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Tripterine nitrogen-containing five-membered heterocyclic derivative as well as preparation method and application thereof

A technology of tripterine and five-membered heterocyclic rings, which is applied in the field of compounds and their preparation, can solve the problem of few natural anticancer drugs, and achieve the effects of excellent antitumor activity, high yield, and mild reaction conditions

Inactive Publication Date: 2020-10-30
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, a variety of natural active ingredients have been proven to have anti-tumor activity, but there are few natural anti-cancer drugs with good activity on the market

Method used

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  • Tripterine nitrogen-containing five-membered heterocyclic derivative as well as preparation method and application thereof
  • Tripterine nitrogen-containing five-membered heterocyclic derivative as well as preparation method and application thereof
  • Tripterine nitrogen-containing five-membered heterocyclic derivative as well as preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Embodiment 1: the preparation of intermediate II-1

[0034] In a two-necked flask, add 69.07mg 1H-1,2,4-triazole (1.0mmol, 1.0eq), 138mg K 2 CO 3 (1.0mmol, 1.0eq), dissolved in 10ml of acetone, ice bath, in N 2 Under protection, stirred, 259.7μl 1,2-dibromoethane (3mmol, 3eq) was added dropwise, after 3h, the ice bath was removed, and the reaction was carried out at room temperature for 3 days. Spin to dry the solvent, add 25ml ethyl acetate to dilute, wash 5-6 times with water, combine the organic layers, wash with saturated NaCl solution (30ml), anhydrous NaCl 2 SO 4 Dry, filter, concentrate the organic phase, purify by column chromatography (PE / EA=2:1), and dry in vacuo overnight to obtain Intermediate II-1 as a transparent oily liquid, 75.9 mg, yield 43.1%.

[0035] ESI-MS: Bromine isotope characteristic peaks 176.0, 178.0 [M+H] + .

[0036] The reaction formula is as follows:

[0037]

Embodiment 2

[0038] Embodiment 2: the synthesis of I-1

[0039] Dissolve 45.1mg (0.1mmol, 1.0eq) tripterine in 5ml DMF, add 33.6mg NaHCO 3(0.4mmol, 4.0eq), stirred, added 26.4g (0.15mmol, 1.5eq) of intermediate II-1, and heated to reflux at 60°C. Until the TLC detection shows that the reaction is complete, add 40ml ethyl acetate to dilute, wash 5-6 times with water, combine the organic layers, wash with saturated NaCl solution (30ml), anhydrous NaCl 2 SO 4 Dry, filter, concentrate the organic phase, column chromatography (DCM / MeOH=50:1), and vacuum dry overnight to obtain 26.5 mg of I-1 (orange-red solid), with a yield of 48.7%.

[0040] ESI-MS: 546.3[M+H] + .

[0041] 1 H-NMR (300MHz, CDCl 3 , TMS), δppm: 0.51(3H,s), 1.08(3H,s), 1.17(3H,s), 1.25(3H,s), 1.43(3H,s), 2.19(3H,s), 3.86- 3.92(1H,m),3.96-4.02(1H,m),4.22(2H,t),6.33(1H,d,J=6.0Hz),6.51(1H,s),7.10(1H,d,J= 6Hz), 7.92(1H,s), 8.04(1H,s).

[0042]

Embodiment 3

[0043] Embodiment 3: the preparation of intermediate II-2

[0044] The 1,2-dibromoethane in Example 1 was replaced with 304.5 μl (3 mmol, 3.0 eq) of 1,3-dibromopropane, and other conditions remained unchanged, to obtain 128.4 mg of white solid II-2 with a yield of 67.6%.

[0045] ESI-MS: Bromine isotope characteristic peaks 190.0, 192.0 [M+H] + .

[0046] The reaction formula is as follows:

[0047]

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Abstract

The invention discloses a tripterine nitrogen-containing five-membered heterocyclic derivative as well as a preparation method and application thereof, the tripterine nitrogen-containing five-memberedheterocyclic derivative is a compound with a structure as shown in a formula I, and R1, R2, R3, R4 and R5 are respectively selected from H, alkyl, heteroatom-containing alkyl, halogen, cyano nitro orformate group; X is selected from saturated, unsaturated, linear or branched aliphatic hydrocarbon fragments containing 2 to 6 carbon atoms. The preparation method of the compound has the advantagesof mild reaction conditions, low toxicity of used reagents, accessible raw materials, convenient post-treatment and higher yield. Pharmacological experiment research shows that the compound has excellent anti-tumor activity and can be well applied to preparation of anti-tumor drugs.

Description

technical field [0001] The present invention relates to a compound and its preparation method and use, in particular to tripterine derivatives and its preparation method and use. Background technique [0002] Cancer, also known as malignant tumor, is one of the major diseases that seriously threaten human life and health. According to data from the Global Cancer Observatory (GCO) website in 2018, the global incidence and mortality of the disease were 10.8 million and 9.56 million, respectively. Since 2010, cancer has become the number one cause of death in China. [0003] Due to their wide range of sources and diverse structures, natural products can provide a variety of active ingredients with potential anticancer effects, and have become a treasure trove of cancer drugs. At present, a variety of natural active ingredients have been proven to have anti-tumor activity, but there are few natural anti-cancer drugs with good activity on the market. Therefore, the development...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J63/00A61K31/58A61P35/00
CPCA61P35/00C07J63/008
Inventor 陈莉陈称李娜雷志超石志贤居伟
Owner CHINA PHARM UNIV
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