MYF-03-42

To a suspension of 60% NaH (323 mg, 8.1 mmol) in THF (20 mL) was added the solution of 1H-pyrazole (551 mg, 8.1 mmol) in THF (5 mL), the mixture was stirred at 0 °C under N₂ for 30 min, and then tert-butyl 6-oxa-3-azabicyclo[3.1.0] hexane-3-carboxylate (1.0 g, 5.4 mmol) was added. The resulting mixture was heated at 60 °C under N₂ for 16 hr. After cooled down to room temperature the mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated and purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether = 40% v/v) to afford compound 3 as solid (600 mg, yield 44%). LC-MS (ESI) m/z: 254 [M+H]⁺.

A mixture of compound 3 (300 mg, 1.18 mmol), 1-(bromomethyl)–4-(trifluoromethyl)benzene (283 mg, 1.18 mmol) and 60% NaH (47 mg, 1.18 mmol) in DMF (10 mL) was stirred at room temperature under N₂ for 2 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2), the combined organic was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to obtain compound 5 as yellow oil (400 mg, yield 82%). LC-MS (ESI) m/z: 356 [M-56+H]⁺.

A mixture of compound 5 (300 mg, 0.72 mmol) and TFA (3 mL) in DCM (10 mL) was stirred at room temperature for 2 hr. The mixture was concentrated to leave crude compound 6 (250 mg) as yellow oil, which was used directly in the next step. LC-MS (ESI) m/z: 312[M+H]⁺.

A mixture of compound 6 (70 mg, 0.22 mmol), acryloyl chloride (20 mg, 0.22 mmol), and TEA (44 mg, 0.44 mmol) in DCM (10 mL) was stirred at room temperature under N₂ for 2 hr. The mixture was concentrated, the residue was purified by prep-HPLC to afford MYF-03–42 as yellow oil (50 mg, yield 62%). LC-MS (ESI) m/z: 366[M+H]⁺.

¹H-NMR (400 MHz, CD₃OD): δ (ppm) 7.74 (dd, J=5.2, 2.4 Hz, 1 H), 7.63 (d, J=8.0 Hz, 2 H), 7.56 (d, J=1.6 Hz, 1 H), 7.47 (d, J=8.1 Hz, 2 H), 6.66–6.59 (dd, J=16.8, 10.4 Hz, 1 H), 6.36–6.30 (m, 2 H), 5.85–5.74 (m, 1 H), 5.18–5.02 (m, 1 H), 4.68 (d, J=5.8 Hz, 2 H), 4.51–4.42 (m, 1 H), 4.28–4.08 (m, 2 H), 4.01–3.93 (m, 1 H), 3.83–3.65 (m, 1 H).

was synthesized through the same route as MYF-03–42 except 1-(bromomethyl)–3-(trifluoromethyl)benzene was used in Step 2 instead of 1-(bromomethyl)–4-(trifluoromethyl)benzene. MYF-02–111 was obtained as light yellow oil. LC-MS (ESI) m/z: 366[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (ddd, J=9.3, 2.3, 0.7 Hz, 1 H), 7.69–7.54 (m, 4 H), 7.53–7.48 (m, 1 H), 6.61 (dd, J=16.8, 10.3 Hz, 1 H), 6.30 (dt, J=3.4, 2.1 Hz, 1 H), 6.17 (dt, J=16.7, 2.5 Hz, 1 H), 5.70 (td, J=9.9, 2.3 Hz, 1 H), 5.13 (ddt, J=33.6, 7.8, 3.4 Hz, 1 H), 4.66 (d, J=4.0 Hz, 2 H), 4.39 (ddd, J=25.5, 4.1, 1.7 Hz, 1 H), 4.19–4.09 (m, 0.5 H), 4.07–3.87 (m, 1.5 H), 3.86–3.70 (m, 1.5 H), 3.52 (dd, J=13.0, 4.0 Hz, 0.5 H).