FMOC-DAB(BOC)-OH

White powder

B. The suspension 50g146 . 8nmolFmoc-Dab-OH with 700 ml acetone: water = 1:in 1(v/v), in 0-10 °C add 38.4g176 . 1nmol (Boc)H-PHE-NH2 hydrochloride (114.2 mg, 200.7 g/mol, 0.57 mmol, 1 eq, Advanced ChemTech) was dissolved in 2 ml of dry DMF/DCM (1/1) and TEA (95 T, 101.19 g/mol, 0.73 G/CM3, 0.68 mmol, 1.2 eq) was added. After 30 mi- nutes, a DMF/DCM (1/1, 4 ML) solution containing Fmoc-Dbu (Boc)-OH (250.2 mg, 440.5 g/mol, 0.57 mmol, 1 eq), DIC (89 LLI, 126.20 g/mol, 0.805 G/CM3, 0.57 mmol, 1 eq) and HOBt (77.6 mg, 135.12 g/mol, 0.57 mmol, 1eq) was added. After overnight stirring, solvent was evaporated and DCM (30 ML) was added. Organic phase was washed three times with water (10 ML) and once with brine (10 ml). Part of the product precipitated from the water phase and after filtration it was combined with the evaporated organic phase. 333 mg of 4-(N-Boc-amino)-N'-((S)-1-carbamoyl-2-phenylethyl)-(S)-2-(N''-Fmoc-ami- no) butanamide was obtained as a white powder with quantitative yield.Fmoc-Dbu (Boc) -OH (1.00 g, 440.5 G/MOL, 2.27 mmol, 1 eq), DIC (355 PI, 126.20 G/MOL, 0.806 G/CM3, 2.27 MMOL, 1 eq) and HOBt (308.2 mg, 135.12 G/MOL, 2.27 MMOL, 1 eq) were dissolved in dry DMF/DCM (1/1, 10 ML). After 5 minutes, benzylamine (248 lli, 107.16 g/mol, 2.27 mmol, 1 eq, Acros) was added to the reaction mixture and temperature raised to 35°C. After over- night stirring, solvent was evaporated and residue dissolved in DCM and washed twice with water and once with brine. Organic phase was dried with NA2SO4 and solvent evaporated. Residue was purified with silica column chromatography (mobile phase from DCM up to 5percent MEOH in DCM). N-Benzyl- 4- (N'-Boc-amino)- (S)-2- (N'-Fmoc-amino) butanamide was obtained with quan- titative yield.To a round bottomed flask with stir bar under nitrogen wasadded carboxylic acid 1 (500 mg, 1.13 mmol) and anhydrous DCM (25 mL). Benzylamine (0.15 mL, 1.4 mmol), HOBt (229 mg, 1.50 mmol), and EDCHCl (433 mg, 2.26 mmol) were added andthe reaction was stirred under nitrogen for 2 h. A sample aliquotwas taken from the reaction, concentrated under reduced pressure, dissolved in a minimal amount of HPLC grade MeCN, and analyzedwith LC-MS to confirm reaction completion. The reaction wasdiluted with DCM (75 mL) and washed with saturated NaHCO3(30 mL), 1 M HCl (30 mL), brine, dried over MgSO4, filtered, andconcentrated under reduced pressure to give 2 (588 mg) as a whitesolid in 98percent yield. mp = 154'156 C; LC-MS tR = 6.09 min (CharacterizationMethod A); m/z = 530.05 (M+H+); 1H NMR (300 MHz, CDCl3) d = 7.76 (d, J = 7.6 Hz, 2H), 7.61'7.49 (overlapping signals, 3H), 7.43'7.22 (m, 9H), 5.96 (d, J = 6.7 Hz, 1H), 5.11 (br. m., 1H), 4.50'4.13 (overlapping m, 6H), 3.48'3.32 (br s., 1H), 3.04'2.90(br m., 1H), 1.97'1.71 (overlapping signals, 2H), 1.45'1.37 (m, 9H); 13C NMR (75 MHz, CDCl3) d = 171.2, 157.2, 156.3, 143.9, 141.5, 138.0, 128.8, 127.9, 127.8, 127.6, 127.3, 125.3, 120.2, 80.1, 67.2, 52.2, 47.3, 43.8, 37.0, 34.9, 28.6.Synthesis of (S)-4-methylnaphthalene-1 -sulfonic acid (3-amino-1-benzyI- aminomethylpropyl)amide (compound 2); Step .; [0068] Fmoc-L-Dab(Boc)-OH (1.00 g, 440.50 g/mol, 2.27 mmol, 1 eq), DIG (355 mul, 126.20 g/mol, 0.806 g/cm3, 2.27 mmol, 1 eq) and HOBt (308 mg, 135.12 g/mol, 2.27 mmol, 1 eq) were dissolved in DMF/DCM (1/1 , 10 ml, dry). EPO Solid-Phase Synthesis of Compound 102 (Scheme AB) Benzenepropanamide, N-[(1S)-3-amino-1-[[(phenylmethyl)amino] carbonyl]propyl]-alpha-[[[[1-[(2, 6-d ichlorophenyl)methyl]-3-(1-pyrrolidinylmethyl)-1H-indol-6-yl]amino]carbonyl]amino]-3, 4-difluoro-, (AS)- (Compound 102) [0149] To a solution of N-alpha-Fmoc-N-gamma-Boc-diaminobutyric acid (4.0 g, 9.1 mmol) and BnNH2 (1.07 g, 10 mmol) in CH3CN (150 mL), HOBt (1.85 g, 13.7 mmol) and DCC (2.82 g, 13.7 mmol) were added.The mixture was stirred at about rt for about 2.5 h, at which time TLC indicated that reaction was complete.The resulting white precipitates (a mixture of the desired product and dicyclohexylurea) were collected by filtering and washing with CH3CN. The combined filtrates were concentrated under vacuo and the residue was dissolved in EtOAc (150 mL).The solution was washed with saturated NaHCO3, H2O and brine, then dried (Na2SO4) and evaporated to give a white powder which was recrystallized from CH3CN to afford an additional product. The combined crude products were treated with 50percent TFA in CH2Cl2 (80 mL) at about rt for about 1 h. The volatiles were removed under vacuo, and the residue was triturated with Et2O to give AB2 as a colorless solid. 1H NMR showed the product was a mixture of AB2 and dicyclohexylurea (ratio 1:1.4). To a solution of the crude AB2 (6.16 g, 7.14 mmol) and DIEA (2.71 g, 21.0 mmol) in DCM-DMF (1:1, 120 mL), 2-chlorotrityl chloride resin (4.0 g, 4.2 mmol) was added; the suspension was stirred at about rt for about 20 h. The reaction mixture was filtered on a sintered glass funnel and washed with DMF (2*), MeOH (3*) and DCM (3*), then dried in vacuo to give the resin. A portion of the resin (4.9 g) was treated with 20percent piperidine in DMF (80 mL) at about rt for about 2 h, then filtered and washed with DMF (2*), MeOH (2*), DCM (2*) and Et2O (2*) and dried in vacuo to afford resin AB3 (loading level of 0.81 mmol/g, based on the mass loss during removing Fmoc group). A portion of AB3 (1.6 g, 1.3 mmol) was suspended in DMF (50 mL) and treated with Fmoc-3, 4-diF-Phe-OH (1.65 g, 3.9 mmol), HOBT (0.53 g, 3.9 mmol), DIEA (1.01 g, 7.8 mmol) and HBTU (1.48 g, 3.9 mmol). The suspension was stirred at about rt for about 20 h, then filtered and washed with DMF, MeOH and DCM. The resulting resin was treated with 20percent piperidine in DMF (40 mL) at about rt for about 2 h, then filtered and washed with DMF (2*), MeOH (2*), DCM (2*) and Et2O (2*) to afford resin AB4. To 4-Nitrophenyl chloroformate (613 mg, 3.0 mmol) in dry DCM (60 mL) at about -20° C., a solution of AA2b (1.14 g, 3.9 mmol) and DIEA (1.0 g, 8.0 mmol) in DCM (20 mL) was added over about 4 min and then stirred at about -20° C. for about 20 min. The dipeptidyl resin AB4 (1.14 g, 0.80 mmol) was added and stirred at about -20° C. for about 25 min and then at about rt for about 18 h. The suspension was filtered and washed with DMF, MeOH, DCM and Et2O and then dried in vacuo to give resin AB5. To a solution of pyrrolidine (2.33 g, 33.0 mmol) and formaldehyde (37percent, 2.14 g, 26.4 mmol) in 1, 4-dioxane/glacial acetic acid (4:1; 60 mL) was added resin AB5 (1.20 g, 0.66 mmol) in one portion. The suspension was stirred at about rt for about 16 h, then filtered and washed with MeOH, DCM and Et2O and dried in vacuo to afford resin. A portion of the resin (400 mg, 0.23 mmol) was treated with TFA:DCM:anisole (30:70:0.50, 12 mL) at about rt for about 1.5 h; the reaction mixture was then filtered and washed with fresh 30percent TFA in DCM. The filtrates were combined and evaporated in vacuo and the residue triturated with diethyl ether (3*) to give the crude product as a light purple solid (>95percent purity by HPLC). The crude product was purified by reverse-phase HPLC to give Compound 102 as a colorless solid. 1H NMR (CD3OD) delta 7.83 (s, 1H), 7.62-7.02 (m, 14H), 5.43 (d, J=2.7 Hz, 2H), 4.53-4.46 (m, 2H), 4.44 (s, 2H), 4.38 (d, J=5.6 Hz, 2H), 3.42-3.31 (m, 2H), 3.29-2.93 (m, 6H), 2.22-1.85 (m, 6H). ES-MS m/z 790 (MH+). Anal. calcd. for C41H43Cl2F2N7O32.74 CF3CO2H * 0.50H2O (790.74/1112.18): C, 50.20; H, 4.24; N, 8.82; F, 17.46. Found: C, 50.17; H, 4.10; N, 8.79; F, 17.73.

Fmoc-Dab(Boc)-OH,

Molecular Weight:440.5
XLogP3:3.7
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:10
Exact Mass:440.19473662
Monoisotopic Mass:440.19473662
Topological Polar Surface Area:114
Heavy Atom Count:32
Complexity:654
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes