BTK inhibitor and uses thereof
A solvate, compound technology, applied in the field of BTK inhibitors
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Embodiment 1
[0163] Example 1(E)-1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl )piperidin-1-yl)-4-((4aR,7aS)-tetrahydro-2H-[1,4]dioxin[2,3-c]pyrrol-6(3H)-yl)butan-2 -en-1-one
[0164]
[0165] Step 1) Synthesis of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine:
[0166] 1H-pyrazolo[3,4-d]pyrimidin-4-amine (15.0 g, 111.1 mmol) was dissolved in DMF (150 mL), and N-iodosuccinimide was slowly added to the reaction solution (37.5 g, 166.6 mmol), and the reaction was stirred at 80 °C for 12 h. Heating was stopped, cooled, water (40 mL) was added to the reaction solution, suction filtered, the solid was washed with water (80 mL), washed with ethanol (60 mL), and dried to obtain a yellow solid (24.9 g, 86%).
[0167] Step 2) Synthesis of (S)-tert-butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate:
[0168] (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate (1.50 g, 7.47 mmol) was dissolved in dichloromethane (30 mL), and then triethylamine (1.35 mL, 9.71 mL) was added ...
Embodiment 2
[0188] Example 2 (S, E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piper Pyridin-1-yl)-4-(2-oxo-6-azaspiro[3.3]heptane-6-yl)but-2-en-1-one
[0189]
[0190] (R,E)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1 -yl)-4-bromobut-2-en-1-one (200mg, 0.37mmol) was dissolved in DMF (15mL), and 2-oxo-6-aza-spiro[3,3]heptane was added Salt (0.14g, 0.75mmol) and potassium carbonate (149mg, 1.50mmol), react at 60°C for 4h. The solvent was evaporated under reduced pressure, water (20 mL) was added, extracted with dichloromethane (50 mL×3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the crude product was separated and purified by column chromatography (2 Chloromethane / methanol (V / V)=10 / 1) to give a white powder (79mg, 40%).
[0191] MS-ESI: (ESI, pos.ion) m / z: 276.7[M / 2+1] + ;
[0192] 1 HNMR (400MHz, CDCl 3 ): δ7.63(d, J=7.6Hz, 2H), 7.38(...
Embodiment 3
[0193] Example 3 (R, E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piper Pyridin-1-yl)-6-morpholinylhex-2-en-1-one
[0194]
[0195] Step 1) Synthesis of 4-((tert-butyl(dimethyl)silyl)oxy)butan-1-ol:
[0196]Dissolve butane-1,4-diol (6.5 g, 72 mmol) in dichloromethane, add tert-butyl(dimethyl)chlorosilane (5.4 g, 36 mmol), and slowly add triethylamine ( 5mL, 35.9mmol), then stirred at room temperature for 5h, extracted with dichloromethane (150mL×3), washed with saturated brine (60mL), dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain the product (6.82g, 93% ).
[0197] Step 2) Synthesis of 4-((tert-butyl(dimethyl)silyl)oxy)butyraldehyde:
[0198] Under nitrogen protection, oxalyl chloride (10 mL), dichloromethane (150 mL) were added, and DMSO (5 mL) was slowly added dropwise at -78 °C. After stirring for 15 min, 4-((tert-butyl) was slowly added at -78 °C. (dimethyl)silyl)oxy)butan-1-ol (6....
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