Dihydropyrimidine-phosphoramide derivative, and preparation method and application thereof

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

Active Publication Date: 2018-12-18
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, through the...

Method used

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  • Dihydropyrimidine-phosphoramide derivative, and preparation method and application thereof
  • Dihydropyrimidine-phosphoramide derivative, and preparation method and application thereof
  • Dihydropyrimidine-phosphoramide derivative, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1. Preparation of Compound 2

[0043]Take a 100mL round-bottomed flask, dissolve 2-thiazolecarboxamidine hydrochloride (0.50g, 3.05mmol) in 50mL of absolute ethanol, and add 2-bromo-4-fluorobenzaldehyde (0.93g, 4.60mmol) successively at room temperature ), ethyl acetoacetate (600μL, 4.60mmol), sodium acetate (0.50g, 6.13mmol), reflux at 80°C for 6h; after the reaction, cool to room temperature, spin evaporate to remove absolute ethanol, add water (60mL), Extracted three times with ethyl acetate (25mL x 3), combined the organic phases, washed once with saturated brine (25mL), dried over anhydrous sodium sulfate; concentrated, dry-loaded, separated by flash preparative silica gel column, mixed dichloromethane-n-hexane Solvent recrystallization gave 0.75 g of a yellow solid with a yield of 58% and a melting point of 153-156°C.

[0044]

[0045] Compound 2 spectral data: 1 H NMR (400MHz, CDCl 3 )δ7.81(d, J=2.8Hz, 1H), 7.46(s, 1H), 7.38–7.28(m, 2H), 6.97(t, ...

Embodiment 2

[0046] Embodiment 2. Preparation of Compound 3

[0047] Take a 100mL round-bottomed flask, dissolve Intermediate 2 (0.50g, 1.17mmol) in 50mL carbon tetrachloride, slowly add NBS (0.22g, 1.24mmol), and reflux at 50°C for 2h; after the reaction, cool to room temperature , carbon tetrachloride was removed by rotary evaporation, water (50mL) was added, ethyl acetate extracted (20mL x 3), the organic phases were combined, washed once with saturated brine (25mL), dried over anhydrous sodium sulfate; concentrated, dry loading, Flash preparative chromatography on a silica gel column and recrystallization from a dichloromethane-n-hexane mixed solvent gave 0.35 g of a yellow solid with a yield of 59% and a melting point of 123-128°C.

[0048]

[0049] Spectral data of compound 3: 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,1H),4.61(s,1H),4.09(d,J=7.0Hz,2H),1.16(t,J =7.1Hz, 3H); EI-MS...

Embodiment 3

[0050] Embodiment 3. Preparation of Compound 4

[0051] Take a 10mL round bottom flask, dissolve intermediate 3 (1.00g, 2.00mmol) in 3mL triethyl phosphite, heat the reaction at 160°C for 2h; after the reaction, cool to room temperature, remove triethyl phosphite by rotary evaporation, 5 mL of ethyl acetate was added to mix the sample, the sample was loaded by dry method, separated on a silica gel column by flash preparative chromatography, and recrystallized from a mixed solvent of dichloromethane-n-hexane to obtain 0.75 g of a yellow solid with a yield of 67%.

[0052]

[0053] Compound 4 spectral analysis data: 1 H NMR (400MHz, DMSO) δ9.63(s, 1H), 8.00(d, J=3.1Hz, 1H), 7.93(d, J=3.1Hz, 1H), 7.57(dd, J=8.5, 2.3Hz ,1H),7.46(dd,J=8.6,6.2Hz,1H),7.24(td,J=8.5,2.3Hz,1H),6.00(d,J=2.4Hz,1H),4.10–3.99(m, 6H), 3.95(q, J=7.1Hz, 2H), 1.15-1.25(m, 6H), 1.04(t, J=7.1Hz, 3H); EI-MS: 560.2[M+H] + .

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Abstract

The invention discloses a dihydropyrimidine-phosphoramide derivative, and a preparation method and an application thereof. The above compound has a structure represented by formula I. The invention also relates to the preparation method of the compound represented by formula I, a medicinal composition containing the compound, and the application of the compound in the preparation of anti-HBV drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to dihydropyrimidine-phosphoramide derivatives, a preparation method and pharmaceutical use thereof. Background technique [0002] Viral hepatitis type B (viral hepatitis type B), referred to as hepatitis B (Hepatitis B), is a major infectious disease caused by hepatitis B virus (HBV), long-term development can lead to acute and chronic viral hepatitis, severe hepatitis, liver cirrhosis and primary hepatocellular carcinoma (hepatocellular carcinoma, HCC). The drugs currently used to prevent and treat chronic hepatitis B (CHB) mainly include vaccines, interferon, immunomodulators and DNA polymerase inhibitors. However, due to their shortcomings such as drug resistance, side effects, rebound after drug withdrawal, and inability to completely clear HBV, it is of great significance to develop new non-nucleoside HBV inhibitors with high efficiency, low toxicity, and drug re...

Claims

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Application Information

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IPC IPC(8): C07F9/6558A61P31/20A61K31/675
CPCA61P31/20C07F9/65583
Inventor 展鹏俞霁刘新泳贾海永张硕
Owner SHANDONG UNIV
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