2-Chloro-5-iodo-4-pyridinamine

Under nitrogen atmosphere, mixture of 2-chloro-4-aminopyridine (15 g, 0.116 mol, 1 eq) was dissolved in acetonitrile (200 ml), was heated in an oil bath to 70°C, was slowly added NIS (33 g, 0.139 mol, 1.2 eq.), stirred for 16 hours. Cooled to room temperature, saturated aqueous sodium carbonate was added and the reaction member system PH value was adjusted to 9-10, ethyl acetate (500 ml) and extracted. The organic phase was separated and washed with saturated washed twice with brine (100 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo to give 2-chloro-4-amino-5-iodopyridine (23 g, yield: 78.1 percent).To 2-chloro-4-amino pyridine (33 g, 1 eq), in a 2-neck 2 L round bottomed flask, acetic acid (1.5 L) was added and stirred for 10 min. To this mixture, potassium acetate (50 g, 2 eq) was added and stirred for 10 min. Iodine monochloride (50 g, 1.2 eq) was added slowly to the mixture and the contents refluxed at 120°C for 4 h while monitoring by TLC. After completion, the acetic acid was distilled off under vacuum and the residue was basified with NaHC02-Chloro-pyridin-4-ylamine 1b* (3.2 g, 0.025 mol) and sodium acetate (4.1 g, 0.05 mol) were stirred in acetic acid (20 ml). A solution of iodine monochloride (4.1 g, 0.025 mol) in acetic acid (10 ml) was added and the reaction mixture was heated to 70 °C for approximately 3 h (NB: solution at -50 °C, brown colour faded and precipitate formed as the reaction proceeded). The reaction mixture was cooled to room temperature, then poured onto water (700 ml), and extracted with EtOAc. The organic layer was carefully washed with a solution of Na10.1 Iodine monochloride (0.758 g, 4.67 mmol) was added to a solution of 2-chloro-4-amino pyridine (0.500 g, 3.89 mmol) and potassium acetate (0.763 g, 7.78 mmol) in acetic acid (30 ml_). The reaction mixture was heated under reflux for 4 hr. The solvent was removed in vacuo and the residue was partitioned between aqueous sodium hydrogenocarbonate (50 ml.) and ethyl acetate (50 ml_). The organic phase was dried (MgSOTo 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 partitionedbetween EtOAc and water and the layers were separated. The organic layer was dried over Na2SO4, filtered, and concentrated. The product was purified via column chromatography (10percent EtOAc/pet ether) to afford 2-chloro-5-iodopyridin-4-amine (4 g, 39percent yield). ‘H NIVIR (400MHz, DMSO-d6) ö 8.20 (s, 1H), 6.64 (s, 1H), 6.50 (br s, 2H); LC/MS: 254.8 (Mj. Further elution with 12percent EtOAc/pet ether afforded 2-chloro-3- iodopyridin-4-amine (4 g, 39percent yield).N-iodosuccinimide (15.75 g, 70 mmol) was added to a solution of 2-chloropyridin-4-amine (9.00 g, 70 mmol) in N, N'-dimethylformamide (140 mL) and the mixture was stirred at 80 °C for 6 hours. N-lodosuccinimide (24.75 g, 110.0 mmol) was added to a solution of 2-chloro-pyridin-4-ylamine (12.85 g, 100.0 mmol) in acetonitrile (400 mL) and the mixture stirred and held at reflux overnight. Upon cooling to room temperature the solvent was removed in vacuo and residue partitioned between EtOAc (250 mL), saturated sodium thiosulfate (100 mL) andwater (250 mL). The organic layer was separated, washed with water (2 >< 250 mL), separated and the solvent removed in vacuo to afford an orange oil that was subjected to column chromatography on silica. Gradient elution with 30-50percent EtOAc in petrol afforded a pale orange solid that was rinsed with 25percent EtOAc in petrol (80 mL). Solids were collected by filtration and sucked dry to afford the title compound (7.32 g) as an off-white solid. Themother liquors were concentrated to dryness in vacuo and the residues subjected to columnchromatography on silica. Elution with 30-50percent EtOAc in petrol afforded further pure material(1.90 g). Combined yield: (9.22 g, 36percent) 1H NMR (DMSO-d6) 8.20 (1H, 5), 6.64 (1H, 5), 6.50(2H, br 5). MS: [M+H] 255.Preparation 10: 2-Chloro-5-iodo-pyridin-4-ylamineN-lodosuccinimide (24.75 g, 110.0 mmol) was added to a solution of 2-chloro-pyridin-4-ylamine(12.85 g, 100.0 mmol) in acetonitrile (400 mL) and the mixture stirred and held at refluxovernight. Upon cooling to room temperature the solvent was removed in vacuo and residuepartitioned between EtOAc (250 mL), saturated sodium thiosulfate (100 mL) and water (250 mL). The organic layer was separated, washed with water (2 >< 250 mL), separated and the solvent removed in vacuo to afford an orange oil that was subjected to column chromatography on silica. Gradient elution with 30-50percent EtOAc in petrol afforded a pale orange solid that was rinsed with 25percent EtOAc in petrol (80 mL). Solids were collected by filtration and sucked dry to afford the title compound (7.32 g) as an off-white solid. The mother liquors were concentrated to dryness invacuo and the residues subjected to column chromatography on silica. Elution with 30-50percent EtOAc in petrol afforded further pure material (1.90 g). Combined yield : (9.22 g, 36percent) 1H NMR (DMSO-d6) 8.20 (1 H, 5), 6.64 (1 H, 5), 6.50 (2H, br 5). MS: [M+H] 255.Preparation 7: 2-Chloro-5-iodo-pyridin-4-ylamine N-lodosuccinimide (24.75 g, 110.0 mmol) was added to a solution of 2-chloro-pyridin-4-ylamine (12.85 g, 100.0 mmol) in acetonitrile (400 mL) and the mixture stirred and held at reflux overnight. Upon cooling to room temperature the solvent was removed in vacuo and residue partitioned between EtOAc (250 mL), saturated sodium thiosulfate (100 mL) andwater (250 mL). The organic layer was separated, washed with water (2 >< 250 mL), separated and the solvent removed in vacuo to afford an orange oil that was subjected to column chromatography on silica. Gradient elution with 30-50percent EtOAc in petrol afforded a pale orange solid that was rinsed with 25percent EtOAc in petrol (80 mL). Solids were collected by filtration and sucked dry to afford the title compound (7.32 g) as an off-white solid. Themother liquors were concentrated to dryness in vacuo and the residues subjected to columnchromatography on silica. Elution with 30-50percent EtOAc in petrol afforded further pure material(1.90 g). Combined yield : (9.22 g, 36percent) 1H NMR (DMSO-d6) 8.20 (1H, 5), 6.64 (1H, 5), 6.50(2H, br 5). MS: [M+H] 255.NIS (24.75 g, 110.0 mmol) was added to a solution of 2-chloropyridin-4-ylamine (12.85 g, 100.0 mmol) in MeCN (400 mL), and the mixture was stirred and held at reflux overnight. Uponcooling to r.t. the solvent was removed in vacuo and the residuepartitioned between EtOAc (250 mL), sat. Na2S2O3 (100 mL), andH2O (250 mL). The organic layer was separated, washed withH2O (2 × 250 mL), separated, and the solvent removed in vacuoto afford an orange oil that was subjected to column chromatographyon silica gel. Elution with 30–50percent EtOAc in PE afforded apale orange solid that was rinsed with 25percent EtOAc in PE (80 mL).The solids were collected by filtration and sucked dry to afford2-chloro-5-iodopyridin-4-ylamine (7.32 g) as an off-white solid.The mother liquors were concentrated to dryness in vacuo andthe residues subjected to column chromatography on silica.Elution with 30–50percent EtOAc in PE afforded further pure material(1.90 g). Combined yield 9.22 g, 36percent. 1H NMR (400 MHz, DMSOd6):δ = 8.20 (s, 1 H), 6.64 (s, 1 H), 6.50 (br s, 2 H). MS: m/z = 255, 257 [M + H]+.To a solution of 17.3 (5.0 g, 54.6 mmol, ) in acetic acid (10 ml) was added sodium acetate (8.938 g, 109.0 mmol, 2.0 eq) and iodine monochloride (4.069 g, 65.5 mmol, 1.2 eq). Reaction mixture was heated at 70° C. for 20 hours. After completion of the reaction, mixture was concentrated under reduced pressure and residue was diluted with water and basified with sodium bicarbonate solution. Compound was extracted in EtOAc and washed with brine. Organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford crude material which was purified by chromatography using 12percent to afford pure 17.4 (2.8 g, 28.2percent), m/z=255.1 [M+H]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