Cyclopenta [d] pyrimidine compound, pharmaceutically acceptable salt, solvate or prodrug thereof and application
A solvate and compound technology, applied in the field of medicine, can solve the problem of less HIF-2a inhibitors and achieve the effect of strong in vitro binding ability
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Embodiment 1
[0067] 3-fluoro-5-((7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)oxy)benzonitrile (compound 1)
[0068]
[0069] (1) 4-Chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Intermediate 1-A):
[0070]
[0071] Add 1,5,6,7-tetrahydrocyclopenta[d]pyrimidin-4-one (6.8g, 50.0mmol) into phosphorus oxychloride (60mL), raise the temperature to 110°C, and stir for 10h. TLC showed that the reaction was complete, cooled to room temperature, evaporated the solvent under reduced pressure, poured the residue into water, adjusted the pH to 7 with saturated sodium bicarbonate solution, added ethyl acetate to extract twice, washed the organic phase with saline, and Dry over sodium sulfate and concentrate to dryness to give 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (7.5 g, 98%), which is directly used in the next reaction. LCMS (ESI): m / z: 155.1 [M+1].
[0072] (2) 1-oxo-4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (intermediate 1-B):
[0073]
[0074] To a solution of 4-...
Embodiment 2
[0084] 4-(3,5-Difluorophenoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-7-ol (Compound 2)
[0085]
[0086] (1) 4-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylethyl ester:
[0087]
[0088] Using a method similar to Example 1 (4), it was prepared from 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylethyl ester and 3,5-difluorophenol to produce The rate is 78.1%. 1H NMR (400MHz, CDCl3) δ8.69(s,1H),7.34(s,1H),7.29(dd,1H),7.26(dd,1H),6.16(m,1H),3.11-3.19(m, 1H), 2.94–2.99(m,1H), 2.70–2.79(m,1H), 2.11–2.17(m,4H).LCMS(ESI):m / z:307.1[M+1].
[0089] (2) 4-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-7-ol (compound 2):
[0090] Using a method similar to Example 1 (5), prepared from 4-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylethyl ester , yield 82.5%. 1H NMR (400MHz, CDCl3) δ8.66(s,1H),6.71-6.76(m,3H),5.27(m,1H),4.78(s,1H),3.08-3.15(m,1H),2.83– 2.89 (m, 1H), 2.57–2.66 (m, 1H), 2.04–2.16 (m, 1H). LCMS (ESI): ...
Embodiment 3
[0092] 2-fluoro-5-((7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)oxy)benzonitrile (compound 3)
[0093]
[0094] (1) 4-(3-cyano-4-fluorophenoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylethyl ester (Intermediate 3-A):
[0095]
[0096] Using a method similar to Example 1 (4), from 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl ethyl ester, 2-fluoro-5-hydroxybenzonitrile Preparation, yield 76.5%. LCMS (ESI): m / z: 314.1 [M+1].
[0097] (2) 2-fluoro-5-((7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)oxy)benzonitrile (compound 3):
[0098] Using a method similar to Example 1 (5), from 4-(3-cyano-4-fluorophenoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylethyl The ester was prepared with a yield of 81.5%. 1H NMR (400MHz, CDCl3) δ8.62(s,1H),7.46(m,1H),7.40(m,1H),7.29(m,1H),5.25(m,1H),3.36(s,1H) ,3.09-3.17(m,1H),2.87–2.92(m,1H),2.60–2.69(m,1H),2.09–2.14(m,1H).LCMS(ESI):m / z:272.1[M+ 1].
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