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Halogen or nitrogen-containing group substituted bibenzyl analog, preparation method and uses thereof

A technology of nitrogen-containing groups and analogs, which is applied in the field of drug synthesis, can solve the problems of low content, single structure, and difficulty in obtaining large quantities, and achieve the effects of mild reaction conditions, simplified experimental process, and easy repeatability

Inactive Publication Date: 2017-02-22
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Natural bibenzyl has anti-tumor, plant growth regulation, and anti-angiogenesis effects, but their structures are relatively single, mainly due to the changes in the position and quantity of hydroxyl and methoxy substitutions on the benzene ring
And the content of these natural bibenzyls in plants is small, and it is not easy to obtain in large quantities

Method used

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  • Halogen or nitrogen-containing group substituted bibenzyl analog, preparation method and uses thereof
  • Halogen or nitrogen-containing group substituted bibenzyl analog, preparation method and uses thereof
  • Halogen or nitrogen-containing group substituted bibenzyl analog, preparation method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1 4-hydroxyl-3,5-dimethoxy-3', the preparation of 4'-dichlorobibenzyl (compound 1)

[0035] a. 3,5-dimethoxy-4-acetoxybenzaldehyde

[0036]

[0037] Add 8.33 g (0.046 mol) of syringaldehyde (4-hydroxyl-3,5-dimethoxybenzaldehyde) powder in a 100 mL single-necked bottle, 10 mL of dichloromethane, and catalytically measure DMAP (4-dimethylaminopyridine), Stir to fully dissolve. Slowly add 4.75 mL (0.051 mol) of acetic anhydride dropwise, and react at room temperature for 1 h. Add water to wash away DMAP and acetic anhydride, wash 3 times in total, each time with 10 mL of water. Anhydrous Na 2 SO 4 The organic layer was dried and concentrated to recover dichloromethane to obtain 10.19 g of white crystals with a yield of 99.8%. It was identified as 3,5-dimethoxy-4-acetoxybenzaldehyde.

[0038] ESI-MS m / z: 225[M+H] + , The relative molecular mass is 224.

[0039] 1 H-NMR (300MHz, CDCl 3 )δ9.93 (1H, s, -CHO), 7.17 (2H, s, H-2, H-6), 3.92 (6H, s, 2×-OCH 3 ...

Embodiment 2

[0061] Example 2 Preparation of 4'-nitro-4-hydroxyl-3,5-dimethoxybibenzyl (compound 2)

[0062]

[0063] Add 200 mg (0.395 mmol) of (3,5-dimethoxy-4-acetoxybenzyl)-triphenylphosphine chloride and 60 mg (0.397 mmol) of p-nitrobenzaldehyde into a 50 mL single-necked bottle. Under the protection of argon, 3 mL of anhydrous THF was added, and stirred to form a light yellow suspension. Under ice-salt bath, 11 mg (0.458 mmol) of NaH was slowly added, and stirred overnight. TLC monitoring generates two new spots namely cis-trans isomerism stilbene ((Z / E)-4'-nitro-3,5-dimethoxy-4-acetoxy stilbene), concentrated sulfuric acid The color developed by ethanol was lavender, which proved that the reaction was successful. The reaction was terminated by adding ice water, extracted three times with dichloromethane, and the organic layer was anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure for later use.

[0064] Dissolve the concentrate in 5mL of methanol, add appropriate...

Embodiment 3

[0067] Example 3 The preparation of 4-hydroxyl-3,5-dimethoxy-4'-chlorobibenzyl (compound 3)

[0068]

[0069] Add 200 mg (0.395 mmol) of (3,5-dimethoxy-4-acetoxybenzyl)-triphenylphosphine chloride and 56 mg (0.398 mmol) of p-chlorobenzaldehyde into a 50 mL single-necked bottle. Add anhydrous THF 3mL under the protection of argon, and stir to form a white suspension. Under ice-salt bath, 11 mg (0.458 mmol) of NaH was slowly added, and stirred overnight. Two new spots generated by TLC monitoring were presumed to be cis-trans isomerism stilbene ((Z / E)-3,5-dimethoxy-4-acetoxy-4'-chlorostilbene), concentrated sulfuric acid The color developed by ethanol was lavender, which proved that the reaction was successful. The reaction was terminated by adding ice water, extracted three times with dichloromethane, and the organic layer was anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure for later use.

[0070] Dissolve the concentrate in 5mL of methanol, add appropriat...

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Abstract

The present invention discloses a halogen or nitrogen-containing group substituted bibenzyl analog or a pharmaceutically acceptable salt, a hydrate thereof, wherein the halogen or nitrogen-containing group substituted bibenzyl analog is represented by a formula I, and A is halogen or nitrogen-containing group substituted phenyl or a 5-membered or 6-membered unsaturated nitrogen-containing heterocyclic ring containing 1-2 N atoms. The present invention further discloses a preparation method of the halogen or nitrogen-containing group substituted bibenzyl analog, and applications of the halogen or nitrogen-containing group substituted bibenzyl analog or the pharmaceutically acceptable salt and the hydrate thereof in preparation of tumor treating drugs and angiogenesis inhibition drugs. According to the present invention, the novel-structure bibenzyl analog is synthesized through the seven-step reaction, such that the reaction steps are simple, the conditions are mild, the yield is high, and the total yield is 32-51%; the bibenzyl analog provides different degrees of activities in preparation of tumor resistance and angiogenesis inhibition; and the important significance is provided for preparation of the tumor inhibition drugs and the angiogenesis inhibition drugs. The formula I is defined in the specification.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a class of bibenzyl analogs and a preparation method and use thereof, in particular to a class of bibenzyl analogs substituted by halogen or nitrogen-containing groups, a preparation method and use thereof. Background technique [0002] Malignant tumor, often called cancer, is a common and frequently-occurring disease that seriously threatens human health. Chemotherapy with traditional cytotoxic antineoplastic drugs or anticancer drugs plays an important role in synthetic therapy of tumors. However, the treatment of solid tumors, which account for more than 90% of malignant tumors, with chemotherapy drugs has not yet achieved satisfactory curative effect. There are two major obstacles in tumor chemotherapy: drug toxicity and drug resistance. Due to the lack of sufficient selectivity for tumor cells, cytotoxic antineoplastic drugs have different degrees of damage to normal tissue cell...

Claims

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Application Information

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IPC IPC(8): C07C43/23C07C41/20C07C205/35C07C201/12C07D213/30A61P35/00A61P9/00
CPCC07C43/23C07C41/20C07C41/26C07C67/08C07C67/287C07C67/29C07C67/293C07C201/12C07C205/35C07D213/30C07F9/5456
Inventor 冯锋曲玮关丽柳文媛林清华陈垒郝艳峰朱慧琳
Owner CHINA PHARM UNIV
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