2-Amino-6-chloronicotinic acid (CAS: 58584-92-2) can be used in the preparation of AZD8055 (CAS: 1009298-09-2). AZD8055 has been utilized in clinical trials focused on the treatment of cancer, lymphomas, solid tumors, malignant glioma, and brainstem glioma, among others.
Application In Synthesis of [ 58584-92-2 ]
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
2-Amino-6-chloronicotinamide (Inter. 3) To a 0.3 M solution of 2-amino-6-chloronicotinic acid (Inter. 2) (1 equiv) in anhydrous THF, under an inert atmosphere, was added thionyl chloride (3.3 equiv) in a dropwise fashion. The reaction mixture was stirred at room temperature for 2 hours. After this time the reaction was concentrated in vacuo to give a crude yellow solid residue. The crude solid was dissolved in THF (equal to initial reaction volume) and concentrated in vacuo again to give a yellow solid residue. The residue was dissolved once more in THF and concentrated as before to give a solid residue which was then dissolved in THF (to give a solution of 0.3M) and ammonia gas bubbled through the solution for 1 hour. The resultant precipitate was removed by filtration and the filtrate concentrated in vacuo to give a yellow precipitate which was triturated with water at 50° C. then dried to give the title compound (92percent yield, 93percent purity), suitably clean to be used without any further purification. m/z (LC-MS, ESP): 172 [M+H]+R/T=3.19 mins
92%
Stage #1: With thionyl chloride In tetrahydrofuran at 20℃; for 2 h; Stage #2: With ammonia In tetrahydrofuran for 1 h;
b) 2-Amino-6-chloronicotinamide (Inter. 3); To a 0.3 M solution of 2-amino-6-chloronicotinic acid (Inter. 2)(1 equiv) in anhydrous THF, under an inert atmosphere, was added thionyl chloride (3.3 equiv) in a dropwise fashion. The reaction mixture was stirred at room temperature for 2 hours. After this time the reaction was concentrated in vacuo to give a crude yellow solid residue. The crude solid was dissolved in THF (equal to initial reaction volume) and concentrated in vacuo again to give a yellow solid residue. The residue was dissolved once more in THF and concentrated as before to give a solid residue which was then dissolved in THF (to give a solution of 0.3M) and ammonia gas bubbled through the solution for 1 hour. The resultant precipitate was removed by filtration and the filtrate concentrated in vacuo to give a yellow precipitate which was triturated with water at 50°C then dried to give the title compound (92percent yield, 93percent purity), suitably clean to be used without any further purification, m/z (LC- MS, ESP): 172 [M+H]+ R/T = 3.19 mins
90%
Stage #1: With thionyl chloride In tetrahydrofuran at 20℃; for 2 h; Stage #2: With ammonia In tetrahydrofuran for 1 h;
To a 0.3 M solution of amino acid (1 equiv) in anhydrous THF, under an inert atmosphere, was added thionyl chloride (3.3 equiv) in a dropwise fashion. The reaction mixture was stirred at room temperature for 2 hours. After this time the reaction was concentrated in vacuo to give a crude yellow solid residue. The crude solid was dissolved in THF (equal to initial reaction volume) and concentrated in vacuo again to give a yellow solid residue. The residue was dissolved once more in THF and concentrated as before to give a solid residue which was then dissolved in THF (to give a solution of 0.3M) and ammonia gas bubbled through the solution for 1 hour. The resultant precipitate was removed by filtration and the filtrate concentrated in vacuo to give a yellow precipitate which was triturated with water at 50 0C then dried to give the title compound (typically 90-95 percent) yield and suitably clean enough to be used without any further purification.2-Amino-6-chloronicotinamide - X=N, Y=C, Z=C: (92 percent yield, 93 percent purity) m/z (LC-MS, ESP): 172 [M+H]+ R/T = 3.19 min
81%
With ammonium chloride; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 25℃; for 16 h;
To a solution of 2-amino-6-chloronicotinic acid (1.0 g, 5.79 mmol), HOBT (932 mg, 6.95 mmol) and EDCI (2.22 g, 11.6 mmol) in 15 mL of DMF was added triethylamine (5.86 g, 57.9mmol) and NH4C1 (1.55 g, 28.9 mmol). Then the mixture was stirred at room temperature for 16 h. The solution was concentrated in vacuo to remove DMF and the residue was suspended in saturated NaHCO3. Finally the 2-amino-6-chloronicotinamide (800 mg, yield: 81percent) was obtained by filtration without further purification. ‘H-NMR (DMSO-d6, 400 MHz) 7.95 (d, J = 8.4 Hz, 1H), 7.62 (s, 2H), 7.39 (s, 2H), 6.59 (d, J = 8.4 Hz, 1H). MS (M+H): 172 / 174.
78%
With thionyl chloride In 1,2-dichloro-ethane; N,N-dimethyl-formamide
Example 140B 2-Amino-6-chloro-nicotinamide To a mixture of Example 140A (11.9 g, 69.2 mmol) in 1,2-dichloroethane (100 mL) was added thionyl chloride (30 mL, 411 mmol) and DMF (catalytic). The mixture was refluxed for 4 h then evaporated. The residue was taken in ether (200 mL) and ammonia was bubbled through for 15 min. The mixture was stirred overnight at rt then washed with water (100 mL) and brine (100 ml). The ether was evaporated off to yield 9.2 g of product (78percent). MS (DCI/NH3) m/z 172 (M+1)+.
78%
Stage #1: With thionyl chloride In 1,2-dichloro-ethane for 4 h; Heating / reflux Stage #2: With ammonia In diethyl ether at 20℃;
Example 140B 2-Amino-6-chloro-nicotinamide To a mixture of Example 140A (11.9 g, 69.2 mmol) in 1,2-dichloroethane (100 mL) was added thionyl chloride (30 mL, 411 mmol) and DMF (catalytic). The mixture was refluxed for 4 h then evaporated. The residue was taken in ether (200 mL) and ammonia was bubbled through for 15 min. The mixture was stirred overnight at rt then washed with water (100 mL) and brine (100 ml). The ether was evaporated off to yield 9.2 g of product (78percent). MS (DCI/NH3) m/z 172 (M+1)+.
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