Synthesis method of 9-0-ethyl ether berberrubine and application of 9-0-ethyl ether berberrubine in preparation of antitumor drugs

A technology of berberine and bromoethyl ether, which is applied in the fields of drug synthesis and medical health, can solve the problems of poor solubility, low bioavailability, and poor druggability of berberine, and achieve anti-osteosarcoma, anti-colon cancer, Proliferation inhibiting, cost-effective effect

Active Publication Date: 2022-03-18
广东宝康生物医药有限公司
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  • Abstract
  • Description
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AI Technical Summary

Problems solved by technology

However, the disadvantages of berberine, such as poor solubility and difficulty in absorption, lead to low bioavailability and poor druggability.

Method used

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  • Synthesis method of 9-0-ethyl ether berberrubine and application of 9-0-ethyl ether berberrubine in preparation of antitumor drugs
  • Synthesis method of 9-0-ethyl ether berberrubine and application of 9-0-ethyl ether berberrubine in preparation of antitumor drugs
  • Synthesis method of 9-0-ethyl ether berberrubine and application of 9-0-ethyl ether berberrubine in preparation of antitumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 19

[0052] Example 1 Preparation of 9-0-ethyl ether berberine

[0053] Weigh 2 g of berberine hydrochloride and place it in a 100 mL round bottom flask, add a stirrer bar, 50 Ml DMF and some zeolite to it, and react with microwave under 240 W for 20 minutes. After the reaction was completed and cooled, the solvent DMF was distilled off under reduced pressure. Purify by dry silica gel column chromatography, the eluent is V (dichloromethane): V (methanol) = 10: 1 for elution, and the solvent is evaporated under reduced pressure to obtain berbererythrine as a dark red solid.

[0054] Take berberine (12g, 37mmol) in a 250mL round-bottomed flask, use DMF (3mL) as a solvent, slowly add 2-bromoethyl ether (24mL, 100mmol) dropwise at 50°C, and react at 50°C for 24 hours . Extract with aqueous sodium bicarbonate (20mL×3), combine the organic phases, extract the organic phases with saturated brine (30mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concent...

Embodiment 1

[0057] Target compound (embodiment 1) structure identification

[0058] 1H-NMR (600MHz, DMSO-d6) δ9.78(s, 1H), 8.97(s, 1H), 8.21(d, J=9.1 Hz, 1H), 8.02(d, J=9.1Hz, 1H), 7.81(s,1H),7.10(s,1H),6.18(s,2H),4.94(t,J=6.2Hz,2H),4.42(t,J=4.5Hz,2H),3.78(t,J =4.4 Hz, 2H), 3.47(dq, J=27.4, 6.7Hz, 2H), 3.33(s, 2H), 3.22(t, J=6.3 Hz, 2H), 1.07(dt, J=18.0, 7.0Hz ,4H).

[0059] 13C NMR(151MHz,DMSO)δ150.85,150.19,148.07,145.76,143.42,143.00,137.79,133.31,130.97,126.97,123.92,122.24,120.83,120.62,115.67, 108.82,105.82,102.48,98.80,73.43,69.24,65.86 , 57.41, 56.39, 55.85, 40.44, 40.33, 40.19, 40.05, 39.91, 39.77, 39.63, 39.49, 29.37, 26.76, 18.94, 15.51.

[0060] Based on the above information, it is determined that the structure of the compound is as shown in formula I, wherein n=1,9-0-ethyl ether berberine nuclear magnetic resonance spectrum is as follows figure 2 shown.

Embodiment 3

[0061] Efficacy test 1 of embodiment 3 product of the present invention

[0062] Study on the effect of 9-0-ethyl ether berberine on the growth of 143B human osteosarcoma cell subcutaneous xenograft 1. Experimental materials Experimental animals: BALB / c-nu nude mice, male, weighing 18±2g, 48. Provided by Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.

[0063] Main drugs: doxorubicin hydrochloride, berberine, 9-0-ethyl ether berberine (prepared in Example 1)

[0064] 2. Experimental method

[0065] (1) Construction of animal model of osteosarcoma: The animal model of ectopic osteosarcoma was established by subcutaneously injecting 143B human osteosarcoma cells in the back of nude mice. After the 143B human osteosarcoma cells were collected, a cell suspension of 5×105 cells / mL was prepared, and 100 μL of the cell suspension was subcutaneously injected into the back of the neck of each nude mouse.

[0066](2) Experimental grouping: 48 male nude mice were random...

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Abstract

The invention discloses a compound with an anti-tumor effect and a preparation method and application thereof.The compound is 9-0-ethyl ether berberrubine and has the structure shown in the formula I (n is 1-50), preferably, n is 1, and experiments prove that the 9-0-ethyl ether berberrubine has the advantages that the anti-tumor effect is remarkable, and the anti-tumor effect is good. Compared with berberine, the berberine derivative has the advantages that the berberine derivative has a better effect than berberine, the safety is good, the medication is simple and convenient, the raw materials are low in price and easy to obtain, and transportation and preservation are convenient, the invention further discloses a method for preparing the compound, and the method is simple in route, capable of effectively saving the synthesis time and reducing the cost, simple to operate, easy to implement, suitable for industrial production and suitable for industrial production. The 9-0-ethyl ether berberrubine disclosed by the invention has a wide application prospect as an anti-tumor drug.

Description

technical field [0001] The invention relates to a preparation method and application of a new anti-tumor compound 9-0-ethyl ether berbererythine, which belongs to the fields of drug synthesis and medicine and hygiene. Background technique [0002] Malignant tumors (cancer) have become one of the major public health problems that seriously threaten the health of the Chinese population. According to the data released in the "2020-2026 China Cancer Treatment Precision Medicine Industry Market Analysis and Forecast and Investment Value Consulting Report", the global new The number of cancer patients increased by 18.1 million, and the number of cancer deaths was 9.6 million. my country is a country with a large population and a high incidence of cancer. In 2018, the number of new cases in my country was 3.804 million, accounting for more than 20% of the number of new cancer cases in the world. Among them, the incidence rate of malignant tumors was 278.07 / 100,000, and the mortalit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D455/03A61P35/00A61P35/04A61K31/4375
CPCC07D455/03A61P35/00A61P35/04Y02P20/55
Inventor 杜伟杰聂丹
Owner 广东宝康生物医药有限公司
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