixture was stirred at reflux for 16-18h (monitored by TCL), cooled and concentrated in vacuo. The residue was diluted with water (30 mL), acidified by 5% HC1 to pH = 7 and extracted with CH2C12 (2 x 50 mL). The organic layer was washed with water, saturated sodium chloride, dried over Na2504, filtered and concentrated in vacuo. The solids were triturated with MTBE to give the target compound (1, 1 g, 49 % yield).Compound 100 (1, 202 g, 8, 68 mmol, 1.0 eq) was added to the cooled (0 C) solution of sodium methoxide (0, 5 16 g, 9, 55 mmol, 1.1 eq) in methanol (20 mL). The reaction mixture was stirred at room temperature for 2h to give 101, then cooled to 0 C. Compound 16 (1, 364 g, 8, 68 mmol, 1.0 eq) and sodium methoxide (0, 5 16 g, 9, 55 mmol, 1.1 eq) were added to the resulting mixture at 0 C. The reaction mixture was stirred at reflux for 16-18h (monitored by TCL), cooled and concentrated in vacuo. The residue was diluted with water (30 mL), acidified by 5% HC1 to pH = 7 and extracted with CH2C12 (2 x 50 mL). The organic layer was washed with water, saturated sodium chloride, dried over Na2504, filtered and concentrated in vacuo. The solids were triturated with MTBE to give the target compound (1, 1 g, 49 % yield).

Molecular Weight:134.14
XLogP3:0.9
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:134.048012819
Monoisotopic Mass:134.048012819
Topological Polar Surface Area:45.9
Heavy Atom Count:10
Complexity:149
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes