Pyrimidinylpiperazine derivative, and preparation method and application thereof
A technology of pyrimidine piperazine and derivatives, applied in the fields of organic synthesis and pharmaceutical applications
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Embodiment 1
[0033] Example 1: Preparation of intermediate 2-chloro-N-(p-tolyl)thiophene[2,3-d]pyrimidin-4-amine (2a)
[0034] Weigh p-methylaniline (0.15g, 1mmol) and potassium carbonate (0.17g, 1.2mmol) in a 50mL round bottom flask, add 5mL N,N-dimethylformamide solution to dissolve, stir at room temperature for 15min, then add 2, 4-Dichlorothieno[3,2-d]pyrimidine (0.21g, 1mmol) was stirred at room temperature for 2h (reaction completion monitored by TLC). At this time, a large amount of white solid was formed, and 25 mL of ice water was slowly added thereto, filtered, vacuum-dried, and DMF-H 2 Recrystallization from O afforded intermediate 2a. Yield: 76%, mp: 103-104°C. 1 H NMR (400MHz, DMSO-d 6 )δ8.73(s,1H),7.71(d,J=6.9Hz,1H), 7.55(d,J=7.1Hz,1H),7.41–7.35(m,2H),7.21(dq,J=7.6 ,0.7Hz,2H),2.35(s,3H).ESI-MS: m / z 276.14[M+1] + .C 13 h 10 ClN 3 S(275.03).
Embodiment 2
[0035] Example 2: Preparation of intermediate 2-(piperazin-1-yl)-N-(p-tolyl)thieno[2,3-d]pyrimidin-4-amine (4a)
[0036] Weigh compound 2a (1.0g, 3.17mmol), 4-Boc-piperazine (0.83g, 3.80mmol) and potassium carbonate (0.87g, 6.33 mmol) in a 50mL round bottom flask, add 5mL of N,N-di Methylformamide was dissolved and then heated to reflux for 12h. After the reaction was cooled to room temperature, the reaction solution was slowly added dropwise to 20 mL of aqueous solution, stirred, and a large amount of yellow solid was formed. Filter and dry to obtain the crude product 3. Weighed 3 (1.26g, 2.53mmol) and dissolved it in 4mL of dichloromethane, then slowly added trifluoroacetic acid (2.22mL, 30mmol) to it, and stirred at room temperature for 6h (TLC detected that the reaction was complete). Add 10 mL of water to the reaction solution, adjust the pH to 9 with saturated sodium bicarbonate solution, extract with dichloromethane (3×5 mL), wash with saturated sodium chloride soluti...
Embodiment 3
[0037] Embodiment 3: the general preparation method of final product 5a-c
[0038] Weigh compound 4(a-c) in 10mL of dichloromethane, add triethylamine and substituted benzenesulfonyl chloride (0.6mmol) sequentially under ice-bath condition, transfer to room temperature, stir for 4-12h (TLC detection completion of the reaction). The solvent was distilled off under reduced pressure, then 20 mL of saturated brine was added, washed with ethyl acetate (3×10 mL), the organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The target compound was separated by flash column chromatography, and then recrystallized in ethyl acetate-petroleum ether system to obtain the target compound. .
[0039] 2-(4-((4-Chlorophenyl)sulfonyl)piperazin-1-yl)-N-(p-tolyl)thieno[2,3-d]pyrimidin-4-amine (5a). White Powdery solid, yield: 76%, mp: 120-121°C. 1 H NMR (400MHz, DMSO-d 6)δ9.24(s,1H),7.68(d,J=8.6Hz,2H),7.60(d,J=8.5Hz,2H),7.52(dd,J=9.6,7.1Hz,3H),7.08( dd, J...
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