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Dihydropyrimidine-spiro derivatives, preparation method and application thereof

A technology of dihydropyrimidine and derivatives, applied in the field of medicine, can solve the problems of strong liver toxicity, poor water solubility, poor metabolic stability and the like

Active Publication Date: 2022-06-17
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are currently no drugs on the market for related targets
Aiming at the disadvantages of strong hepatotoxicity, poor water solubility and poor metabolic stability of current clinical candidate drugs, a novel class of dihydrogenases was designed and synthesized through target-based rational drug design based on the crystal complex structure of core protein and ligands. Pyrimidine-spiro compounds, such compounds have no relevant reports in the prior art

Method used

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  • Dihydropyrimidine-spiro derivatives, preparation method and application thereof
  • Dihydropyrimidine-spiro derivatives, preparation method and application thereof
  • Dihydropyrimidine-spiro derivatives, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Example 1. Preparation of Compound 2

[0059] Dissolve 2-thiazolecarboxamidine hydrochloride (0.50g, 3.05mmol), 2-bromo-4-fluorobenzaldehyde (0.93g, 4.60mmol), sodium acetate (0.50g, 6.13mmol) in 50mL of absolute ethanol In the solution, ethyl acetoacetate (600 μL, 4.60 mmol) was added at room temperature, and the reaction was refluxed at 80° C. for 8 h; after the reaction, filtered to remove salts. The mother liquor was cooled to room temperature, and yellow crystals (2) were precipitated. The remaining mother liquor was decompressed to remove absolute ethanol, water (60 mL) was added, extracted with ethyl acetate (25 mL×3), the organic phases were collected and combined, extracted once with saturated sodium chloride (25 mL), and the organic phase was extracted with anhydrous magnesium sulfate dry. Filtration, dry loading, separation by flash column chromatography, and recrystallization from dichloromethane-n-hexane system to obtain a yellow powder, which was combine...

Embodiment 2

[0061] Example 2. Preparation of Compound 3

[0062] Intermediate 2 (0.50 g, 1.17 mmol) was dissolved in 50 mL of dichloromethane, N-bromosuccinimide (0.22 g, 1.24 mmol) was slowly added, and the reaction was carried out under reflux at 40 °C for 1.5 h; after the reaction was completed, cooled After reaching room temperature, the solvent was removed by rotary evaporation, water (50 mL) was added, extracted three times with ethyl acetate (20 mL×3), the organic phases were combined, extracted once with saturated sodium chloride solution (25 mL), and dried over anhydrous sodium sulfate; The sample was loaded, separated on a silica gel column by rapid preparative chromatography, and recrystallized from a dichloromethane-n-hexane mixed solvent to obtain 0.35 g of a yellow solid with a yield of 59%; the melting point was 123-128°C.

[0063] 1 H NMR (400MHz, CDCl 3 )δ7.84(d,J=3.1Hz,1H),7.52(s,2H),7.44-7.35(m,1H),7.32(dd,J=8.1,2.6Hz,1H),7.02(t,J =8.0Hz,1H),6.09(s,1H),4.94(d,J=8.9Hz...

Embodiment 3

[0064] Example 3. Preparation of compounds 4(a-c)

[0065] Different substituted spiro rings (0.442 mmol) and NaH (54 mg, 1.33 mmol) were dissolved in dry tetrahydrofuran solution and stirred at room temperature for 0.5-1 h until the substituted spiro rings were dissolved. A solution of Intermediate 3 (220 mg, 0.440 mmol) in tetrahydrofuran was added dropwise. Stir at room temperature for 0.5 h. After the reaction was completed, tetrahydrofuran was removed under reduced pressure, water (25 mL) was added, extracted with ethyl acetate (20 mL×3), the organic phases were collected and combined, extracted once with saturated sodium chloride (25 mL), and the organic phase was dried over anhydrous magnesium sulfate . Filtration and flash column chromatography. The target compound 4(a-c) was obtained by recrystallization from dichloromethane-n-hexane system.

[0066] The substituted spiro ring used was tert-butyl 7-oxo-2,6-diazaspiro[3,4]octane-2-carboxylate. The product 4a is a ...

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Abstract

The invention provides a dihydropyrimidine-spiro derivative and its preparation method and application. The compound has the structure shown in formula I. The present invention also relates to a preparation method containing the compound of formula I, a pharmaceutical composition and the application of the above compound in the preparation of anti-HBV medicines.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of a dihydropyrimidine-spirocyclic derivative and an anti-HBV drug use. Background technique [0002] Viral hepatitis type B, referred to as hepatitis B, is a major infectious disease caused by hepatitis B virus (HBV). and primary hepatocellular carcinoma (hepatocellular carcinoma, HCC). The drugs currently used for the prevention and treatment of chronic hepatitis B mainly include vaccines, interferon, immunomodulatory drugs and DNA polymerase inhibitors. However, they have shortcomings such as drug resistance, side effects, rebound after drug withdrawal, and inability to completely clear HBV. Therefore, it is of great scientific significance to develop a new generation of non-nucleoside HBV inhibitors that are safe, efficient, low toxicity and drug resistance. . [0003] Core protein is the main structural protein composed of HBV nucleocapsi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04C07D471/04C07D491/056A61K31/506A61P31/20
CPCC07D487/04C07D471/04C07D491/056A61P31/20
Inventor 展鹏马悦刘新泳赵树洁任玉洁
Owner SHANDONG UNIV
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