2-AMINO-5-CYANO-4-PICOLINE

Copper(ll)cyanide (2.87 g, 32 mmol) was added to the solution of 5-bromo-4-methyl-pyridin- 2-ylamine (3.0 g, 16.0 mmol) in DMA (12 ml) and the reaction was stirred under an atmosphere of argon at 170°C for 24 h. After cooling to rt the reaction mixture was added to the solution of ethylenediamine (60 ml) in water (240 ml) and stirred for 15 min. Then, the mixture was diluted with EtOAc, washed with water and NaCI-soln., dried (NaA mixture of 2-amino-5-bromo-4-methylpyridine (2.0 g, 10.7 mmol) and CuCN (1.1 g, 12.3 mmol) in DMF (2.5 mL) wasrefluxed for 4 h. After the mixture was cooled to room temperature, NaCN (2.15 g) and H2O (6.5mL) were added, and the mixture was stirred and extracted by AcOEt. The solution was washedby aq. 10percent CuCN and brine. After the solvent was removed under vacuo, the residue waschromatographed on silica gel (AcOEt/hexane = 1 : 1) to give 2-amino-5-cyano-4-methylpyridine (829 mg, 58percent). A solution of 2-amino-5-cyano-4-methylpyridine (706 mg, 5.3mmol) in EtOH (8.8 mL) and aq. 10N NaOH (8.8 mL) was refluxed for 24 h. After cooled toroom temperature, the mixture was diluted by adding H2O (35 mL), neutralized by aq. HCl, and filtered. The solid was washed by ether and H2O to give 6-amino-4-methylpicolinic acidcontaining NaCl (879 mg), which was dissolved in MeOH (16 mL). To this mixture was addedSOCl2 (0.7 mL, 6.7 mmol) and the mixture was refluxed for 20 h. After cooled to roomtemperature, the solvent was removed under vacuo. To the residue H2O (20 mL) was added andpH was adjusted to 13 by aq. 1N NaOH and filtered. The solid was washed by H2O and driedunder vacuo to give 2-amino-5-methoxycarbonyl-4-methylpyridine (484 mg), which wasdissolved in aq 15percent H2SO4 (10.4 mL). To the solution was added NaNO2 (402 mg, 5.81 mmol)at 0 °C and the mixture was stirred for 2 h at 0 °C and, then, 2 h at room temperature. Themixture was extracted by AcOEt and the solvent was removed under vacuo. The residue waschromatographed on silica gel (AcOEt) to give 2bd (105 mg, 21percent):Description 97; 6-Amino-4-methyl-3-pyridinecarbonitrile (D97); A mixture of 5-bromo-4-methyl-2-pyridinamine (0.50 g, 2.7 mmol) and copper (I) cyanide (0.263 g, 2.9mmol) in DMF (12 mL) was heated at 2000C for a total of 1.75 h in a microwave reactor. The reaction mixture was diluted with EtOAc and water. The resulting thick dark precipitate was filtered off. The filtrate was extracted with EtOAc (x3) and the combined extracts were dried and concentrated to give a dark yellow solid (0.115 g). The filter cake was and washed with 1 :1 DCM/MeOH (1 L) which was concentrated to give a second batch of dark yellow solid (0.047 g). The filter cake was washed with 2M NH3 in MeOH (200 mL) which was concentrated to give a dark green solid (0.533 g). These 3 batches of solids were purified by column chromatography using 0-100% EtOAc/hexane as the eluent to give the title compound as a white solid (total yield: 0.213 g). deltaH (CDCI3, 400MHz) 8.28 (1 H, s), 6.36 (1 H, s), 4.87 (2H, br.s), 2.40 (3H, s). MS (ES): MH+ 134.1.To a solution of 2-amino-5-cyanomethylpyridine(385 mg, 2.89 mmol) in aq. 15% H2SO4 was added NaNO2 (400 mg, 5.8 mmol)at 0 C and the mixture was stirred for 2 h at 0C and, then, 2 h at room temperature. Themixture was extracted by AcOEt, washed by brine, and dried by Na2SO4. The solvent wasremoved under vacuo and the residue was chromatographed on silica gel (AcOEt) to give 2be(217 mg, 56%): 1H NMR (500MHz, CD3OD): delta 8.02 (s, 1H, Ar), 6.47 (s, 1H, Ar), 2.34 (s, 3H, Me); 13C NMR (125.65 MHz, CD3OD): delta 164.4, 153.6, 143.9, 120.3, 116.4, 95.2, 20.3.[1] V. Kvita, Synthesis (1991), 883.(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2, 6-dimethylphenyl)quinazolin-2-yl)amino)-4- methylnicotinonitrilc- Compound 18 Synthesis of (£)-6-((4-amino-8-(4-(2-cyanovinyl)-2, 6-dimethylphenyl)quinazolin-2- yl)amino)-4-methylnicotinonitrile (compound 18) [0282] Compound 2a (20 mg, 0.06 mmol), To a solution of General procedure: A mixture of 30 (500mg, 2.67mmol), Zn(CN)2 (188mg, 1.60mmol), Pd2(dba)3 (122mg, 0.13mmol), and dppf (148mg, 0.27mmol) was added degassed DMF/ H2O (99:1, 3.1mL). The reaction mixture was heated using conventional heating at 120C for 24h. The resulting mixture was cooled to rt, and sat. aq. NH4Cl/ conc. NH3/H2O (4:1:4, 10mL) was added resulting in precipitation. The mixture was cooled to 0C and filtered. The precipitate was washed with sat. aq. NH4Cl/conc. NH3/H2O (4:1:4, 10mL) and H2O at 5C and dried under vacuum affording the product as dark orange solid (279mg, 78%).Synthesis of 6-^is(4-methoxyben2yl)amino)-4-methymicotinonitrile (4-3) To a stirred mixture of 6-ammo-4-methylnicotinonitrile 4-2, which was prepared by using a similar method described in WO 199618616 (669 mg, 5.02 mmol) and AVV-dimethylformamide (15.0 mL) at 0 C under an atmosphere of nitrogen gas was added sodium hydride (60 % dispersion in mineral oil; 605 mg, 15.1 mmol). To the mixture was added 4-methoxybenzyl chloride (1.70 mL, 12.5 mmol) at 0 C. The resulting mixture was stirred at 0 C for 2 hours under an atmosphere of nitrogen gas. The reaction mixture was quenched with methanol (5.0 mL) and concentrated under reduced pressure. To the resulting residue was added water (50 mL) and the resulting mixture was extracted with dichloromethane (60 mL, 30 mL chi 2). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel 30 g, step gradient eluting with 10:1, 5:1, and 2:1 hexane/ethyl acetate) to give 1.78 g (95%) of 4-3 as a pale brown solid: 1H NMR (300 MHz, CDC13) delta 8.39 (1H, s), 7.11 (4H, m), 6.85 (4H, m), 6.32 (1H, s), 4.71 (4H, br s), 3.79 (6H, s), 2.33 (3H, s); ESI-MS m/z 374 [C23H23N3Q2 + H]+.

Molecular Weight:133.15
XLogP3:0.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:133.063997236
Monoisotopic Mass:133.063997236
Topological Polar Surface Area:62.7
Heavy Atom Count:10
Complexity:158
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes