4-(4-Cyclopropyl-1-naphthalenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione

Preparation of 4-(4-cyclopropylnaphthalen-l-yl)-4H-l, 2, 4-triazole-3-thiol [070] To a round bottom flask added 4-(4-cyclopropyl-naphthalen-l-yl) -1-formylamino-thiourea (64.0 g, 225 mmol), DMF (300 mL) and 1 mol/L aqueous sodium hydroxide solution (225 mL) to form a mixture, the mixture was heated to about 30°C after stirred for about 16 hours, the mixture was cooled to room temperature (about 20°C). 1 mol/L hydrochloric acid (about 200 mL) was added into the mixture until the pH value of the mixture was about 6.0, then water (about 500 mL) was added. The mixture was stirred for about 15 minutes and filtered. The filter cake was washed with water, and the product was dried in vacuum at about 50°C for about 5 hours to obtain gray-green solid 4-(4-cyclopropylnaphthalen-l-yl)-4H-l, 2, 4-triazole-3 -thiol, 54.0 g, yield 90percent. LC-Ms: m/z (ESI): 268(M+H)In a 100 ml three-necked flask equipped with a stirrer and a thermometer, 50 ml of tetrahydrofuran was added, and the intermediate(II) 2.62 g, 30 ml of 0.5 mol / L cyclopropylmagnesium bromide / THF solution was added;Add, stir for 2 hours, add saturated ammonium chloride quenching, filtration, the filtrate concentrated to remove THF, then add dichloromethane 25mlAnd the mixture was concentrated twice to give dichloromethane to give 2.4 g of product, i.e., intermediate (III), and the yield89.89percent.A pressure vessel containing the compound of Formula (5) (10 g, 37.40 mmol) and methyl 3-bromopropionate (7.73 g, 44.88 mmol) in N, N-dimethylformamide (70 mL) was sealed and heated to an external temperature of 60 C. for 3 days. The reaction was then cooled to room temperature to allow for a sample of the reaction mixture to be taken for 1H-NMR analysis (91% conversion). Methyl 3-bromopropionate (97%, 1.25 g, 7.48 mmol) was charged to the vessel and the reaction was re-sealed and heated to an external temperature of 60 C. for 24 hours. Following completion of the reaction, the reaction solution was concentrated in vacuo at 35-40 C. to remove the N, N-dimethylformamide. The resulting oil residue was then dissolved in dichloromethane (100 mL) and washed with a saturated aqueous sodium bicarbonate solution (50 mL), with the organic phase being dried over anhydrous sodium sulfate and concentrated in vacuo at 30-35 C. to afford a green oil (17.07 g). The oil was purified by silica gel column chromatography (column 27 cm*6 cm), using a gradient system of ethyl acetate and heptanes (2 L, 40:60 ethyl acetate:heptanes; 1 L, 50:50 ethyl acetate:heptanes; 2 L, ethyl acetate) to afford the compound of Formula (11) (9.75 g; 67% yield from the compound of Formula (5)) as a dark oil. 1H-NMR (CDCl3, 300 MHz) delta: 0.78-0.93 (2H, m), 1.12-1.21 (2H, m), 2.42 (1H, tt, J=5.44 Hz, 8.46 Hz), 2.91 (2H, t, J=6.77 Hz), 3.47 (2H, t, J=6.86 Hz), 3.64 (3H, s), 7.30 (1H, d, J=8.25 Hz), 7.35 (2H, s), 7.57 (1H, apparent dt, J=1.02 Hz, 8.22 Hz), 7.66 (1H, apparent dt, J=1.02 Hz, 8.04 Hz), 8.30 (1H, s), 8.54 (1H, d, J=8.44 Hz).