Preparation method and application of glycyrrhetinic acid series derivative (TNGA-X) with anti-tumor effect
An anti-tumor effect, glycine technology, applied in anti-tumor drugs, medical preparations containing active ingredients, organic chemistry, etc., can solve the problems of toxic side effects, poor selectivity, etc., and achieve the effect of reduced cytotoxic activity and good selectivity
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Embodiment 1
[0058] The preparation of embodiment 1 compound 2-methylamino-3,5,6-trimethylpyrazine (compound 3)
[0059] Prepared according to the method of "Design, Synthesis and Anti-platelet Aggregation Activity of Ligustrazine Aromatic Acid Derivatives", Zhong Guochen. Master's Thesis, Shandong University, 2011, 13-14. Add 5.2g (19mmol) N-(3,5,6-trimethylpyrazine-2-methylene) isoindole-1,3-dione compound 2, 100mL absolute ethanol and 1mL (18mmol) 80% hydrazine hydrate; reflux reaction at 90°C for 5h, TLC [V (petroleum ether): V (acetone) = 2: 1] detected that the reaction was basically complete; after the reaction liquid was cooled, suction filtered, and the filtrate recovered the solvent After that, add 30mL CH 2 Cl 2 Ultrasonic dissolution, a white precipitate precipitated out; suction filtration, transfer the solution to a 100mL volumetric flask, dilute to the mark, and seal (concentration: 46.8mg / mL); HRMS (ESI) m / z: 152.10930[M+H] + , calcd.for C 8 h 13 N 3 152.11430.
Embodiment 2
[0060] Example 2 Synthesis of compound TNGA-X1.
[0061] Weigh 500mg (0.826mmol) of TNGA, 1.00mmol of Boc-L-glycine, 1.65mmol of EDCI, and 0.413mmol of DMAP in a reaction flask, add 10mL of dichloromethane, stir overnight at room temperature, TLC monitors that the basic reaction of TNGA is complete, and stop the reaction; The reaction solution was transferred to a separatory funnel, washed with water and saturated brine successively, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and the product was separated on a silica gel column [V (dichloromethane): V (methanol) = 50:1 ] to obtain a white solid, namely TNGA-X1: Yield 88%, white solid, m.p.158.2-159.9℃ 1 H-NMR (500MHz, CDCl 3 ) δ (ppm) 7.51 (s, 1H, N-H), 5.70 (s, 1H, H-12), 4.57 (m, 1H, H-3), 3.90 (m, 2H, -NHC H 2), 2.82(m, 1H, H-18) 2.56, 2.51, 2.48(s, each, 3*CH3, methyl on the pyrazine ring), 2.22-1.02(21H, methylene and Hydrogen of methine) 1.41(brs, 3*CH3, methyl on amino acid), 1.20,...
Embodiment 3
[0062] The synthesis of embodiment 3 compound TNGA-X2
[0063] Take 200mg (0.262mmol) of TNGA-X1, dissolve it in 5mL of dichloromethane, add 500uL of trifluoroethane under ice bath conditions, remove the ice bath after half an hour, and monitor the reaction every half hour. When the reaction is basically completed, The reaction solution was neutralized with saturated sodium bicarbonate, and when the pH was neutral, it was washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and the product was separated on a silica gel column [V (dichloromethane): V (methanol)=50:1] to obtain white solid namely TNGA-X2: Yield 65%, white solid, m.p.173.7-174.8°C 1 H-NMR (500MHz, CDCl 3 )δ (ppm) 7.50 (s, 1H, N-H), 5.71 (s, 1H, H-12), 4.56 (m, 1H, H-3), 3.43 (m, 2H, -NH 2 C H 2 -), 2.82(m, 1H, H-18), 2.55, 2.50, 2.46(s, each, 3*CH3, methyl on the pyrazine ring), 2.33-1.02(21H, methylene on the triterpenoid core and hydrogen of ...
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