A kind of coumarin nedd8 activating enzyme inhibitor and its preparation method and application
A compound and anti-tumor drug technology, applied in the field of biochemistry, can solve problems such as the lack of similar products
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Embodiment 1
[0104]Example 1 Preparation of 7-(4-(phenethylamino)piperidine-1-substituted)-4-benzylamino-coumarin (I-1)
[0105] Steps:
[0106] (1) Synthesis of ethyl 1-(4-bromo-2-hydroxy-phenyl)pyruvate (1)
[0107] Add 1000mL of anhydrous toluene and 31g of NaH into a 2L four-neck round bottom flask, and stir in an ice bath for 5min under nitrogen protection. 400 mL of a toluene solution dissolved with 60 g of 4-bromo-2-hydroxyacetophenone was added dropwise under ice-bath conditions. After the dropwise addition was completed, the mixture was stirred in an ice bath for 20 min. Then 67 g of diethyl carbonate were added dropwise. After the dropwise addition was completed, it was heated to reflux and stirred overnight. After the reaction was detected by TLC, the temperature was cooled in an ice bath, and the pH was adjusted to acidity with concentrated hydrochloric acid. Filtration, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to the crude product. ...
Embodiment 2
[0120] Example 2 (R)-7-(4-(phenethylamino)piperidine-1-substituted)-4-(1-phenethyl-1-substituted)amino-coumarin (I-2)
[0121] The preparation method is the same as in Example 1, except that in step (7), the raw materials used are 0.215g of intermediate 7, 0.044g of (R)-α-methylbenzylamine and 0.036g of triethylamine to obtain the product 90.1 mg, yield 50.3%, purity 98.1%.
[0122] HNMR (500MHz, DMSO-d6) δ: 8.11 (d, J = 9.5Hz, H), 7.64 (d, J = 6.5Hz, H), 7.22-7.39 (m, 10H), 6.70 (d, J = 9Hz ,H)4.71(m,2H),4.03(d,J=13Hz,2H),3.35(s,1H),3.22(s,2H),2.87(m,4H),2.06(d,J=11Hz, 2H),1.54(m,5H).CNMR(500MHz,DMSO-d6)δ:162.41,155.42,153.31,152.83,144.52,137.54,129.09,129.06,128.99,127.36,127.25,126.15,124.28,1105. 101.23,81.29,54.77,52.41,46.11,46.07,15.22,32.23,27.52,24.01. MS(ESI)(m / z):467.9[M+1] +
Embodiment 3
[0123] Example 3 (S)-7-(4-(phenethylamino)piperidine-1-substituted)-4-(phenethyl-2-substituted)amino-coumarin (I-3)
[0124] The preparation method is the same as in Example 1, except that in step (7), the raw materials used are 0.215g of intermediate 7, 0.044g of (S)-α-methylbenzylamine and 0.036g of triethylamine to obtain product 83.0 mg, yield 46.4%, purity 96.1%.
[0125] HNMR (300MHz, DMSO-d6) δ: 8.10(d, J=9.1Hz, 1H), 7.61(d, J=6.4Hz, 2H), 7.21-7.39(m, 10H), 6.98(d, J=8.0 Hz,1H),6.74(s,1H),4.70(d,2H),4.01(d,J=12.8Hz,2H),3.34(s,1H),3.22(s,2H),2.85(m,4H ), 2.06(d, J=10.8Hz, 2H), 1.54(m, 5H). ,127.26,126.14,124.26,111.10,105.18,101.23,81.27,54.75,52.39,46.09, 46.05,45.21,32.23,27.51,24.05.MS(ESI)(m / z):467.8[M+1] + .
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