[Synthesis]
General procedure for the synthesis of 2-amino-5-methylpyrazine from tert-butyl (2S)-2-[(4-methylphenyl)sulfonyloxymethyl]morpholine-4-carboxylate:
[0386] 5-Methylpyrazine-2-carboxylic acid (2.76 g, 20 mmol) and oxalyl chloride (1.83 mL, 2.66 g, 21 mmol) were dissolved in dichloromethane (40 mL) and catalyzed by the addition of N,N-dimethylformamide. The mixture was stirred at 25 °C for 1 h and then filtered and the filtrate was concentrated under vacuum to give an oily solid. The solid was dissolved in acetone (120 mL), cooled to 0 °C, and a solution of sodium azide (1.03 g, 20 mmol) in water (50 mL) was slowly added dropwise. After the dropwise addition was completed, stirring was continued at 0 °C for 30 min. The reaction mixture was poured into ice-cold water (100 mL) and extracted with dichloromethane (3 x 100 mL). The organic phases were combined and washed sequentially with water (100 mL), saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution (1:1, 100 mL) and dried over anhydrous sodium sulfate. After filtration and vacuum concentration, 5-methylpyrazine-2-carbonyl azide (1.46 g, 45%) was obtained as a brown solid.
5-Methylpyrazine-2-carbonyl azide (500 mg, 3.07 mmol) was mixed with benzyl alcohol (0.63 mL, 663 mg, 6.14 mmol) and slowly heated to 90 °C with vigorous gas release. After the gas release stopped, the temperature was raised to 120°C and stirring was continued for 10 minutes. After cooling, it was ground with ether/hexane (1:4) to give (5-methylpyrazin-2-yl)carbamic acid phenyl ester (438 mg, 58%) as a yellow solid.
Phenyl (5-methylpyrazin-2-yl)carbamate (500 mg, 2.2 mmol) and 10% palladium carbon (212 mg) were dissolved in ethanol (30 mL) and stirred at 25 °C for 1 h under hydrogen atmosphere. Upon completion of the reaction, the catalyst was removed by filtration and the filtrate was concentrated in vacuum to give 2-amino-5-methylpyrazine (183 mg, 76%) as a brown solid, which was used directly in the next step of the reaction.
[0387] 2(R)-(3-Chloro-4-methylsulfonylphenyl)-3-(4-oxocyclohexyl)propanoic acid (263 mg, 0.73 mmol) and triphenylphosphine (250 mg, 0.95 mmol) were dissolved in dichloromethane (5.0 mL), cooled to 0 °C, and N-bromosuccinimide (167 mg, 0.95 mmol) was added in batches. After addition, the temperature was slowly increased to 25°C with stirring for 30 minutes. Subsequently, 2-amino-5-methylpyrazine (160 mg, 1.46 mmol) and 2,6-dimethylpyridine (0.36 mL, 2.92 mmol) were added and stirred at 25 °C for 4 hours. The reaction mixture was diluted with dichloromethane (25 mL), washed sequentially with 10% aqueous hydrochloric acid (20 mL), saturated aqueous sodium bicarbonate (20 mL), and water (20 mL), and dried over anhydrous sodium sulfate. After filtration and concentration, it was purified by Biotage chromatography (FLASH 40S, silica gel, 65/35 hexanes/ethyl acetate to 3/7 hexanes/ethyl acetate) to afford 2(R)-(3-chloro-4-methylsulfonylphenyl)-N-(5-methylpyrazin-2-yl)-3-(4-oxocyclohexyl)propanamide (158 mg, 48%) as a white foam: [α]23? ?? = -41.52° (c = 0.33, chloroform); EI-HRMS m/z calculated value C??H??ClN?O?S [M+H]+ 450.1249, measured value 450.1253. |