CN114426538B

CN114426538B - Berberine canagliflozin derivative and preparation method and application thereof

Info

Publication number: CN114426538B
Application number: CN202210100275.7A
Authority: CN
Inventors: 赵子剑; 谢伟东; 车诗莹; 李金晟; 郝文慧; 张雨薇; 张祎
Original assignee: Huaihua University; Shenzhen International Graduate School of Tsinghua University
Current assignee: Huaihua University; Shenzhen International Graduate School of Tsinghua University
Priority date: 2022-01-27
Filing date: 2022-01-27
Publication date: 2023-01-17
Anticipated expiration: 2042-01-27
Also published as: CN114426538A

Abstract

The invention relates to a novel derivative compound of berberine canagliflozin, which is characterized in that berberine hydrochloride (BBR) and Canagliflozin (CAN) are linked by a chemical synthesis method under the condition of not changing basic skeletons of the berberine and the canagliflozin to synthesize a novel compound BC. The invention also relates to a preparation method of the compound, which has the advantages of high yield, less side reaction, high product purity, low requirement on reaction equipment and easy industrial production. The prepared compound has a certain hypoglycemic effect, shows excellent antibacterial activity and broad-spectrum antibacterial action, CAN inhibit the activity of gram-positive bacteria and gram-negative bacteria simultaneously, has a greatly reduced MIC value compared with BBR and CAN, particularly for pseudomonas aeruginosa, greatly reduces the dosage of a patient, and is beneficial to preventing the evolution of drug-resistant microbial strains.

Description

Berberine canagliflozin derivative and preparation method and application thereof

Technical Field

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a berberine canagliflozin derivative and a preparation method and application thereof.

Background

The structural modification and modification of natural medicines are important ways for drug researchers to develop new medicines. Berberine (BBR, C20H19NO5, MW 336.37), also called berberine, is an isoquinoline alkaloid separated and extracted from Chinese herbal medicines such as Coptis chinensis (Coptis chinensis). The active alkaloid exists in traditional Chinese medicines such as coptis chinensis, phellodendron amurense and berberis juliana schneid, and researches in recent years show that the active alkaloid has various pharmacological activities such as anti-inflammation, blood sugar reduction, blood fat reduction, pathogenic microorganism resistance and tumor resistance, and a good blood sugar reduction effect can be achieved only by high dosage. Berberine has a unique structure and is therefore popular in the synthesis of chemical science and medicine. There have been some reports of the conversion of general molecules to heterocyclic compounds from berberine as the starting material. However, because berberine has poor lipid solubility, is difficult to permeate cell membranes of bacteria, and is difficult to absorb when being orally taken, thereby limiting the clinical application range of berberine. Therefore, the related research of changing the structural characteristics of the drug molecules and further changing the in vitro and in vivo antibacterial activities through the molecular structure modification is urgently needed. Canagliflozin (Canagliflozin) is a novel diabetes treatment drug and is a sodium-glucose cotransporter 2 (SGLT 2) inhibitor, but has more side effects when in use, such as acute kidney injury, female extrinsic negative mycotic infection and the like. The structure of canagliflozin is rarely reported as a new drug on the market in recent years.

Disclosure of Invention

In view of the above, the present invention aims to provide a berberine canagliflozin derivative with a stronger antibacterial activity, and also provides a preparation method and an application of the derivative.

In order to achieve the purpose, the invention provides the following technical scheme:

1. a berberine canagliflozin derivative has a structural formula shown in formula I:

2. a preparation method of a berberine canagliflozin derivative comprises the following steps:

a. reducing berberine hydrochloride to obtain berberine;

b. brominating the hydroxy silyl ether of canagliflozin to obtain a product 11, and then performing acetic acid reaction to obtain a product 4;

c. and finally reacting the berberine with the product 11 or the berberine with the product 4 to obtain the berberine canagliflozin derivative with the structural formula shown in the formula I.

Further, the preparation method of the berberine canagliflozin derivative comprises the following specific steps of reducing berberine hydrochloride in the step a to obtain berberine: dissolving berberine hydrochloride in acid-binding agent, adding 1-4eq NaBH ₄ Reacting at 0-25 deg.c for 0.5-3 hr, and water washing to obtain reduced berberine product.

Further, in the preparation method of the berberine canagliflozin derivative, the specific steps of preparing the product 11 in the step b are as follows: dissolving canagliflozin in DMF, starting stirring, adding triphenylphosphine under the protection of argon, cooling the reaction solution to 0 ℃, slowly adding NBS into the reaction system, reacting for 4 hours at 50 ℃ after dropwise addition is finished, and separating by column chromatography to obtain a product 11.

Further, in the preparation method of the berberine canagliflozin derivative, in the specific step of preparing the product 11 in the step b, the eluent for column chromatography is dichloromethane: methanol 20.

Further, the preparation method of the berberine canagliflozin derivative comprises the steps of dissolving the product 11 in pyridine, adding acetic anhydride, stirring and reacting for 4 hours at room temperature, and separating by column chromatography to obtain a product 4.

Further, in the preparation method of the berberine canagliflozin derivative, the eluent of the product 4 obtained by column chromatography separation is petroleum ether: ethyl acetate 10:1.

further, the preparation method of the berberine canagliflozin derivative comprises the following specific steps of: and (3) taking the product 4 or the product 11 and the reduced berberine to be placed in anhydrous acetonitrile, adding an iodine compound, reacting for 10-24 hours at the temperature of 80-130 ℃, and separating by column chromatography to obtain a target product which is an orange yellow solid.

Further, in the preparation method of the berberine canagliflozin derivative, the iodine compound is NaI.

Further, in the preparation method of the berberine canagliflozin derivative, the reaction in the step c is carried out under the protection of argon.

3. The application of the berberine canagliflozin derivative in any one of the technical schemes in preparing antibacterial drugs.

Further, the berberine canagliflozin derivative is applied to the preparation of antibacterial drugs, and the bacteria are gram-positive bacteria and gram-negative bacteria.

Further, the berberine canagliflozin derivative is applied to preparation of antibacterial drugs, and the bacteria are escherichia coli, staphylococcus aureus and/or pseudomonas aeruginosa.

The invention has the beneficial effects that: according to the invention, through a plurality of tests, under the condition that the basic frameworks of berberine and canagliflozin are not changed, berberine hydrochloride (BBR) and Canagliflozin (CAN) are linked through a chemical synthesis method to synthesize a brand new compound BC, which has a certain hypoglycemic effect, shows excellent antibacterial activity and broad-spectrum antibacterial action, and CAN simultaneously inhibit the activity of gram-positive bacteria and gram-negative bacteria. The invention also relates to a preparation method of the compound, which has the advantages of high yield, less side reaction, high product purity, low requirement on reaction equipment and easy industrial production.

Drawings

In order to make the purpose, technical scheme and beneficial effect of the invention more clear, the invention provides the following drawings for explanation:

FIG. 1 is a high performance liquid chromatogram of product BC;

FIG. 2 is a schematic diagram showing the hypoglycemic effect of each drug group;

FIG. 3 is a graph showing the results of in vitro inflammatory factor inhibition experiments for each drug group;

FIG. 4 is a graph showing the results of an antibacterial test for each drug group;

FIG. 5 is a schematic representation of the inhibition of bacterial biofilm formation by CAN, BBR + CAN, BC at a concentration of 0.1mM for 24 h;

FIG. 6 is a SDS-PAGE analysis of Pseudomonas aeruginosa intracellular soluble proteins treated with 0.1mM compound BC for 24 hours.

FIGS. 7-10 in sequence are for compound BC ¹ H、 ¹³ C、 ¹⁹ F-NMR and High Resolution Mass Spectrometry (HRMS) spectra;

FIGS. 11-13 are, in sequence, compounds BA-C ¹ H、 ¹³ C、 ¹⁹ F-NMR spectrum.

FIG. 14 is of esterified canagliflozin ¹ H–NMR。

FIGS. 15-17 are sequential views of canagliflozin bromide (Br-C) ¹ H、 ¹³ C、 ¹⁹ F-NMR。

FIG. 18 is a scheme showing the reduction of berberine ¹ H NMR chart.

Detailed Description

Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings. The experimental procedures, in which specific conditions are not specified in the examples, are generally carried out under conventional conditions or under conditions recommended by the manufacturers.

Through a plurality of tests, berberine hydrochloride (BBR) and Canagliflozin (CAN) are linked by a chemical synthesis method under the condition of not changing the basic skeleton of the raw material compound, so that a brand-new compound BC with a pharmaceutical application prospect is synthesized. The structural formulas of the raw materials and the target product are as follows:

a target product BC:

example 1

The following route was designed (route 1):

reaction 1: reducing berberine hydrochloride 1 to obtain reduced berberine (HB); berberine hydrochloride (1g, 2.66mol) was dissolved in 15ml pyridine, and 2eq NaBH was added ₄ After reacting for 1h at room temperature, washing with water to obtain a product 2 with small reductionBerberine, 65% yield.

In the preparation method of the reduced berberine: dissolving berberine hydrochloride (1g, 2.66mol) in 15ml pyridine (or other acid-binding agent), and adding 1-4eq NaBH ₄ After reacting for 0.5-3h at 0-25 ℃, the product of the reduced berberine 2 can be obtained by washing with water.

The reaction method also comprises dissolving berberine hydrochloride in methanol solution containing potassium carbonate, and reacting at 0 deg.C for 8 hr to obtain 46% yield.

Reaction 2 (reaction step a): esterifying canagliflozin to obtain a product 3 (Ac-C); dissolving canagliflozin in pyridine, adding acetic anhydride, and reacting for 4 hours to obtain a product 3.

Reaction 3 (reaction step b): brominating the product 3 to obtain a product 4 (BA-C); however, reaction 3 failed to detect the progress of the reaction, i.e., failed to obtain the desired product. In this reaction, the progress of the reaction was not detected regardless of whether the solvent was changed, the ratio of the reaction system was changed, or the temperature of the reaction system was changed. So that the subsequent reaction does not proceed smoothly. Synthesis of canagliflozin derivatives: reagents and conditions: a) Acetic anhydride, pyridine, rt,4h,82% ₃ ,CH ₂ Cl ₂ ,0℃,12h。

Preparation of product 3 (2r, 3r,4r,5s, 6r) -2- (acetoxymethyl) -6- (3- (5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) tetrahydro-2H-pyran-3, 4, 5-triacetate: dissolving canagliflozin (1 mmol) in 1ml pyridine, adding acetic anhydride (5 mmol), stirring and reacting for 4 hours at room temperature, and performing column chromatography to obtain a white solid (82%), wherein the eluent is petroleum ether: ethyl acetate 10:1 (volume ratio).

¹ H NMR(400MHz,CDCl3)δ7.51–7.43(m,2H),7.18(d,J＝7.1Hz,3H),7.01(d,J＝8.8Hz,3H),6.61(s,1H),5.32(t,J＝9.2Hz,1H),5.23(t,J＝9.5Hz,1H),5.14(t,J＝9.4Hz,1H),4.36(d,J＝9.7Hz,1H),4.33–4.25(m,1H),4.19–4.04(m,3H),3.82(d,J＝7.6Hz,1H),2.29(s,3H),2.06(d,J＝3.0Hz,6H),2.00(s,3H),1.76(s,3H).)

Reaction 4 (reaction step c): connecting the reduced berberine 2 with the product 4 to obtain a product 5;

reaction 5 (reaction step d): the product 5 is hydrolyzed to obtain the final product, product 6. Aims to convert hydroxyl at the hydroxyl silyl ether of canagliflozin into a halogen group for substitution, and increase the activity of reaction with reduced berberine, so that the canagliflozin is easily connected with the berberine in structure.

Example 2

To obtain product 4 (BA-C), continuing attempts to modify canagliflozin by protecting and deprotecting it with hydroxysilyl ether were made (scheme 2):

reaction 6 (reaction step e): protecting hydroxyl at the hydroxy silyl ether of canagliflozin to obtain a product 7;

reaction 7 (reaction step f): esterifying the product 7 to obtain a product 8;

reaction 8 (reaction step g): carrying out deprotection on the product 8 to obtain a product 9;

reaction 9 (reaction step h): bromination of product 9 affords product 10.

It is worth mentioning that in reaction 6 we tried TBDPSCl (t-butyldiphenylchlorosilane), trimethylchlorosilane, tipsccl (triisopropylchlorosilane) as protecting groups, and by performing TLC plate spotting on the product system, the target substance could be detected only when TBDPSCl was used as protecting group. The target product was successfully detected in reaction 7 with high yield. However, the target product cannot be detected in reaction 8, so that the subsequent reaction cannot proceed smoothly.

Example 3

After several attempts, the synthesis of canagliflozin was finally performed using direct bromination followed by esterification (scheme 3):

reaction 10 (reaction step i): synthesis of canagliflozin derivative, reagents and conditions: i) CBr4, PPh3, py, ar,50 deg.C

Reaction 10: canagliflozin (1 mmol) was dissolved in 2ml of ultra dry pyridine under argon protection, stirring was started and triphenylphosphine (2 mmol) was added. Cooling the reaction solution to 0 ℃, slowly adding carbon tetrabromide (1 mmol) into the reaction system, reacting for 4 hours at 50 ℃ after dropwise adding, and separating by column chromatography to obtain a product, wherein a developing agent is dichloromethane: methanol 40:1, but preliminary characterization by nuclear magnetism, not the target product.

Reaction 11 (reaction step j and reaction step k): synthesis of canagliflozin derivative, reagents and conditions: j) NBS, PPh ₃ DMF, ar,50 ℃,4h; k) Acetic anhydride, pyridine, rt,4h

Preparation of product 11: canagliflozin (1 mmol) was dissolved in 1ml DMF and stirring was started and triphenylphosphine (2 mmol) was added under argon protection. The reaction solution is cooled to 0 ℃, NBS (2 mmol) is slowly added into the reaction system, after the dropwise addition, the reaction is carried out for 4 hours at the temperature of 50 ℃, and the product 11 is obtained by column chromatography separation and is white solid powder (72%). (column chromatography packing can be silica gel, aluminum oxide, diatomite and other common packing for chromatography with 200-300 meshes), and the eluent is dichloromethane: methanol 20.

Preparation of product 4 BA-C: dissolving the white solid (1 mmol) obtained in the previous step in 1ml of pyridine, adding acetic anhydride (5 mmol), stirring and reacting for 4 hours at room temperature, and performing column chromatography to obtain a white solid (80%), wherein the eluent is petroleum ether: ethyl acetate 10:1 (volume ratio).

¹ H NMR(400MHz,CDCl3)δ7.47(dd,J＝8.7,5.3Hz,2H),7.18(q,J＝7.6Hz,3H),7.06–6.97(m,3H),6.62(d,J＝3.5Hz,1H),5.32(t,J＝9.4Hz,1H),5.21(t,J＝9.5Hz,1H),5.12(t,J＝9.6Hz,1H),4.40(d,J＝9.8Hz,1H),4.17–4.03(m,2H),3.86–3.78(m,1H),3.54(dd,J＝11.4,2.7Hz,1H),3.43(dd,J＝11.4,5.5Hz,1H),2.29(s,3H),2.08(s,3H),2.00(s,3H),1.76(s,3H).

¹³ C NMR(100MHz,CDCl3)δ170.42,169.46,168.82,163.30,160.84,143.07,141.56,138.11,137.09,134.23,130.78,128.39,127.13,127.05,126.04,125.46,122.72,115.84,115.63,79.68,76.74,74.13,72.75,71.00,33.98,31.46,31.22,30.22,29.71,20.72,20.68,20.43,19.31.

¹⁹ F NMR(300MHz,CDCl3)δ-115.08.)

The product system of the reaction 10 is detected to generate new compounds through TCL fluorescence, but the obtained substances are found to be non-target compounds through H spectrum characterization, and then the j reaction is carried out by using NBS, and finally the target compound 11, namely the canagliflozin bromide (Br-C) and the product 4 (BA-C) are obtained.

After the target product 4 is obtained, the reaction 4 and the reaction 5 in the route 1 are carried out, and meanwhile, the reaction of Br-C and berberine is directly tried, so that the following route (the route 4, the reaction step i) is obtained and is the final synthetic route of the target product. Synthesis of BC, reagents and conditions: l) NaI, meCN, ar,130 ℃ for 16h.

Preparation method 1 of BC: taking Br-C (1 mmol) and reduced berberine HB (1.5 mmol) in 2ml of anhydrous acetonitrile, adding NaI (0.1mmol, 0.1-0.5mmol can be added) under the protection of argon, reacting for 16 hours at 130 ℃, and separating by column chromatography (using common fillers such as silica gel, aluminum oxide, diatomite and the like), wherein an eluent is dichloromethane in volume ratio: methanol: triethylamine =20:1:0.2% -1:1:0.2% isolated the desired product as an orange-yellow solid (60%). (80 ℃ can also react, the yield is 40%, and the yield is 26% under the condition of no argon protection). Other similar iodine-containing compounds may also be used, or the same effect may be achieved by adjusting the reaction temperature and time.

Preparation method 2 of BC: taking BA-C (1 mmol) and reduced berberine HB (1.5 mmol) in 2ml of anhydrous acetonitrile, adding NaI (0.1mmol, 0.1-0.5mmol can be added) under the protection of argon, reacting for 16 hours at 130 ℃, and performing column chromatography (by using common fillers such as silica gel, aluminum oxide, diatomite and the like) to obtain a eluent which is dichloromethane in volume ratio: methanol: triethylamine =20:1:0.2% -1:1:0.2% was isolated as a yellow-orange solid.

¹ H NMR(400MHz,CD3OD)δ9.83(s,1H),8.88(s,1H),8.15(d,J＝9.1Hz,1H),7.95(d,J＝9.0Hz,1H),7.74(s,1H),7.64(d,J＝16.1Hz,2H),7.54(dd,J＝7.9,5.2Hz,1H),7.38–7.29(m,1H),7.21(t,J＝7.7Hz,1H),7.17–7.07(m,2H),7.04(s,1H),6.12(s,2H),5.70(s,1H),5.02–4.78(m,3H),4.17(t,J＝6.5Hz,3H),4.04(d,J＝10.8Hz,9H),3.18–3.12(m,3H),2.23(t,J＝12.0Hz,3H),2.13(t,J＝7.4Hz,2H),1.63–1.55(m,3H).

13C NMR(100MHz,CD3OD)δ177.82,172.99,152.12,151.96,149.87,145.71,139.59,135.09,134.94,134.84,134.45,134.34,131.84,131.50,131.37,131.13,131.00,130.94,128.26,128.07,126.11,124.54,123.26,121.80,121.47,109.39,106.53,103.65,62.59,57.66,57.21,36.63,35.37,35.27,33.04,30.91,30.75,30.45,26.73,23.71,22.59,22.55,14.71,14.44.

19F NMR(300MHz,CD3OD)δ-115.39.)

It should be noted that the reaction can be carried out under the conditions of no argon protection and high temperature of 130 ℃, but the yield is low.

Purity determination of BC: high performance liquid chromatography, using an ODS C18 column, eluting with acetonitrile: h ₃ PO ₄ Aqueous solution (pH = 3) V: V =98:2 is a mobile phase and the purity of the product is 99.175% at a wavelength of 365nm, measured at a flow rate of 0.5 ml/min. FIG. 1 is a high performance liquid chromatogram of product BC.

Example 4

In order to evaluate the hypoglycemic effect of the BBR-CAN compound (BC) compared with the combined use of BBR and CAN drugs. We used streptozotocin-induced diabetic male NIH mice, animals were grouped and administered the drugs berberine (BBR), canagliflozin (CAN), BBR-CAN compound (abbreviated BC), BBR + CAN combination (abbreviated B + C), and solvent 0.5% CMC-Na for dissolving the drugs as a control by gavage, 1 time per day, and fasting blood glucose for 6h was measured on the 6 th day of administration. The final result is shown in fig. 2: BC has better blood sugar reducing effect than BBR, but does not achieve the effect of combining BBR and CAN. Presumably, the hydroxyl group of the hydroxy silyl ether of canagliflozin is changed, and the original inhibition effect on sodium-glucose co-transporter 2 (SGLT 2) is influenced.

In order to evaluate the anti-inflammatory effect of BBR-CAN compounds compared with BBR and CAN drugs. As shown in figure 3, the in vitro inflammatory factor inhibition experiment is carried out on lipopolysaccharide-induced mouse mononuclear macrophage J774A.1, and the following results are obtained, and the figure shows that the inhibition effect of BC on inflammatory factors such as IL-1 beta, TNF-alpha and the like is better than that of BBR, CAN, BBR + CAN combined drug.

To further evaluate the anti-inflammatory effects of BBR-CAN compounds compared to BBR and CAN drug combinations. According to the relevant standards of American society for clinical laboratory standardization, the MIC values of different drugs are detected by adopting a trace broth dilution method, and finally BBR, B + C and BC are found to show antibacterial activity to staphylococcus aureus, pseudomonas aeruginosa and escherichia coli, and the compound BC shows stronger antibacterial activity and broad-spectrum antibacterial action which are greatly superior to BBR and B + C and can simultaneously inhibit the activities of gram-positive bacteria and gram-negative bacteria. The bacteriostatic effect of B + C is superior to that of BBR used alone, which shows that BBR and CAN CAN produce certain synergistic bacteriostatic effect. The antibacterial effect of the compound BC is strongest and is better than the synergistic effect of BBR and CAN. The results are shown in table 1 below and fig. 4.

TABLE 1 Minimum Inhibitory Concentrations (MICs) of BBR, BBR + CAN, BC for different strains

Fig. 4 shows the effect of CAN, BBR + CAN, BC on the growth of e.coli, s.aureus and p.aeruginosa, the curves corresponding to the legend on the right in sequence from top to bottom, wherein CK represents the control group, p <0.05, p <0.01, p <0.001 compared to the BC group. (a) - (c) Pseudomonas aeruginosa and Staphylococcus aureus, and the inhibiting effect of Escherichia coli on CAN, BBR + CAN and BC under MIC changes with time. (d) The (f) is pseudomonas aeruginosa and staphylococcus aureus, and the inhibition effect of the escherichia coli on CAN, BBR + CAN and BC under 1/2MIC changes along with time.

FIG. 5 shows the inhibition of bacterial biofilm formation by CAN, BBR + CAN, BC at a concentration of 0.1mM for 24h, observed with 0.1% crystal violet. Wherein the bacterial strain: the compound is prepared from (a) pseudomonas aeruginosa, (b) staphylococcus aureus, (c) escherichia coli, and (d) a crystal violet staining pattern of the pseudomonas aeruginosa. BBR, B + C and BC have an inhibiting effect on biofilm formation of pseudomonas aeruginosa, wherein the inhibiting effect of BC is the most obvious; for escherichia coli and staphylococcus aureus, the effect of CAN on biofilm formation is small, the inhibition effect of BBR on biofilm formation is weak, but the inhibition effect of B + C and BC groups on biofilm formation is obvious, and the inhibition effect of BC group is best. Fig. 5d shows the result of crystal violet staining of biofilm adsorbed on the pore walls, which is more intuitive that BC is most strongly inhibited.

FIG. 6 is a SDS-PAGE analysis of P.aeruginosa intracellular soluble proteins 24h after 0.1mM BC treatment. BC-treated P.aeruginosa intracellular soluble protein was significantly different from the control group. The protein band after BC treatment becomes shallow and fuzzy obviously, which shows that BC has destructive effect on the protein in the pseudomonas aeruginosa cell, thereby achieving the bacteriostatic effect. Protein bands in the BBR and B + C groups were also reduced compared to the control group, but the effect was much lower than in the BC-treated group.

FIGS. 7-9 in sequence are for compound BC ¹ H、 ¹³ C、 ¹⁹ F-NMR; FIG. 10 is a High Resolution Mass Spectrometry (HRMS) spectrum of Compound BCDrawing; FIGS. 11-13 are, in sequence, compounds BA-C ¹ H、 ¹³ C、 ¹⁹ F-NMR spectrum; FIG. 14 is of esterified canagliflozin ¹ H-NMR; FIGS. 15-17 are sequential views of canagliflozin bromide (Br-C) ¹ H、 ¹³ C、 ¹⁹ F-NMR; FIG. 18 is a scheme showing the reduction of berberine ¹ H NMR chart.

Finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.

Claims

1. A berberine canagliflozin derivative is characterized in that the structural formula is shown as the formula I:

2. the preparation method of the berberine canagliflozin derivative of claim 1, which is characterized by comprising the following steps:

a. reducing berberine hydrochloride to obtain dihydroberberine;

b. brominating the canagliflozin to obtain a product 11, wherein the preparation method of the product 11 comprises the following specific steps: dissolving canagliflozin in DMF, starting stirring, adding triphenylphosphine under the protection of argon, cooling the reaction solution to 0 ℃, slowly adding NBS into the reaction system, reacting for 4 hours at 50 ℃ after dropwise addition is finished, and separating by column chromatography to obtain a product 11;

c. and finally reacting the dihydroberberine with the product 11 under NaI to obtain the berberine canagliflozin derivative with the structural formula shown in the formula I.

3. The method for preparing the berberine canagliflozin derivative according to claim 2, wherein the step a of reducing the berberine hydrochloride to obtain the dihydroberberine comprises the following specific steps: dissolving berberine hydrochloride in acid-binding agent, adding 1-4eq NaBH4, reacting at 0-25 deg.C for 0.5-3 hr, and washing with water to obtain product dihydroberberine.

4. The preparation method of the berberine canagliflozin derivative of claim 2, which is characterized in that the preparation in the step c specifically comprises the following steps: and (3) putting the product 11 and dihydroberberine in anhydrous acetonitrile, adding NaI, reacting for 10-24 hours at 80-130 ℃, and separating by column chromatography to obtain a target product which is an orange yellow solid.

5. The method for preparing berberine canagliflozin derivative according to claim 4, wherein the reaction of the step c is performed under the protection of argon.

6. The use of the berberine canagliflozin derivative of claim 1 in the preparation of an antibacterial medicament.

7. The use of the berberine canagliflozin derivative according to claim 6 in the preparation of an antibacterial medicament, characterized in that the bacteria are gram-positive and gram-negative bacteria.