Fmoc-9-amino-4,7-dioxanonanoic acid

To a 200mL flask were added 5.0g BP103a (1.0eq), 50 ml water, 3.5 g NaHCOThe compound S9 (17.1 mg, 0.018 mmol) was dissolved in DMF (0.4 mL) and diethylamine (0.4 mL) was added to the solution at room temperature. After 1 h, the mixture was concentrated and the Fmoc-deprotected compound was afforded. In other flask, a mixture of Fmoc-1 1-amino-3, 6, 9-trioxaundecanoic acid (7.6 mg, 0.018 mmol, Broadpharm), NHS (3.0 mg, 0.026 mmol) and EDCHC1 (5.1 mg, 0.026 mmol) in DMF (0.4 mL) was prepared and the mixture was added to the Fmoc-deprotected compound in DMF (0.8 mL).After 16 h, the reaction was quenched with 15% citric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The crude compound was immediately used without further purification.The crude compound was dissolved in DMF (0.4 mL) and diethylamine (0.4 mL) was added to the solution at room temperature. After 1 h, the mixture was concentrated and theFmoc-deprotected compound was afforded. The residue was chromatographed on silica gel (3 g) with DCM/MeOH (30:1 to 5:1) to afford 6 (10.8 mg, 65% for the 3 steps). Pale yellow oil. HRMS (ESI) Calcd. For C38H73N11O16Na [M+Naf: 962.5129. Found: 962.5129. 'H NMR (300 MHz, CD3OD) oe 4.42 (dd, J= 8.5, 5.6 Hz, 1H), 4.08 (s, 2H), 4.05 (s, 2H), 4.00 (s, 2H), 3.79-3.54 (m, 42H), 3.47 (t, J 5.4 Hz, 3H), 3.43-3.37 (m, 5H), 3.27 (t, J= 7.1 Hz, 2H), 3.17 (t, J 5.0 Hz, 2H), 1.91-1.68 (m, 3H), 1.64-1.53 (m, 2H), 1.49-1.33 (m, 3H), 1.32 (s, 2H), 0.99-0.83 (m, 1H).The cmde compound S8 was dissolved in DMF (1 mL) and diethylamine (1 mL) was added to the solution at room temperature. After 1 h, the mixture was concentrated and the Fmoc-deprotected compound was afforded. In other flask, a mixture of Fmoc- 11-amino- 3, 6, 9-trioxaundecanoic acid (217.3 mg, 0.51 mmol, Broadpharm), NHS (116.5 mg, 1.01 mmol) and EDCHC1 (194.0 mg, 1.01 mmol) in DMF (2 mL) was prepared and the mixture was added to the Fmoc-deprotected compound in DMF (2 mL). After 15 h, the reaction wasquenched with 15% citric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel (20 g) with DCM/MeOH (50:1 to 10:1) to afford S9 (186.1 mg, 42% for the 5 steps). Pale yellow oil. HRMS (ESI) Calcd. For C45H69N10014 [M+Hj: 973.4989. Found:973.4981. 'H NMR (300 MHz, CD3OD) oe 7.80 (d, J 7.7 Hz, 2H), 7.65 (d, J= 7.5 Hz, 2H), 7.39 (t, J 7.0 Hz, 2H), 7.31 (t, J 7.5 Hz, 2H), 4.45-4.31 (m, 3H), 4.21 (t, J= 6.7 Hz, 1H), 4.01 (s, 2H), 3.95 (s, 2H), 3.72-3.56 (m, 27H), 3.51 (t, J= 5.3 Hz, 3H), 3.36 (td, J= 4.8, 3.2Hz, 6H), 3.22 (t, J= 7.0 Hz, 2H), 1.90-1.62 (m, 2H), 1.60-1.46 (m, 2H), 1.45-1.32 (m, 3H), 1.29 (s, 2H), 0.97-0.82 (m, 1H).The crude compound S7 was dissolved in DMF (2.5 mL) and diethylamine (2.5 mL)was added at room temperature. After 1 h, the mixture was concentrated and the Fmocdeprotected compound was afforded. In other flask, the mixture of 1 1-azido-3, 6, 9- trioxaundecanoic acid (133.0 mg, 0.57 mmol), NHS (131.7 mg, 1.14 mmol) and EDCHC1 (219.3 mg, 1.14 mmol) in DMF (1.5 mL) was prepared and the mixture was added to the Fmoc-deprotected compound in DMF (3.5 mL). After 21 h, the reaction was quenched with15% citric acid and extracted with ethyl acetate. The residue was chromatographed on silica gel (20 g) with DCM/MeOH (50:1 to 20:1) to afford SlO (154.7 mg, 53% for the 3 steps). Pale yellow oil. HRMS (ESI) Calcd. For C27H52N9O10 [M+Hf: 662.3832. Found: 662.3836. 'H NMR (300 MHz, CD3OD) oe 8.16 (t, J 5.6 Hz, 1H), 7.88 (d, J 8.1 Hz, 1H), 4.43 (td, J = 8.3, 5.6 Hz, 1H), 4.06 (s, 2H), 3.78-3.61 (m, 20H), 3.57 (t, J 5.4 Hz, 2H), 3.40 (t, J 5.1Hz, 6H), 3.10-2.99 (m, 2H), 1.91-1.65 (m, 2H), 1.59-1.48 (m, 3H), 1.45 (s, 9H), 1.43-1.32 (m, 2H).Fmoc-PEG-acetic acid (5.7 g, 13 mmol), HBTU (4.9 g, 13 mmol), HOBT (2.0 g, 13 mmol), and DIPEA (3.4 g, 26 mmol) were dissolved in DMF (25 mL). GFLG-MEDA-Z (5.1 g, 8.8 mmol) was dissolved in DMF (13 mL) and DIPEA (3.7 g, 29 mmol) and added to the previous solution prepared. The reaction mixture was stirred for 1.5 h at room temperature. DMF was removed under reduced pressure and the obtained residue was dissolved in 200 mL CH2Cl2, the solution was washed twice with 0.1 N HCl (200 mL) and followed by washing with water (200 mL). It was then dried over MgSO4 and CH2Cl2 was removed under vacuum to yield crude product. It was then purified by flash column chromatography to yield white solid product, FMOC-PEG-GFLG-MEDA-Z (6.2 g, 72%).To a 100mL three-necked flask were added compound BP103m20 6.2g (1.053eq), 6.7g BP103a06 (1.0eq), dichloromethane 50ml, DIEA 6.3g (3.0 eq), DEPC 4.0g (1.5 eq). After the completion of the reaction under the monitor of TLC, they were washed with 0.1mol/L HCl/water, sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate, and then chromatographed in a column to give 9.5 g BP103m21 as an oil.To a 200mL flask were added 5.0g BP103a (1.0eq), 50 ml water, 3.5 g NaHCO3(2.0eq), and stirred. A solution of 7.3 gFmoc-HOSU (1.0eq) in 50ml DME (ethylene glycol dimethyl ether) was added dropwise, it was replenished with 50ml THF, and stirred overnight. After the completion of the reaction under the monitor of TLC, the organic solvents were evaporated off, adjusted to pH=2 with dilute hydrochloric acid, extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 7.6g compound BP103a06 as an off-white solid.

Molecular Weight:429.5
XLogP3:2.2
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:14
Exact Mass:429.17875220
Monoisotopic Mass:429.17875220
Topological Polar Surface Area:103
Heavy Atom Count:31
Complexity:536
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes