| 72% |
Stage #1: 1,4-Diazacycloheptane; 4-picolylchloride hydrochloride With ethanol; acetyl chloride In ethanol for 17.5h; Heating / reflux;
Stage #2: With potassium hydroxide In dichloromethane; water |
[00324] A solution of acetyl chloride (6.34 mL, 0.084 mol, 4 equiv) dissolved in anhydrous EtOH (50 mL) was stirred for 0.5 h and added to a solution of homopiperazine (10.4 g, 0.1 mol, 5 equiv) in EtOH (250 mL). The reaction mixture was heated to reflux for 1 h, cooled to 25° C. and a solution of 4-picolyl chloride hydrochloride 93.44 g, 0.021 mol) in EtOH (40 mL) was added. The reaction mixture was heated to reflux for 16 h, cooled to 25° C. and the solvent was removed under vacuum. The residue was diluted with CH2Cl2 (300 mL) and was washed with 2N KOH (1×300 mL). The aqueous layer was extracted with CH2Cl2 (1×300 mL) and the organic phase was washed with 2N KOH (150 mL), dried (MgSO4) and concentrated. Chromatography (SiO2, 5% H2O-5% NH4OH-1PrOH) afforded the desired product (2.88 g, 4.01 g theoretical, 72%) as a yellow oil. TLC Rf 0.45 (5% H2O-5% NH4OH-1PrOH): 1H NMR (CDCl3, 300 MHz) δ 8.77 (d, J=5.9 Hz, 2H), 7.53 (d, J=5.7 Hz, 2H), 3.91 (s, 2H), 3,19 (m, 4H), 2.92 (m, 4H), 2.04 (m, 2H). |
| 39% |
With potassium carbonate In methanol at 20℃; for 16h; |
2-(4-(2-(4-(pyridin-4-ylmethyl)-1,4-diazepan-1-yl)ethoxy)phenyl)-4H-chromen-4-one (FM14)
2-(4-(2-(4-(pyridin-4-ylmethyl)-1,4-diazepan-1-yl)ethoxy)phenyl)-4H-chromen-4-one (FM14) (0115) To a well stirred mixture of diamine 20 (17 g, 170 mmol) and 4-chloromethylpyridine hydrochloride (12 g, 73 mmol) and K2CO3 (11 g, 80 mmol) in MeOH (100 mL) at room temperature, was stirred for 16 h. After that, the mixture was poured into separating funnel containing 5% NaOH solution (200 mL) and extracted with DCM (50 mL×3). The combined organic layers were dried over MgSO4, filtered and evaporated to crude brown oil which was subjected to vacuum distillation to furnish diamine 21 (5.4 g, 28 mmol) in 39% yield. To a well stirred mixture of diamine 21 (5.0 g, 26 mmol), 2-bromoethanol (3.6 g, 29 mmol) and K2CO3 (4.0 g, 29 mmol) in ACN (60 mL), was heated to reflux for 14 h. The mixture was filtered and evaporated under reduced pressure to give brown oil which was subjected flash column chromatography on silica gel with gradient elution (3% MeOH in DCM to 8% MeOH in DCM) to furnish alcohol 22 (3.1 g, 13 mmol) in 50% yield. To a well stirred mixture of alcohol 22 (0.64 g, 2.7 mmol), 4′-hydroxyflavone (0.64 g, 2.7 mmol) and PPh3 (0.80 g, 3.1 mmol) in THF (30 mL), was added DIAD (0.61 g, 3.0 mmol) dropwise. The reaction mixture was further headed to reflux for 12 h. The reaction mixture was evaporated under reduced pressure to give brown oil which was subjected flash column chromatography on silica gel with gradient elution (20% acetone in DCM to 80% acetone to DCM) to furnish the desired product FM14 (0.36 g, 0.79 mmol) in 29% yield: 1H NMR (400 MHz, CHLOROFORM-d) δ 8.51 (d, J=5.38 Hz, 2H), 8.19 (d, J=7.82 Hz, 1H), 7.84 (d, J=8.80 Hz, 2H), 7.63-7.67 (m, 1H), 7.52 (d, J=8.31 Hz, 1H), 7.37 (t, J=7.34 Hz, 1H), 7.26 (d, J=5.87 Hz, 4H), 7.00 (d, J=8.80 Hz, 2H), 6.71 (s, 1H), 4.12 (t, J=5.87 Hz, 2H), 3.58-3.69 (m, 2H), 3.00 (t, J=5.87 Hz, 2H), 2.82-2.90 (m, 4H), 2.62-2.75 (m, 6H), 1.74-1.85 (m, 2H), 1.20-1.25 (m, 2H); 13C NMR (101 MHz, CHLOROFORM-d) δ 178.3, 163.3, 161.7, 156.1, 149.7, 148.9, 133.5, 128.0, 125.6, 125.0, 124.0, 123.9, 123.6, 117.9, 115.0, 106.1, 66.8, 61.7, 56.4, 55.7, 55.3, 54.6, 54.5, 27.8, 22.0; LRMS (ESI) m/z 456 (M++H, 100); HRMS (ESI) calcd for C28H30N3O3 (M++H) 456.2287. Found 456.2277. |
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