Methyl 4-hydroxynicotinate

white powder

Step 1 Methyl 4-hydroxynicotinate 4-Hydroxynicotinic acid (5.00 g, 35.94 mmol) was dissolved in methanol (50.00 mL), added with sulfuric acid (18M, 100.00 uL), and then stirred at 70 C. under nitrogen atmosphere for 12 hours. After the reaction mixture was concentrated, the residue was dissolved in dichloromethane (50.00 mL) and the system was adjusted to pH=8 with saturated sodium bicarbonate solution. A white solid was slowly precipitated and filtered to give Step 2 Methyl 4-(2-((3R, 4aR, 6aS, 7R, 10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2, 1-d][1, 3]dioxin-7-yl)ethoxy) nicotinate (3R, 4aR, 6aS, 7R, 10bR)-7-(2-bromoethyl)-3-cyclopentyl-6a, 10b-dimeth yl-8-dihydromethylene-1H-naphtho[2, 1-d][1, 3]dioxin (300.00 mg, 729.20 umol) was dissolved in N, N-dimethylformamide (5.00 mL), and potassium carbonate (201.57 mg, 1.46 mmol) and methyl 4-hydroxynicotate (223.34 mg, 1.46 mmol) were added successively and then stirred at 70 C. for 12 hours under nitrogen atmosphere. The reaction was quenched by adding 30 mL water and then extracted with ethyl acetate (30.00 mL). The organic phase was successively washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (silica, petroleum ether/ethyl acetate=1/1) to give methyl 4-(2-((3R, 4aR, 6aS, 7R, 10bR)-3-cyclopentyl-6a, 10b-dimethyl-8-dihydromethylene decahydro-1H-naphtho[2, 1-d][1, 3]dioxin-7-yl)ethoxy) nicotinate (a yellow oil, 200 mg, yield: 56.71%). 1H NMR (400 MHz, CDCl3) 8.89 (s, 1H), 8.51 (d, J=6.0 Hz, 1H), 6.80 (d, J=5.8 Hz, 1H), 4.88 (s, 1H), 4.66-4.50 (m, 2H), 4.24-4.14 (m, 1H), 4.03 (d, J=11.3 Hz, 1H), 3.98-3.85 (m, 4H), 3.54-3.39 (m, 2H), 2.42 (d, J=12.3 Hz, 1H), 2.27 (dq, J=3.0, 13.2 Hz, 1H), 2.16-2.04 (m, 2H), 1.95-1.87 (m, 3H), 1.83-1.76 (m, 1H), 1.72-1.67 (m, 3H), 1.54 (td, J=7.4, 19.3 Hz, 4H), 1.49-1.38 (m, 3H), 1.36 (s, 3H), 1.30-1.24 (m, 3H), 0.79 (s, 3H).