4-Chloropyridine-2-carboxamide

A heterogeneous mixture of 4-chloropicolinic acid (TCI America, 5.4 g, 34.2 mmol, 1.0 eq) and thionyl chloride (30 mL) were heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was treated with an ammonia in MeOH solution (7N, 45 mL) in an ice bath and the reaction mixture was stirred for 15 minutes. The ice bath was then removed and the reaction was warmed to room temperature and then stirred for 3 h. The reaction mixture was concentrated in vacuo and the residue purified by recrystallization from EtOAc to afford the product (5.14 g, 96percent) as a solid. 2-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-N-(2, 4-difluorophenyl)nicotinamide, hydrochloride salt; A) 4-Chloropicolinamide; A heterogeneous mixture of 4-chloropicolinic acid (TCI America, 5.4 g, 34.2 mmol, 1.0 eq) and thionyl chloride (30 mL) was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was treated with an ammonia in MeOH solution (7N, 45 mL) in an ice bath and the reaction mixture was stirred for 15 minutes. The ice bath was then removed and the reaction was warmed to room temperature and then stirred for 3 h. The reaction mixture was concentrated in vacuo and the residue purified by recrystallization from EtOAc to afford the desired product (5.14 g, 96percent) as a solid. A mixture of 4-chloropicolinic acid (10.0 g, 63.4 mmol), thionyl chloride (40 ml) and a catalytic amount of DMF were heated at 80 °C for 3 h. Then the reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was dissolved in 30 ml of CHStep 1) 4-chloropicolinamide [0212] To a solution of 4-chloropicolinic acid (100 mg, 0.64 mmol) in DCM (10 mL) was added one drop DMF and SOCIStep 1) Methyl 4-chloropicolinate (2) (32.49g, 190mmol) was stirred in 100mL water for 15min, then concentrated ammonium hydroxide (50mL, 25percent∼28percent) was added slowly. After the addition of concentrated ammonium hydroxide was complete, the reaction mixture was stirred for 1h at room temperature. The mixture was filtered and washed with water, then dried at 55–60°C to give compound 4-chloropicolinamide (3) as a white solid [26]. Yield: 24.61g, 83percent. mp: 160–162°C. Ammonium hydroxide (2 ml) was added to methyl 4-chloropyridine-2-carboxylate (100 mg, 0.58 mmol) in MeOH (4 ml) in a sealed tube and heated at 50 580 g of 2-pyridinecarboxylic acid was slowly added to 1.68 kg of thionyl chloride, and after completion, 48 g of sodium bromide was added thereto, and the reaction liquid was refluxed for 2 to 16 hours until the reaction of the raw materials was completed, and the thionyl chloride was recovered. 680 g of 4-chloropyridine-2-acid chloride were obtained; 4-Chloropyridine-2-acid chloride is added in batches to 4 kg of 30percent ammonia water and stirred at room temperature for 5-16 hours until the reactionAfter completion, most of the water is removed, the temperature is lowered to 0-5 ° C, and the white solid is precipitated to give 4-chloropyridine-2-amide, 550 g, yield.95percent.General procedure: In an oven dried glass tube containing a mixture of pyridine 1a (100 mg, 1.26 mmol), and potassium persulphate (683 mg, 2.53 mmol), formamide 2a (2 ml) was added and the reaction mixture was heated at 70 °C. Upon the completion of the reaction (monitored by TLC), saturated sodium bicarbonate solution (5 mL) was added and the crude product was extracted in ethyl acetate (3 X 5 mL). The crude product was purified by column chromatography to furnish compound 3aa as a white crystalline solid (122 mg, 79percent yield)35 g of Example 3 4-Chloro-pyridin-2-ylamine (4). 4-Chloro-pyridine-2-carboxylic acid amide (3) (120 mg, 0.93 mol) was added to a rapidly stirring solution of Br2 (57 mul) in NaOH (1.7 ml of 2.5 N). The reaction mixture was heated to 80 C. for 90 minutes. The reaction was judged complete by MS, and was partitioned between ethyl acetate and brine. The ethyl acetate was washed with brine one additional time, and then the solvents were removed under vacuum to yield the title product 4 (60 mg (64%), 0.59 mmol) as a white solid. 1H NMR (DMSO-d6): delta 7.89 (d, J=5.5 Hz, 1H), 6.55 (dd, J=5.5 Hz, 1.9 Hz, 1H), 6.47 (m, 1H), 6.25 (bs, 2H). MS (ESI-POS): [M+H]+=129.Sodium hydroxide (39.6g, 990mmol) was dissolved in water (200mL) and cooled to 0-5C. Bromine (10mL) was slowly dropped at 0C and stirred for half hour. Then Step - II: Preparation of 4-chloro 2-aniino pyridine; Dissolved sodium hydroxide in water (120 gm, 900 ml) and cooled to 0 to 5 C. Charged Bromine (45 ml) slowly at 0 C and stirred for half hour. Charged 4- chloropyridine-2- carboxamide (60 gm) of at 0 C and stirred for 5 minutes. Heated the reaction mass to 1000C and maintained at reflux to get clear solution. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 0 to 5 C in one hr, filtered the precipitated solid, washed with chilled water, and dried at 50 to 55 C for 3 to 4 hrs. Dry wt: 28gm (Stage II)Aqueous NH40H (40%, 250 mL) was added dropwise at 0 C to a suspension of 4-chloro-pyridine-2-carbonyl chloride (75 g, 533 mmol) in EtOAc. Upon addition, the temperature rose to 30 C. The mixture was stirred for 2 h at RT then kept at RT for 12 h without stirring. MTBE (250 mL) was added to the mixture and the resulting emulsion was filtered. The solid was washed with EtOAc. The MTBE/EtOAc layer was washed twice with water and once with 5% Na2CO3, then dried over MgS04 and concentrated under vacuum. The resulting solid was suspended in EtOAc several times and filtered out to give the desired compound.A heterogeneous mixture of 4-chloropicolinic acid (TCI America, 5.4 g, 34.2 mmol, 1.0 eq) and thionyl chloride (30 mL) were heated at 80 C. for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was treated with an ammonia in MeOH solution (7 N, 45 mL) in an ice bath and the reaction mixture was stirred for 15 minutes. The ice bath was then removed and the reaction was warmed to room temperature and then stirred for 3 h. The reaction mixture was concentrated in vacuo and the residue purified by recrystallization from EtOAc to afford the product (5.14 g, 96%) as a solid. 1H NMR (DMSO-d6) delta 8.61-8.63 (m, 1H), 8.21 (m, 1H), 8.03-8.04 (m, 1H), 7.76-7.83 (m, 2H); MS(ESI+) m/z 157 (M+H)+.A heterogeneous mixture of 4-chloropicolinic acid (TCI America, 5.4 g, 34.2 mmol, 1.0 eq) and thionyl chloride (30 mL) was heated at 80 C for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was treated with an ammonia in MeOH solution (7N, 45 mL) in an ice bath and the reaction mixture was stirred for 15 minutes. The ice bath was then removed and the reaction was warmed to room temperature and then stirred for 3 h. The reaction mixture was concentrated in vacuo and the residue purified by recrystallization from EtOAc to afford the product (5.14 g, 96%) as a solid. 1H NMR (DMSO-J15) delta 8.61-8.63 (m, IH), 8.21 (m, IH), 8.03-8.04 (m, IH), 7.76-7.83 (m, 2H); MS(ESl+) m/z 157 (M + H)+.EXAMPLE 22 Preparation of Amides within the scope of substituted benzoylalkylamino are ... m-methoxycarbonylbenzoylbutylamide, o-carboxybenzoylbutylamide, o-hydroxybenzoylmethylamide. alpha-pyridylamide; beta-pyridylamide, and gamma-pyridylamide. 4-methyl-alpha-pyridylamide, 4-methyl-beta-pyridylamide, 4-chloro-alpha-pyridylamide, and 4-chloro-beta-pyridylamide. alpha-pyridylmethylamide, beta-pyridylmethylamide, gamma-pyridylmethylamide, alpha-pyridylethylamide, beta-pyridylethylamide, gamma-pyridylethylamide, ...Amides within the scope of substituted benzoylalkylamino are ... gamma-pyridylpropylamide, alpha-pyridylbutylamide, beta-pyridylbutylamide, and gamma-pyridylbutylamide. 4-methyl-alpha-pyridylmethylamide, 4-methyl-beta-pyridylmethylamide, 4-chloro-alpha-pyridylmethylamide, 4-chloro-beta-pyridylmethylamide, 4-methyl-alpha-pyridylpropylamide, 4-methyl-beta-pyridylpropylamide, ...Example A25 General procedure: To a solution of 4-chloro-pyridine-2-carbonyl chloride (27.6 g, 0.16 mol) in anhydrous THF (100 mL) at 0 C was added dropwise a solution of MeNH2 in EtOH. The resulting mixture was stirred at 3 C for 4h. The reaction mixture was concentrated under reduced pressure to yield a solid, which was suspended in EtOAc and filtered. The filtrate was washed with brine (2 x 100 mL), dried and concentrated to yield 4-chloro-N- methylpicolinamide (16.4 g, 60% yield) as a yellow solid. FontWeight='Bold' FontSize='10' H NMR (400 MHz, DMSO- d6) delta 8.78 (br s, 1H), 8.55 (d, J = 5.2 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7. 66 (m, 1H), 2.82 (d, J = 4.8 Hz, 3H); MS (ESI) m/z: 171.0 (M+H+).General procedure: To a solution of 3-bromo-5-chlorobenzoic acid (2.88 g; 12.2 mmol; Note 1) and pyridine (1.04 mL; 12.8 mmol) in MeCN (100 mL) at room temperature was added (Boc)2O (3.47 g; 15.9 mmol) in one portion. The mixture was aged 30 min, (NH4)2CO3was added in one portion. After stirring approximately 16 h at room temperature, volatiles were removed in vacuo. The residue was partitioned between EtOAc/water and the layers were separated. The aqueous layer was extracted with EtOAc (×2), combined organics were washed (10% HCl, brine), dried over Na2SO4and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless solid.

Molecular Weight:156.57
XLogP3:0.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:156.0090405
Monoisotopic Mass:156.0090405
Topological Polar Surface Area:56
Heavy Atom Count:10
Complexity:140
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes