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Dihydrooxazolo[5,4-d]pyrrolo[1,2-a]pyrimidine-9(5H)-one derivative and application thereof

A technology of dihydrooxazole and 4-d, which is applied in drug combination, organic chemistry, antineoplastic drugs, etc.

Active Publication Date: 2021-04-30
XINJIANG TECHN INST OF PHYSICS & CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are few reports on finding anti-cancer active ingredients with low toxicity and high curative effect from natural animals and plants. Therefore, chemically synthesized anti-cancer drugs are still one of the hotspots of domestic and foreign scientists in recent years.

Method used

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  • Dihydrooxazolo[5,4-d]pyrrolo[1,2-a]pyrimidine-9(5H)-one derivative and application thereof
  • Dihydrooxazolo[5,4-d]pyrrolo[1,2-a]pyrimidine-9(5H)-one derivative and application thereof
  • Dihydrooxazolo[5,4-d]pyrrolo[1,2-a]pyrimidine-9(5H)-one derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103] Preparation of Compound A:

[0104] At -10°C, dissolve 57.3ml, 0.83mol of sodium nitrite and 100g, 0.83mol of ethyl cyanoacetate in 700ml of pure water, then slowly add 36.6ml, 0.055mol of 85% concentrated phosphoric acid, dropwise After the time lasted for 3 hours, the temperature was raised to 45°C and stirred for 1 hour, then 74ml of concentrated hydrochloric acid, 0.88mol was added, and the stirring was continued at 0°C overnight, a large amount of white solids precipitated, filtered to obtain white compound A as 2-cyano -Ethyl 2 hydroxyiminoacetate, no purification is required for the next step reaction;

[0105] Preparation of Compound B:

[0106] At room temperature, the obtained white compound A was 43 g of ethyl 2-cyano-2 hydroxyiminoacetate, 0.3 mol was dissolved in 500 ml of pure water, and 350 ml of saturated sodium bicarbonate solution was slowly added dropwise under stirring, Then add 156g of sodium dithionite, 0.9mol, heat up to 35°C, react for 1 hour, ...

Embodiment 2

[0158] Preparation of compounds D1-D48:

[0159] Dissolve 10 mmol of the compounds C1-C48 of Example 1 in anhydrous dichloromethane, then slowly add 10 mL of trifluoroacetic acid dropwise, react at room temperature until all raw materials disappear, concentrate the reaction solution, and use forward silica gel column chromatography gradient elution, The eluent is sherwood oil with a volume ratio of 2:1: ethyl acetate, and compounds D1-D48 are obtained respectively;

[0160] Compound D1 is 2-methyl-5-amino-4-carboxylic acid ethyl oxazole, yield: 84%, light yellow solid;

[0161] 1 H NMR (400MHz, CDCl 3 )δ5.31(s, 2H), 4.33(q, J=7.2Hz, 2H), 2.34(s, 3H), 1.37(t, J=7.1Hz, 3H);

[0162] Compound D2 is 2-ethyl-5-amino-4-carboxylic acid ethyl oxazole, yield: 80%, light yellow solid,

[0163] 1 H NMR (400MHz, CDCl 3 )δ5.58(s, 2H), 4.25(q, J=7.1Hz, 2H), 2.58(q, J=7.6Hz, 2H), 1.28(t, J=7.1Hz, 3H), 1.20(t, J=7.6Hz,3H);

[0164] Compound D3 is ethyl oxazole 2-propyl-5-amino-4-carbo...

Embodiment 3

[0255] Preparation of compound E1:

[0256] The compound D1 obtained in Example 2 is 2-methyl-5-amino-4-formic acid ethyl oxazole 0.17g, 10mmol is dissolved in 20mL of anhydrous dioxane, and pyrrolidone 0.13g, 15mmol is added, and then Slowly add phosphorus oxychloride 0.38g, 2.5mmol, reflux reaction until all the raw materials disappear, extract with dichloromethane, dry over anhydrous sodium sulfate, concentrate under reduced pressure, use forward silica gel column chromatography gradient elution, eluent For pure ethyl acetate, compound E1 was obtained as 2-methyl-6,7-dihydrooxazolo[5,4-d]pyrrolo[1,2-a]pyrimidin-9(5H)-one, yielding Yield: 73%, pale yellow solid, mp 120-122℃;

[0257] 1 H NMR (400MHz, CDCl 3 ) δ 4.24 (t, J = 8.0Hz, 2H), 3.20 (t, J = 8.0Hz, 2H), 2.58 (s, 3H), 2.34 (m, 6H).

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Abstract

The invention relates to a dihydrooxazolo[5,4-d]pyrrolo[1,2-a]pyrimidine-9(5H)-one derivative and application. The preparation method comprises the following steps: by taking ethyl cyanoacetate as an initial raw material, generating a hydroxylamine compound (A) under the action of sodium nitrite and phosphoric acid, reducing with sodium hydrosulfite to obtain ethyl 2-aminocyanoacetate (B), reacting with different substituted acyl chlorides respectively under an alkali condition, generating different substituted oxazole compounds D1-D48 of 5-amino-4-formate under the action of trifluoroacetic acid, and reacting with pyrrolidone under the action of phosphorus oxychloride to obtain a dihydrooxazolo[5,4-d]pyrrolo[1,2-a]pyrimidine-9(5H)-one compound E1-E48. According to the invention, the inhibition activity of 48g of the compounds on Hela cervical cancer cells, MCF7 breast cancer cells and A549 lung cancer cells is investigated, and results show that the compounds E5, E10, E13, E16, E18, E19, E24, E42 and E43 have inhibition activity on Hela cervical cancer cells, the compounds E22, E24, E47 and E48 have inhibitory activity on MCF7 breast cancer cells, and the compounds E18 and E20 have inhibitory activity on A549 lung cancer cells.

Description

technical field [0001] The present invention relates to a dihydrooxazolo[5,4-d]pyrrolo[1,2-a]pyrimidin-9(5H)-one derivative and its use. The result of cell activity screening of this kind of compound shows that: There are 9 compounds that have inhibitory activity on Hela cervical cancer cells; 4 compounds that have inhibitory activity on MCF-7 breast cancer cells; and 2 compounds that have inhibitory activity on A549 lung cancer cells. Background technique [0002] According to the statistics of the World Health Organization, there are about 10 million cancers in the world every year, and about 7 million deaths. Cardiovascular disease is the second killer of humans. Although most of the chemically synthesized anticancer drugs also produce toxic and side effects on normal cells of the human body. However, there are few reports on finding anticancer active ingredients with low toxicity and high curative effect from natural animals and plants. Therefore, chemically synthesize...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/14A61P35/00
CPCC07D498/14A61P35/00
Inventor 阿吉艾克拜尔·艾萨曾艳聂礼飞胡尔西地·博扎罗夫赵江瑜
Owner XINJIANG TECHN INST OF PHYSICS & CHEM CHINESE ACAD OF SCI
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