Carrageenate base analogue, preparation method thereof and application in analgesic drug
A compound, reaction temperature technology, applied in drug combinations, antipyretics, pharmaceutical formulations, etc., can solve problems such as addictive side effects, tolerance and addiction, and clinical application limitations
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Embodiment 1
[0056] Take a 500mL three-necked bottle, dissolve R-carvone (3g, 20mmol) in 150mL dichloromethane, add CeCl 3 ·H 2 O (8.2g, 22mmol) in water (100mL) solution, mechanically stirred, NaClO aqueous solution (8%, 160mL) was added dropwise with a dropping funnel at 0°C, and continued to stir at 0°C for 3 hours until the thin layer chromatography detected that the raw material disappeared . Dilute with water, then slowly add saturated Na 2 S 2 o 3 Quench the reaction with aqueous solution, extract three times with dichloromethane, combine the organic phases, wash with saturated NaCl aqueous solution, anhydrous NaCl 2 SO 4 Dry and concentrate to obtain a light yellow oily liquid which is directly used in the next reaction.
[0057] The crude product obtained above was dissolved in 25 mL of methanol, and H 2 o 2 Aqueous solution (35%, 10 mL) and NaOH aqueous solution (2.0 M, 5 mL) were reacted at 0° C. for 30 minutes and then raised to room temperature for 3 hours. Dilute w...
Embodiment 2
[0064] Compound 2: Dissolve compound 1 (1.6g, 5.0mmol) in DMF (30mL), add NaN 3 (650 mg, 10 mmol). The mixture was heated to 70°C for 15 hours. Concentrate, add water to dilute the residue, then extract three times with ethyl acetate, the obtained organic phase is washed with saturated NaCl aqueous solution, anhydrous NaCl 2 SO 4 Dry and concentrate to obtain a yellow oily liquid which is directly used in the next reaction.
[0065] The product obtained above was dissolved in 30 mL of tetrahydrofuran, and triphenylphosphine (1.6 g, 6.0 mmol) and water (0.9 mL, 50 mmol) were added. Heat to reflux for 12 hours. After concentration, column chromatography gave compound 2 as a white solid, 1.2 g, and the total yield of the two steps was 90%.
[0066] 1 HNMR (400MHz, CDCl 3 , 1:1 mixture of epimericacetals, data for both thepimericacetalsgiven) δ 6.83 (brs, 2H), 4.89 (brs, 3H), 4.86 (s, 1H), 4.73 (m, 1H), 4.58 (m, 1H), 4.12 (m, 1H) , 4.03(m, 1H), 3.90-3.84(m, 4H), 3.71(m, ...
Embodiment 3
[0069] Compound 3: Compound 2 (5.7 g, 21.6 mmol) was dissolved in 70 mL of methanol, and palladium / carbon (10%, 1.1 g, 1.1 mmol) was added under the protection of argon. Replace the argon with hydrogen and place it in a hydrogenation instrument (4atmH 2 ) for 15 hours. The palladium / carbon was filtered out with celite, and the filtrate was concentrated and separated by column chromatography to obtain compound 3, a white solid, 3.86 g, with a yield of 67%.
[0070] 1 HNMR (400MHz, CDCl 3 , 1:1 mixture of epimericacetals, data for both thepimericacetalsgiven) δ6.62 (brs, 2H), 4.69 (m, 1H), 4.56 (m, 1H), 4.09 (m, 1H), 4.00 (m, 1H), 3.90-3.83 (m, 2H), 3.50-3.45(m, 2H), 3.06-2.98(m, 3H), 2.74-2.66(m, 1H), 2.64-2.55(m, 1H), 2.44(m, 2H), 2.15-2.01( m, 5H), 1.89-1.75(m, 4H), 1.73-1.64(m, 2H), 1.59-1.48(m, 9H), 1.41-1.34(m, 1H), 1.27(d, J=6.9Hz, 3H), 1.14(d, J=6.9Hz, 3H), 0.89(d, J=6.9Hz, 3H), 0.88(d, J=6.9Hz, 3H).
[0071] Compound 4: Compound 4, a stereoisomer of Compound 3, ...
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