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Berberine canagliflozin derivative as well as preparation method and application thereof

A technology of berberine and its derivatives, applied in the field of berberine canagliflozin derivatives and its preparation, achieving the effects of excellent antibacterial activity, less side reactions, and low requirements for reaction equipment

Active Publication Date: 2022-05-03
HUAIHUA UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As a new drug launched in recent years, canagliflozin has few reports on its structural modification

Method used

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  • Berberine canagliflozin derivative as well as preparation method and application thereof
  • Berberine canagliflozin derivative as well as preparation method and application thereof
  • Berberine canagliflozin derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] The following route (route 1) is designed:

[0043] Reaction 1: reduce berberine hydrochloride 1 to obtain reduced berberine (HB); after dissolving berberine hydrochloride (1g, 2.66mol) in 15ml pyridine, add 2eq of NaBH 4 , after reacting at room temperature for 1 h, product 2 reduced berberine can be obtained by washing with water, and the yield is 65%.

[0044]

[0045] In the preparation method of the above-mentioned reduced berberine: take berberine hydrochloride (1g, 2.66mol) and dissolve in 15ml pyridine (other acid-binding agents are also acceptable), add 1-4eq of NaBH 4 , after reacting at 0°C-25°C for 0.5-3h, the product reduced berberine 2 can be obtained by washing with water.

[0046] In this reaction method, berberine hydrochloride is dissolved in methanol solution containing potassium carbonate, and the reaction can also be carried out at 0° C., but it needs to be reacted for 8 hours, and the yield is 46%.

[0047] Reaction 2 (reaction step a): esteri...

Embodiment 2

[0056] In order to obtain the product 4 (BA-C), we continued to try to modify canagliflozin by protecting and deprotecting the hydroxysilyl ether, and made the following attempts (route 2):

[0057] Reaction 6 (reaction step e): the hydroxyl group at the canagliflozin hydroxysilyl ether is protected to obtain product 7;

[0058] Reaction 7 (reaction step f): product 7 is esterified to obtain product 8;

[0059] Reaction 8 (reaction step g): product 8 is deprotected to obtain product 9;

[0060] Reaction 9 (reaction step h): Bromination of product 9 affords product 10.

[0061]

[0062] It is worth mentioning that in Reaction 6, we tried to use TBDPSCl (tert-butyldiphenylchlorosilane), trimethylchlorosilane, TIPSCl (triisopropylchlorosilane) as protecting groups, and carried out TLC to the product system The spot plate found that the target substance could be detected only when TBDPSCl was used as the protecting group. Reaction 7 successfully detected the target product w...

Embodiment 3

[0064] After many attempts, finally use the synthesis of canagliflozin that is directly brominated and then esterified (route 3):

[0065] Reaction 10 (reaction step i): Synthesis of canagliflozin derivatives, reagents and conditions: i) CBr4, PPh3, Py, Ar, 50°C

[0066]

[0067] Reaction 10: Dissolve canagliflozin (1 mmol) in 2 ml of ultra-dry pyridine, start stirring under the protection of argon, and add triphenylphosphine (2 mmol). The temperature of the reaction solution was lowered to 0°C, and carbon tetrabromide (1 mmol) was slowly added to the reaction system. After the dropwise addition, the reaction was carried out at 50°C for 4 hours, and the product was separated by column chromatography. The developer was dichloromethane: Methanol 40:1, but preliminary characterization by NMR, not the target product.

[0068] Reaction 11 (reaction step j and reaction step k): synthesis of canagliflozin derivatives, reagents and conditions: j) NBS, PPh 3 , DMF, Ar, 50℃, 4h; k)...

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Abstract

The invention relates to a novel derivative compound of berberine and canagliflozin, which is characterized in that berberine hydrochloride (BBR) and canagliflozin (CAN) are linked through a chemical synthesis method under the condition of not changing basic frameworks of berberine and canagliflozin to synthesize a brand new compound BC. The invention also relates to a preparation method of the compound, which has the advantages of high yield, few side reactions, high product purity, low requirements on reaction equipment and easiness in industrial production. The prepared compound has a certain hypoglycemic effect, shows excellent antibacterial activity and broad-spectrum antibacterial action, and can simultaneously inhibit the activities of gram-positive bacteria and gram-negative bacteria, compared with BBR and CAN, the MIC value is greatly reduced, especially for pseudomonas aeruginosa, the dosage of the compound for a patient is greatly reduced, and the cost is reduced. The evolution of drug-resistant microbial strains is favorably prevented.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a berberine canagliflozin derivative and a preparation method and application thereof. Background technique [0002] Structural transformation and modification of natural medicines is an important way for pharmaceutical researchers to develop new medicines. Berberine (berberine, BBR, C20H19NO5, MW 336.37), also known as berberine, is an isoquinoline alkaloid isolated and extracted from Chinese herbal medicines such as Coptis chinensis. It is an active alkaloid that exists in traditional Chinese medicines such as Coptis chinensis, Cortex Phellodendron, and Sangezhen. In recent years, studies have found that it has various pharmacological activities such as anti-inflammatory, hypoglycemic, hypolipidemic, anti-pathogenic microorganisms, and anti-tumor. However, it requires high Dosage can achieve a good hypoglycemic effect. Berberine is popular in the synth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D455/03A61P31/04A61K31/4375
CPCC07D455/03A61P31/04Y02A50/30
Inventor 赵子剑谢伟东车诗莹李金晟郝文慧张雨薇张祎
Owner HUAIHUA UNIV
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