2,6-Dichloro-3-pyridinamine

crystal

To a solution of 2, 6-dichloro-3-nitropyridine (100 g, 0.518 mol) in acetic acid (1 L) was added iron powder (86.49 g, 1.555 mol) portion wise. The resulting reaction mixture was stirred at room temperature for 6 h. The completion of the reaction was confirmed by checking TLC system (PE/EA =8:2). The reaction mass was concentrated under high vacuum. The crude was dissolved in water (1 L) and EtOAc (2 L). While stirring, the pH of the aqueous solution was adjusted to 6.5 using powder NaStep 1. 2, 6-Dichloropyridin-3-amine: 3-Nitro-2, 6-dichloropyridine (1.34 kg, 6.95 mol) and ammonium chloride (3.00 kg, 56.1 mol) were suspended/dissolved in asolution of MeOH (12 L) and water (2.4 L). Iron powder (2.54 kg, 45.5 mol, 70 mesh)was added, and the resulting dark grey mixture was heated to reflux (70.8—72.4 °Cinternal temperature over the course of the reaction) under nitrogen with stirring. After 10 2.0 h, the mixture had become a dark, red-brown color. Heating was suspended, andmore iron powder (532 g 9.53 mol, 70 mesh) was added. Refluxing was then resumed. After 2.0 h, heating was again suspended, iron powder (549 g, 9.83 mol, 70 mesh) was added, and refluxing was resumed. A final addition of iron powder (261 g, 4.67 mol, 70 mesh) was made 2.0 h later, and refluxing was continued subsequently for 14 h. After15 cooling to ca. 40 °C, the reaction mixture was filtered over Celite®. The filter cake was rinsed with MeOH (7x2 L), and the combined filtrates were concentrated under reduced pressure to give a dark green solid. (Care must be taken so that the filter cakes do not run dry; unreacted iron powder is reactive towards oxygen and can ignite a fire.) The solid was partitioned between EtOAc (14 L) and water (9 L), and the aqueous phase20 was further extracted with EtOAc (2x5 L). The combined organic phases were washed with water (2x3 L) and brine (3 L) and dried over Na2SO4. The aqueous phases were filtered through Celite®, and the residual organic phases were isolated. All of the organic phases were combined, filtered through Celite®, and evaporated under reduced pressure to afford 2, 6-dichloropyridin-3-amine as a beige solid (1050 g, 92.6percent), which25 was used in the next step without further purification.Preparation of 3-amino-2-chloropyridine 2 using hydrogen peroxide; 3-Aminopyridine 3 (30.0 g, 0.32 mole) was add to 300 mL of 37percent aqueous HC1 in a 1-L Morton flask with overhead stirring at about 30-35 °C. After the mixture was cooled to about 10 °C, 23 g (0.34 mol) of 50 percent hydrogen peroxide was added over 20 minutes at about 10-12 °C. The mixture was held at about 10 °C for 2 hours and then was allowed to warm to about 19 °C over 2 hours and held at that temperature for additional 4 hours. HPLC analysis showed approximately 90 percent conversion of 3-aminopyridine 3. After cooling the reaction mixture to 10 °C, a solution of 6 g of sodium sulfite in 50 mL of water was added. To the mixture were added 50 mL of toluene and 200 g (2.5 mol) of 50 percent aqueous sodium hydroxide at about 25-35 °C. Then water was added to dissolve precipitated NaCl, and the layers were separated. The organic phase was back-extracted with 45 g of 10 percent aqueous HC1 to recover some 3-amino-2-chloropyridine 2 in the toluene extract, and this was added back to the original aqueous phase. The combined aqueous phases were neutralized to pH 3 with 50 percent aqueous NaOH and extracted with toluene for 3 times. The toluene extracts were combined, washed with 30 mL of saturated aqueous NaCl, and concentrated to dryness to afford 33 g of crude 3-amino-2-chloropyridine 2 (76 percent yield) with 94 percent purity. The product contained about 3 wt percent 3-amino-2, 6-dichloropyridine by HPLC assay. Preparation of 3-amino-2-chloropyridine 2 using chlorine; 3-Aminopyridine 3 (21.0 g, 0.223 mol) was added to 90 mL (ca. 108 g, 1. 08 mol) of concentrated aqueous HC1 (ca. 37percent) in a 300-mL sidearm flask with magnetic stirring at 30-35 °C. The mixture was cooled to 15 °C (thick slurry) and chlorine gas was sparged just above the surface over about 1.5 hours at 15-20 °C. HPLC analysis showed approximately 93 percent conversion of 3-aminopyridine 3. The mixture was cooled to 10 °C and a solution of 6 g of sodium sulfite in 50 mL of water was added. To the mixture was added 30 mL of toluene and 80 g (1.0 mol) of 50 percent aqueous sodium hydroxide at about 25-40 °C. Then water was added to dissolve precipitated NaCI, and the layers were separated. The aqueous phase was extracted once more with 30 mL of toluene. To the aqueous phase was added 10 g of 50 percent NaOH, and extracted with another 50 mL of toluene to remove 3-amino-2, 6- dichloropyridine. The combined organic phase was back-extracted with 40 mL of 0.2 N aqueous HC1 to recover some 3-amino-2-chloropyridine 2 in the toluene extracts, and this was added back to the original aqueous phase. The combined aqueous phases were diluted with 100 mL of toluene and neutralized to pH 3 with about 20 g of 50percent aqueous NaOH at about 35 °C. The aqueous phase was extracted with two 50-mL portions of toluene. The toluene layers were combined and washed with 20 mL of saturated aqueous NaCI. The solution was concentrated to dryness to afford 21.4 g of crude 3-amino-2-chloropyridine 2 (74 percent yield) with 98.6 percent purity, which contained about 1.4 wt percent 3-amino-2, 6- dichloropyridine.

Molecular Weight:163.00
XLogP3:1.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:161.9751535
Monoisotopic Mass:161.9751535
Topological Polar Surface Area:38.9
Heavy Atom Count:9
Complexity:99
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes