Pyrazolopyrimidine compound and preparation method therefor and use thereof in preparation of Anti-cancer drug
a technology of pyrazolopyrimidine and compound, which is applied in the field of medicinal chemistry, can solve the problems of drug resistance, patient deterioration, tumor deterioration, etc., and achieve the effects of improving cancer treatment options, improving drug choice, and excellent pi3k inhibitory activity
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embodiment 1
of Compound I-1
[0054]Compound I-1 was synthesized through the following route:
1.1. Synthesis of Compound 2
Compound 2: methyl 5-fluoro-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylate
[0055]
[0056]5-fluoroorotic acid (Compound 1) (40 g, 0.23 mol) was dissolved in N,N-dimethylformamide (500 mL), DBU (35.0 g, 0.23 mol) was slowly added dropwise, and the system was stirred at room temperature for 1 h, then iodomethane (32.0 g, 0.23 mol) was slowly added dropwise, and the system was stirred at 60° C. for 4 h. Upon the reaction completion, 100 mL of ice water was added with stirring to precipitate solids, filtered, and the filter cake was washed with water (100 mL×3) and vacuum dried to give Compound 2 (30 g, yield=70%). Measured: 1H NMR (CDCl3, 400 MHz): δ 11.85 (s, 1H), 10.84 (s, 1H), 3.88 (s, 3H).
1.2. Synthesis of Compound 3
Compound 3: methyl 2,6-dichloro-5-fluoropyrimidine-4-carboxylate
[0057]
[0058]Compound 2 (46.0 g, 0.24 mol), N,N-dimethylformamide (0.5 mL), 1,4-dioxane (20 mL) wer...
embodiment 2
of Compound I-2
[0074]Compound I-2 was synthesized through the following route:
2.1. Synthesis of Compound 11
Compound 11
1-(4-(2-hydroxypropan-2-yl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea
[0075]
[0076]To a solution of Compound 8 (100 mL, from 4.34 g of Compound 7, 19.8 mmol) at 0° C. was added an amine
2.0 g, 13.2 mmol). The system was stirred at 0° C. for 15 minutes, naturally warmed to room temperature, and stirred at room temperature for another 4 hours. After LC-MS detection showed the reaction completion, the system was washed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to dryness, and diethyl ether (10 mL) was added to the residue, and the system was filtered and vacuum dried to give a white solid, namely Compound 11 (5.0 g, yield=96%). Measured: ESI-MS m / z=397 [M+1]+
2.2. Synthesis of Compound 12
Compound 12
1-(4-(4-cyano-5-fluoro-6-morpholinopyrimidin-2-yl)p...
embodiment 3
of Compound I-3
[0081]Compound I-3 was synthesized through the following route:
3.1. Synthesis of Compound 14
Compound 14: N-(methylsulfonyl)-2-(4-nitrophenyl)acetamide
[0082]
[0083]Compound 13 (6.0 g, 0.033 mol) was dissolved in dichloromethane (100 mL), CDI (10.7 g, 0.066 mol, N,N′-carbonyldiimidazole) was added, stirred at room temperature for 1 h, and methane sulfonamide (3.45 g, 0.036 mol) was added. The reaction solution was stirred at room temperature overnight, DBU (10.0 g, 0.066 mol) was added, and then stirred at room temperature overnight. The reaction solution was adjusted to pH=1 with hydrochloric acid (4N), the organic phase was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was vacuum concentrated, filtered, and the filter cake was washed with dichloromethane. The filter cake was vacuum dried to give a yellow solid, namely Compound 14 (4.4 g, yield=59.7%). Measured: ESI-MS m / z=257 [M−1]+. 1H NMR (DMSO-d6, 400 MHz): δ 12.07 (s, 1H), 8.22-...
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