5-ethoxypyridin-2-amine

2-Bromo-3-hydroxy pyridine(11.95 mmol), iodoethane (23.91 mmol), and K2CO3 (21.51 mmol) are diluted in DMF (20 mL) and heated to 80° C. for 2 h. The solvent is removed under reduced pressure and the residue diluted with H2O (20 mL), extracted with EtOAc (3.x.25 mL). The combined organics are washed with H2O (25 mL), brine (25 mL), dried (MgSO4), and the solvent is removed to give 2-bromo-3-ethoxypyridin as an off-white solid (1.99 g, 83percent yield). 2-Bromo-3-ethoxypyridine (0.01 mol) is added to fuming nitric acid (8 mL) and sulfuric acid (8 mL) at 0° C. The clear yellow solution is heated to 55° C. for 1 h, cooled back to RT and added dropwise to ice H2O (400 mL). The solid is filtered to give 2-bromo-3-ethoxy-6-nitropyridine as a light yellow solid (1.40 g, 57percent yield). 2-Bromo-3-ethoxy-6-nitropyridine is dissolved in a minimal amount of EtOAc (10 mL) and diluted with EtOH (55 mL). 10percent Pd/C catalyst is added as a slurry in EtOAc and the mixture is then put on the Parr apparatus under hydrogen for 1 h (40 psi to 18 psi). The reaction mixture is filtered over Celite to remove the catalyst and the filtrate is concentrated. The residue is diluted with 6M HCl (50 mL), extracted with EtOAc (3.x.50 mL) and the solvent is removed. The residue is diluted with 1M NaOH (50 mL) and extracted with EtOAc (3.x.50 mL), dried (MgSO4), and the solvent is removed to give 5-ethoxypyridin-2-amine as a brown oil (722 mg, 94percent yield). Example 307 is obtained according to Method C, making non-critical variations. Yield 40percent. HRMS (ESI) calculated for C11H10F3N5O2S+H 335.0585 found 335.0584.Prepared in step 1 of 6- (diethylamino) -1, 3-dimethyl--1H- pyrazolo [3, 4-b] pyridine-5-carbaldehyde (100 mg, 0.41 mmol), 5- ethoxy pyridine - 2- amine (61.7 mg, 0.45 mmol), acetic acid (36.5 muL, 0.61 mmol) and sodium triacetoxyborohydride (258 mg, 1.22 mmol) was dissolved in ethanol (3.0 mL), with stirring at 90 C for 24 hours . Ethyl acetate - extracted from the water, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel preparative thin layer chromatography (hexane: ethyl acetate = 1: 1) , to give the title compound (39.6 mg, 27%) as a yellow oil.Synthesis of 5-Ethoxypyridin-2-amine (compound 18-3)[0000142] A mixture of crude compound 18-2 (4.59 g, 20.67 mmol, 1.0 equiv) and 3M HC1 (75 mL) was refluxed with a Dean- Stark trap to collect pivalic acid that was formed. After 2 hours, the mixture was cooled to room temperature followed by an ice bath. The mixture was made basic (pH 9) by the slow addition of 6N sodium hydroxide. The mixture was extracted with ethyl acetate (1 xlOO mL, 1 x 50 mL) . The combined organic layers were washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 18-3 (2.54 g, 86% yield) as a tan solid that was used in the next step.Synthesis of 4- (5-Ethoxypyridin-2-ylamino) -3-nitrobenzonitrile (compound 18-4)[0000143] Triethylamine (2.04 g, 2.8 mL, 20.16 mmol, 1.15 equiv) was added to a solution of crude compound 18-3 (2.54 g, 18.40 mmol, 1.05 equiv) and 4-fluoro-3-nitrobenzonitrile (2.90 g, 17.53 mmol, 1.0 equiv) in acetonitrile (70 mL) . The yellow- orange solution was heated to reflux. The mixture became red- orange that deepened to red. After 4 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (300 mL) and H20 (250 mL) . Some insoluble red solid was present at the interface. The organic phase was filtered to remove the small amount of red solid (LC-MS showed the solid was 18-4) The filtrate was washed with H20 (20 mL), saturated brine (100mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residual solid was combined with that from above, triturated with tert-butyl methyl ether, filtered and dried to give compound 18-4 (2.20 g, 42% yield, 87% purity) as a red solid.

Molecular Weight:138.17
XLogP3:0.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:138.079312947
Monoisotopic Mass:138.079312947
Topological Polar Surface Area:48.1
Heavy Atom Count:10
Complexity:97.6
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes