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Synthesis and use of 9-O-aryl substituted berberine derivatives

A technology of berberine and its derivatives, which is applied in the synthesis method and its antibacterial application field, can solve the problems of rarely used modification, etc., and achieve the effect of wide range of drug effects, wide substrate applicability, and excellent physiological activity

Active Publication Date: 2019-01-18
CHANGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Aryl groups are a class of substituents with high lipophilicity, however, they are rarely used in the modification of BBR

Method used

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  • Synthesis and use of 9-O-aryl substituted berberine derivatives
  • Synthesis and use of 9-O-aryl substituted berberine derivatives
  • Synthesis and use of 9-O-aryl substituted berberine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053]

[0054] (1) Synthesis of Berberine

[0055] Take 5.4 mmol of berberine, place it in a round-bottomed flask, heat it under vacuum at 20-30 mmHg, 190°C for 1 h, cool to room temperature after the reaction, and obtain 4.8 mmol of berberine 2 with a yield of 90%, without purification Proceed directly to the next reaction.

[0056] (2) Synthesis of Tetrahydroberberine

[0057] Take 6.0 mmol of berberine, put it in a round bottom flask, add HCl / EtOH (1:10) solution and stir at room temperature for 1 h, after the reaction is completed, filter and dry to obtain protonated tetrahydroberberine, Yield 95%. Take 2.0 mmol of protonated tetrahydroberbererythrine, put it in a round bottom flask, add methanol to dissolve it, and then add 10.0 mmol of NaBH in batches under a water bath 4 , the addition was completed, stirred overnight at 50° C., the reaction was completed, filtered, washed with methanol, dissolved in ethyl acetate, and the ethyl acetate was spun off under reduced...

Embodiment 2

[0066]

[0067] 4b: Pale yellow solid, 69% yield, mp 153-155°C. 1 H NMR (300MHz, CDCl 3 ):δ7.20(dd,1H,J=0.8Hz,J=7.3Hz,Ar-H),7.03-6.96(m,2H,Ar-H),6.91-6.85(m,2H,Ar-H) ,6.74(s,1H,H-1),6.57(s,1H,H-4),6.44-6.41(m,1H,Ar-H),5.92(q,2H,J=1.4Hz,-OCH 2 O-), 4.05(d, 1H, J=15.8Hz, H-8), 3.72(s, 3H, H-10), 3.56-3.52(m, 1H, H-14), 3.43(d, 1H, J=15.8Hz, H-8), 3.30-3.24(m, 1H, H-13), 3.12-3.03(m, 2H, H-6&H-5), 2.91-2.82(m, 1H, H-5) ,2.64-2.48(m,2H,H-6&H-13); 13 C{ 1 H}NMR (75MHz, CDCl 3 ): δ156.0, 150.3, 146.2, 146.0, 139.8, 130.9, 130.7, 129.3, 128.1, 127.8, 126.7, 126.1, 125.4, 121.3, 112.3, 111.3, 108.4, 105.5, 100.8 (-OCH 2 O-), 59.5 (C-14), 56.2 (10-OCH 3 ), 53.6(C-8), 51.2(C-6), 36.3(C-13), 29.4(C-5), 16.3(-CH 3 ); HRMS(ESI): m / z for C 26 h 26 NO 4 + [M+1] + calcd 416.1856, found 416.1861.

[0068] 5b: Yellow solid, 84% yield, mp 252-254°C. 1 H NMR (300MHz, DMSO-d 6 ):δ9.78(s,1H,H-8),9.07(s,1H,H-13),8.30(d,1H,J=9.2Hz,H-12),8.20(d,1H,J= 9.2Hz, H-11),7.82(s,1H,H-1),7.35...

Embodiment 3

[0070]

[0071] 4c: Pale yellow solid, 90% yield, mp 158-160°C. 1 H NMR (300MHz, CDCl 3 ): δ7.12(t, 1H, J=7.8Hz, Ar-H), 7.02(d, 1H, J=8.4Hz, H-11), 6.87(d, 1H, J=8.4Hz, H-12 ),6.80(d,1H,J=7.5Hz,Ar-H),6.73(s,1H,H-1),6.70-6.69(m,1H,Ar-H),6.62(dd,1H,J= 2.4Hz, J=8.2Hz, Ar-H), 6.57(s, 1H, H-4), 5.92(q, 2H, J=1.4Hz, -OCH 2 O-), 4.06(d, 1H, J=15.9Hz, H-8), 3.74(s, 3H, H-10), 3.56-3.51(m, 1H, H-14), 3.43(d, 1H, J=15.9Hz, H-8), 3.30-3.24(m, 1H, H-13), 3.11-2.99(m, 2H, H-6&H-5), 2.91-2.81(m, 1H, H-5) ,2.62-2.49(m,2H,H-6&H-13); 13 C{ 1 H}NMR (75MHz, CDCl 3 ):δ157.9,150.3,146.2,145.9,139.6,139.2,130.7,129.6,129.2,128.1,127.8,125.6,122.4,115.4,111.5,111.2,108.4,105.5,100.8(-OCH 2 O-), 59.5 (C-14), 56.1 (10-OCH 3 ), 53.7(C-8), 51.2(C-6), 36.4(C-13), 29.5(C-5), 21.5(-CH 3 ); HRMS(ESI): m / z for C 26 h 26 NO 4 + [M+1] + calcd 416.1856, found 416.1862.

[0072] 5c: Yellow solid, 93% yield, mp 239-241°C. 1 H NMR (300MHz, DMSO-d 6 ):δ9.77(s,1H,H-8),9.07(s,1H,H-13),8.31(d,1H,J=9...

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Abstract

The invention provides a novel method for synthesizing a 9-O-aryl substituted berberine derivative 5 and a 9-O-phenyl bridged berberine dimer 7. The method comprises the steps: removing methyl of a site 9 from berberine 1, which serves as a raw material, so as to obtain berberrubine 2, and subjecting the berberrubine 2 to protonation and reduction, so as to prepare tetrahydro berberrubine 3; subjecting the tetrahydro berberrubine 3 and iodo aromatic hydrocarbon to a C-O cross-coupling reaction under nitrogen protection so as to obtain a product 4, and then, carrying out oxidation, so as to obtain the target 9-O-aryl substituted berberine derivative 5; coupling the tetrahydro berberrubine 3 and 4o, and carrying out oxidation, thereby obtaining the berberine dimer 7. The berberine derivatives synthesized by the method have the advantages of good fat solubility, simple preparation method, high yield and the like. Discovered by in-vitro experiments, this kind of berberine derivatives havea relatively good inhibiting action on staphylococcus aureus, thereby having a potential application value in the field of antibacterial drugs.

Description

technical field [0001] The invention belongs to the field of organic synthesis and medicine, and specifically relates to a synthesis method of a 9-O-aryl substituted berberine derivative and its antibacterial application. Background technique [0002] Berberine (BBR), also known as berberine, is light yellow powder at room temperature. Berberine is a natural alkaloid extracted from the Ranunculaceae, Rutaceae, and Berberidaceae with a tetracyclic isoquinoline core unit that exhibits a wealth of therapeutic potency, including: antibacterial [Clin.Microbial.2014,3,150- 153], tumor cell inhibition [(a) J.Ethnopharmacol.2015,176,35-48, (b)Mini-Rev.Med.Chem.2016,16,104-119] and treatment of various chronic diseases [Adv.Exp . Med. Biol. 2016, 928, 27-45]. In most cases, the quaternary ammonium structure proves to be the core functional component, however, this structure results in increased lipophobicity of BBR, making it difficult to absorb. Therefore, the intake of high-dose...

Claims

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Application Information

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IPC IPC(8): C07D455/03C07D519/00A61P31/04
CPCA61P31/04C07D455/03C07D519/00
Inventor 滕巧巧孟启朱信辉蒋卫华缪春宝杨海涛
Owner CHANGZHOU UNIV
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