CN117924271A - Berberine and its derivatives and efficient preparation method thereof - Google Patents

Berberine and its derivatives and efficient preparation method thereof Download PDF

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CN117924271A
CN117924271A CN202311823816.XA CN202311823816A CN117924271A CN 117924271 A CN117924271 A CN 117924271A CN 202311823816 A CN202311823816 A CN 202311823816A CN 117924271 A CN117924271 A CN 117924271A
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berberine
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宋颖
白金彤
李瑞敏
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Nanning Normal University
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Nanning Normal University
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Abstract

The invention relates to the technical field of organic compounds, and in particular discloses a high-efficiency preparation method of berberine and derivatives thereof, which comprises the following steps: stirring the substituted benzoic acid and the substituted phenethylamine at room temperature under the action of a dehydrating agent to synthesize substituted amide; reacting substituted amide under the action of cobalt catalyst to synthesize substituted isoquinolone intermediate; the substituted isoquinolone intermediate reacts under the action of palladium catalyst to synthesize and derivate thereof. The invention synthesizes berberine and derivatives thereof through amidation reaction, cobalt catalyzed isoquinolone synthesis reaction and Heck reaction, has novel route, simple and convenient operation, short synthesis route and high total yield, can be suitable for synthesizing berberine analogues with different substituents, and has certain commercial application value and scientific research value.

Description

Berberine and its derivatives and efficient preparation method thereof
Technical Field
The invention relates to the technical field of organic synthesis, in particular to berberine and derivatives thereof as well as a high-efficiency preparation method thereof.
Background
The berberine alkaloid has a tetracyclic skeleton, is an important natural product, and widely exists in medicinal plants. Currently, more than 100 berberine has been isolated from medicinal plants. The broad research interests of the pharmaceutical and organic synthesis industries are brought about by the antimicrobial, antipsychotic, antioxidant and analgesic effects. They are also ideal synthetic intermediates for the synthesis of other types of alkaloid natural products containing berberine structural fragments. In addition, the synthesis of similar structures using natural products as lead compounds is an important method for the development of bioactive substances. By structural modification of natural products, molecules with better activity and low toxicity can be obtained. Therefore, the research on the high-efficiency synthesis method of the berberine and the derivatives thereof has commercial value and scientific significance.
At present, the synthesis of berberine and its derivatives are mainly adopted in literature report: 1) Olefin metathesis (Won-Jea Cho et al tetrahedron 2009,65,10142-10148); 2) Rhodium catalyzes an intramolecular ring closure reaction (Erik v.van DER EYCKEN ET al.chem. Commun.2017,53, 12394-12397); 3) Lewis acid mediated intramolecular hydroamidation of internal alkynes (Peinian Liu et al J.org.chem.2014,79, 4602-4614); 4) Rhodium catalyzes the transalkylation reaction (Masahiro Miura et al. Acs catalyst. 2019,9, 11455-11460). The above synthesis method requires several steps for intermediate synthesis, resulting in low overall yield. Part of the routes also use expensive rhodium catalysts, which are difficult to prepare on a large scale. In addition, when synthesizing berberine containing free hydroxyl groups, a protecting group (Wayne W. Harding et al tetrahedron 2015,71,1227-1231) must be used, which adds two steps of protection and deprotection, makes the procedure cumbersome and reduces the overall yield. Therefore, the development of a new, efficient and protective group-free synthetic route for preparing berberine and derivatives thereof has important academic significance and industrial application value.
Disclosure of Invention
Aiming at the defects, the invention provides a high-efficiency preparation method of berberine and derivatives thereof, wherein the synthetic route does not need a protecting group, the operation is simple, the synthetic efficiency is high, and the defects and defects of difficult preparation of intermediates, long synthetic route, need of a protecting group and the like in the background technology are overcome. The specific technical scheme is as follows:
A high-efficiency preparation method of berberine and its derivatives comprises the following steps:
Wherein, R 1、R2、R3、R4、R5 and R 6 are hydrogen, methoxy, methyl, hydroxyl, halogen atom, acetamido or methylthio.
Preferably, the high-efficiency preparation method of the berberine and the derivatives thereof specifically comprises the following steps:
(1) Dissolving substituted benzoic acid and substituted phenethylamine in an organic solvent, adding EDCI, HOBT and triethylamine or N, N-Diisopropylethylamine (DIPEA), stirring for reaction, and extracting, washing, drying, concentrating and purifying after the reaction is finished to obtain substituted amide;
(2) Adding the substituted amide, cobalt catalyst, silver hexafluoroantimonate, vinylene carbonate and acid auxiliary agent obtained in the step (1) into an organic solvent, reacting in a protective atmosphere, filtering, concentrating and purifying to obtain a substituted isoquinolone intermediate;
(3) And (3) adding the substituted isoquinolinone intermediate, palladium catalyst, ligand, tetrabutylammonium bromide and alkali obtained in the step (2) into an organic solvent to react in a protective atmosphere to obtain a berberine product.
Preferably, in the efficient preparation method of berberine and its derivatives, the organic solvent is one of chloroform, tetrahydrofuran, trifluoroethanol, hexafluoroisopropanol, N-dimethylformamide, N-dimethylacetamide, acetonitrile or toluene.
Preferably, in the above efficient preparation method of berberine and its derivatives, in the step (1), the reaction temperature is 20-30 ℃ and the reaction time is 3-60 min.
Preferably, in the above efficient preparation method of berberine and its derivatives, in the step (1), the reaction temperature is 25 ℃, and the reaction time is 5min.
Preferably, in the above efficient preparation method of berberine and its derivatives, in the step (2), the reaction temperature is 60-100 ℃ and the reaction time is 24 hours.
Preferably, in the above efficient preparation method of berberine and its derivatives, in the step (3), the reaction temperature is 100-120 ℃ and the reaction time is 12 hours.
Preferably, in the above efficient preparation method of berberine and its derivatives, in the step (1), the substituted benzoic acid: substituted phenethylamines: HOBT: EDCI: alkali: the molar volume ratio of the organic solvent is 1mmol:1 to 1.5mmol:1 to 1.5mmol: 1-3 mmol: 5-10 mL.
Preferably, in the efficient preparation method of berberine and its derivatives, in the step (2), the substituted amide: vinylene carbonate: cobalt catalyst: silver hexafluoroantimonate: acid adjuvant: the molar volume ratio of the organic solvent is 1mmol: 1-10 mmol:0.01 to 0.03mmol:0.03 to 0.09mmol: 0.02-0.06 mmol: 1-25 mL.
Preferably, in the efficient preparation method of berberine and its derivatives, in the step (3), an intermediate of isoquinolinone is substituted: palladium catalyst: ligand: tetrabutylammonium bromide: alkali: the molar volume ratio of the organic solvent is 1mmol:0.01 to 0.1mmol:0 to 0.2mmol: 1-5 mmol: 1-3 mmol: 1-30 mL.
The invention also provides berberine and derivatives thereof, which are prepared by the high-efficiency preparation method of the berberine and derivatives thereof, and have the structural formula:
Wherein R 1、R2、R3、R4、R5 and R 6 are hydrogen, methoxy, methyl, hydroxyl, halogen atom, acetamido or methylthio.
Compared with the prior art, the invention has the beneficial effects that:
1. In the high-efficiency preparation method of the berberine and the derivatives thereof, the berberine and the derivatives thereof are synthesized through amidation reaction, cobalt catalyst catalyzed isoquinolone synthesis reaction and Heck reaction, the route is novel, the operation is simple and convenient, the synthetic route is short, the total yield is high, the method is applicable to the synthesis of berberine analogues with different substituents, and the method has certain commercial application value and scientific research value.
2. In the high-efficiency preparation method of the berberine and the derivatives thereof, the protecting group is not needed, the protecting and deprotecting steps are avoided, and the synthesis process is simplified.
3. In the high-efficiency preparation method of berberine and derivatives thereof, the alkaloids and derivatives thereof can be effectively prepared, and 8-Oxodehydrodiscretamine natural products and 2-Demethyl-oxypalmatine natural products are extracted from natural plants, so that the method has the advantages of high efficiency and high purity, is favorable for better researching the biological activity of berberine derivatives, and has certain commercial application value and scientific research value.
Detailed Description
The following detailed description of specific embodiments of the invention is, but it should be understood that the invention is not limited to specific embodiments. Unless defined otherwise, all technical and scientific terms used hereinafter have the same meaning as commonly understood by one of ordinary skill in the art. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the scope of the present invention. Unless otherwise specifically indicated, the various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or may be prepared by existing methods.
Example 1
A berberine derivative has the structural formula:
the synthetic route of the berberine derivative of this embodiment is as follows:
the embodiment also provides a high-efficiency preparation method of the berberine derivative, which comprises the following steps:
(1) To a 10mL round bottom flask equipped with a stirrer was added 1a (5 mmol), 2a (6 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (7.5 mmol), 1-Hydroxybenzotriazole (HOBT) (7.5 mmol), triethylamine (12.5 mmol) and DMF (25 mL) in sequence. The reaction was stirred at 25℃and monitored by TLC until 1a was consumed. After completion of the reaction, 10mL of water was added to the reaction mixture, and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed once with water and brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the corresponding amide 3a in 95% yield (1.61 g,4.75 mmol);
the nmr and high resolution data for amide 3a are:
1H NMR(500MHz,CDCl3)δ8.23(dd,J＝7.8,1.5Hz,1H),7.91(s,1H),7.58(d,J＝7.9Hz,1H),7.46–7.39(m,1H),7.28(dt,J＝14.7,6.8Hz,2H),7.10(ddd,J＝19.5,11.5,4.5Hz,2H),6.94(d,J＝8.3Hz,1H),3.82(s,3H),3.78(q,J＝6.7Hz,2H),3.10(t,J＝6.9Hz,2H).
13C NMR(126MHz,CDCl3)δ165.3,157.4,138.7,132.9,132.7,132.2,131.1,128.2,127.5,124.7,121.4,121.2,111.2,55.7,39.4,35.8.
HRMS(ESI-TOF)m/z:[M+H]+Calcd for C16H17BrNO2334.0443；Found 334.0444.
(2) To a 25mL round bottom flask equipped with a stirrer was added [ Cp Co (CO) I 2](3mol％),AgSbF6 (9 mol%), amide 3a (1 mmol), vinylene carbonate (3 mmol), 2, 6-dimethylbenzoic acid (6 mol%) and Trifluoroethanol (TFE) (10 mL) in order. And (3) inserting a condensing reflux pipe, pumping argon three times, inserting an argon balloon, and reacting for 24 hours at 100 ℃. The reaction solution was diluted with a small amount of ethyl acetate, filtered through a pad of silica gel, and the filtrate was concentrated under reduced pressure and purified by silica gel chromatography to give the corresponding substituted isoquinolinone intermediate 4a in 42% (0.15 g,0.42 mmol).
4A are nuclear magnetic resonance and high resolution data:
1H NMR(400MHz,CDCl3)δ7.58–7.49(m,2H),7.24–7.16(m,2H),7.12–7.06(m,1H),7.02(d,J＝7.8Hz,1H),6.90(d,J＝8.2Hz,1H),6.83(d,J＝7.3Hz,1H),6.27(d,J＝7.3Hz,1H),4.16(dd,J＝8.0,6.8Hz,2H),4.02(s,3H),3.27–3.23(m,2H).
13C NMR(101MHz,CDCl3)δ160.9,160.8,140.4,137.8,132.8,132.8,132.5,131.6,128.4,127.8,124.5,118.2,115.7,107.9,105.4,56.1,49.6,35.3.
HRMS(ESI-TOF)m/z:[M+H]+Calcd for C18H17BrNO2358.0443；Found 358.0431.
(3) To a 10mL round bottom flask equipped with a stirrer was added Pd (OAc) 2 (10 mol%), tetrabutylammonium bromide (TBAB) (1 mmol), substituted isoquinolinone intermediate 4a (0.2 mmol), K 2CO3 (0.6 mmol) and anhydrous DMF (4 mL) in sequence. And (3) inserting a condensing reflux pipe, pumping argon three times, inserting an argon balloon, and reacting for 12 hours at 120 ℃. Cooled to room temperature, diluted with water, the aqueous layer extracted with ethyl acetate, the organic phases combined and the organic layer washed once with brine. The organic layer was dried over anhydrous sodium sulfate, concentrated under pressure, and purified by column chromatography to give berberine derivative 5a in 80% yield (44.3 mg,0.16 mmol).
The nmr and high resolution data of 5a are:
1H NMR(400MHz,CDCl3)δ7.80(dd,J＝5.2,3.8Hz,1H),7.51(t,J＝8.0Hz,1H),7.33(dt,J＝7.2,3.6Hz,2H),7.26(dd,J＝7.7,4.3Hz,1H),7.11(d,J＝7.8Hz,1H),6.91(s,1H),6.86(d,J＝8.1Hz,1H),4.32(dd,J＝8.0,4.4Hz,2H),4.01(s,3H),3.00–2.94(m,2H).
13C NMR(101MHz,CDCl3)δ160.8,160.6,139.5,137.9,135.6,132.8,130.0,129.3,127.9,127.3,124.9,118.6,114.5,107.8,102.4,56.1,39.1,28.6.
HRMS(ESI-TOF)m/z:[M+H]+Calcd for C18H16NO2278.1181；Found 278.1175.
Example 2
A berberine derivative has the structural formula:
the synthetic route of the berberine derivative of this embodiment is as follows:
The preparation method is the same as in example 1, except that: the reaction in step (1) replaced 1a with 1b (5 mmol) as reactant, resulting in a substituted amide 3b with a yield of 82% (1.37 g,4.1 mmol); substituted isoquinolinone intermediate 4b in 57% yield (0.20 g,0.57 mmol); berberine derivative 5b was produced in 79% (41.9 mg,0.158 mmol).
3B is:
1H NMR(500MHz,CDCl3)δ7.77–7.73(m,2H),7.57(d,J＝8.0Hz,1H),7.27(d,J＝4.2Hz,2H),7.14–7.06(m,3H),6.41(s,1H),3.73(dd,J＝12.9,6.8Hz,2H),3.10(t,J＝7.0Hz,2H).
13C NMR(126MHz,CDCl3)δ166.6,164.6(d,J＝252.2Hz),138.3,133.0,131.0,130.7,129.2(d,J＝9.1Hz),128.4,127.7,124.6,115.5(d,J＝21.9Hz),39.9,35.6.
19F NMR(377MHz,CDCl3)δ-106.86.
HRMS(ESI-TOF)m/z:[M+H]+Calcd for C15H14BrFNO 322.0243；Found 322.0242.
4b is as follows:
1H NMR(400MHz,CDCl3)δ8.46(dd,J＝8.9,5.8Hz,1H),7.55(d,J＝8.0Hz,1H),7.21–7.14(m,3H),7.13–7.06(m,2H),6.84(d,J＝7.4Hz,1H),6.30(d,J＝7.4Hz,1H),4.25–4.19(m,2H),3.23(t,J＝7.3Hz,2H).
13C NMR(101MHz,CDCl3)δ165.0(d,J＝252.5Hz),161.5,139.3(d,J＝10.3Hz),137.4,133.2,132.9,131.4,131.0(d,J＝10.1Hz),128.6,127.8,124.5,122.8,115.4(d,J＝23.4Hz),110.6(d,J＝21.8Hz),105.1(d,J＝3.2Hz),49.3,35.4.
19F NMR(377MHz,CDCl3)δ-106.85.
HRMS(ESI-TOF)m/z:[M+H]+Calcd for C17H14BrFNO 346.0243；Found 346.0240.
the nmr and high resolution data of 5b are:
1H NMR(500MHz,CDCl3)δ8.45(dd,J＝8.8,5.8Hz,1H),7.84–7.79(m,1H),7.41–7.35(m,2H),7.29(dd,J＝5.6,3.0Hz,1H),7.21–7.13(m,2H),6.95(s,1H),4.37–4.35(m,2H),3.03–3.00(m,2H).
13C NMR(101MHz,CDCl3)δ165.2(d,J＝252.1Hz),161.5,138.7(d,J＝4.2Hz),138.7,135.5,131.2(d,J＝9.8Hz),129.8,129.6,128.0,127.5,125.1,121.5,115.2(d,J＝23.5Hz),110.7(d,J＝21.8Hz),102.1,39.6,28.4.
19F NMR(377MHz,CDCl3)δ-106.86.
HRMS(ESI-TOF)m/z:[M+H]+Calcd for C17H13FNO 266.0981；Found 266.0974.
Example 3
A berberine derivative has the structural formula:
the synthetic route of the berberine derivative of this embodiment is as follows:
The preparation method is the same as in example 1, except that: the reaction in step (1) replaced 1a with 1c (5 mmol) as reactant, resulting in a substituted amide 3c with 67% (1.21 g,3.35 mmol); substituted isoquinolinone intermediate 4c in 74% yield (0.28 g,0.74 mmol); berberine derivative 5c was produced in 79% (48.1 mg,0.158 mmol).
The nmr and high resolution data of 3c are:
1H NMR(400MHz,DMSO)δ10.22(s,1H),8.54(t,J＝5.6Hz,1H),7.84(d,J＝8.7Hz,2H),7.70(d,J＝8.7Hz,2H),7.60(d,J＝7.9Hz,1H),7.37–7.30(m,2H),7.16(td,J＝7.9,2.0Hz,1H),3.59–3.52(m,2H),3.01(t,J＝7.2Hz,2H),2.11(s,3H).
13C NMR(101MHz,DMSO)δ169.1,166.3,142.3,139.1,132.9,131.5,129.2,128.8,128.4,128.2,124.4,118.5,35.8,24.5.
HRMS(ESI-TOF)m/z:[M+H]+Calcd for C17H18BrN2O2361.0552;Found 361.0547.
4c is:
1H NMR(400MHz,DMSO)δ10.29(s,1H),8.15(d,J＝8.7Hz,1H),7.94(t,J＝15.6Hz,1H),7.65–7.46(m,2H),7.27(dd,J＝7.9,5.8Hz,2H),7.20–7.11(m,2H),6.46(d,J＝7.4Hz,1H),4.23–4.09(m,2H),3.16–3.04(m,2H),2.11(s,3H).
13C NMR(101MHz,DMSO)δ169.4,161.0,143.0,138.4,138.0,133.6,133.0,131.6,129.1,128.5,128.3,124.5,121.2,118.7,114.1,105.4,48.4,35.1,24.6.
HRMS(ESI-TOF)m/z:[M+H]+Calcd for C19H18BrN2O2385.0552;Found 385.0550.
the nmr and high resolution data of 5c are:
1H NMR(400MHz,DMSO)δ10.31(s,1H),8.15(d,J＝8.7Hz,1H),8.11(s,1H),8.04–8.01(m,1H),7.53(dd,J＝8.7,1.8Hz,1H),7.40-7.35(m,3H),7.26(s,1H),4.21(t,J＝6.1Hz,2H),2.99(t,J＝6.1Hz,2H),2.12(s,3H).
13C NMR(101MHz,DMSO)δ169.4,160.9,143.1,137.9,137.8,135.8,130.1,129.7,128.6,128.4,127.7,125.8,120.1,118.8,114.5,102.6,39.4,28.1,24.6.
HRMS(ESI-TOF)m/z:[M+H]+Calcd for C19H17N2O2305.1290;Found 305.1278.
Example 4
A berberine derivative has the structural formula:
the synthetic route of the berberine derivative of this embodiment is as follows:
The preparation procedure is as in example 1, except that: the reaction in step (1) replaces 1a with 1d (5 mmol) as reactant to give 3d of substituted amide in 93% (1.63 g,4.65 mmol); substituted isoquinolinone intermediate 4d in 70% (0.26 g,0.70 mmol); berberine derivative 5d was produced in 75% (44.0 mg,0.15 mmol).
The nmr and high resolution data for 3d are:
1H NMR(500MHz,CDCl3)δ7.66(d,J＝8.5Hz,2H),7.57(d,J＝7.9Hz,1H),7.26(d,J＝4.2Hz,2H),7.23(d,J＝8.5Hz,2H),7.11(dt,J＝8.9,4.5Hz,1H),6.39(s,1H),3.73(q,J＝6.8Hz,2H),3.10(t,J＝6.9Hz,2H),2.51(s,3H).
13C NMR(126MHz,CDCl3)δ167.0,143.3,138.4,132.9,131.1,130.6,128.3,127.7,127.3,125.4,124.6,39.8,35.7,15.0.
HRMS(ESI-TOF)m/z:[M+H]+Calcd for C16H17BrNOS 350.0214；Found 350.0210.
the nmr and high resolution data of 4d are:
1H NMR(400MHz,CDCl3)δ8.31(d,J＝8.6Hz,1H),7.54(d,J＝7.8Hz,1H),7.31(dd,J＝8.6,1.4Hz,1H),7.19(s,1H),7.17–7.12(m,2H),7.11–7.04(m,1H),6.79(d,J＝7.3Hz,1H),6.26(d,J＝7.3Hz,1H),4.20(t,J＝7.3Hz,2H),3.22(t,J＝7.3Hz,2H),2.53(s,3H).
13C NMR(101MHz,CDCl3)δ161.9,144.5,137.58,137.52,132.9,132.7,131.5,128.5,127.9,127.7,124.58,124.53,122.9,120.7,105.1,49.3,35.4,14.8.
HRMS(ESI-TOF)m/z:[M+H]+Calcd for C18H17BrNOS 374.0214；Found 374.0210.
the nmr and high resolution data of 5d are:
1H NMR(500MHz,CDCl3)δ8.31–8.29(m,1H),7.80(dd,J＝5.2,3.9Hz,1H),7.36(dd,J＝5.5,3.5Hz,2H),7.30–7.26(m,3H),6.92(s,1H),4.37–4.33(m,2H),3.03–2.96(m,2H),2.57(s,3H).
13C NMR(126MHz,CDCl3)δ161.8,144.6,138.1,137.0,135.4,130.1,129.4,128.1,128.0,127.4,125.0,124.4,121.8,121.0,102.1,39.5,28.5,14.9.
HRMS(ESI-TOF)m/z:[M+H]+Calcd for C18H16NOS294.0953；Found 294.0940.
Example 5
A berberine derivative has the structural formula:
the synthetic route of the berberine derivative of this embodiment is as follows:
The preparation procedure is as in example 1, except that: the reaction in step (1) was carried out with 1e (5 mmol) and 2b (6 mmol) as reactants to give the substituted amide 3e in 59% (1.17 g,2.95 mmol); substituted isoquinolinone intermediate 4e in 30% yield (0.13 g,0.30 mmol); berberine derivative 5e was produced in 92% (62.4 mg,0.184 mmol).
3E nuclear magnetic resonance and high resolution data are:
1H NMR(500MHz,CDCl3)δ7.64–7.60(m,1H),7.56–7.51(m,1H),7.03–6.97(m,2H),6.75(s,1H),6.38(s,1H),3.85(s,3H),3.78(s,3H),3.68(q,J＝6.8Hz,2H),3.01(t,J＝7.0Hz,2H),2.28(s,3H).
13C NMR(126MHz,CDCl3)δ166.8,163.2(d,J＝250.8Hz),148.4(d,J＝21.8Hz),130.6(d,J＝6.0Hz),130.2,130.1,126.2(d,J＝8.7Hz),125.3(d,J＝17.9Hz),115.5,115.2,115.0,114.1,113.4,56.1,56.0,40.1,35.2,14.5.
19F NMR(377MHz,CDCl3)δ-112.41.
HRMS(ESI-TOF)m/z:[M+H]+Calcd for C18H20BrFNO3396.0611；Found 396.0607.
4e nuclear magnetic resonance and high resolution data are:
1H NMR(400MHz,CDCl3)δ8.27(d,J＝7.8Hz,1H),7.04(d,J＝9.9Hz,1H),6.98(s,1H),6.75(d,J＝7.3Hz,1H),6.56(s,1H),6.26(d,J＝7.3Hz,1H),4.16(t,J＝7.2Hz,2H),3.83(s,3H),3.61(s,3H),3.12(t,J＝7.2Hz,2H),2.38(s,3H).
13C NMR(101MHz,CDCl3)δ164.0(d,J＝252.2Hz),161.5,148.4(d,J＝1.1Hz),137.2(d,J＝10.4Hz),132.4,131.0(d,J＝6.9Hz),129.2,125.4(d,J＝19.4Hz),122.4(d,J＝1.6Hz),115.4,114.1,113.6,110.3(d,J＝23.0Hz),105.0(d,J＝3.0Hz),56.1,55.9,49.5,34.8,14.8(d,J＝3.6Hz).
19F NMR(377MHz,CDCl3)δ-110.84.
HRMS(ESI-TOF)m/z:[M+H]+Calcd for C20H20BrFNO3420.0611；Found420.0604.
the nmr and high resolution data of 5e are:
1H NMR(400MHz,CDCl3)δ8.25(d,J＝7.7Hz,1H),7.23(s,1H),7.13(d,J＝10.0Hz,1H),6.76(d,J＝15.4Hz,2H),4.33(t,J＝5.6Hz,2H),3.99(s,3H),3.94(s,3H),2.99–2.88(m,2H),2.39(s,3H).
13C NMR(101MHz,CDCl3)δ164.2(d,J＝252.8Hz),161.5,150.4,148.5,137.82,136.8(d,J＝5.4Hz),131.3(d,J＝7.1Hz),128.7,124.8(d,J＝9.7Hz),122.1,120.9,110.4,110.1(d,J＝23.0Hz),107.8,100.7(d,J＝1.6Hz),56.2,56.0,39.7,28.0,14.9.
19F NMR(377MHz,CDCl3)δ-111.15.
HRMS(ESI-TOF)m/z:[M+H]+Calcd for C20H19FNO3340.1349；Found 340.1341.
Example 6
A berberine derivative has the structural formula:
the synthetic route of the berberine derivative of this embodiment is as follows:
The preparation method is the same as in example 1, except that: the reaction in step (1) was carried out with 1f (5 mmol) and 2b (6 mmol) as reactants, resulting in 59% yield of substituted amide 3f (1.17 g,2.95 mmol); substituted isoquinolinone intermediate 4f in 30% yield (0.13 g,0.30 mmol); the yield of berberine derivative 5f was 56% (44.5 mg,0.112 mmol).
The nmr and high resolution data of 3f are:
1H NMR(500MHz,CDCl3)δ6.99(d,J＝6.5Hz,3H),6.76(s,1H),6.42(t,J＝5.2Hz,1H),3.86(s,9H),3.84(s,3H),3.79(s,3H),3.68(q,J＝6.6Hz,2H),3.02(t,J＝6.9Hz,2H).
13C NMR(126MHz,CDCl3)δ167.3,153.1,148.6,148.4,140.7,130.2,129.9,115.4,114.1,113.4,104.2,60.9,56.2,56.1,56.0,40.3,35.1.
HRMS(ESI-TOF)m/z:[M+H]+Calcd for C20H25BrNO6454.0865；Found454.0861.
the nmr and high resolution data of 4f are:
1H NMR(600MHz,CDCl3)δ7.64(s,1H),6.97(s,1H),6.73(d,J＝7.4Hz,1H),6.58(d,J＝5.9Hz,2H),4.15(t,J＝7.4Hz,2H),3.95(d,J＝1.1Hz,6H),3.90(s,3H),3.82(s,3H),3.61(s,3H),3.11(t,J＝7.3Hz,2H).
13C NMR(151MHz,CDCl3)δ161.3,153.1,148.4,148.4,147.3,145.6,130.0,129.3,126.9,122.2,115.4,114.1,113.6,103.8,100.2,61.4,61.0,56.1,55.8,49.6,34.9.
HRMS(ESI-TOF)m/z:[M+H]+Calcd for C22H25BrNO6478.0865；Found478.0846.
the nmr and high resolution data of 5f are:
1H NMR(600MHz,CDCl3)δ7.66(s,1H),7.30(s,1H),7.10(s,1H),6.75(s,1H),4.36(t,J＝5.7Hz,2H),4.04(d,J＝0.5Hz,3H),4.01-4.00(m,9H),3.94(s,3H),2.94(t,J＝5.8Hz,2H).
13C NMR(151MHz,CDCl3)δ161.3,152.8,150.1,148.4,147.4,145.6,135.7,128.3,126.4,122.7,120.7,110.4,108.0,104.1,95.6,61.6,61.0,56.3,56.2,56.0,39.9,28.1.
HRMS(ESI-TOF)m/z:[M+H]+Calcd for C22H24NO6398.1604；Found 398.1588.
Example 7
A berberine natural product 8-Oxodehydrodiscretamine has the structural formula:
the synthetic route of berberine natural product 8-Oxodehydrodiscretamine of this embodiment is:
the embodiment also provides a preparation method of berberine 8-Oxodehydrodiscretamine, which comprises the following steps:
(1) To a 50mL round bottom flask equipped with a stirrer were added 6a (5 mmol,1.1552 g), ammonium acetate (10 mmol,0.7708 g) and acetic acid (20 mL) and the mixture was stirred at room temperature for 5 min; nitromethane (20 mmol,1.1 mL) was then slowly added and the reaction mixture was refluxed in an oil bath at 120℃for 4 hours; after cooling to room temperature, ice water was added to the mixture to precipitate a yellow solid precipitate; the precipitate was filtered, washed with ice water and dried to give 6b in 66% yield (0.90 g,3.3 mmol). 6b was used directly in the next reaction without further purification.
(2) To a 100mL three-necked flask equipped with a stirrer were added LiAlH 4 (10 mmol,0.3795 g) and anhydrous THF (20 mL), followed by a reflux condenser and a dropping funnel containing a solution of 6b (1.6 mmol,0.4385 g) in THF (5 mL). Argon is pumped for three times, the mixture is refluxed in an oil bath at 70 ℃, 6b solution is dripped into the reaction liquid, the dripping time is controlled to be 1 hour, and the mixture is refluxed for 2 hours after dripping; after the reaction was completed and cooled to room temperature, it was cooled to 0℃in ice water, and quenched with 5mL of ice water. Subsequently, the reaction solution was transferred to a round-bottomed flask, and THF was distilled under reduced pressure; after completion, 2M HCl (5 mL) was added and the mixture was stirred for 5 minutes, the aqueous phase was extracted with ethyl acetate, and tartaric acid (11.2 mmol,1.6810g,7 eq.) was added to the aqueous phase and stirred for 5 minutes; then adding 25% -28% ammonia water, and adjusting the pH of the solution to be more than 10; the aqueous phase was extracted several times with dichloromethane DCM and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to give 6c in 56% yield (0.2205 g,0.89 mmol); 6c was used directly in the next reaction without further purification.
(3) To a 25mL round bottom flask equipped with a stirrer were added 6c (1.2 mmol,0.2953 g), 6d (1 mmol,0.1681 g), EDCI (1.5 mmol,0.2876 g), HOBT (1.5 mmol,0.2027 g), N-diisopropylethylamine DIPEA (2.5 mmol,0.3231 g) and DMF (5 mL) in this order, and the reaction mixture was stirred at room temperature for 24 hours. After completion, adding water to quench the reaction; the aqueous phase was extracted three times with ethyl acetate and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography gave 6e in 60% (0.24 g,0.6 mmol).
The nmr and high resolution data of 6e are:
1H NMR(400MHz,DMSO)δ9.58(s,1H),9.24(s,1H),8.26(s,1H),7.08(s,1H),7.04(d,J＝3.7Hz,1H),6.96-6.92(m,2H),6.82(s,1H),3.76(s,3H),3.70(s,3H),3.55–3.38(m,2H),2.87–2.80(m,2H).
13C NMR(101MHz,DMSO)δ166.0,150.7,147.5,146.5,145.8,130.8,130.0,124.3,119.9,119.1,117.9,116.3,112.0,61.0,56.4,39.6,34.9.
HRMS(ESI-TOF)m/z:[M+H]+Calcd for C17H19BrNO 396.0446；Found 396.0441.
(4) To a 10mL round bottom flask equipped with a stirrer were added successively [ Cp *Co(CO)I2](3mol％)、AgSbF6 (9 mol%), reactant 6e (0.2 mmol), vinylene carbonate (1 mmol), 2, 6-dimethylbenzoic acid (6 mol%) and TFE (2 mL); and (3) inserting a condensing reflux pipe, pumping argon three times, inserting an argon balloon, and reacting for 24 hours at 100 ℃. The reaction solution was diluted with a small amount of ethyl acetate, filtered through a pad of silica gel, and the filtrate was concentrated under reduced pressure and purified by silica gel chromatography to give the corresponding substituted isoquinolinone intermediate 6f in 74% yield (61.7 mg,0.148 mmol).
The nmr and high resolution data of 6f are:
1H NMR(500MHz,DMSO)δ9.38(s,1H),9.23(s,1H),7.20(dd,J＝21.1,8.5Hz,2H),7.06(s,1H),6.96(d,J＝7.3Hz,1H),6.74(s,1H),6.36(d,J＝7.3Hz,1H),4.04(t,J＝7.2Hz,2H),3.75(s,6H),2.93(t,J＝7.2Hz,2H).
13C NMR(101MHz,DMSO)δ159.2,149.4,147.7,146.68,146.60,132.0,130.4,130.0,122.7,120.5,117.9,116.2,112.2,105.2,61.5,56.3,48.9,34.4.
HRMS(ESI-TOF)m/z:[M+H]+Calcd for C19H19BrNO5420.0447；Found420.0437.
(5) Pd (PPh 3)4 (10 mol%,0.0058 g), TBAB (0.1 mmol,0.0322 g), 6f (0.05 mmol,0.0210 g), dicyclohexylamine (0.15 mmol, 32. Mu.L) and anhydrous N, N-dimethylacetamide DMA (1 mL) were added sequentially to a 10mL round bottom flask equipped with a stirrer, a condensing reflux tube was inserted, argon was added three times, and the mixture was reacted at 120℃for 12 hours, cooled to room temperature, diluted with water, ethyl acetate extracted the aqueous layer, the organic phase was combined, and the organic layer was washed once with brine, dried over anhydrous sodium sulfate, concentrated under pressure, and purified by column chromatography to give berberine 8-Oxodehydrodiscretamine in 53% (9.1 mg,0.025 mmol).
The nuclear magnetic resonance data of 8-Oxodehydrodiscretamine are:
1H NMR(400MHz,DMSO)δ9.31(s,2H),7.32(s,1H),7.22(q,J＝8.6Hz,2H),7.00(s,1H),6.65(s,1H),4.05(t,J＝5.8Hz,2H),3.81(s,3H),3.72(s,3H),2.75(t,J＝5.7Hz,2H).
13C NMR(101MHz,DMSO)δ159.3,148.9,148.2,147.6,146.5,135.2,131.7,128.7,123.2,123.0,121.0,118.7,114.9,109.0,100.7,61.4,56.4,39.4,27.6.
example 8
A berberine natural product 2-Demethyl-oxypalmatine has the structural formula:
the synthetic route of the berberine natural product 2-Demethyl-oxypalmatine of the embodiment is as follows:
the embodiment also provides a preparation method of berberine 2-Demethyl-oxypalmatine, which comprises the following steps:
(1) To a 50mL round bottom flask equipped with a stirrer were added 7a (5 mmol,1.1552 g), ammonium acetate (10 mmol,0.7708 g) and acetic acid (20 mL), and the mixture was stirred at room temperature for 5 minutes; nitromethane (20 mmol,1.1 mL) was then slowly added and the reaction mixture was refluxed in an oil bath at 120℃for 4 hours; after cooling to room temperature, ice water was added to the mixture, and a yellow solid precipitate precipitated. The precipitate was filtered, washed with ice water and dried to give 7b in 76% yield (1.03 g,3.8 mmol). 7b was used directly in the next reaction without further purification.
(2) To a 100mL three-necked flask equipped with a stirrer were added LiAlH 4 (10 mmol,0.3795 g) and anhydrous THF (20 mL), followed by a reflux condenser and a dropping funnel containing 7b (1.6 mmol,0.4385 g) of THF (5 mL). Argon is pumped for three times, the mixture is refluxed in an oil bath at 70 ℃, 7b solution is added dropwise into the reaction liquid, the dropwise adding time is controlled to be 1 hour, and the mixture is refluxed for 2 hours after the dropwise adding is finished. After the reaction was completed and cooled to room temperature, it was cooled to 0℃in ice water, and quenched with 5mL of ice water. Subsequently, the reaction solution was transferred to a round-bottomed flask, and THF was distilled under reduced pressure; after completion, 2M HCl (5 mL) was added and the mixture was stirred for 5 min; the aqueous phase was extracted with ethyl acetate, and tartaric acid (11.2 mmol,1.6810g,7 eq.) was added to the aqueous phase and stirred for 5 minutes; then adding 25% -28% ammonia water, and adjusting the pH value of the solution to be more than 10. The aqueous phase was extracted several times with DCM and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to give 7c in 48% yield (0.1887 g,0.77 mmol). 7c was used directly in the next reaction without further purification.
(3) To a 25mL round bottom flask equipped with a stirrer were added 7c (2.4 mmol,0.5906 g), 7d (2 mmol,0.3643 g), EDCI (3 mmol,0.5752 g), HOBT (3 mmol,0.4054 g), DIPEA (5 mmol,0.6462 g) and DMF (10 mL) in this order, and the reaction mixture was stirred at room temperature for 24 hours. After completion, adding water to quench the reaction; the aqueous phase was extracted three times with ethyl acetate and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography gave 7e in 81% yield (0.6610 g,1.62 mmol).
The nmr and high resolution data of 7e are:
1H NMR(500MHz,DMSO)δ9.37(s,1H),8.26(t,J＝5.4Hz,1H),7.16–7.13(m,1H),7.11(d,J＝4.4Hz,2H),6.95(d,J＝15.8Hz,2H),3.82(s,3H),3.74(s,3H),3.69(s,3H),3.49(dd,J＝12.9,6.7Hz,2H),2.86(t,J＝7.0Hz,2H).
13C NMR(126MHz,DMSO)δ165.9,152.9,147.7,146.7,146.5,130.2,129.0,124.4,121.0,119.2,115.1,114.8,113.9,61.3,56.3,56.1,35.0.
HRMS(ESI-TOF)m/z:[M+H]+Calcd for C18H21BrNO5410.0603；Found 410.0595.
(4) To a 10mL round bottom flask equipped with a stirrer were added successively [ Cp *Co(CO)I2](3mol％),AgSbF6 (9 mol%), reactant 6e (0.5 mmol,0.2051 g), vinylene carbonate (1.5 mmol), 2, 6-dimethylbenzoic acid (6 mol%) and TFE (5 mL); inserting a condensing reflux pipe, pumping argon for three times, then inserting an argon balloon, and reacting for 24 hours at 100 ℃; the reaction solution was diluted with a small amount of ethyl acetate, filtered through a pad of silica gel, and the filtrate was concentrated under reduced pressure and purified by silica gel chromatography to give the corresponding substituted isoquinolinone intermediate 7f in 63% (0.1377 g,0.315 mmol).
The nmr and high resolution data of 7f are:
1H NMR(400MHz,DMSO)δ9.29(s,1H),7.42(d,J＝8.6Hz,1H),7.26(d,J＝8.6Hz,1H),6.91(d,J＝7.1Hz,1H),6.85(s,1H),6.71(s,1H),6.31(d,J＝7.1Hz,1H),4.00(t,J＝6.3Hz,2H),3.79(s,3H),3.67(s,3H),3.54(s,3H),2.92(t,J＝6.2Hz,2H).
13C NMR(101MHz,DMSO)δ159.3,151.5,148.9,147.7,146.6,132.8,131.1,128.1,122.5,120.5,119.1,114.8,114.1,104.8,61.3,56.7,55.9,48.9,34.3.
HRMS(ESI-TOF)m/z:[M+H]+Calcd for C20H21NO5434.0603；Found434.0596.
(5) To a 10mL round bottom flask equipped with a stirrer was added Pd(OAc)2(0.01mmol,0.0022g)、PPh3(0.02mmol,0.0052g)、7f(0.1mmol,0.0434g)、TBAB(0.2mmol,0.0644g),Dicyclohexylamine(0.15mmol,64μL) and anhydrous DMA (2 mL) in sequence. And (3) inserting a condensing reflux pipe, pumping argon three times, inserting an argon balloon, and reacting for 12 hours at 120 ℃. Cooled to room temperature, diluted with water, the aqueous layer extracted with ethyl acetate, the organic phases combined and the organic layer washed once with brine. The organic layer was dried over anhydrous sodium sulfate, concentrated under pressure, and purified by column chromatography to give berberine 2-Demethyl-oxypalmatine in 60% yield (21.3 mg,0.06 mmol).
The nuclear magnetic resonance data of 2-Demethyl-oxypalmatine are:
1H NMR(400MHz,DMSO)δ9.07(s,1H),7.48(d,J＝8.7Hz,1H),7.44(d,J＝8.8Hz,1H),7.28(s,1H),6.91(d,J＝12.7Hz,2H),4.12(t,J＝6.0Hz,2H),3.86(s,3H),3.83(s,3H),3.78(s,3H),2.86(t,J＝5.9Hz,2H).
13C NMR(101MHz,DMSO)δ159.3,151.2,149.3,148.7,146.1,135.6,132.4,127.1,123.0,122.2,119.5,118.8,111.8,111.5,100.5,61.2,56.8,56.1,27.7.
The foregoing descriptions of specific exemplary embodiments of the present invention are presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain the specific principles of the invention and its practical application to thereby enable one skilled in the art to make and utilize the invention in various exemplary embodiments and with various modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims and their equivalents.

Claims (10)

1. The efficient preparation method of the berberine and the derivatives thereof is characterized in that the synthetic route of the berberine and the derivatives thereof is as follows:
Wherein R 1、R2、R3、R4、R5 and R 6 are hydrogen, methoxy, methyl, hydroxyl, halogen atom, acetamido or methylthio.
2. The efficient preparation method of berberine and derivatives thereof according to claim 1, which is characterized by comprising the following steps:
(1) Dissolving substituted benzoic acid and substituted phenethylamine in an organic solvent, adding EDCI, HOBT and triethylamine or DIPEA, stirring for reaction, and extracting, washing, drying, concentrating under reduced pressure and purifying after the reaction is finished to obtain substituted amide;
(2) Adding the substituted amide, cobalt catalyst, silver hexafluoroantimonate, vinylene carbonate and acid auxiliary agent obtained in the step (1) into an organic solvent, reacting in a protective atmosphere, filtering, concentrating and purifying to obtain a substituted isoquinolone intermediate;
(3) And (3) adding the substituted isoquinolinone intermediate, palladium catalyst, ligand, tetrabutylammonium bromide and alkali obtained in the step (2) into an organic solvent to react in a protective atmosphere to obtain berberine and derivatives thereof.
3. The efficient preparation method of berberine and derivatives thereof according to claim 2, wherein the organic solvent is one of chloroform, tetrahydrofuran, trifluoroethanol, hexafluoroisopropanol, N-dimethylformamide, N-dimethylacetamide, acetonitrile or toluene.
4. The efficient preparation method of berberine and derivatives thereof according to claim 2, wherein in the step (1), the reaction temperature is 20-30 ℃ and the reaction time is 3-60 min.
5. The efficient preparation method of berberine and derivatives thereof according to claim 2, wherein in the step (2), the reaction temperature is 60-100 ℃ and the reaction time is 24h.
6. The efficient preparation method of berberine and derivatives thereof according to claim 2, wherein in the step (3), the reaction temperature is 100-120 ℃ and the reaction time is 12h.
7. The efficient preparation method of berberine and derivatives thereof according to claim 2, wherein in the step (1), the substituted benzoic acid: substituted phenethylamines: HOBT: EDCI: alkali: the molar volume ratio of the organic solvent is 1mmol:1 to 1.5mmol:1 to 1.5mmol: 1-3 mmol: 5-10 mL.
8. The efficient preparation method of berberine and derivatives thereof according to claim 2, wherein in the step (2), the substituted amide: vinylene carbonate: cobalt catalyst: silver hexafluoroantimonate: acid adjuvant: the molar volume ratio of the organic solvent is 1mmol: 1-10 mmol:0.01 to 0.03mmol:0.03 to 0.09mmol: 0.02-0.06 mmol: 1-25 mL.
9. The efficient preparation method of berberine and derivatives thereof according to claim 2, wherein in the step (3), the isoquinolinone intermediate is substituted: palladium catalyst: ligand: tetrabutylammonium bromide: alkali: the molar volume ratio of the organic solvent is 1mmol:0.01 to 0.1mmol:0 to 0.2mmol: 1-5 mmol: 1-3 mmol: 1-30 mL.
10. The berberine and the derivatives thereof are characterized in that the berberine and the derivatives thereof are prepared by the efficient preparation method of the berberine and the derivatives thereof according to any one of claims 1 to 9, and the structural formula is as follows:
Wherein R 1、R2、R3、R4、R5 and R 6 are hydrogen, methoxy, methyl, hydroxyl, halogen atom, acetamido or methylthio.
CN202311823816.XA 2023-12-28 2023-12-28 Berberine and its derivatives and efficient preparation method thereof Pending CN117924271A (en)

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