A kind of preparation method of indiplon intermediate
A technology for indiplon and intermediates, which is applied in the field of preparation of indiplon intermediates, can solve the problems of poor cyclization regioselectivity, long reaction time, cumbersome post-processing and the like, achieves easy operation, reduced synthesis cost, The effect of increasing productivity
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Embodiment 1
[0021] Preparation of compound 3
[0022]
[0023] Add m-nitrobenzaldehyde 1 (75.5mg, 0.5mmol), 3-amino-4-cyanopyrazole 2 (54mg, 0.5mmol), triethylamine (101mg, 1mmol), ammonium iodide in a 35mL sealed tube (72.5mg, 0.5mmol), di-tert-butyl peroxide (219mg, 1.5mmol) and toluene (2mL), then placed in an oil bath at 130°C and stirred for 10h. Add 50mL of water to quench the reaction, extract with ethyl acetate (50mL×3), and then the organic phase is treated with 10% Na 2 S 2 o 3 The solution was washed successively with saturated brine, and dried over anhydrous sodium sulfate. It was filtered, spin-dried, and separated by silica gel column (petroleum ether / ethyl acetate=3 / 1, v / v) to obtain compound 3 (114 mg, 86%) as a yellow solid product. The characterization data of this compound are as follows: 1 H NMR (400MHz, DMSO-d 6 ): δ (ppm) 8.97 (d, J = 1.6Hz, 1H), 8.95 (d, J = 4.8Hz, 1H), 8.88 (s, 1H), 8.48 (dd, J = 8.0, 2.0Hz, 2H) ,7.92(t,J=8.0Hz,1H),7.72(d,J=4.4Hz,1H); 13...
Embodiment 2
[0025] Preparation of Compound 4
[0026]
[0027] Iron powder (184.8 mg, 3.3 mmol) and glacial acetic acid (20 mL) were put into a three-necked flask, stirred, heated to reflux for 10 min, and a solution of compound 3 (265 mg, 1 mmol) in glacial acetic acid (25 mL) was added dropwise. Maintain the reflux state, after the dropwise addition is completed, reflux for 4h. The reaction was quenched by adding 50 mL of water, extracted with ethyl acetate (50 mL×3), and then the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtered, spin-dried, and dried to give compound 4 (230 mg, 83%) as a white solid. The characterization data of this compound are as follows: 1 H NMR (400MHz, DMSO-d 6 ):δ(ppm)10.25(s,1H),8.89(d,J=4.4Hz,1H),8.86(s,1H),8.32(t,J=1.8Hz,1H),7.85–7.81(m, 1H), 7.70–7.67(m, 1H), 7.54(t, J=8.0Hz, 1H), 7.50(d, J=4.8Hz, 1H), 2.08(s, 3H); 13 C NMR (100MHz, DMSO-d 6 ):δ(ppm)168.7,153.8,151.1,147.5,147.3,139.4,129.9,129.1,124.3,...
Embodiment 3
[0029] Preparation of compound 5
[0030]
[0031] Sodium hydride (58mg, 2.4mmol) and anhydrous DMF (2mL) were put into a three-necked flask filled with nitrogen, stirred in an ice-water bath, a solution of compound 4 (110.8mg, 0.4mmol) in DMF (6mL) was added dropwise, and After the addition was completed, the reaction was carried out for 5 minutes, and methyl iodide (568 mg, 4 mmol) was added dropwise, and stirring was continued for 30 minutes in an ice-water bath. The reaction was quenched by adding 50 mL of water, extracted with ethyl acetate (50 mL×3), and then the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, spin-drying, and drying gave white solid compound 5, the target product indiplon intermediate (103.6 mg, 89%). The characterization data of this compound are as follows: 1 H NMR (400MHz, CDCl 3): δ (ppm) 8.83 (d, J = 4.4Hz, 1H), 8.45 (s, 1H), 8.02–7.95 (m, 2H), 7.70 (t, J = 7.6Hz, 1H), 7.51 (d, J=7.6Hz, 1H),...
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