Boc-Dap-OtBu

To a stirring solution of /er/-butyl bV)-3-amino-2-(/c/7- butoxycarbonyl)amino)propanoate 4 (3.1 g, 11 mmol) in CH2CI2 (25 mL) under inert atmosphere were added /V-methyl morpholine (3 mL, 2.69 mol) an d N, Af '-di cycl oh ex yl carb odi i m i de (18.96 g 0.11 mol) at 0 C and stirred at the same temperature for 30 min. To this were added S- tritylcysteine (4.25 g, 11 mmol), /V-methyl morpholine (3 mL, 2.69 mol) at 0 C. The reaction mixture was gradually warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (100 mL) and the precipitated solid was filtered and dried under vacuum to obtain the crude. The crude was purified through silica gel column chromatography using 25-30% EtOAc/ heptanes and further purified by precipitation using methyl tert butyl ether: -pentane (1 : 7, 150 mL) to afford compound 5(4.5g, 55%) as white solid. NMR (400 MHz, DMSO- is): d 7.37 - 7.17 (m, 15H), 7.10 - 6.97 (m, 1H), 6.59 - 6.42 (m, 1H), 6.34 - 6.23 (m, 1H), 4.22 - 4.04 (m, 1H), 3.92 - 3.79 (m, 1H), 3.44 - 3.32 (m, 1H), 3.21 - 3.09 (m, 1H), 2.47 - 2.39 (m, 2H), 1.40, 1.38 (s, 18H).To 5.0 g of compound 6 (11.9 mmol), 50 ml of acetonitrile and 3.53 g of Boc-DAP-OtBu (11.9 mmol) were added, and then stirred at 8 C. Triethylamine (3.5 ml) (25 mmol) was added dropwise, and then the mixture was stirred overnight at room temperature. Under reduced pressure, the solvent was evaporated, and then 25 ml of ethyl acetate and 5 ml of water were added for extraction. The organic layer was washed with 5 ml of water, the solvent was evaporated, and then 50 ml of tetrahydrofuran was added. The solution was cooled to 8 C., and then aged for 1 hour. The precipitated solid was filtered under reduced pressure, washed with 10 ml of tetrahydrofuran, and then dried overnight at 60 C. under reduced pressure, to obtain 6.3 g of the target product as a white solid.To 50 g of ACTS (225.6 mmol), 375 mL of MeCN (7.5 L/kg vs ACTS) and 38.1 mL of Py (473.7 mmol, 2.1 eq.) were added, and then stirred at 25 C. ClCO2Ph (phenyl chloroformate) (29.9 mL) (236.8 mmol, 1.05 eq.) was added dropwise. After 30 minutes of stirring, the completion of the carbamate forming reaction was confirmed by HPLC. Boc-DAP-OtBu (68.9 g) (232.4 mmol) was added, and then 97.5 mL of TEA (699.3 mmol, 3.1 eq.) was added dropwise. After 3 hours of stirring at 25 C., the completion of the urea forming reaction was confirmed by HPLC. Here, from among the total amount of 517.43 g, 103.5 g of the reaction solution was used and transferred to the next step (down to ACTS 10 g scale).Water (30 mL) was added and then the solution was concentrated to an amount of 77.0 g at 40 C. and 5 kPa. AcOEt (100 mL) (10 L/kg) was added for liquid separation operation, and then 30 mL of water was added to the organic layer to perform liquid separation operation again. The organic layer was concentrated to an amount of 47.6 g at 40 C. and 10 kPa, and then 15 mL of AcOEt (1.5 L/kg) and 100 mL of THF (10 L/kg) were added. The solution was concentrated again to an amount of 50.7 g, and then THF was added to give the total amount of the solution is 146 g. The solution was concentrated again to an amount of 35.5 g, and then up to 30 mL of AcOEt (3 L/kg) and 100 mL of THF (10 L/kg) were added, to precipitate a solid. The solid was cooled to 5 C., and then aged overnight. The precipitated solid was filtered under reduced pressure, washed with 20 mL of THF (2.0 L/kg), dried at 30 C. overnight and then at 40 C. for 3 hours under reduced pressure, to obtain 24.9 g of the target product as a white solid (net 23.0 g, 83.6%).1H-NMR (400 MHz, DMSO-d6): delta 8.86 (bs, 1H), 8.09 (s, 1H), 7.88 (s, 1H), 7.25 (d, 1H, J=1.6 Hz), 7.14 (d, 1H, J=7.6 Hz), 6.60 (t, 1H, J=5.6 Hz), 4.00-3.90 (m, 1H), 3.60-3.50 (m, 1H), 3.30-3.20 (m, 1H), 3.15-3.05 (m, 6H), 2.19 (s, 3H), 1.50-1.30 (m, 18H), 1.20-1.10 (m, 9H)To 150.2 g of CDI (926.6 mmol, 1.1 eq. vs Boc-DAP-OtBu), 750 mL of acetone (3.0 L/kg) was added and then stirred at 5 C. Boc-DAP-OtBu (250 g) (842.6 mmol) was added in 2 portions, and then 125 mL of acetone (0.5 L/kg) was added to wash. After 30 minutes of stirring, the completion of imidazoyl carbonylation was confirmed by HPLC. ACHB (282.6 g) (1263.8 mmol, 1.5 eq.) was added in 3 portions, and then 125 mL of acetone (0.5 L/kg) was added to wash. The temperature was increased to 30 C., the reaction solution was stirred for 18 hours, and then the completion of the urea forming reaction was confirmed by HPLC. The reaction solution was cooled to 5 C., and then 124.5 mL of concentrated hydrochloric acid (1432.4 mmol, 1.7 eq.) was added, followed by 1 hour of stirring. The precipitated undesired substances were filtered off, and then the precipitated undesired substance was washed with 1000 mL of acetone (4.0 L/kg). The filtrate was concentrated to an amount of 1018 g (4.1 kg/kg), the temperature was increased to 50 C., and then 625.0 mL of concentrated hydrochloric acid (7187 mmol, 8.5 eq.) was added dropwise. After 30 minutes of stirring, the completion of deprotection was confirmed by HPLC, and then 750 mL of water was added (3.0 L/kg). The solution was concentrated to an amount of 1730 g (6.9 kg/kg) under reduced pressure, to precipitate a solid. After 14 hours of stirring at 20 C., filtration under reduced pressure was performed. The filtered solid was washed with 500 mL of acetone (2.0 L/kg), and then dried under reduced pressure at 60 C. for 6 hours, to obtain 201.4 g of the target product (64.5%).

Molecular Weight:260.33
XLogP3:0.9
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:7
Exact Mass:260.17360725
Monoisotopic Mass:260.17360725
Topological Polar Surface Area:90.6
Heavy Atom Count:18
Complexity:302
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes