13-substituted berberine derivatives and preparation method thereof, and uses of 13-substituted berberine derivatives as anti-tuberculosis drugs
A kind of berberine, 10-technology, applied in the field of medicinal chemistry, can solve the problem of anti-tuberculosis candidates with no new structure skeleton, since the mid-1970s, etc.
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[0133] Example 1: Synthesis of 2,3-methylenedioxy-9,10-dimethoxy-13-n-octylprotoberberine chloride (Y-191)
[0134] A 5% sodium hydroxide (10ml) solution containing sodium borohydride (0.80g, 21mmol) was added dropwise to methanol (250ml) containing berberine (7.43g, 20mmol) and potassium carbonate (8.3g, 60mmol) ) In the solution system, stir at room temperature for two hours, collect the precipitated dark green solid by suction filtration, wash the filter cake several times with water, and then recrystallize with 95% ethanol to obtain the intermediate dihydroberberine.
[0135] The intermediate dihydroberberine (5.0g, 15mmol) was dissolved in 80% ethanol (200ml), and then 10ml of n-octanal and 50ml of acetic acid were added successively. The mixture was heated to 85~95℃ and refluxed for 5 hours to reduce the reaction solution. Concentrate by pressure to obtain a dark red oil, soak in ether for a period of time, filter with suction, collect the ether layer, add 2% hydrochloric aci...
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[0139] Example 2: Synthesis of 2,3-methylenedioxy-9-hydroxy-10-methoxy-13-n-octylprotoberberine chloride (A-18)
[0140] Put Y-191 (1.2g, 2.48mmol) in a 250ml flask, keep the vacuum at 30-40mmHg, heat it to 195~210℃ and react for 10-15min. It is found that the color of the solid quickly changes from the initial yellow to deep red. After the reaction, the concentrated hydrochloric acid: ethanol (5:95) was acidified and recrystallized. The solid was not crystallized, and it was evaporated to dryness to obtain 1.14 g of solid. Yield: 98%. mp 122-124°C.
[0141] MS-ESI(M / Z): 434.2【M-Cl】 +
[0142] 1 H-NMR(CD 3 OD, δppm): 0.85 (t, J = 7.2 Hz, 3H), 1.23~1.41 (m, 10H), 1.82 (s, 2H), 3.04 (t, J = 6.0 Hz, 2H), 3.33 (t, J =8.4Hz, 2H), 4.03(s, 3H), 4.67((t, J=6.0Hz, 2H), 6.06(s, 2H), 6.96(s, 1H), 7.23(s, 1H), 7.79( d, J=9.2 Hz, 1H), 7.96 (d, J=9.2 Hz, 1H), 9.72 (s, 1H); 13 C NMR (DMSO-d6) δ: 148.8, 146.5, 145.2, 144.6, 144.4, 134.8, 133.9, 133.6, 131.6, 124.6, 120.5, 117.2, 115.9, 109.1, 108...
Example Embodiment
[0144] Example 3: Synthesis of 2,3-methylenedioxy-9-ethoxy-10-methoxy-13-n-octylprotoberberine chloride (B-7)
[0145] Dissolve A-18 (200mg, 0.43mmol) in DMF (10ml), add finely ground KOH (78.4mg, 1.4mmol) and bromoethane (37.3μl, 0.5mmol), stir at room temperature for about one day, and concentrate under reduced pressure The solvent was removed, dilute hydrochloric acid acidified, and finally analyzed and purified with a reduced pressure silica gel column to obtain 82 mg of pure product, with a yield of 35.7%. mp 86-88°C.
[0146] MS-ESI(M / Z): 462.0【M-Cl】 +
[0147] 1 H-NMR(CD 3 OD, δppm): 0.84 (t, J=7.2Hz, 3H), 1.24~1.48 (m, 13H), 1.81 (t, J=7.6Hz, 2H), 3.06 (t, J=6.0Hz, 2H), 3.37(t, J=8.0Hz, 2H), 4.06(s, 3H), 4.43(q, J=6.8Hz, 2H), 4.74(t, J=6.0Hz, 2H), 6.07(s, 2H), 6.98(s, 1H), 7.24(s, 1H), 8.10(d, J=9.2Hz, 2H), 9.67(s, 1H); 13 C NMR(CD 3 OD)δ: 151.8, 151.3, 148.7, 145.3, 145.1, 137.7, 136.3, 135.1, 134.4, 127.0, 123.5, 122.1, 121.8, 110.4, 109.3, 103.7, 71.5, 58.9, 57.5, 32.9,...
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