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Quinazoline nitrogen-containing heterocyclic ring derivative as well as preparation method and application thereof

A quinazoline and derivative technology, applied in the field of medicinal chemistry synthesis, can solve the problems of inability to effectively prevent the onset of diabetes, unclear molecular mechanism, etc., and achieve the effects of high yield, easy repeatability, and mild reaction conditions

Active Publication Date: 2022-04-12
XIAN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although the prevalence of diabetes is becoming more and more serious, the relevant molecular mechanisms are still unclear; current drugs for the treatment of diabetes mainly include insulin and its analogues, GLP-1 receptor agonists, biguanides, α-glucosidase inhibitors, Glides Naphthalene, DPP-4 inhibitors, etc., they are limited to the phenotype of diabetes to relieve symptoms, and cannot effectively prevent the onset of diabetes

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  • Quinazoline nitrogen-containing heterocyclic ring derivative as well as preparation method and application thereof
  • Quinazoline nitrogen-containing heterocyclic ring derivative as well as preparation method and application thereof
  • Quinazoline nitrogen-containing heterocyclic ring derivative as well as preparation method and application thereof

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Experimental program
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preparation example Construction

[0018] A kind of preparation method of quinazoline nitrogen-containing heterocyclic derivative of the present invention, specifically implement according to the following steps:

[0019] Step 1, brominated hydrocarbon, catalyst K 2 CO 3 In an eggplant-shaped bottle, add DMF, place it in a magnetic stirrer and stir to form a mixed solution; then dissolve 4-hydroxyquinazoline in DMF, slowly add it dropwise to the mixed solution at room temperature for reaction, and you can get Intermediate;

[0020] Brominated hydrocarbon is any one of 1,2-dibromoethane, 1,3-dibromopropane, 1,4-dibromobutane, 1,5-dibromopentane;

[0021] Step 2, the intermediate and nitrogen heterocyclic compound are dissolved in acetonitrile, and catalyst K is added 2 CO 3 , the reaction was carried out at 80 ° C, and the GF254 silica gel plate was used to monitor continuously during the reaction. After the reactant was completely reacted, water and ethyl acetate were added for extraction, and the organic l...

Embodiment 1

[0028] The preparation of embodiment 1 intermediate

[0029] a, 4-(2-bromoethoxy) quinazoline (A), the structural formula is as follows:

[0030]

[0031] First measure 1,2-dibromoethane (2.101mL, 24.63mmol) and catalyst K 2 CO 3 (4.17g, 30.17mmol) In an eggplant-shaped bottle, add about 30mL of DMF and stir in a magnetic stirrer. Then 4-hydroxyquinazoline (3.00 g, 20.12 mmol) was dissolved in 10 mL of DMF, and slowly added dropwise at room temperature. About 0.5 h after the DMF solution of 4-hydroxyquinazoline was added dropwise, the reaction was complete. After the solution was washed three times with 50 mL of water, it was washed with anhydrous Na 2 SO 4The organic layer was dried and concentrated under reduced pressure to obtain a reaction product. A small amount of the reaction product was dissolved in methanol, and detected by thin-layer chromatography (petroleum ether: acetone = 2:1) under ultraviolet light. The reaction product had two dark spots with large di...

Embodiment 2

[0050] Example 2 Preparation of 4-(2-(1H-pyrazol-1-yl)ethoxy)quinazoline (A-1), the structural formula of compound A-1 is as follows:

[0051]

[0052] Dissolve intermediate A (250mg, 0.99mmol) and pyrazole (80mg, 1.16mmol) in 10mL of acetonitrile, add catalyst K 2 CO 3 (410mg, 2.97mmol), reacted at 80°C. Continue to use GF during the reaction 254 The silica gel plate was used for monitoring, and after about 40 hours, the reactant reacted completely. Water (30mL) and ethyl acetate (3×30mL) were added for extraction, and the organic layer was washed with anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure. 200 mg of white crystal A-1 was obtained with a yield of 84.3%, which was identified as 4-(2-(1H-pyrazol-1-yl)ethoxy)quinazoline.

[0053] mp 117-119°C; 1 H-NMR (400MHz, CDCl 3 )δ8.15(1H,d,J=7.6Hz,H-8),8.08(1H,s,H-2),7.70(1H,t,J=7.6Hz,H-6),7.60(1H, s, H-5), 7.58 (1H, d, J=5.2Hz, pyrazole), 7.42 (1H, t, J=7.6Hz, H-7), 6.32 (1H, s, pyrazole), 4.14 (2H, t...

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Abstract

The invention discloses a quinazoline nitrogen-containing heterocyclic derivative as well as a preparation method and application thereof, and the preparation method specifically comprises the following steps: adding brominated hydrocarbon and K2CO3 into DMF (Dimethyl Formamide), and stirring to form a mixed solution; dissolving 4-hydroxyquinazoline in DMF (Dimethyl Formamide), and dropwise adding into the mixed solution for reaction to obtain an intermediate; the intermediate and a nitrogen heterocyclic compound are dissolved in acetonitrile, K2CO3 is added for a reaction, after reactants completely react, water and ethyl acetate are added for extraction, drying and vacuum concentration, and the quinazoline nitrogen heterocyclic derivative can be obtained. The quinazoline nitrogen-containing heterocyclic ring derivative is synthesized through two-step reaction, the reaction condition is mild, the method is easy to repeat, and the yield is high. The islet cell protection activity of the quinazoline nitrogen-containing heterocyclic ring derivative is researched, and the quinazoline nitrogen-containing heterocyclic ring derivative is a potential new chemical entity for treating diabetes. The important significance is realized on the research and development of anti-diabetic medicines.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and specifically relates to a quinazoline nitrogen-containing heterocyclic derivative, and also relates to a preparation method and application of the quinazoline nitrogen-containing heterocyclic derivative. Background technique [0002] Diabetes has become a major public health problem affecting the health of Chinese residents. As of 2019, 463 million adults worldwide (accounting for 1 / 11 of the global total) suffer from diabetes; by 2030, the number of diabetic patients is expected to reach 578 million. my country's diabetic population has become the largest in the world. In 2019, there were about 116 million domestic diabetic patients, and this number is expected to reach 150 million in 2040. Diabetes-induced coronary heart disease, stroke and other diseases, as well as complications such as diabetic foot, diabetic retinopathy, and diabetic nephropathy, are important...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12C07D239/88A61K31/517A61K31/5377A61P3/10
CPCY02P20/55
Inventor 关丽李慧瑾劳可静陈云梅王春阳赵惠茹李伟泽宋旭雯
Owner XIAN MEDICAL UNIV
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