2-CHLORO-3-IODOPYRIDIN-4-AMINE

A 50 mL single necked round bottom flask equipped with a magnetic stirrer bar, reflux condenser and nitrogen line was charged with 2-chloropyridin-4-amine 12 (2.50 g, 19.4 mmol, 1.0 equiv), sodiumacetate trihydrate (3.97 g, 29.2 mmol, 1.5 equiv), iodine monochloride(3.47 g, 21.4 mmol, 1.1 equiv) and glacial acetic acid(13.0 mL) and heated at 70 °C with magnetically facilitated stirring under nitrogen for 16 h, at which point tlc and GC/MS (EI) analysisshowed that the starting material had been consumed. The reactionmixture was cooled and transferred to a separating funnel where itwas carefully quenched with portion wise addition of solidpowdered sodium hydrogencarbonate (32.3 g), water (75 mL) and ethyl acetate (75 mL). The resultant effervescence was allowed to subside and the mixture was not shaken. The layers were thenseparated and the aqueous layer was extracted with ethyl acetate(6 x 25 mL), with shaking. The organic layers were combined anddried over magnesium sulfate and the solvent was removed viarotary evaporation. The residue was purified by portionwise flashcolumn chromatography over silica using n-hexane/ethyl acetate(94:6 to 60:40) mixtures as eluent to give 2-chloro-3-iodopyridin-4-amine 13 as a light brown solid (2.21 g, 45percent), a sample of whichhad 1H NMR spectral data and low resolution GC/MS (EI) massspectral data identical to those in the literature [12].2-Chloro-4-aminopyridine (1.8 g, 14 mmol) was dissolved in 28 ml dimethylformamide. N-lodosuccinimide (3.15 g, 14 mmol) was added and the mixture was stirred at room temperature overnight.PREPARATION 41 2-Chloro-3-iodopyridin-4-amine 2-Chloro-4-aminopyridine (1 .8 g, 14 mmol) was dissolved in 28 ml dimethylformamide. N-lodosuccinimide (3.15 g, 14 mmol) was added and the mixture was stirred at room temperature overnight. Additional N-iodosuccinimide (3.15 g, 14 mmol) was added and the mixture wasa stirred at 55 °C overnight. The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The aqueous was extracted with ethyl acetate and the combined organics were dried over sodium sulphate, filtered and evaporated under reduced pressure. Purification by flash chromatography (ethyl acetate-hexane gradient, 15:85 rising to 25:75) gave 1 .5 g (5.9 mmol, 42percent) of the title compound as a purple solid. 2-Chloro-4-aminopyridine (1.8 g, 14 mmol) was dissolved in 28 ml dimethylformamide. N-Iodosuccinimide (3.15 g, 14 mmol) was added and the mixture was stirred at room temperature overnight. Additional N-iodosuccinimide (3.15 g, 14 mmol) was added and the mixture wasa stirred at 55 ºC overnight. The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The aqueous was extracted with ethyl acetate and the combined organics were dried over sodium sulphate, filtered and evaporated under reduced pressure. Purification by flash chromatography (ethyl acetate-hexane gradient, 15:85 rising to 25:75) gave 1.5 g (5.9 mmol, 42percent) of the title compound as a purple solid. [0369] 2-Chloro-pyridin-4-ylamine 1a* (3.2 g, 25 mmol) and sodium acetate (4.1 g, 50 mmol) were stirred in acetic acid (20 mL). A solution of iodine monochloride (4.1 g, 25 mmol) in acetic acid (10 mL) was added and the reaction mixture was heated to 70 °C for approximately three h (NB: reaction mixture became a solution at -50 °C, the brown colour faded and a precipitate formed as the reaction proceeded). The reaction mixture was cooled to room temperature, then poured onto water (700 mL), and extracted with AcOEt (2 χ 750 mL). The organic phase was carefully washed with a saturated aqueous solution of sodium carbonate (500 mL) followed by a 10percent solution of sodium thiosulfate (500 mL), dried over MgSO10.3 4-Amino-2-chloro-5-iodopyridine (11); [00197] 4-Amino-2-chloropyridine (3.20 g 25 mmole) was stirred in acetic acid (20 mL) with sodium acetate (4.1 g 50 mmol) To the mixture was added a solution of iodine monochloride (4.1 g 25 mmol) in acetic acid (10 mL) and the reaction was heated at 70 °C for 3.5 h. Most of the acetic acid was evaporated and the reaction diluted with water (200 mL). The products were extracted with ethyl acetate (80, 70, 70 mL). The combined extracts were washed with 10percent sodium carbonate solution (100 mL), with 5percent sodium thiosulfate solution and with brine; then dried and evaporated. The crude product was purified by flash column chromatography on silica; eluting with 5percent ethyl acetate in dichloromethane, with 10percent ethyl acetate in dichloromethane and with 20percent ethyl acetate in dichloromethane to give first a small amount of di-iodinated product (618mg, 6.5percent); then the desired product 4-amino-5-iodo-2-chloropyridine (11 ) (2.64 g, 41 percent) and then the isomeric 4-amino-2-chloro-3-iodopyridine (12) (2.61 g, 41 percent). 4-Amino-5-iodo-2- chloropyridine (11 ) : 4-Amino-2-chloro-5-iodopyridine (11) Intermediate 252A: 2-chloro-5-iodopyridin-4-amine To a stirred solution of 2-chloropyridin-4-amine (5 g, 39 mmol) in DMF (50 mL) was added NIS (8.75 g, 39 mmol). The reaction mixture was then heated at 80 °C for 3 h. The mixture was cooled and the DMF removed in vacuo. The residue was partitioned between EtOAc and water and the layers were separated. The organic layer was dried over Na2S04, filtered, and concentrated. The product was purified via column chromatography (10percent EtO Ac/pet ether) to afford 2-chloro-5-iodopyridin-4-amine (4 g, 39percent yield). LCMS: 254.8 (M+). Further elution with 12percent EtO Ac/pet ether afforded 2- chloro-3-iodopyridin-4-amine (4 g, 39percent yield).2-Chloro-4-aminopyridine (25 g, 194 mmol)And potassium acetate (19. 05 g, 194 mmol) were dissolved in 250 mL acetic acid and heated to 80 ° C. A solution of (31.56 g, 194 mmol) in acetic acid (40 mL) was added dropwise and the reaction mixture was stirred at 80 C for 3 h. The reaction mixture was cooled to room temperature and neutralized with saturated aqueous NaHC03 solution. A dark, off-white solid precipitated, which was dissolved in dichloromethane and washed with saturated aqueous NaHSO3, dried over Na2S04, concentrated and purified by column chromatography using hexane and ethyl acetate as eluents. 1. 6 g of the title compound were isolated, Along with 13. 4 g of the non-targeted isomer.A mixture of 2-chloro-4-amino pyridine 1 (20g, 0.15mol), potassium acetate (22.9g, 0.23mol) and ICl (27.7g, 0.17mol) in glacial acetic acid (200mL) was heated to 70°C for 4h. The solvent was concentrated under reduced pressure. The residue was neutralized with 10percent NaHCOA mixture of 2-chloro-4-amino pyridine 1 (20g, 0.15mol), potassium acetate (22.9g, 0.23mol) and ICl (27.7g, 0.17mol) in glacial acetic acid (200mL) was heated to 70°C for 4h. After completion of the reaction, the solvent was concentrated under reduced pressure. The residue was neutralized with 10percent NaHCO

Molecular Weight:254.45
XLogP3:1.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:253.91077
Monoisotopic Mass:253.91077
Topological Polar Surface Area:38.9
Heavy Atom Count:9
Complexity:101
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes