Preparation method and application of Smo inhibitor based on Nebivolol
An inhibitor and reaction technology, applied in the field of Smo inhibitor and its preparation and application, can solve problems such as drug resistance, and achieve the effects of high activity, good inhibitory activity and good drug-like properties
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Embodiment 1
[0042] The synthesis of embodiment 1 lead compound nebivolol
[0043] The synthetic route of lead compound nebivolol is as follows:
[0044]
[0045] 1. Preparation of compound 2, namely 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol
[0046]
[0047] Add raw material compound 1, namely 6-fluorochroman-2-carboxylic acid (0.20g, 1mmol) into a round-bottomed flask, then add 20ml of solvent tetrahydrofuran, stir the mixed solution at 0°C, and slowly add boron dropwise to it Sodium hydride (0.11g, 3mmol), after dropping the temperature down to 0°C, slowly add 4ml of concentrated H dissolved in 8ml of ether to it 2 SO 4 (98%wt) (that is, 4ml of concentrated sulfuric acid dissolved in 8ml of ether), after stirring for a period of time, the reaction solution was placed at 35°C and stirred for 30min. Use a TLC plate to detect whether the reaction is over. After the reaction is over, place the reaction solution in an ice-water bath, then add methanol to it to quench the react...
Embodiment 2
[0084] The preparation of embodiment 2A series derivatives
[0085] The synthetic route of derivative A1 is as follows:
[0086]
[0087] The preparation method of target compound A1 is as follows:
[0088] Take compound 1 (0.39g, 2mmol) in a round-bottomed flask, add 10ml of anhydrous DMF (N,N-dimethylformamide) to dissolve, and then stir the solution at 0°C, add HOBt (1 -Hydroxybenzotriazole, 0.21g, 1.5mmol), EDCi (1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, 0.38g, 2mmol), DIPEA (N, N -diisopropylethylamine, 0.3ml, 3mmol) and catalytic amount of DMAP (chemical full name is 4-dimethylaminopyridine), after activation for 1h, compound 1,3-propanediamine (0.074g, 1mmol), and reacted at room temperature for 12h. After the reaction was completed, ethyl acetate was added to extract 2-3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a crude produc...
Embodiment 3
[0104] Embodiment 3: Preparation of B series derivatives
[0105] The synthetic route of derivative B1 is as follows:
[0106]
[0107] The preparation method of compound B1 is as follows:
[0108]Take compound 1 (0.24g, 1.2mmol) in a round bottom flask, add 5ml of anhydrous DMF to dissolve, then place the solution under stirring at 0°C, add HOBt (0.21g, 1.5mmol), EDCi (0.38g , 2mmol) and NMM (N-methylmorpholine, 0.3ml, 3mmol), after activation for 1h, compound 9 ((2S,6R)-2,6-dimethyl-4-(5-nitro Pyridin-2-yl)morpholine), 0.21g, 1mmol), and reacted at room temperature (25°C) for 12h. After the reaction, extract 2-3 times with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product, which is purified by column chromatography to obtain a dark brown solid compound B1 (0.29 g, yield 75%).
[0109] The detection data of compound B1 are as follows:
[0110...
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