akr1c3 inhibitor or pharmaceutically acceptable salt thereof, preparation method and use thereof
A technology of inhibitor and application, applied in the field of aldehyde and ketone reductase and its preparation
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Embodiment 1
[0033] (1) Synthesis of diethyl 2-(3-fluoro-4-nitrophenyl)-2-methylmalonate (intermediate 2a)
[0034] 2,4-Difluoronitrobenzene 1a (2.2ml, 20mmol) was dissolved in DMF solution, NaOH solid (800mg, 20mmol) was added, and diethyl methylmalonate (3.68ml, 21.6 mmol), stirred overnight at room temperature. After the reaction was completed, 120ml of water was added, extracted three times with DCM, washed three times with brine, combined the organic layers, and dried over anhydrous sodium sulfate. Spin dry, and separate by column chromatography (eluent: PE / EA=20 / 1, v / v). A pale yellow oily liquid was obtained with a yield of 87%. 1 H NMR (300MHz, DMSO-d 6 ): δ8.17(t, J=8.4Hz, 1H), 7.61(dd, J=13.0, 2.0Hz, 1H), 7.45-7.36(m, 1H), 4.22(q, J=7.1Hz, 4H) , 1.82(s, 3H), 1.19(t, J=7.1Hz, 6H).
[0035] (2) Synthesis of diethyl 2-(4-amino-3-fluorophenyl)-2-methylmalonate (intermediate 3a)
[0036] To a solution of intermediate 2a (3.23 g, 10.3 mmol) in ethanol (100 mL) was added 10% Pd / C ...
Embodiment 2
[0042] Synthesis of 2-(2-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propionic acid
[0043] Referring to the synthesis method of Example 1, the raw material was replaced with 3-trifluoromethylphenylboronic acid, separated by column chromatography (eluent: PE / EA=20 / 1, v / v) to obtain a yellow solid, which was detected by TLC as One point, there is fluorescence under the ultraviolet lamp at 254nm, but no fluorescence at 365nm, the yield is 59%, m.p.50-52°C. 1 H NMR (500MHz, CDCl 3 ): δ7.80(s, 1H), 7.74(d, J=7.6Hz, 1H), 7.65(d, J=7.7Hz, 1H), 7.58(t, J=7.7Hz, 1H), 7.43(t , J=8.0Hz, 1H), 7.31-7.16(m, 2H), 3.83(q, J=7.1Hz, 1H), 1.59(d, J=7.2Hz, 3H). 13 C NMR (125MHz, DMSO-d 6 ): δ175.23, 160.30, 158.34, 144.53, 136.34, 133.27, 131.23, 130.13, 129.80, 125.57, 124.90, 124.68, 123.47, 115.8, 115.63, 44.63, 18.68. MS (ESI) for m 16 h 12 f 4 o 2 [M-H] - 311.0807; found 311.0715. HPLC (75% methanolin water with 0.1% HCOOH): t R =12.17min, 98.91%.
Embodiment 3
[0045] Synthesis of 2-(2-fluoro-3'-hydroxy-[1,1'-biphenyl]-4-yl)propionic acid
[0046] Referring to the synthesis method of Example 1, the raw material was replaced with 3-hydroxyphenylboronic acid, and when the acid was adjusted (pH=2) during hydrolysis and decarboxylation post-treatment, a white solid was precipitated, and a white solid was obtained after suction filtration, which was detected by TLC as one point, and the ultraviolet There is fluorescence at 254nm and no fluorescence at 365nm. The yield is 54%, m.p.153-155°C. 1 H NMR (300MHz, DMSO-d 6 ): δ12.70(s, 1H), 9.57(s, 1H), 7.46(dt, J=16.7, 8.5Hz, 1H), 7.35-7.15(m, 3H), 7.03-6.89(m, 2H), 6.86-6.73(m, 1H), 3.77(q, J=7.1Hz, 1H), 1.41(d, J=7.1Hz, 3H). 13 C NMR (125MHz, DMSO-d 6 ):δ175.35,160.27,158.32,157.86,143.43,143.37,136.56,130.99,130.96,130.05,127.24,127.14,124.41,124.38,119.87,119.85,116.05,116.03,115.69,115.50,115.24,44.57,18.72. MS(ESI)m / z calcd for C 15 h 13 FO 3 [M-H] -259.0849; found 259.0784. HPLC ...
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