Preparation method of benzothiophene derivative
A technology for benzothiophene and derivatives, which is applied in the field of preparation of benzothiophene derivatives, can solve the problems of many reaction steps, low reaction yield, and high production cost, and achieves fewer reaction steps, high purity, and fewer reaction by-products. Effect
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Embodiment 1
[0051] Preparation of formula compound 3
[0052]
[0053] 7-Aminobenzothiophene (1.49g, 0.01mol), ethylene oxide (4ml) and tetrahydrofuran (40ml) were mixed and stirred for 12 hours. Sampling was performed to detect that the reaction was complete, and the solvent was spin-dried to obtain 2.2g of a yellow oily substance of formula II. The crude product goes directly to the next step;
[0054] 1H NMR (CDCl 3 ): δ: 7.59-7.13 (5H, m), 3.65 (4H, t, J = 4Hz), 3.42 (4H, t, J = 4Hz), 2.79 (2H, br).
[0055] The crude compound of the above formula II (2.2g) was dissolved in 30ml of dichloromethane, triethylamine (3ml, 0.022mol, 2.2eq) was added, stirred in an ice bath, and after the reaction was cooled to below 10°C, methanesulfonyl chloride (2.31g , 0.02mol, 2eq), the addition is completed, the temperature is naturally raised and stirred for 3h, and the sample is tested. Wash with 1N hydrochloric acid, saturated aqueous sodium bicarbonate and saturated brine, dry over anhydrous...
Embodiment 2
[0057] The preparation of formula compound 4
[0058]
[0059] Trans-2-(4-Bocaminocyclohexyl)ethyl p-toluenesulfonate (3.97g, 0.01mol, 1eq) was dissolved in DMF (20ml), and sodium azide (0.8g, 0.012mol, 1.2 eq), after the addition, stir at room temperature for 4 hours, take a sample to detect the complete reaction of the raw materials, pour the reaction solution into 150ml of ice water, extract with ethyl acetate (50ml*3), combine the organic phases, wash with saturated saline, and dry over anhydrous sodium sulfate , filtered with suction, and spin-dried to obtain 3.2 g of white solid;
[0060] Dissolve 3.2 g of the above intermediate in THF (30 ml), add palladium carbon (0.5 g), replace with hydrogen 3 times, stir and react at room temperature for 4 hours, take a sample to detect the complete reaction of raw materials, filter out palladium carbon, and spin dry to obtain 2.3 g of a light yellow solid (formula compound 4);
[0061] 1H NMR (CDCl 3 )δ: 4.37 (1H, br), 3.39 (...
Embodiment 3
[0063] The preparation of formula compound 2
[0064]
[0065] Formula compound 4 (2.42g, 0.01mol), formula compound 3 (3.93g, 0.01mol, 1eq), potassium carbonate (4.14g, 0.03mol, 3eq) and acetonitrile (50ml) were mixed and heated under reflux for 16h, and the reaction was detected by sampling Finally, the solvent was spin-dried, the residue was stirred with water and ethyl acetate, separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, spin-dried, and column chromatography Purification, eluent: petroleum ether: ethyl acetate = 1:1 ~ 0:1, to obtain compound 2, white solid 2.88g, yield 65%;
[0066] 1H-NMR (CDCl 3 )δppm: 7.81 (1H, brs), 7.78 (1H, d, J = 5.5Hz), 7.73 (1H, d, J = 8.1Hz), 7.41 (1H, m), 7.30 (1H, d, 7.6Hz) , 6.94(1H,d,J=7.6Hz), 3.54(1H,m), 3.35-3.23(8H,m), 2.46(2H,m), 1.86-1.65(8H,m), 1.51-1.49(1H ,m), 1.42(9H,s), 1.37-1.35(2H,m).
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