Pyrrolo [2, 3-d] pyrimidine derivative targeting EGFR mutation as well as preparation method and application of pyrrolo [2, 3-d] pyrimidine derivative
A use and drug technology, applied in the field of pyrrolo[2,3-d]pyrimidine derivatives and their preparation, can solve problems such as the occurrence of osimertinib resistance, achieve good application prospects, significant inhibitory effect, and good inhibitory effect Active and Selective Effects
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Embodiment 1
[0078] Embodiment 1, the synthesis of key intermediate 1
[0079] The synthetic route of key intermediate 1 is as follows:
[0080]
[0081] in,
[0082] When X=Br, intermediate 1 is compound 10, and key intermediate 1 is compound 14;
[0083] When X=I, intermediate 1 is compound 11, and key intermediate 1 is compound 15;
[0084] When X=OH, intermediate 1 is compound 12, and key intermediate 1 is compound 16;
[0085] X=OCH 3 , the intermediate 1 is compound 13, and the key intermediate 1 is compound 17.
[0086] Alternatively, the synthetic route of the key intermediate 1 is as follows:
[0087]
[0088] X=NO 2 , the key intermediate 1 is compound 18.
[0089] The specific preparation method is as follows:
[0090] (1) Synthesis of 1-(2-iodo-4-nitrobenzene)-4-methylpiperazine (11): 4-fluoro-3-iodonitrobenzene (1.34g, 5.0mmol), N- The mixed solution of methylpiperazine (about 6ml, 52mmol) was heated to 90°C, reacted for more than 5h, left at room temperature, d...
Embodiment 2
[0099] Embodiment 2, the synthesis of key intermediate 2
[0100] The synthetic route of key intermediate 2 is as follows:
[0101]
[0102] The specific preparation method is as follows:
[0103] Synthesis of compound 19: Add 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (4.68g, 0.025mol) into a round bottom flask, dissolve in THF, and then add chloromethyl pivalate (7.5g, 0.05mol) and potassium carbonate (0.1mol, 13.8g), stirred at room temperature for 5 minutes, then raised the temperature to 80°C to reflux. Continue to react for about 12h, TLC monitoring shows that the reaction is complete (developing agent: CH 2 Cl 2 ). After the reaction solution is cooled, spin the reaction solution to dryness, add 150ml of water and CH 2 Cl 2 (300ml×3) for extraction, combined the organic phases, added an appropriate amount of anhydrous sodium sulfate to dry, filtered, and concentrated. The crude product was separated by silica gel column chromatography (eluent: CH 2 Cl 2 ) to o...
Embodiment 3
[0105] Embodiment 3, the synthesis of compound 1 of the present invention
[0106] The synthetic route of compound 1 is as follows:
[0107]
[0108] The specific preparation method is as follows:
[0109] Synthesis of compound 21: add t-BuOH (50ml), key intermediate 2 (compound 20) (1.21g, 3mmol), 3-fluoro-4-(4-methylpiperazine)-aniline ( 522 mg, 2.5 mmol). The above reaction solution was stirred at room temperature for 5-10 min. Potassium carbonate (690mg, 5mmol), Pd 2 (dba) 3 (230mg, 0.25mmol, a catalyst that catalyzes the formation of carbon-nitrogen bonds), XPhos (ie 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl, 120mg, 0.25mmol), the reaction was mixed The solution was refluxed and stirred for about 6 hours at 110°C, and the reaction was monitored by TLC (developing agent: CH 2 Cl 2 / CH 3 OH=10 / 1, v / v). The reaction solution was cooled to room temperature, spin-dried, extracted, dried, concentrated, and separated by silica gel column chromatography (elu...
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