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Berberine drug as well as preparation method and application thereof

A diabetes drug and reaction technology, applied in the field of medicine, can solve problems such as high risk, many side effects, and increased impurities, and achieve the effect of overcoming poor solubility

Active Publication Date: 2017-05-31
上海维京生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] In the prior art, the synthesis process of trexagliptin needs to use the sealing reaction, which is a high temperature and high pressure reaction, which is very dangerous to scale up, poor in operability, high in equipment requirements, and high in cost ; In addition, under high temperature and high pressure conditions, there are many side reactions and impurities increase; subsequent purification is difficult

Method used

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  • Berberine drug as well as preparation method and application thereof
  • Berberine drug as well as preparation method and application thereof
  • Berberine drug as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1: the preparation of intermediate 1

[0049]

[0050] Suspend 2 g of berberine (purchased from Sichuan Weikeqi Biotechnology Co., Ltd.) in 50 ml of sodium hydroxide solution (concentration 0.1 mol / L), add 1 times the amount of succinic anhydride at 10 degrees Celsius, and stir for 1 hour after adding, Add 0.5 mol / L hydrochloric acid solution dropwise in an ice bath to adjust the pH to about 6.5, collect the solid by filtration, and dry under reduced pressure to obtain the product intermediate 1, which is directly used in the next reaction. Yield 65%. LC-Ms: ESI: 423.3 (M+H).

Embodiment 2

[0051] Embodiment 2: the preparation of compound BT-1 of the present invention

[0052]

[0053] Suspend 2 g of the intermediate 1 obtained in Example 1 in 50 ml of anhydrous tetrahydrofuran, add 1 times the amount of trexagliptin, add 1.2 times the amount of triethylamine, add 1 times the amount of HATU (purchased from Jill Biochemical) in an ice bath, and naturally Raise the temperature to 20°C and stir for 2 hours.

[0054] Add 100 ml each of dichloromethane and water, separate the organic layer, wash once with water, dry, and concentrate. The crude product was subjected to silica gel column chromatography (methanol:dichloromethane=20:1) to obtain product BT-1 with a yield of 52%.

[0055] 1 H NMR (400MHz, DMSO-d 6 )δ8.68(s,1H),8.50(d,J=8.2Hz,1H),7.84-8.46(m,9H),5.8(s,2H),4.2(s,1H),3.32-3.86(m , 11H), 2.52(t, 2H), 2.41-2.51(m, 8H), 2.22(t, 2H), 1.82-1.91(m, 4H). LC-Ms: ESI: 762.3 (M+H).

Embodiment 3

[0056] Embodiment 3: drug solubility experiment test

[0057] Test method: Weigh 100 mg of the drug to be tested (the reference substance berberine hydrochloride, purchased from Shanghai Yuanye Biotechnology Co., Ltd.), add 1 ml of pure water at 25 degrees Celsius, and shake for 30 seconds every 5 minutes. To dissolve, add 0.1ml of pure water each time, and shake for 30 seconds at intervals of 2 minutes until the drug is completely dissolved.

[0058] The experiment was repeated 3 times for each drug, and the results are shown in Table 1.

[0059] Table 1 Solubility test results

[0060]

[0061]

[0062] Take the average value of the test results of 3 solubility experiments:

[0063] The amount of water to dissolve 50 mg of berberine hydrochloride is (24.9+25.2+25.2) / 3=25.1 (ml)

[0064] The amount of water to dissolve 50mgBT-1 is (4.7+4.8+4.9) / 3=4.8(ml)

[0065] The above experimental results show that the water solubility of the medicine of the present invention i...

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Abstract

The invention relates to the technical field of medicine, in particular to a novel berberine drug as well as a preparation method and an application thereof in preparation of drugs for treating diabetes. The chemical structural formula of the compound is shown in formula I, and the compound overcomes the defects of poor solubility and low bioavailability of berberine. An alpha-amylase activity inhibition experiment on the compound verifies that the compound can be used for treating diabetes.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a novel berberine drug, a preparation method thereof, and an application in preparing a drug for treating diabetes. Background technique [0002] Berberine (berberine), also known as berberine, is a common isoquinoline alkaloid, which exists in many plants of ten genera in four families including Berberidaceae. Yellow needle-like crystals can be precipitated from ether; melting point 85-86°C; soluble in water, insoluble in benzene, ether and chloroform. [0003] [0004] Berberine is usually used to treat dysentery and enteritis. Experiments have shown that berberine can significantly lower blood sugar in experimental diabetic animals. Pathological anatomy showed that its hypoglycemic mechanism is to promote the repair of islet β cells. The repair and proliferation of islet β cells can lead to increased insulin release, thereby reducing blood sugar without obvious side effe...

Claims

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Application Information

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IPC IPC(8): C07D455/03A61K31/506A61P3/10
CPCC07D455/03
Inventor 栾德刚秦立玙栾松平孙扣珍
Owner 上海维京生物医药科技有限公司
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