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4-aminoquinazoline compound containing morpholinyl aromatic heterocycle and hydroximic acid structure and preparation method thereof

A technology of aminoquinazoline and compounds, which is applied in the field of synthesis of 4-aminoquinazoline compounds, can solve the problems of drug resistance and other problems, and achieve the effects of high yield, mild reaction conditions, and safe and easy operation

Pending Publication Date: 2022-08-02
JIANGSU FOOD & PHARMA SCI COLLEGE
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The results of clinical and animal experiments over the years have shown that most tumor cells rely on multiple signaling pathways to maintain their growth and survival. There are quite complex signaling pathways for compensation and dialogue during tumor development. Single-target drugs have already Inability to sensitize responses to these drugs, leading to resistance to these drugs

Method used

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  • 4-aminoquinazoline compound containing morpholinyl aromatic heterocycle and hydroximic acid structure and preparation method thereof
  • 4-aminoquinazoline compound containing morpholinyl aromatic heterocycle and hydroximic acid structure and preparation method thereof
  • 4-aminoquinazoline compound containing morpholinyl aromatic heterocycle and hydroximic acid structure and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1: Methyl 4-((4-((4-morpholinylpyridin-2-yl)amino)-7-methoxyquinazolin-6-yl)amino)-4-oxobutyrate Preparation of (2a)

[0051] Add N to a single-neck bottle 4 -(4-Morpholinylpyridin-2-yl)-7-methoxyquinazoline-4,6-diamine (1a) 0.8 mmol, 12 mL of pyridine, after stirring to dissolve, 2 mmol of monomethyl succinate was added , 1-ethyl-3-(3-dimethylpropylamine) carbodiimide hydrochloride (EDCI) 3mmol, reacted at room temperature for 6h, distilled under reduced pressure to dryness, added water, suction filtered, washed with saturated sodium bicarbonate, washed with water , or washed with water, placed at room temperature with water, filtered with suction, washed with saturated sodium bicarbonate, washed with water, and dried under vacuum at 40 °C for 24 h to obtain a light yellow solid 4-((4-((4-morpholinopyridin-2-yl)amino) -7-Methoxyquinazolin-6-yl)amino)-4-oxobutyric acid methyl ester (2a) 0.31g, yield 83.1%;

[0052] 1 HNMR (400MHz, DMSO-d 6 ), δ: 9.77(s, 1H)...

Embodiment 2

[0053] Example 2: Methyl 5-((4-((4-morpholinylpyridin-2-yl)amino)-7-methoxyquinazolin-6-yl)amino)-5-oxopentanoate Preparation of (2b)

[0054] According to the preparation method of Example 1, succinate monomethyl ester was replaced with glutaric acid monomethyl ester to obtain yellow solid 5-((4-((4-morpholinopyridin-2-yl)amino)-7 -Methoxyquinazolin-6-yl)amino)-5-oxopentanoate methyl ester (2b) 0.34 g, yield 88.4%.

[0055] 1 HNMR (400MHz, DMSO-d6), δ: 9.77(s, 1H), 9.26(s, 1H), 8.98(s, 1H), 8.80(s, 1H), 7.97(d, J=7.5Hz, 1H) , 7.29(s, 1H), 6.24(dd, J=7.4,1.5Hz, 1H), 6.01(d, J=1.5Hz, 1H), 4.01(s, 3H), 3.75(t, J=7.1Hz, 4H), 3.62(s, 3H), 3.39(t, J=7.1Hz, 4H), 2.46(dt, J=10.1,7.1Hz, 4H), 1.97-1.92(m, 2H); 13 CNMR(100MHz,DMSO-d6),δ:173.13, 171.89, 155.85, 154.84, 154.48, 154.13, 151.30, 147.49, 147.39,128.64, 114.14, 112.01, 104.32, 97.96, 97.36, 66.62(2C), 56.14, 51.38, 48.31(2C), 36.29, 33.01, 21.57.

Embodiment 3

[0056] Example 3: Methyl 6-((4-((4-morpholinylpyridin-2-yl)amino)-7-methoxyquinazolin-6-yl)amino)-6-oxohexanoate Preparation of (2c)

[0057] According to the preparation method of Example 1, monomethyl succinate was replaced with monomethyl adipate to obtain yellow solid 6-((4-((4-morpholinopyridin-2-yl)amino)-7 -Methoxyquinazolin-6-yl)amino)-6-oxohexanoic acid methyl ester (2c) 0.31 g, yield 78.3%.

[0058] 1 HNMR (400MHz, DMSO-d6), δ: 9.77(s, 1H), 9.27(s, 1H), 8.97(s, 1H), 8.79(s, 1H), 7.97(d, J=7.5Hz, 1H) , 7.30(s, 1H), 6.24(dd, J=7.4,1.5Hz, 1H), 6.01(d, J=1.5 Hz, 1H), 4.01(s, 3H), 3.75(t, J=7.1Hz, 4H), 3.62(s, 3H), 3.39(t, J=7.1Hz, 4H), 2.34(td, J=7.0,3.0Hz, 4H), 1.71-1.67(m, 2H), 1.61-1.56(m , 2H); 13 CNMR (100MHz, DMSO-D6), Δ: 173.68, 171.80, 155.86, 154.88, 154.46, 154.13,151.17, 147.85, 147.26, 128.63, 112.07, 104.22, 97.67, 56.14, 56.14, 56.14, 56.3. 48.31(2C), 36.70, 33.60, 24.09, 24.02.

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Abstract

The invention discloses a 4-aminoquinazoline compound containing a morpholinyl aromatic heterocycle and a hydroximic acid structure and a preparation method of the 4-aminoquinazoline compound, and particularly discloses a 4-aminoquinazoline compound containing a morpholinyl aromatic heterocycle and a hydroximic acid structure and a preparation method of the 4-aminoquinazoline compound containing a morpholinyl aromatic heterocycle and a hydroximic acid structure. 2, 6-diamine is amidated with dicarboxylic acid monomethyl ester and subjected to a substitution reaction with hydroxylamine to obtain the 4-aminoquinazoline compound (formula 1) containing morpholinyl heteroaromatic rings and hydroximic acid structures and having various structures, X, Y and Z are independently N or CH, R is H, Cl, OCH3 or 4-morpholinyl, and L is (CH2) 2, (CH2) 3, (CH2) 4, o-C6H4, p-C6H4 or (CH2) 6. The method is mild in reaction condition, high in target product yield, safe, simple and convenient to operate, free of toxic and harmful thionyl chloride and environment-friendly, and an efficient, simple and green method is provided for synthesizing the 4-aminoquinazoline compound containing morpholinyl aromatic heterocycle and hydroximic acid structures. The invention provides a theoretical basis and clinical application value for designing and developing novel anti-drug-resistance micromolecular multi-target antitumor drugs. Formula 1.

Description

technical field [0001] The invention relates to the synthesis of 4-aminoquinazoline compounds, in particular to a quinazoline-4,6-diamine compound containing morpholino aromatic heterocycles by amidation with dicarboxylic acid monomethyl ester and substitution with hydroxylamine The invention discloses a method for preparing a 4-aminoquinazoline compound containing a morpholino aromatic heterocycle and a hydroxamic acid structure by reaction, belonging to the technical field of organic synthesis. Background technique [0002] Molecular targeted drugs are therapeutic drugs designed for specific targets at the cellular and molecular level, mainly including kinase inhibitors (small molecules), monoclonal antibodies (proteins), angiogenesis inhibitors, etc. At present, the targets of molecular targeted drugs are mainly concentrated in target protein families such as GPCRs, ion channels, nuclear receptors, and kinases. GPCRs and kinase targets are the hot spots of drug research i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D239/94A61P35/00
CPCC07D401/12C07D239/94A61P35/00Y02A50/30
Inventor 刘长春周鑫鑫张祥
Owner JIANGSU FOOD & PHARMA SCI COLLEGE
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