AKR1C3 selective inhibitor as well as preparation method and application thereof

[0038] Example 1

[0039] (1) Synthesis of methyl 2-((3,5-dimethylisoxazol-4-yl)methoxy)benzoate (intermediate 2a)

[0040] Methyl 2-hydroxybenzoate 1a (130 μL, 1.21 mmol) was dissolved in acetonitrile (6.57 ml), and 4-(chloromethyl)-3,5-dimethylisoxazole (163 μL) was added to the reaction solution successively. , 1.21 mmol), potassium carbonate solid (268 mg, 1.97 mmol), potassium iodide solid (114 mg, 0.66 mmol), heated and stirred at 80° C. overnight. After the reaction was completed, 20 mL of water was added, extracted three times with ethyl acetate, the organic layers were combined, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, silica gel column chromatography was performed (eluent: PE / EA=15 / 1, v / v). The intermediate methyl 2-((3,5-dimethylisoxazol-4-yl)methoxy)benzoate was obtained (white solid, 100 mg, 30% yield). 1 H NMR (300MHz, DMSO-d 6 )δ7.67(dd,J=7.7,1.8Hz,1H),7.59(ddd,J=9.1,7.4,1.8Hz,1H),7.31(d,J=8.1Hz,1H)

[0046] Example 2

[0047] Synthesis of 2-((3,5-Dimethylisoxazol-4-yl)methoxy)-N-(4-sulfamoylbenzyl)benzamide

[0048] To a solution (12 mL) of intermediate 3a (200 mg, 0.8 mmol) in DMF was added 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylureahexanol at room temperature Fluorophosphate (460 mg, 1.2 mmol) and N,N-diisopropylethylamine (400 μL, 2.4 mmol) were activated for half an hour and then added 4-(aminomethyl)benzenesulfonamide hydrochloride (270 mg, 1.2 mmol) . After the reaction was completed, 60 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After the solvent was distilled off under pressure, the obtained solid was recrystallized to obtain 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(4-sulfamoylbenzyl)benzamide (Compound 2, off-white solid, 170 mg, yield 53%), TLC detected as one point, dark spot under UV lamp 254nm, no

[0049] Example 3

[0050] Synthesis of 2-((3,5-Dimethylisoxazol-4-yl)methoxy)-4-methyl-N-(4-sulfamoylphenethyl)benzamide

[0051] With reference to the synthetic method of Example 1, the methyl 2-hydroxybenzoate in Example 1 was replaced with methyl 2-hydroxy-4-methylbenzoate to obtain 2-((3,5-dimethylisooxane Azol-4-yl)methoxy)-4-methyl-N-(4-sulfamoylphenethyl)benzamide (compound 3), detected as one point by TLC, dark spot under UV lamp 254nm, 365nm no fluorescence. 1 H NMR(300MHz,DMSO-d6)δ8.03(t,J=5.5Hz,1H),7.77-7.70(m,2H),7.55(d,J=7.8Hz,1H),7.38-7.28(m, 4H), 7.11–7.05(m, 1H), 6.87(d, J=7.8Hz, 1H), 5.03(s, 2H), 3.48(q, J=6.8Hz, 2H), 2.79(t, J=7.1 Hz,2H),2.41(s,3H),2.34(s,3H),2.19(s,3H).HPLC(80%methanol in water with 0.1%HCOOH):t R =14.091min, 96.153%.