A chromone substituted thiazolidinedione compound and its application for treating diabetes
A technology of thiazolidinediones and compounds, applied in metabolic diseases, drug combinations, organic chemistry, etc., can solve problems such as toxic side effects and lack of novelty, and achieve the effect of less adverse reactions
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Embodiment 1
[0069] Example 1: 5,7-dibenzyloxy-3-hydroxymethyl-4H-coumarin-4-one (compound 3)
[0070] Step A: Under the protection of argon, a 100mL double-necked round-bottom flask containing 30mL of anhydrous ethyl formate was placed in a low-temperature reactor, and cooled to 0°C, and then newly prepared sodium methoxide (1.625g, 30mmol) was added After stirring for 5 min, return to room temperature and stir. A solution of 2,4-dibenzyloxy-6-hydroxyacetophenone (3.48 g, 10 mmol) in anhydrous THF was slowly added dropwise. After the dropwise addition was completed, the stirring reaction was continued for 0.5 hours. Subsequently, 50 mL of ice water, 2.25 mL of acetic acid were added, and the reaction was stirred for 10 minutes. The reaction mixture was separated in a separatory funnel, and the aqueous phase was extracted with ethyl formate (50ml×4). The combined ethyl formate was washed with dilute sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was evaporated i...
Embodiment 2
[0072] Embodiment 2: Preparation of compound 1
[0073] Step A: Under the protection of argon, a 100 mL double-necked round-bottom flask filled with 20 mL of anhydrous tetrahydrofuran was placed in a low-temperature reactor and cooled to -5°C. Add phosphorus tribromide (0.32 mL, 3.33 mmol) and stir at -5 °C for 10 min. A solution (0.4 mL) of anhydrous pyridine (0.14 mL) in anhydrous tetrahydrofuran was added. Subsequently, anhydrous THF solution (20mL ), after the dropwise addition was completed, return to room temperature and continue to stir the reaction for 20h. The reaction mixture was filtered through celite, washed with tetrahydrofuran, concentrated immediately, crystallized with petroleum ether + dichloromethane (1:5) and dried in vacuo to obtain the product 5,7-dibenzyloxy-3-bromomethyl-4H- Coumarin-4-one (4.41 g), yield 98%. 1 H NMR (400MHz, CDCl 3 ,ppm): δ=7.93(1H,s),7.62(2H,d,J=7.6Hz),7.44-7.33(8H,m),6.53(2H,s),5.22(2H,s),5.11( 2H,s),4.34(2H,s).
[0074]Step ...
Embodiment 3
[0075] Embodiment 3: Preparation of compound 2
[0076] Under the protection of argon, the 5,7-dibenzyloxy-3-bromomethyl-4H-coumarin-4-one (5mmol, 2.25g) and cuprous iodide (0.25mmol , 25mg), (1R, 2R)-cyclohexyl-1,2-diamine ((0.285g, 30μl), 5-(4-hydroxybenzyl)thiazole-2,4-dione (6mmol, 1.338g) , potassium phosphate (10mmol, 2.12g) and anhydrous 1,4-dioxane (40mL) were successively added into a 100mL double-neck round bottom flask, stirred and heated to 110°C for 6 hours. After the reaction was completed, cool to At room temperature, add 150mL of water, extract with ethyl acetate (100mL×3), combine the ethyl acetate, remove the solvent in vacuo, and the residue is eluted with a gradient of petroleum ether: ethyl acetate (1:1-1:2). Compound 2 (2.91 g) was prepared with a yield of 98%. 1 H NMR (400MHz, CDCl 3 ,ppm): δ=7.50(2H,d,J=7.2Hz),7.39-7.25(8H,m),7.22(1H,s),7.02(2H,d,J=8.8Hz),6.78(2H, J=8.8Hz),6.46(1H,d,J=2.4Hz),6.43(1H,d,J=2.0Hz),5.18(2H,s),5.00(2H,s),4.62(2H,dd, J 1...
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