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2-methoxyphenoxy pyrimidine antitumor compound as well as preparation method and application thereof

A technology of methoxyphenoxypyrimidine and methoxyphenoxy is applied in the field of 2-methoxyphenoxypyrimidine anti-tumor compounds and their preparation, and the preparation method is simple and feasible, with high yield and easy The effect of mass production

Active Publication Date: 2021-05-11
中国医科大学
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, by analyzing the structure of the pyrimidine ring, by optimizing the structure of the pyrimidine compound, a series of anti-malignant melanoma compounds containing the pyrimidine ring are designed and synthesized, and the structures of these compounds have not been reported in the prior art, and they are new structures. Pyrimidines

Method used

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  • 2-methoxyphenoxy pyrimidine antitumor compound as well as preparation method and application thereof
  • 2-methoxyphenoxy pyrimidine antitumor compound as well as preparation method and application thereof
  • 2-methoxyphenoxy pyrimidine antitumor compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045]Example 1 Preparation of 2-((6-amino-5-(2-methoxyphenoxy)-2-phenylpyrimidin-4-yl)oxy)ethan-1-ol (A1).

[0046] a. Preparation of diethyl 2-bromomalonate.

[0047] Put diethyl malonate (30.00g, 187.30mmol), NBS (35.00g, 196.67mmol) and 100ml of chloroform into a 250ml flask, and then add two drops of concentrated sulfuric acid as a catalyst. The reaction was carried out at 50° C. for 12 hours, and the progress of the reaction was monitored by thin-layer chromatography. After the reaction was completed, wash the reaction solution with saturated sodium sulfite solution, then wash the reaction solution with saturated sodium chloride solution, then dry the reaction solution with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and obtain 43.65 g of a colorless transparent liquid product. Yield 97.48%.

[0048] b. Preparation of diethyl 2-(2-methoxyphenoxy)malonate.

[0049] Diethyl 2-bromomalonate (43.65g, 182.59mmol), guaiacol (22.67g, 182.59mmol), ...

Embodiment 2

[0061] Example 2 Preparation of 2-((6-amino-5-(2-methoxyphenoxy)-2-(m-tolyl)pyrimidin-4-yl)oxy)ethan-1-ol (A2) .

[0062] Using diethyl malonate as a raw material, according to the steps of Example 1a, 1b, 2-(2-methoxyphenoxy) diethyl malonate was obtained, and then using m-toluonitrile as a raw material, according to Example 1c , 1d, 1e, 1f steps make 6-chloro-5-(2-methoxyphenoxy)-2-(m-tolyl)pyrimidin-4-amine, according to the steps of Example 1g, make 2-(( 6-Amino-5-(2-methoxyphenoxy)-2-(m-tolyl)pyrimidin-4-yl)oxy)ethan-1-ol (A2), white solid, yield: 61.37% .

[0063] 1 H NMR (500MHz, DMSO-d 6 )δ8.16–8.01(m, 2H), 7.36(t, J=7.0Hz, 1H), 7.28(d, J=6.8Hz, 1H), 7.07(d, J=7.6Hz, 1H), 6.99( t,J=7.1Hz,1H),6.81(t,J=7.1Hz,1H),6.67(d,J=7.9Hz,1H),6.56(s,2H),4.71(t,J=4.9Hz, 1H), 4.39(t, J=5.0Hz, 2H), 3.86(s, 3H), 3.60(d, J=5.1Hz, 2H), 2.38(s, 3H).

Embodiment 3

[0064] Example 3 2-((6-amino-5-(2-methoxyphenoxy)-2-(p-tolyl)pyrimidin-4-yl)oxy)ethan-1-ol (A3) preparation.

[0065] Using diethyl malonate as a raw material, according to the steps of Example 1a, 1b to prepare 2-(2-methoxyphenoxy) diethyl malonate, and then using p-toluonitrile as a raw material, according to Example 1c , 1d, 1e, 1f steps make 6-chloro-5-(2-methoxyphenoxy)-2-(p-tolyl)pyrimidin-4-amine, according to the steps of Example 1g, make 2-(( 6-Amino-5-(2-methoxyphenoxy)-2-(p-tolyl)pyrimidin-4-yl)oxy)ethan-1-ol (A3), white solid, yield: 57.19 %.

[0066] 1 H NMR (500MHz, DMSO-d 6 )δ8.17(d, J=7.8Hz, 2H), 7.28(d, J=7.8Hz, 2H), 7.07(d, J=8.0Hz, 1H), 6.98(t, J=7.7Hz, 1H) ,6.80(t,J=7.6Hz,1H),6.67(d,J=8.0Hz,1H),6.52(s,2H),4.70(t,J=4.9Hz,1H),4.39(t,J= 5.2Hz, 2H), 3.86(s, 3H), 3.60(d, J=5.2Hz, 2H), 2.37(s, 3H).

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Abstract

The invention belongs to the technical field of medicines, relates to a compound with anti-tumor activity and a specific chemical structure, and particularly relates to a 2-methoxyphenoxy pyrimidine compound as well as a preparation method and application thereof. The structural general formula of the 2-methoxyphenoxy pyrimidine compound is shown in the specification, wherein an R group is a hydrogen atom, or a 2-position monosubstituted fluorine atom, or 3-position and 4-position monosubstituted methyl, methoxy, fluorine atom, chlorine atom, bromine atom and iodine atom. Experimental research shows that the prepared 2-methoxyphenoxy pyrimidine compound shows a good result in an in-vitro anti-tumor activity test, has certain inhibitory activity on human malignant melanoma A375 cells, can be used for preparing anti-tumor drugs, and opens up a new way for developing new anti-tumor drugs. The preparation method provided by the invention is simple and feasible, relatively high in yield and easy for large-scale production.

Description

technical field [0001] The invention belongs to the technical field of medicine and relates to a class of compounds with specific chemical structures having antitumor activity, in particular to a 2-methoxyphenoxypyrimidine antitumor compound and its preparation method and application. Background technique [0002] At present, non-communicable diseases are the cause of most deaths in the world, among which cancer is an important malignant disease that threatens human health. With the rapid growth and aging of human beings worldwide, the incidence and mortality of cancer are increasing rapidly worldwide. As one of the important methods to treat cancer, although drug therapy has good effects, it has the disadvantages of high toxicity and low selectivity. Therefore, it is more and more important to develop anticancer drugs with low toxicity and high selectivity. Due to its unique chemical structure, pyrimidine compounds in the body participate in the DNA synthesis and replicati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/52A61K31/505A61P35/00
CPCC07D239/52A61P35/00
Inventor 孟繁浩刘凯利薛文涵钱欣画李馨阳王德普李帅
Owner 中国医科大学