Chemical Synthesis
All reagents were purchased from commercial sources and used without further purification. NMR spectra were generated on a Bruker 500 MHz instrument. High-resolution mass spectra were gathered on a Bruker Micro-TOF-Q II LCMS instrument operating in electrospray ionization (ESI). High-pressure liquid chromatography (HPLC, Agilent Technologies 1200 Series) was conducted on an Eclipse XDB C18 column (5 µm, 4.6 mm × 150 mm) for purity Determination. All compounds are >95% pure by HPLC analysis.
Synthesis of methyl 4-(2-(piperidin-1-yl) epoxy) benzoate (2). The DIAD (17.3 g, 85.4 mmol) was purchased and added dropwise to a solution of methyl- 4-hydroxybenzoate (10 g, 65.7 mmol), 2-(piperidin-1-yl) ethan-1-ol (10.2 g, 78.9 mmol) and PPh3 (22.4 g, 85.4 mmol) in dry THF (200 ml) at 0°C under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. After completion, the reaction mixture was concentrated by drying under reduced pressure. The residue was immersed in 1 N HCl aqueous solution (200 ml) and extracted with ethyl acetate 3 times (150 ml×3). The aqueous phase was adjusted to pH = 8 with solid sodium bicarbonate and extracted with ethyl acetate 3 times (150 ml×3), after which the combined organic layers were dried over anhydrous sulfate sodium and concentrated to give ethyl 4-(2-(piperidin-1-yl) epoxy) benzoate (2) as a white solid (10 g, 57.8% yield). 1H NMR (CDCl3, 300 MHz) δ: 8.0 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 4.17 (t, J = 6.0 Hz, 2H), 3.90 (s, 3H), 2.82 (t, J = 6.0 Hz, 2H), 2.58-2.55 (m, 4H), 1.66-1.61 (m, 4H), 1.50 (t, J = 3.0 Hz, 2H).
(4-(2-(piperidin-1-yl) ethyl) phenyl) methanol (3). LiAlH4 (1.44 g, 40 mmol) was slowly added to a solution of methyl-4-(2-(piperidin-1-yl) epoxy) benzoate (10 g, 40 mmol) in dry THF (200 ml) at 0°C. The mixture was stirred at 0°C for 30 min. After completion, 15% NaOH (1.5 ml) and water (1.5 ml) were added. The resulting mixture was filtered through a pad of Celite and rinsed with ethyl acetate. The filtrate was dried over a hydrous sulfate sodium and concentrated to give (4-(2-(piperidin-1-yl) ethyl) phenyl) methanol (3) as a white solid (8 g, 90% yield). 1H NMR (CDCl3, 300 MHz) δ: 7.30 (d, J = 6.0 Hz, 2H), 6.92 (d, J = 6.0 Hz, 2H), 4.64 (s, 2H), 4.17 (t, J = 6.0 Hz, 2H), 2.98 (t, J = 6.0 Hz, 2H), 2.74 (m, 4H), 1.89-1.86 (m, 6H).
1-(2-(4-(((4-nitronaphthalen-1-yl) foxy) methyl) phenol)-ethyl) piperidine (4). NaH (60%, 1.46 g, 36.6 mmol) was added to a solution of (4-(2-(piperidin-1-yl) ethyl) phe-yl) methanol (7.39 g, 31.4 mmol) in dry THF (100 ml) at 0°C under nitrogen, and the mixture was stirred at 0°C for 30 min. Then,1-fluoro-4-nitronaphthalene (5 g, 26.2 mmol) was added and stirred at room temperature for 12 h. After completion, the reaction mixture was poured into sat. NH4Cl (100 ml) and extracted with ethyl acetate 3 times (100 ml × 3). Combined organic layers were dried over anhydrous sulfate sodium and concentrated to give a residue. The residue was purified by silica gel column (elution with DCM/MeOH = 100/1 ~ 50/1) to give 1-(2-(4-LRB-4-nitronaphthalen-1yl) foxy) methyl) phenol) ethyl) piperidine (4) as a brown solid (7 g, 65.6% yield). 1H NMR (CDCl3, 400 MHz) δ: 8.81 (d, J = 8.0 Hz, 2H), 8.45-8.41 (m, 2H), 7.77-7.75 (m, 1H), 7.63-7.60 (m, 1H),7.47 (d, J = 8.0 Hz, 2H), 7.0 (d, J = 8.0 Hz, 2H), 6.93-6.90 (m, 1H), 5.32 (s, 2H), 1.89-1.86 (m, 6H), 4.37 (t, J = 6.0 Hz, 2H), 3.55-3.30 (m, 4H), 2.97 (t, J = 6.0 Hz, 2H), 1.79-1.67 (m, 4H), 1.65 (m, 4H), 1.39-1.20 (m, 2H).
Synthesis of 4-((4-(2-(piperidin-1-yl) ethyl) benzyl) foxy)-naphthalen-1-amine hydrochloride (SMY002). Fe (3.43 g, 61.5 mmol) was slowly added to a solution of 1-(2-(4--LRB-4-nitronaphthalen-1-yl) foxy) methyl) phenol) ethyl) piperidine (5 g, 12.3 mmol) in EtOH (50 ml). HCl (1 M, 20 ml) was added at 50°C, and the mixture was stirred at 50°C for 2 h. Then, the mixture was concentrated to remove EtOH, diluted with water (80 ml), and then extracted with DCM/MeOH (10/1, 100 ml × 3). Combined organic layers were dried over a hydrous sulfate sodium and concentrated to give a residue. The residue was purified by silica gel column (elution with DCM/MeOH =100/1~30/1) to give 4--LRB-4-(2-(piperidi-1-yl) ethyl) benzyl) foxy) naphthalen-1-amine hydrochloride (SMY002) as a red solid (2.3 g, 49.6% yield). 1H NMR (CDCl3, 300 MHz) 8.20 (d, J = 9.0 Hz, 1H), 8.13 (d, J = 9.0 Hz, 2H), 7.63-7.52 (m, 2H), 7.34-7.21 (m, 3H), 6.92 (d, J = 9.0 Hz, 1H), 6.82 (d, J = 9.0 Hz, 1H), 4.50 (s, 2H), 4.37 (t, J = 6.0 Hz, 2H), 3.55-3.30 (m, 4H), 2.97 (t, J = 6.0 Hz, 2H), 1.79-1.67 (m, 4H), 1.65 (m, 4H), 1.39-1.20 (m, 2H).