5-AMINO-3-(TRIFLUOROMETHYL)PICOLINONITRILE

In ethyl acetate (1 ml) and acetic acid (1 ml), a mixture of2-cyano-3- (trifluoromethyl) -5-nitropyridine A10 (0.095 g, 0.44 mmol) and ironpowder (0.112 g, 2 mmol) was heated for 15 hours. The solid particles werefiltered through Celite, the filtrate was concentrated and subjected tochromatography (EtOAc: pentane, 1: 1) to give compound A11 (0.075g, 0.4mmol, 91percent).Synthesis of 2-cyano-3-(trifluoromethyl)-5-aminopyridine, A11 (0058) A mixture of 2-cyano-3-(trifluoromethyl)-5-nitropyridine A10 (0.095 g, 0.44 mmol) and iron powder (0.112 g, 2 mmol) in ethyl acetate (1 ml) and acetic acid (1 ml) was heated for 15 hours. The solid particle was filtered through Celite and the filtrate was concentrated and chromatographed (EtOAc:pentane, 1:1) to yield compound A11 (0.075 g, 0.4 mmol, 91percent). 5-amino-2-cyano-3-trifluoromethylpyridine [0068] 2-cyano-5-nitro-3-trifluoromethylpyridine (7 mg, 0.032 mmol) is dissolved in1 :1 EtOAc/AcOH (1 mL) and heated to 65 Synthesis of 5-amino-3-trifluoromethyl-2-cyanopyridine (Intermediate 5) To a solution of compound 4 (1.15g, 4.9mmoles) in EA (20ml) and AcOH (4ml) was added Fe (890mg) portion-wise under NA solution of 2-hydroxy-3-(trifluoromethyl)pyridine C in a mixture of N-iodosuccinimide (NIS), acetonitrile, and dimethylformamide (DMF) is heated at 80° C. for 2 hours to produce 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I (greater than 80percent yield). The 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I is then mixed with POCl5-amino-2-cyano-3-trifluoromethylpyridine H: TFA (1 niL) is added dropwise to a solution of pyridine L (83 mg, 0.27 mmol) in dry DCM (0.5 mL) under argon. The solution is stirred overnight at room temperature. After completion of the reaction, the solvent is evaporated and the residue is purified by flash chromatography on silica gel (Hexane/EtOac) to afford the desired product quantitatively. Add ammonium thiocyanate (40 mmol) and 50 mL of acetone to a two-necked round bottom flask, add p-methoxybenzoyl chloride (40 mmol), Stir for 10 min at room temperature, and heat to reflux for 1 hour. Then add 5-amino-3- (trifluoromethyl) -2-cyanopyridine (35mmol) in acetone. After refluxing for 6 hours, cool to room temperature and pour into 100 mL of water , The pH was adjusted to 8.0 with sodium bicarbonate to give the product A4 as a yellow solid (9.05 g, yield 68%).Add ammonium thiocyanate (45 mmol) and 50 mL of acetone to a two-necked round bottom flask, add o-methylbenzoyl chloride (45 mmol), Stir at room temperature for 10 min, raise the temperature to reflux for 1 hour, and then add 5-amino-3- (trifluoromethyl) -2-cyanopyridine (30 mmol) in acetone.After refluxing for 6 hours, it was cooled to room temperature, poured into 100 mL of water, adjusted to pH 8.0 with sodium bicarbonate, and filtered with suction to obtain a pale yellow solid product A3 (8.19 g, yield 75%).Add ammonium thiocyanate (35 mmol) and 40 mL of acetone to a two-necked round-bottomed flask, add p-methylbenzoyl chloride (35 mmol), Stir at room temperature for 10 min, raise the temperature to reflux for 1 hour, and then add 5-amino-3- (trifluoromethyl) -2-cyanopyridine (30 mmol) in acetone.After refluxing for 6 hours, it was cooled to room temperature, poured into 200 mL of water, adjusted to pH 8.0 with sodium bicarbonate, and filtered with suction to obtain a light yellow solid product A2 (7.1 g, yield 65%).Add ammonium thiocyanate (40 mmol) and 50 mL of acetone to a two-necked round bottom flask, add benzoyl chloride (40 mmol), Stir at room temperature for 10 min, and raise the temperature to reflux for 1 hour, and then add 5-amino-3- (trifluoromethyl) -2-cyanopyridine (30 mmol) in acetone. After refluxing for 6 hours, cool to room temperature.Poured into 200 mL of water, adjusted the pH to 8.0 with sodium bicarbonate, and filtered with suction to obtain the light yellow solid product A1 (7.05 g, yield 67%).Add 18.7 g (0.1 mo1) of Step 3: Add 150g of intermediate 2 to the reaction flask, add 77g of sulfur powder, 10g of PDFA (Ph3PCF2CO2), 200mL of chloroform, and heat up to 60 C reaction.After the reaction is over, add water, filter, and extract with EA.Dry, distill the solvent under reduced pressure, 154 g of product 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-cyano, Yield: 84%.Under a nitrogen atmosphere, 200 mg (0.57 mmol, 1.0 eq) of JD1001-002-23, 3 mL of THF, 144 mg (1.71 mmol, 3 eq) of NaHCO3, 85.73 mg (0.456 mmol, 0.8 eq) were sequentially added to a 25 mL reactor.2, 3-difluoro-5-aminopyridine, heated to 60 C, stirred for 3 hours, TLC detection of the completion of the reaction (developing agent: PE / EA = 1 / 1, UV254), stop the reaction, add water to quench the reaction, The organic phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate.After purification by HPLC, 26 mg of a white solid was obtained. The yield is 15.4%Take the light yellow solid obtained in the previous step, Add 90 mL of dry THF to it in turn.1.9 g (22.2 mmol, 1.5 eq) of NaHCO3, 3.3 g (17.8 mmol, 1.2 eq) of

Molecular Weight:187.12
XLogP3:1.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:6
Exact Mass:187.03573163
Monoisotopic Mass:187.03573163
Topological Polar Surface Area:62.7
Heavy Atom Count:13
Complexity:229
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes