6-CHLORO-2-CYANO-3-NITROPYRIDINE

Light yellow Cryst

Prior synthesis of pyrido[3, 2-d]pyrimidines utilized ethoxyethanol and aniline for substitution on 3 (Scheme 1) whereas for substituted anilines, strong bases such as LDA were used to facilitate the reaction. Both methods suffer from long durations and stringent reaction conditions, respectively. A simpler and versatile synthetic route to obtain 4-18 from 3 was envisioned using appropriate anilines at reflux in isopropanol at 120 °C, a highly versatile reaction process that provided good yields (75-83percent). Reduction of the nitro group was performed using iron in cone. HCl (Bechamp reduction) or using HTo a solution of 2, 6-dichloro-3-nitropyridine (6.00 g, 31.1 mmol) in NMP (23.0 mL) was added copper(I) cyanide (3.06 g, 34.2 mmol) at room temperature. After stirred for 40 min at 180° C., the reaction mixture was cooled to room temperature, and then poured into ice water. After stirring for 10 min, the mixture was extracted with EtOAc, washed with brine, dried over anhydrous NaStep 1) A mixture of 2, 6-dichloro-3-nitro-pyridine (3.00 g, 16 mmol), cuprous cyanide (2.87 g, 32 mmol) and N-methylpyrrolidone (10 mL) was stirred at 180 °C for 3 h. The reaction solution was then cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (30 mL) twice, then the ethyl acetate layer was combined, and concentrated under vacuum to afford the title compound (1.10 g, 39 percent). A mixture of 2, 6-dichloro-3-nitro-pyridine (3.00 g, 16 mmol), cuprous cyanide (2.87 g, 32 mmol) and N-methylpyrrolidone (10 mL) was stirred at 180° C. for 3 h. The reaction solution was then cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (30 mL) twice, then the ethyl acetate layer was combined, and concentrated under vacuum to afford the title compound (1.10 g, 39percent). EXAMPLE 78The synthesis of 6-chloro-4-anilino-pyrido[3, 2-d][1, 2, 3]triazineStep A: General procedure for the synthesis of 2-cyano-3-nitro-6-chloropyridine; 2, 6-dichloro-3-nitropyridine (5 g, 26 mmol), Cuprous cyanide (4.64 g, 0.59 mml) and appropriate amount of N-methyl pyrrolidone were mixed to form a solution which was heated to 180° C. to react for 15 min, then cooled to 10° C. and poured into ice-water (200 mL) and stirred for 30 min. The solution was then filtered, washed with water and dried. A mixture of the filter cake and Toluene (50 mL) were stirred and heated under reflux for 10 min, then filtered while still hot. Repeated the above operation 3 times, and combined the filtrate. The filtrate was washed with water for 3 times, then with saturated sodium chloride solution for 1 time. The organic phase was dried with anhydrous magnesium sulfate and kept overnight. After filteration, the solution was evaporated under reduced pressure to dryness, and then filtered with a mixture of petroleum ether/aather (4:1) and air-dried to yield 1.78 g of orange yellow solid product with a recovery rate of 37.55percent.Step 1: 6-chloro-3-nitropicolinonitrile To a stirred mixture of 2, 6-dichloro 3-nitropyridine (10 g, 0.0518 mol) in NMP (100 mL) was added CuCN (9.7 g, 0.1083 mol) and the reaction mixture was heated at 180°C for 1 h. The reaction mixture was cooled to room temperature and the deep brown mixture was poured into ice-cold water (300 mL) and filtered through Celite® reagent. The solid was extracted with 10percent methanol in DCM (4x250 mL) and the aqueous layer was extracted with EtOAc (3x500 mL). The pooled organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified using column chromatography (100-200 mesh silica gel; 10percent EtOAc in hexane) to afford the title compound (3.5 g, 36percent).In a 500 mL three-necked flask charged with condenser, 2, 6-dichloro-3-nitropyridine (20 g, 104 mmol) and cuprous cyanide (18.56 g, 208 mmol) were dissolved in 300 mL NMP, thereaction mixture was heated to 180 °C quickly and stirred for 1.5 hours, after completion, the reaction mixturewas cooled to room temperature, poured into 800 mL cool water and stirred for 30 minutes to precipitate. Thesediment was filtered in vacuum to obtain the residue, washed by water for three times. The crude productdissolved in 500 mL toluene in a 1000 mL flask was heated to reflux for 10 minutes, the mixture was filteredwhile hot, the residue was operated repeatedly twice, the filtrate was collected, washed with water (500 mL×3)and saturated salt solution successively, the solution was dried with MgSO4 and concentrated in vacuum. Theresidue was recrystallized with diethyl ether/Petroleum ether (v/v=4:1), the residue was filtered, and dried in airto give 2 as orange-yellow solid (31.0percent).to N-methylpyrrolidone (25 mL) solutionof 2, 6-dichloro-3-nitropyridine (2.50 g), copper cyanide(I) (2.32g) was added at room temperature & stirred for 1 hour at 180 ° C.The reaction mixture was cooled to room temperature, ethyl acetate and waterwere added, the insoluble material was removed by filtration. The filtrate waswashed with saturated saline solution, the aqueous layer was re-extracted withethyl acetate. The combined organic layers were washed with water, brine, driedover anhydrous magnesium sulfate, and then distilled off under reducedpressure. The resulting crude product was purified by silica gel columnchromatography (eluting solvent: n- hexane / ethyl acetate = 90 / 10~70 / 30)to give the title compound (0.90 g).At room temperature2, 6-dichloro-3-nitropyridine (2.50 g) of N-methylpyrrolidone (25 mL) Copper cyanide (1) (2.32 g), and stirred at 180 ° C for 1 hour.After the reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the mixture was filtered through celite. The filtrate was washed with saturated brine, and the aqueous layer was re-extracted with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the organic layer. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90/10 to 70/30) to obtain the title compound (0.90 g).Reference Example 19 (0113) 6-Chloro-3-nitropyridine-2-carbonitrile (0114) To a solution of 2, 6-dichloro-3-nitropyridine (2.50 g) in N-methylpyrrolidone (25 mL) was added copper (I) cyanide (2.32 g) at room temperature, and the mixture was stirred at 180° C. for 1 hour. The reaction mixture was cooled to room temperature, and to the mixture were added ethyl acetate and water. The mixture was filtered through a Celite pad. The filtrate was washed with brine, and the separated aqueous layer was re-extracted with ethyl acetate. The combined organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=90/10-70/30) to give the title compound (0.90 g).19.3 g of 2, 6-dichloro-3-nitropyridine and 200 ml of N-methylpyrrolidone were used as a solvent, and 17.9 g of copper(I) cyanide was added thereto, and the mixture was reacted at 180 ° C for 0.5 h under nitrogen atmosphere.After completion of the reaction, 1500 ml of ethyl acetate was added to the reaction mixture, stirred for 30 min, filtered, and the filter cake was washed with a small portion of ethyl acetate. The obtained ethyl acetate solution was washed three times with saturated brine, dried over anhydrous sodium sulfate and evaporated. The obtained crude product was recrystallized from petroleum ether and ethyl acetate system.An off-white solid was obtained which was dried and weighed 9.1 g.Synthesis of (+/-)-9-[acetyl-(3, 5-bis-trifluoromethylbenzyl)aminoj-2-chloro-6, 7, 8, 9- tetrahydro-pyrido[3, 2-b]azepine-5-carboxylic acid isopropyl ester; Step 1;. Preparation of 6-chloro-3-nitro-pyridine-2-carbonitrile; Combine 2, 6-dichloro-3-nitro-pyridine (5.0 g, 25.9 mmol) and copper (I) cyanide (2.55 g, 28.5 mmol) in N-methyl pyrrolidinone (19 mL) and heat at 180 °C for 15 min. Cool the reaction mixture to room temperature, pour onto ice-water, and stir for 10 min. Separate the water and extract the oil with boiling toluene and then with ethyl acetate. Dry over sodium sulfate, filter, and concentrate under reduced pressure. Triturate the solid with diethyl ether and filter to afford the title compound (1.76 g, 39percent). IH-NMR (CDC13, 300 MHz) : 8 7.78 (d, J = 8.9 Hz, 1H), 8.54 (d, J = 8.9 Hz, 1H).Example 6a

Molecular Weight:183.55
XLogP3:1.7
Hydrogen Bond Acceptor Count:4
Exact Mass:182.9835540
Monoisotopic Mass:182.9835540
Topological Polar Surface Area:82.5
Heavy Atom Count:12
Complexity:231
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes