(S)-3-phenyl-2-(pyrazine-2-carboxamido)propanoic a

The product N-pyrazineformyl-L-phenylalanine methyl ester (1.0g, 3.51mmol) in Preparation was dissolved with 10ml of acetone, 2N NaOH was added dropwise slowly until a pH value of 12∼13 was obtained, and the solution was kept reacting under the condition of ice water bath, the reaction was monitored by TLC and completed after 2h. The product 6a (1mmol) was dissolved in 10mL THF and was added 3N LiOH dropwise at 0°C until TLC showed methyl ester 6a was disappeared completely (1h). The reaction solution was acidified to pH 2. The precipitate was filtered and washed with water until pH value reached 6–7. After dryness, the acid 7a was obtained with high yield and used exactly without further purification, 93percent yield; mp: 166–169°C. To a solution of 8a (1.44 g, 5.05 mmol) in THF (5 mL) were added 1 M aq LiOH(6 mL) dropwise with the aid of ice-water bath followed by stirring to r.t. over 2 h.The reaction mixture were diluted with water (20 mL) and extracted with EtOAc (3×5mL). The alkaline water layer were acidized to pH = 2-3 with 1 M aq HCl to give awhite suspension, which were filtrated, washed to pH = 6-7 by water, and dried togive the title compound 9a (1.22 g, 89percent) as a white solid;Step B. Preparation of (S)-3-Phenyl-2-[(pyrazine-2-carbonyl)-amino] -propionic acid (i.e., acid of Formula II, wherein RA second 500 ml three neck round bottomed flask is equipped with a stir bar, thermocouple, pressure equalizing dropping funnel, nitrogen inlet/ outlet and ice/water cooling bath. E-Phenylalanine, 20.2 g (0.122 mol) is added, followed by 28.2 g (0.266 mol) ofsodium carbonate and 225 mE of deionized watet The aqueous solution is cooled to 10.0°C. During this time the addition flannel is charged with the acid chloride/toluene solution prepared in Step A (.-125 mE). This toluene solution is added dropwise to the aqueous reaction over approximately 10 mm-utes at .—10° C. Once the addition is complete, the reaction is warmed to room temperature (.-22-25° C.) and vigorously stirred for 3 h. The reection mixture is then transferred to a reparatory flannel and the two layers are separated. The lower aqueous phase is then recharged to the reaction flask. Metha40 nol (125 mE) is then added to the red solution followed by pHadjustment (target pH=1 -2) with 3.0 M HC1 (.-175 mE), keeping the temperature at 15-20° C. Some off-gassing occurs at .-pH=5, followed by precipitation of the product at pH=3. The slurry is allowed to stir at room temperature for 30 minutes atambient temperature post pH adjustment. The resulting pink solid precipitate is collected by vacuum filtration, (mother liquor losses <2 mg/mE), washed with deionized water (1 x50 ml) then dried in a vacuum oven at 40° C. with a nitrogen sweep to a constant weight to provide 11.92 g (0.43.9 mmol, 36percent) of the title compound with an HPEC purity of 99 A percent. ‘HNMR(d6-DMSO, 400 MHz)ö 13.04(s, 1H), 9.14(d, 1H, J=1.44 Hz), 8.88 (dd, 2H, J=2.48, 6.16 Hz), 8.75 (dd, 1H, J=1.52, 2.4 Hz), 7.25 (m, 4H), 7.18 (m, 1H), 4.75 (dt, 1H, J=5.48, 8.08 Hz), 3.2 (dd, 2H, J=1.79, 5.32 Hz).N, O-Bis(trimethylsilyl)acetamide (BSA, 2.49 mL, 10.05 mmol) was added to a solution of L-phenylalanine (0.83 g, 5.02 mmol) and dichloromethane (8 mL), and the reaction mixture was stirred at room temperature for 16 h. In another 100 mL reaction flask, 1, 1'-carbonyldiimidazole (1.7 g, 10.48 mmol) was added to a solution of pyrazinecarboxylic acid (1 g, 8.06 mmol) and dichloromethane (17 mL). After stirring at room temperature for 16 h, the reaction mixture was cooled in a −40 °C bath and the above solution of L-phenylalanine-BSA was added dropwise over 30 min. The reaction mixture was stirred at room temperature for another 16 h, citric acid(aq) (0.78 M, 17 mL) was added, and extracted with dichloromethane (10 mL × 3). The organic layers were separated, combined, dried over anhydrous Na2SO4 and concentrated. The crude product was recrystallized in dichloromethane/hexanes to give N-(2-pyrazinylcarbonyl)-L-phenylalanine (8, R = benzyl; R' = pyrazinyl, 0.96 g, 3.54 mmol, 70percent) as a colorless solid.(S) -3-phenyl-2-[(pyrazine-2-carbonyl) amino] propionic acid (Compound 1) (5.0 g, 18.4 mmol, 1.0 eq) was dissolved in N, N-dimethylformamide (200 mL), triethylamine (5.60 g, 55.3 mmol, 3.0 eq) and HATU (10.5 g, 27.7 mmol, 1.5 eq) were added, followed by stirring at room temperature for 30 min, and then ammonium chloride (1.48 g, 27.7 mmol, 1.5 eq) and react at room temperature for 12 hours. After that, the reaction solution was washed with saturated brine (100 mL × 3), and then dried over anhydrous Na 2 SO 4, and the solvent was removed by rotary evaporation under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain 4.40 g of a yellow solid (Compound 2) with a yield of 88.3%.

Molecular Weight:271.27
XLogP3:1
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:5
Exact Mass:271.09569129
Monoisotopic Mass:271.09569129
Topological Polar Surface Area:92.2
Heavy Atom Count:20
Complexity:343
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes