CN111377913B - 9-alkoxy berberine salt, synthesis method and application - Google Patents
9-alkoxy berberine salt, synthesis method and application Download PDFInfo
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Abstract
The invention provides a 9-alkoxy berberine salt, which has the following molecular structure: c19+nH16+2nO4N.X wherein X is an anion such as F-, Cl-, Br-, I-, etc.; n is 2, 4, 6, 8, 10, 12. The invention also provides a preparation method and application of the 9-alkoxy berberine salt, and the application in the aspect of antibacterial activity, especially Hp resistance. The anti-Hp activity of the 9-O-alkyl berberine salt is obviously higher than that of other derivatives of the berberine salt and the berberine, the yield is high, and the price is low.
Description
Technical Field
The invention is applied to the technical field of traditional Chinese medicine preparations, and particularly relates to a preparation method and application of an anti-Hp coptis traditional Chinese medicine preparation.
Background
Berberine (Berberine), also known as Berberine, is a traditional natural antibacterial active substance extracted from Coptis chinensis and is clinically mainly used for treating intestinal bacterial infection. In recent years, pharmacological research discovers that berberine hydrochloride and certain structural derivatives thereof have various pharmacological activities of resisting bacteria, resisting inflammation, resisting tumors, reducing blood sugar, reducing blood fat and the like, so that intensive research and structural modification work on the pharmacological action of berberine hydrochloride have attracted wide interest. Iwasa and other research results show that after the berberine molecules are grafted with lipophilic groups, the bioactivity of the berberine derivative, such as bacteriostasis, can be increased. However, many derivatives of berberine with an alkyl group introduced at the 8-position have been reported so far, such as 8-butyl berberine salt, 8-hexyl berberine salt, 8-octyl berberine salt and the like, but no research report on anti-Hp of derivatives of berberine with an alkyl group introduced at the 9-position has been found.
Disclosure of Invention
The invention provides a 9-alkoxy berberine salt, a synthesis method and an application aiming at the problems in the prior art, and finds out the antibacterial activity, especially the activity on Hp resistance, of the 9-alkoxy berberine salt.
The technical problem to be solved by the invention is realized by adopting the following technical scheme:
a9-alkoxy berberine salt has the following molecular structure:
wherein, X is an anion such as F-, Cl-, Br-, I-, etc.; n is 2, 4, 6, 8, 10, 12.
A method for synthesizing the 9-alkoxy berberine salt comprises the following steps:
(1) taking berberine hydrochloride to perform microwave treatment for 1-20min to obtain berberberrubine;
(2) adding N-DMF and alkyl halide into berberberrubine, performing microwave reaction for 3-10 min, and cooling to room temperature;
(3) concentrating under reduced pressure to obtain solid, adding diethyl ether, and filtering to obtain crystal;
(4) and (4) adding ethanol into the crystal obtained in the step (3) to recrystallize for 2-4 times to obtain the 9-alkoxy berberine salt.
Further, the power level of the microwave treatment in the step (1) is 300-900W.
Further, the amount of the alkyl halide is 1-10 times of the molar ratio of the berberine hydrochloride.
Further, the microwave power of the microwave reaction in the step (2) is 200-600W.
An application of the 9-alkoxy berberine salt in antibacterial activity is provided.
Furthermore, the application of the 9-alkoxy berberine salt in the aspect of resisting Hp.
Measuring the element composition of the purified 9-alkoxy berberine salt by a Perkin Elmer model 2400 element analyzer; i R analysis IR spectra were determined using a Perkin Elmer one type infrared spectrophotometer (KBr pellet); UV analysis is carried out by measuring an ultraviolet spectrum by using a Hitachi U-1800 type ultraviolet spectrophotometer;1HNMR，13CNMR analysis Using BA ruker 300 type nuclear magnetic resonance instrument is used for measuring the hydrogen spectrum and the carbon spectrum of the compound, and the solvents are DMSO-d6，1The internal standard for HNMR measurements was TMS.
By adopting the method, the berberine hydrochloride salt is structurally modified by alkyl halide, and the structural characterization structures of various 9-alkoxy berberine salts are obtained as follows:
the structure characterization result of the 9-O-ethyl berberine hydrochloride is as follows:
2a(9-ethoxyberberine):Yield:78.1％；mp(℃):289-302；Rf:0.31；IR v(cm-1):3433,3040, 3008,2955,2924,2853,1633,1603,1568,1509,1481,1467,1404,1364,1300,1273,1232,1142, 1102,1039,929,874,834,722,617,515,426；1HNMRδ(ppm):1.35(t,3H,-CH3),3.16(t,2H, 5-CH2-),4.03(s,3H,-OCH3),4.30(q,2H,-OCH2-),4.93(t,2H,6-CH2-),6.15(s,2H,-OCH2O-), 7.08(d,1H,11-Ar-H),7.78(d,1H,12-Ar-H),7.96(s,1H,4-Ar-H),8.18(s,1H,1-Ar-H),8.92(s,1H, 13-Ar-H),9.73(s,1H,8-Ar-H)；13CNMRδ(ppm):14.76,26.43,55.42,57.16,70.03,102.17,105.52, 108.50,120.31,120.54,121.75,123.36,126.83,130.79,133.14,137.55,142.99,145.36,147.78, 149.91,150.48；ESI-MS(m/z)[M-Br]+for C21H20BrNO4:Calcd:350.1323；Found:350。
the structure characterization result of 9-O-butyl berberine hydrochloride is as follows:
(9-butoxyberberine):Yield:66.3％；mp(℃):260-263；Rf:0.35；IR v(cm-1):3433,3040,3008, 2955,2924,2853,1633,1603,1568,1509,1481,1467,1404,1364,1300,1273,1232,1142,1102, 1039,929,874,834,722,617,515,426；1HNMRδ(ppm):0.96(t,3H,-CH3),1.49(m,2H,-CH2-), 1.84(m,2H,-O-C-CH2-),3.16(t,2H,5-CH2-),4.03(s,3H,-OCH3),4.25(t,2H,-OCH2-),4.93(t,2H, 6-CH2-),6.15(s,2H,-OCH2O-),7.08(d,1H,11-Ar-H),7.78(d,1H,12-Ar-H),7.96(s,1H,4-Ar-H), 8.18(s,1H,1-Ar-H),8.92(s,1H,13-Ar-H),9.73(s,1H,8-Ar-H)；13CNMRδ(ppm):13.83,18.63, 26.43,31.62,55.42,57.16,74.05,102.17,105.52,108.50,120.31,120.54,121.75,123.36,126.83, 130.79,133.14,137.55,142.99,145.36,147.78,149.91,150.48；ESI-MS(m/z)[M-Br]+for C23H24BrNO4:Calcd:378.1706；Found:378。
the structure characterization result of the 9-O-hexyl berberine hydrochloride is as follows:
(9-hexoxyberberine):Yield:55.8％；mp(℃):233-236；Rf:0.39；IR v(cm-1):3433,3040,3008, 2955,2924,2853,1633,1603,1568,1509,1481,1467,1404,1364,1300,1273,1232,1142,1102, 1039,929,874,834,722,617,515,426；1HNMRδ(ppm):0.86(t,3H,-CH3),1.32(m,4H,-(CH2)2-), 1.44(m,2H,-CH2-),1.84(m,2H,-O-C-CH2-),3.16(t,2H,5-CH2-),4.03(s,3H,-OCH3),4.25(t,2H, -OCH2-),4.93(t,2H,6-CH2-),6.15(s,2H,-OCH2O-),7.08(d,1H,11-Ar-H),7.78(d,1H,12-Ar-H), 7.96(s,1H,4-Ar-H),8.18(s,1H,1-Ar-H),8.92(s,1H,13-Ar-H),9.73(s,1H,8-Ar-H)；13CNMR δ(ppm):14.02,22.15,25.24,26.43,29.56,31.32,55.42,57.16,74.25,102.17,105.52,108.50, 120.31,120.54,121.75,123.36,126.83,130.79,133.14,137.55,142.99,145.36,147.78,149.91, 150.48；ESI-MS(m/z)[M-Br]+for C25H28BrNO4:Calcd:406.2019；Found:406。
the structure characterization result of 9-O-octyl berberine hydrochloride is as follows:
(9-octoxyberberine):Yield:48.0％；mp(℃):219-222；Rf:0.43；IR v(cm-1):3433,3040,3008, 2955,2924,2853,1633,1603,1568,1509,1481,1467,1404,1364,1300,1273,1232,1142,1102, 1039,929,874,834,722,617,515,426；1HNMRδ(ppm):0.85(t,3H,-CH3),1.26(m,8H,-(CH2)4-), 1.46(m,2H,-CH2-),1.85(m,2H,-O-C-CH2-),3.16(t,2H,5-CH2-),4.03(s,3H,-OCH3),4.25(t,2H, -OCH2-),4.93(t,2H,6-CH2-),6.15(s,2H,-OCH2O-),7.08(d,1H,11-Ar-H),7.78(d,1H,12-Ar-H), 7.96(s,1H,4-Ar-H),8.18(s,1H,1-Ar-H),8.92(s,1H,13-Ar-H),9.73(s,1H,8-Ar-H)；13CNMR δ(ppm):14.02,22.15,25.35,26.43,28.75,28.87,29.56,31.32,55.42,57.16,74.35,102.17,105.52, 108.50,120.31,120.54,121.75,123.36,126.83,130.79,133.14,137.55,142.99,145.36,147.78, 149.91,150.48；ESI-MS(m/z)[M-Br]+for C27H32BrNO4:Calcd:434.2332；Found:434。
the structure characterization result of the 9-O-sunflower berberine hydrochloride is as follows:
(9-decoxyberberine):Yield:40.2％；mp(℃):214-216；Rf:0.47；IR v(cm-1):3433,3040,3008, 2955,2924,2853,1633,1603,1568,1509,1481,1467,1404,1364,1300,1273,1232,1142,1102, 1039,929,874,834,722,617,515,426；1HNMRδ(ppm):0.83(t,3H,-CH3),1.24(m,12H, -(CH2)6-),1.45(m,2H,-CH2-),1.85(m,2H,-O-C-CH2-),3.16(t,2H,5-CH2-),4.03(s,3H,-OCH3), 4.25(t,2H,-OCH2-),4.93(t,2H,6-CH2-),6.15(s,2H,-OCH2O-),7.08(d,1H,11-Ar-H),7.78(d,1H, 12-Ar-H),7.96(s,1H,4-Ar-H),8.18(s,1H,1-Ar-H),8.92(s,1H,13-Ar-H),9.73(s,1H,8-Ar-H)； 13CNMRδ(ppm):14.02,22.15,25.35,26.43,28.75,28.80,28.82,28.87,29.56,31.32,55.42,57.16, 74.35,102.17,105.52,108.50,120.31,120.54,121.75,123.36,126.83,130.79,133.14,137.55, 142.99,145.36,147.78,149.91,150.48；ESI-MS(m/z)[M-Br]+for C29H36BrNO4:Calcd:462.2645； Found:462。
the structure characterization result of the 9-O-dodecyl berberine hydrochloride is as follows:
(9-dodecoxyberberine):Yield:31.7％；mp(℃):210-213；Rf:0.52；IR v(cm-1):3433,3040, 3008,2955,2924,2853,1633,1603,1568,1509,1481,1467,1404,1364,1300,1273,1232,1142, 1102,1039,929,874,834,722,617,515,426；1HNMRδ(ppm):0.81(t,3H,-CH3),1.22(m,16H, -(CH2)8-),1.45(m,2H,-CH2-),1.85(m,2H,-O-C-CH2-),3.16(t,2H,5-CH2-),4.03(s,3H,-OCH3), 4.25(t,2H,-OCH2-),4.93(t,2H,6-CH2-),6.15(s,2H,-OCH2O-),7.08(d,1H,11-Ar-H),7.78(d,1H, 12-Ar-H),7.96(s,1H,4-Ar-H),8.18(s,1H,1-Ar-H),8.92(s,1H,13-Ar-H),9.73(s,1H,8-Ar-H)； 13CNMRδ(ppm):14.02,22.15,25.35,26.43,28.75,28.80,28.81,28.81,28.82,28.87,29.56,31.32, 55.42,57.16,74.35,102.17,105.52,108.50,120.31,120.54,121.75,123.36,126.83,130.79, 133.14,137.55,142.99,145.36,147.78,149.91,150.48；ESI-MS(m/z)[M-Br]+for C31H40BrNO4: Calcd:490.2958；Found:490。
the structural characterization result of the berberine hydrochloride is as follows:
Rf＝0.43,UV(CH3OH)λmax:348(0.284),266(0.322)nm；1HNMR(DMSO-d6)δ:3.21(t,2H,
5-CH2),4.07,4.09(each s,6H,-OCH3),4.93(d,2H,6-CH2),6.12(s,2H,-OCH2O-),7.091(s,1H,
4-CH),7.80(s,1H,1-CH),8.00(d,1H,11-CH),8.21(d,1H,12-CH),8.94(s,1H,13-CH),9.89(s, 1H,8-CH)；13CNMR(DMSO-d6)δ：26.65,49.63,57.08,61.57,101.10,105.82,107.54,120.29, 121.19,121.41,124.68，125.25,130.78,132.67,137.83,145.57,147.63,149.66,152.44,160.17. IR(KBr)v:3413,3017,3000,2946,2909,2846,1634,1619,1601,1567,1509,1480,1458cm-1。
the structural representation data show that the obtained compound is 9-O-alkyl berberine halate by carrying out structural modification on the berberine hydrochloride salt by alkyl halide. Comparing the structural characterization data of berberine hydrochloride and 9-alkoxy berberine salt, the proton peak on berberine hydrochloride ring in modified berberine molecule is not affected, but the modified berberine molecule has obvious alkyl peak characteristic. The modification is shown to be not directly acted on the ring, but the 9-position is added with alkyl, and the modified site is 9-O-alkyl berberine salt.
The compounds of the present invention can be administered in the form of a composition by oral, injection, topical, or the like, to a patient suffering from the relevant disease. For oral administration, it can be made into conventional solid preparations such as tablet, powder, granule, capsule, etc., and liquid preparations such as water and oil suspension or syrup, etc.; when used for injection administration, the preparation can be prepared into injection solution or oil suspending agent, etc.; it can be made into plaster or liniment for external use. The above various dosage forms can be prepared according to conventional production methods in the pharmaceutical field. The amount of a compound of the present invention administered may vary depending on the route of administration, the age, weight, type and severity of the condition being treated, etc.
The inventor finds that the compounds of the invention have better anti-Hp bacterial activity than berberine salt. The 9-O-alkyl berberine salt is dissolved by 0.5-3% of emulsifier such as Tween-80 and diluted to 1-100 ppm solution, and the solution can be used as a good anti-Hp drug.
When the present invention is used as a starting material for an anti-Hp drug to prepare a medicament, a therapeutically effective amount of a compound of the present invention is combined with one or more pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers refer to pharmaceutical carriers conventional in the pharmaceutical art, such as: diluents such as alcohol or water, excipients such as water, etc., fillers such as sucrose or starch, etc., binders such as gelatin, disintegrators such as alginic acid, etc., wetting agents such as zinc stearate, etc., colorants such as sucrose, flavoring agents such as sorbitol, etc., adsorbents such as PVP, etc., medicinal polymers, etc., sustained-release materials, etc., emulsifiers such as Tween, etc., matrix materials for floating tablet preparations such as hydroxypropylmethylcellulose K15M, low-density drift aids for floating tablet preparations such as stearyl alcohol, foaming agents for floating tablet preparations such as sodium hydrogencarbonate, release regulators for floating tablet preparations such as polyvinylpyrrolidone K30, etc.
Compared with the prior art, the invention has the beneficial effects that:
(1) the anti-Hp activity of the 9-O-alkyl berberine salt is obviously higher than that of other derivatives of the berberine salt and the berberine.
(2) The 9-O-alkyl berberine salt can be used as a novel anti-Hp substance for development and utilization.
(3) The compound synthesized by the method has high yield, low price and excellent development and utilization values.
Detailed Description
The technical solution of the present invention is further described in detail with reference to the following specific examples. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
In addition, unless otherwise specifically indicated, various starting materials, reagents, equipment and equipment used in the present invention may be commercially available or prepared by existing methods.
Example 1: preparation of 9-O-butyl berberine iodate
(1) Placing 100g berberine hydrochloride into microwave oven, and performing microwave treatment at 300W power for 1-20min to obtain 91.6g berberrubine;
(2) taking 10g (0.3mol) berberberrubine, adding 100ml N, N-DMF, adding 10ml N-iodo-butane, placing in a microwave oven, performing microwave reaction for 3min at 600W power, and cooling to room temperature;
(3) recovering solvent under reduced pressure, adding 10 times of diethyl ether into solid, extracting, and filtering to obtain crystal;
(4) the crystals were recrystallized 4 times from 1-fold ethanol to give 10.6g of 9-O-butyl berberine iodate with 89.9% yield.
Example 2: preparation of 9-O-hexyl berberine hydrochloride
(1) Placing 100g berberine hydrochloride into microwave oven, and performing microwave treatment at 900W power for 1min to obtain 91.0g berberrubine;
(2) taking 10g (0.3mol) of berberberrubine, adding 1000ml of N, N-DMF, adding 100ml of chloron-hexane, placing into a microwave oven, carrying out microwave reaction for 10min at 200W power, and then cooling to room temperature;
(3) recovering solvent under reduced pressure, adding 1 time of diethyl ether into solid, extracting, and filtering to obtain crystal;
(4) the crystals were recrystallized 2 times from 10 times of ethanol to give 11.6g of 9-O-hexyl berberine hydrochloride, 91.3% yield.
Example 3: preparation of 9-O-octyl berberine bromate
(1) Placing 100g berberine hydrochloride into microwave oven, and performing microwave treatment with 600W power for 5min to obtain 91.1g berberrubine;
(2) taking 10g (0.3mol) of berberberrubine, adding 500ml of N, N-DMF, adding 50ml of bromo-N-octane, placing into a microwave oven, carrying out microwave reaction for 6min at 400W power, and then cooling to room temperature;
(3) recovering solvent under reduced pressure, adding 5 times of diethyl ether into solid, extracting, and filtering to obtain crystal;
(4) the crystals were recrystallized 3 times from 5 times of ethanol to give 12.3g of 9-O-octyl berberine hydrochloride, with a yield of 90.4%.
Example 4: preparation of 9-O-decyl berberine fluoate
(1) Placing 100g berberine hydrochloride into microwave oven, and performing microwave treatment with 400W power for 7min to obtain 90.2g berberrubine;
(2) taking 10g (0.3mol) of berberberrubine, adding 200ml of N, N-DMF, adding 20ml of bromo-N-decane, placing in a microwave oven, carrying out microwave reaction for 3min at the power of 500W, and then cooling to room temperature;
(3) recovering solvent under reduced pressure, adding 3 times of diethyl ether into solid, extracting, and filtering to obtain crystal;
(4) the crystals were recrystallized 3 times from 3 times of ethanol to give 12.5g of 9-O-sunflower berberine fluoride salt in 86.2% yield.
Example 5: preparation of 9-O-dodecyl berberine hydrochloride
(1) Placing 100g berberine hydrochloride into microwave oven, and performing microwave treatment with 600W power for 3min to obtain 90.9g berberrubine;
(2) taking 10g (0.3mol) of berberberrubine, adding 600ml of N, N-DMF, adding 60ml of chloro-N-dodecane, putting into a microwave oven, carrying out microwave reaction for 4min at the power of 500W, and then cooling to room temperature;
(3) recovering solvent under reduced pressure, adding 6 times of diethyl ether into solid, extracting, and filtering to obtain crystal;
(4) the crystals were recrystallized 3 times from 6 times of ethanol to give 13.3g of 9-O-dodecyl berberine hydrochloride salt, with a yield of 86.3%.
Example 6: preparation of 9-O-alkyl berberine salt sustained-release capsule
10g of 9-O-alkyl berberine salt (medicine) is taken and added with 10g of polyvinylpyrrolidone (auxiliary material), 20g of sodium hydroxymethyl starch (auxiliary material), 40 g of lactose (auxiliary material) and 20g of corn starch, and the total amount is 100 g. After the medicines are uniformly mixed, 20ml of 95% ethanol is used for granulating, drying and screening by a 16-mesh sieve, thus obtaining the sustained-release granular medicine. And (5) packaging the capsules, wherein each capsule is 0.5 g. Namely each sustained-release capsule containing 50mg of the original medicine. Can be taken orally to be used as anti-Hp medicine.
Example 7: preparation of 9-O-alkyl berberine salt tablet
Taking 10g of 9-O-alkyl berberine salt (medicine), adding 70 g of spherical lactose (auxiliary material), 15 g of magnesium stearate (auxiliary material) and 5g of microcrystalline cellulose (auxiliary material), mixing uniformly and pressing into tablets with 0.5 g. The medicine is 50mg in each tablet. Can be taken orally to be used as anti-Hp medicine.
Example 8: preparation of 9-O-alkyl berberine salt floating tablet
10g of 9-O-alkyl berberine salt (drug) is taken, 60g of hydroxypropyl methyl cellulose, 20g of octadecanol, 10g of sodium bicarbonate, 305 g of PVP-K and 5g of magnesium stearate are added, and after being uniformly mixed, the mixture is pressed into tablets with 0.1 g of tablets. The medicine is 50mg in each tablet. Can be taken orally to be used as anti-Hp medicine.
Example 9: comparison of 9-O-alkyl berberine salts with berberine hydrochloride, 8-alkyl berberine salts, and 3-alkoxy jateorhizine salts for anti-Hp
(ii) experimental materials.
The test drugs are 9-ethoxy berberine salt, 9-butoxy berberine salt, 9-hexyloxy berberine salt, 9-octyloxy berberine salt, 9-decyloxy berberine salt and 9-dodecyloxy berberine salt which are respectively prepared to be 1000 ppm.
The reference drugs are berberine hydrochloride, 8-hexyl berberine salt and 3-hexyloxy group prodrug alkaloid salt, which are respectively prepared to 1000 ppm.
Secondly, strain: escherichia coli, helicobacter pylori (Hp, 11637), Staphylococcus aureus, and Bacillus subtilis
③ culture medium: MH broth and MH agar are all sold.
And fourthly, MIC detection: the MBC of the related drugs is determined according to a sesquidilution method (Chinese medicine basic medicine journal, 2017,23(03): 405-. Taking MH agar medium to obtain 100uL of 3X 108CFU·mL-1The helicobacter pylori bacterial liquid of the helicobacter pylori,uniformly spreading on MH agar medium with disposable applicator, diluting test medicines to concentration of 800, 400, 200, 100, 50, 25, 12.5, 6.25, 3.1, 1.56, 0.78, 0.39, 0.198, 0.099 ug/ml-1Spreading on MH agar medium, and placing in a three-atmosphere incubator (85% N) with blank medium as control2，10％CO2，5％O2) Culturing for 48-72 h, observing the growth condition of bacteria, and taking the lowest drug concentration of the number of bacteria as the minimum bactericidal concentration (MIC). The results of the experiment are shown in Table 1.
TABLE 1 comparison of antibacterial Activity of drugs (. mu.g/mL)
| Bacterial strain | Escherichia coli | Staphylococcus aureus | Bacillus subtilis | Helicobacter pylori (11637) |
| Berberine hydrochloride | 200 | 400 | 400 | 50 |
| 9-O-Ethyl Berberine salt | 50 | 100 | 200 | 12.5 |
| 9-O-butyl berberine salt | 25 | 50 | 100 | 3.1 |
| 9-O-hexyl berberine salt | 25 | 25 | 100 | 0.78 |
| 9-O-octyl berberine salt | 25 | 25 | 100 | 0.39 |
| 9-O-decyl berberine salt | 50 | 50 | 200 | 0.78 |
| 9-O-dodecyl berberine salt | 100 | 100 | 800 | 1.56 |
| 8-hexyl berberine salt | 0.78 | 1.56 | 200 | 3.1 |
| 3-O-hexyl jatrorrhizine salt | 3.1 | 6.25 | 100 | 6.25 |
From the above experimental results, it can be seen that the activity of 8-hexyl berberine against E.coli is significantly higher than other derivatives of berberine; the anti-Hp activity of the 9-O-alkyl berberine salt (especially the 9-O-octyl berberine salt) is obviously better than that of other derivatives of the berberine; the berberine derivative has improved inhibitory activity to bacillus subtilis, but is not obvious; the inhibitory activity of the berberine derivative on staphylococcus aureus is not much different from that of escherichia coli.
The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above-described embodiments. It will be understood by those skilled in the art that various changes, substitutions of equivalents, and alterations can be made without departing from the spirit and scope of the invention.
Claims (5)
1. An application of 9-alkoxy berberine salt in preparing medicine for resisting helicobacter pylori is disclosed, the molecular structure of the 9-alkoxy berberine salt is as follows:
wherein, X is F-, Cl-, Br-, I-anion; n is 2, 4, 6, 8, 10, 12.
2. The use according to claim 1, wherein the synthesis of said 9-alkoxyberberine salt comprises the steps of:
(1) taking berberine hydrochloride to perform microwave treatment for 1-20min to obtain berberberrubine;
(2) adding N-DMF and alkyl halide into berberberrubine, performing microwave reaction for 3-10 min, and cooling to room temperature;
(3) concentrating under reduced pressure to obtain solid, adding diethyl ether, and filtering to obtain crystal;
(4) and (4) adding ethanol into the crystal obtained in the step (3) to recrystallize for 2-4 times to obtain the 9-alkoxy berberine salt.
3. Use according to claim 2, characterized in that: the power level of the microwave treatment in the step (1) is 300-900W.
4. Use according to claim 2, characterized in that: the amount of the alkyl halide is 1-10 times of the molar ratio of the berberine hydrochloride.
5. Use according to claim 2, characterized in that: the microwave power of the microwave reaction in the step (2) is 200-600W.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003051875A1 (en) * | 2000-06-22 | 2003-06-26 | Newtree Industry Co., Ltd. | New derivatives of berberrubine and their salts for antibiotics and antifungal agents |
| CN104208061A (en) * | 2013-06-04 | 2014-12-17 | 中山大学 | Medical application of berberine derivative |
| CN106333947A (en) * | 2016-10-24 | 2017-01-18 | 广州中医药大学 | Application of epiberberine in preparation of urease inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003051875A1 (en) * | 2000-06-22 | 2003-06-26 | Newtree Industry Co., Ltd. | New derivatives of berberrubine and their salts for antibiotics and antifungal agents |
| CN104208061A (en) * | 2013-06-04 | 2014-12-17 | 中山大学 | Medical application of berberine derivative |
| CN106333947A (en) * | 2016-10-24 | 2017-01-18 | 广州中医药大学 | Application of epiberberine in preparation of urease inhibitor |
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| Antimicrobial Activity of 9-O-Acyl- and 9-O-Alkylberberrubine Derivatives;Sung Han Kim et al.;《Planta Med.》;20021231;第68卷;277-281 * |
| Hong-Jhih Lin et al..Synthesis and In Vitro Photocytotoxicity of 9-/13-Lipophilic Substituted Berberine Derivatives as Potential Anticancer Agents.《Molecules》.2020,第25卷(第677期),1-22. * |
| Sung Han Kim et al..Antimicrobial Activity of 9-O-Acyl- and 9-O-Alkylberberrubine Derivatives.《Planta Med.》.2002,第68卷277-281. * |
| Synthesis and In Vitro Photocytotoxicity of 9-/13-Lipophilic Substituted Berberine Derivatives as Potential Anticancer Agents;Hong-Jhih Lin et al.;《Molecules》;20200205;第25卷(第677期);1-22 * |
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