2-Fluoronicotinic acid

Light yellow Cryst

a)2-Fluoronicotinoyl chlorideA mixture of A mixture of To a solution of 2-fluoropyridine (10 g, 100 mmol) in THF(150 mL) under -78°C was added an LDA solution (2M inheptane/THF/ethylbenzene, 60 mL) dropwise. The mixture wasstirred at -78°C for 3 h, then was guenched with a stream ofdry C02. After warming to RT, the mixture was partitionedbetween EtOAc (100 mL) and H20 (200 mL) . The agueous layerwas acidified to pH between 3-4, and extracted with EtOAc.The organic solution was collected and washed with brine anddried over Na2S04. After removing the solvent in vacuum, After removing the solvent in vacuum, Step D-Synthesis of 2-fluoropyridine-3-carbonyl chloride 2-Fluoropyridine-3-carboxylic acid (7 g, Step C) was suspended in SOCl2 (100 mL). After heating under reflux for 2 h, the mixture became homogeneous. Excess SOCl2 was removed in vacuo to afford a brown solid as desired product.Example 8; 2-(4-(1H-Pyrrolo[2, 3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-o-tolylnicotinamide, dihydrochloride salt; A) 2-Fluoro-N-o-tolylnicotinamide; A homogeneous mixture of Example 20; 2-(4-(1H-Pyrrolo[2, 3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-(4-fluorophenyl)-N-methylnicotinamide, dihydrochloride salt; A) 2-Fluoro-N-(4-fluorophenyl)-N-methylnicotinamide; To a suspension of Step D-Synthesis of 2-fluoropyridine-3-carbonyl Chloride 2-Fluoropyridine-3-carboxylic acid (7 g, Step C) was suspended in SOCl2 (100 mL). After heating under reflux for 2 h, the mixture became homogeneous. Excess SOCl2 was removed in vacuo to afford a brown solid as desired product.Step D-Synthesis of 2-fluoropyridine-3-carbonyl Chloride 2-Fluoropyridine-3-carboxylic acid (7 g, Step C) was suspended in SOCl2 (100 mL). After heating under reflux for 2 h, the mixture became homogeneous. Excess SOCl2 was removed in vacuo to afford a brown solid as desired product.2-Fluoropyridine-3-carboxylic acid (7 g) was suspended in SOCI2 (100 mL). After heating under reflux for 2 h, the mixture became homogeneous. Access SOCl2 was removed in vacuo to afford a brown solid as desired compound.2-Fluoro-N-(5-iiitrothiazol-2-yl)iiicotmamide (VPC16alO52). 2-Fluoronicotinic acid (100 mg, 0.71 mmol) was dissolved in CH2Cl2 (2 mL) with a drop of DMF (catalytic) and cooled to 0 °C then (COCl)2 (0.18 mL, 2.12 mmol) was added dropwise to the stirring solution. The slurry was allowed to warm to room temperature for 2 hours then concentrated to dryness using hexanes to remove the excess (COCl)2. The resulting acid chloride was dissolved in THF (7 mL) and DIPEA (0.26 mL, 1.49 mmol) was added. The solution was cooled to -78 °C and 2-amino-5-nitrothiazole (108 mg, 0.78 mmol) was then added in one portion and the solution was held at -78 °C for 10 mins then warmed to room temperature and stirred for 2 days until judged complete by TLC analysis. The resulting suspension was quenched with 2M HCl in Et2O (0.78 mL, 1.56 mmol) and concentrated to dryness then purified by flash column chromatography (1percentMeOH/CH2Cl2) to obtain the title compound VPC16alO52 (118 mg, 62percent) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) delta 13.77 (bs, 1H), 8.70 (s, 1H), 8.54 - 8.44 (m, 1H), 8.41 - 8.35 (m, 1H), 7.63 - 7.50 (m, 1H); 13C NMR (75 MHz, DMSO-(d6) delta 163.0 (d, JCF = 5.9 Hz), 161.5, 159.4 (d, JCF = 242 Hz), 151.3 (d, JCF = 15.2 Hz), 142.4, 142.3, 122.3 (d, JCF = 4.1 Hz), 115.9 (d, JCF = 28.5 Hz); HRMS (ESI) calcd for [C9H5FN4O3S + H]+ 269.0139, found 269.0143.2-FIuoropyridine-3-carboxylic acid (5.02 g, 35.6 mmol) was suspended in dichloromethane (100 mL), treated with thionyl chloride (13, 0 mL5 178 mmol, 5 equiv) and N, JV~dimethylforrnamide (0.138 mL, 1.78 mmol, 0.05 equiv) and placed into a preheated oil bath at 45 0C for 2 hours. The mixture was cooled to ambient temperature, concentrated in vacuo and the residue was concentrated from toluene (2 X 50 mL), providing the titled compound.To a stirred solution of Example 6 Synthesis of compound (1) 1 [0042] [0043] The compound (9) (14.2 g) and 4-toluenesulfonyl chloride (23.2 g) were dissolved in N, N-dimethylformamide (300 mL) to prepare a reaction mixture. N-methylimidazole (24.8 g) was added dropwise to the reaction mixture at an inner temperature of 1 to 8°C under cooling while stirring. The mixture was stirred at an inner temperature of 2 to 14°C for 2.5 hours. A compound (6) (20.0 g: water content: 7.77percent) was added to the reaction mixture and the mixture was stirred at an inner temperature of 2 to 12°C for 1.5 hours. Further, 4-toluenesulfonyl chloride (9.62 g) and N-methylimidazole (4.14 g) were added to the reaction mixture and the mixture was stirred at an inner temperature of 8 to 14°C for 3 hours and allowed to stand overnight at room temperature. Water (600 mL) was added dropwise to the reaction mixture at an inner temperature of 21 to 25°C to precipitate a crystal of the compound (1). Then, the mixture was stirred at an inner temperature of 12 to 15°C for 30 minutes. The precipitated crystal was collected by filtration, and washed with water (200 mL), and deliquored. The obtained wet crystal of the compound (1) (23.1 g) was dried with air flow at 50°C to obtain a crude crystal of the compound (1) (17.1 g) as pale yellow powder. Acetone (800 mL) was added to the crude crystal of the compound (1) (17.1 g) and the compound (1) was dissolved under heating while stirring. Water (800 mL) was added dropwise to the solution of the compound (1) in acetone at an inner temperature of 46 to 47°C to precipitate a crystal of the compound (1). Then, the mixture was stirred at an inner temperature of 46°C for 10 minutes, and further stirred at an inner temperature of 11 to 15°C for 30 minutes. The precipitated crystal was collected by filtration, and washed with a mixed solution of acetone (100 mL) and water (100 mL), and deliquored. The obtained wet crystal of the compound (1) (23.9 g) was dried with air flow at 50°C to obtain the compound (1) (16.4 g) with a yield of 64.8percent as a white powder. Instrument data of compound (1) Melting point (hot plate method): 141 to 143°C 1H-NMR (400 MHz, DMSO-d6) delta: 1.20 (3H, t, J = 7.3 Hz), 3.11 (2H, q, J = 7.3 Hz), 3.93 (3H, s), 7.03 (2H, s), 7.57 - 7.61 (1H, m), 8.48 - 8.50 (1H, m), 8.55 - 8.60 (1H, m). HPLC relative purity: 99.5percent (RT 42.7 min) Column: Inertsil ODS-3, 4.6 mm I.D. × 150 mm Precolumn: Inertsil ODS-3, 4.0 mm I.D. × 10 mm Measurement wavelength: 260 nm Column temperature: 35°C Flow rate: 1.0 mL/min Mobile phase A: acetonitrile Mobile phase B: diluted phosphoric acid (1'1, 000) containing 5 mmol/L sodium 1-octanesulfonate [0044] This diluted phosphoric acid (1'1, 000) means that 1 mL of phosphoric acid is dissolved in water to make 1, 000 mL of solution.2-Fluoronicotinic acid (100mg, 0.71 mmol) was dissolvedin CH2C12 (2 mE) with a drop of DMF (catalytic) and cooledto 0° C. then (COd)2 (0.18 mE, 2.12 mmol) was addeddropwise to the stirring solution. The slurry was allowed towarm to room temperature for 2 hours then concentrated todryness using hexanes to remove the excess (COd)2. Theresulting acid chloride was dissolved in THF (7 mE) andDIPEA (0.26 mE, 1.49 mmol) was added. The solution wascooled to '78° C. and 2-amino-5-nitrothiazole (108 mg, 0.78mmol) was then added in one portion and the solution washeld at '78° C. for 10 mins then warmed to room temperatureand stirred for 2 days until judged complete by TEC analysis.The resulting suspension was quenched with 2M HC1 in Et20(0.78 mE, 1.56 mmol) and concentrated to dryness then purified by flash column chromatography (1percent MeOH/CH2C12) toobtain the title compound VPC16a1O52 (118 mg, 62percent) as ayellow solid. 'H NMR (300 MHz, DMSO-d5) 0 13.77 (bs, 1H), 8.70 (s, 1H), 8.54-8.44 (m, 1H), 8.41-8.35 (m, 1H), 7.63-7.50 (m, 1H); '3C NMR (75 MHz, DMSO-d5) 0 163.0(d, cF= Hz), 161.5, 159.4 (d, JCF=242 Hz), 151.3 (d, JcF=15.2 Hz), 142.4, 142.3, 122.3 (d, JCF=4.1 Hz), 115.9 (d, JcF=28.5 Hz); HRMS (ESI) calcd for [C9H5FN4O3S+H]269.0139. found 269.0143.General procedure: Analogs 6a'o were synthesized as outlined in Scheme 1: Acid(1.2 eq) was dissolved in anhydrous DCM, oxalyl chloride (1.44eq) was added dropwise at 0°C and then one drop DMF was added.The reaction mixture stirred at room temperature for 2 h. The excess oxalyl chloride was removed under reduced pressure, andthe residue dissolved in THF for next transformation.Intermediate 5 (1eq) and triethylamine (1.5 eq) were added sequent to a 25 ml three-neck-bottom flask under a nitrogen atmosphere. Acyl chloride in THF was added dropwise to flask at 0°C.The reaction mixture was stirred at 0°C. After pale yellow solid appeared, the mixture reacted at room temperature until TLC showed 5 disappeared. Ice water was added to reaction mixtureat 0°C, and stirred for another 30 min until no insoluble solid generated.The solid was filtered to get crude product. The crude product further purified by medium pressure column chromatography(C18 padding, ACN: H2O (containing 0.05percent TFA) =1:99'99:1) to getproduct as a solid.

Molecular Weight:141.10
XLogP3:0.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:141.02260653
Monoisotopic Mass:141.02260653
Topological Polar Surface Area:50.2
Heavy Atom Count:10
Complexity:140
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes