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Thiazolyl dihydropyrimidine compound as well as preparation method and application thereof

A dihydropyrimidine and compound technology, applied in the field of thiazolyl dihydropyrimidine compounds, can solve problems such as easy recurrence, inability to be cured, and unfixed course of treatment

Inactive Publication Date: 2018-07-03
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantages of this type of drug are: the course of treatment is not fixed, viral drug resistance is prone to occur, and it is easy to relapse after drug withdrawal.
Patients cannot be cured

Method used

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  • Thiazolyl dihydropyrimidine compound as well as preparation method and application thereof
  • Thiazolyl dihydropyrimidine compound as well as preparation method and application thereof
  • Thiazolyl dihydropyrimidine compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Example 1: 4-(2-chloro-4-fluorophenyl)-6-((3-(difluoromethyl)-3-hydroxyazetidin-1-yl)methyl)-2- Preparation of (thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester

[0079]

[0080] Step 1) Synthesis of compound 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester:

[0081]

[0082] The compound 2-(2-chloro-4-fluorobenzylidene)-3-oxobutanoic acid methyl ester (5.3g, 20.7mmol), 2-thiazole formamidine hydrochloride (2.6g, 15.9mmol) was dissolved in Add potassium acetate (3.1 g, 31.8 mmol) to trifluoroethanol (70 mL), replace with nitrogen three times, and heat to reflux at 80° C. overnight. After the reaction, cool, filter with suction, concentrate the reaction solution, and the residue is separated and purified by column chromatography (n-heptane / ethyl ester (v / v)=9 / 1) to obtain a yellow solid 4-(2-chloro-4- Fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl e...

Embodiment 2

[0093] Example 2: 4-(2-bromo-4-fluorophenyl)-6-((3-(difluoromethyl)-3-hydroxyazetidin-1-yl)methyl)-2- Preparation of (thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester

[0094]

[0095] The compound 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester (195 mg, 0.398mmol) dissolved in CHCl 3 (20mL), add compound 3-(difluoromethyl)azetidin-3-ol (71mg, 0.437mmol), DIPEA (513uL, 3.98mmol), heat at 45°C and stir for 4h. After finishing the reaction, cool, concentrate the reaction solution, dissolve the residue with DCM (50mL), wash with water (50mL×3), extract the aqueous phase with DCM (50mL×2), combine the organic phases, and anhydrous Na 2 SO 4 Dry, filter with suction, concentrate the filtrate, and separate and purify the residue by column chromatography (PE / EA (v / v) = 1 / 1 to pure EA / MeOH (v / v) = 4 / 1), then use PE-EA Recrystallization afforded 4-(2-bromo-4-fluorophenyl)-6-((3-(difluoromethyl)-3-...

Embodiment 3

[0098] Example 3: 4-(2-chloro-4-fluorophenyl)-6-((3-hydroxy-3-methylazetidin-1-yl)methyl)-2-(thiazole-2 Preparation of -yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester

[0099]

[0100] The compound 4-(2-chloro-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester (178 mg, 0.398mmol) dissolved in CHCl 3 (5mL), add compound 3-methylazetidin-3-ol (49mg, 0.398mmol), DIPEA (516mg, 3.98mmol), heat at 45°C and stir for 4h. After finishing the reaction, cool, concentrate the reaction solution, dissolve the residue with DCM (50mL), wash with water (50mL×3), extract the aqueous phase with DCM (50mL×2), combine the organic phases, and anhydrous Na 2 SO 4 Drying, suction filtration, concentration of the filtrate, separation and purification of the residue by column chromatography (PE / EA (v / v) = 1 / 1 to pure EA), and recrystallization with PE-EA to obtain light yellow solid 4-(2- Chloro-4-fluorophenyl)-6-((3-hydroxy-3-methylaz...

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Abstract

The invention provides a thiazolyl dihydropyrimidine compound shown in a formula (I) as shown in the description or pharmaceutical salt, or a tautomer, or an enantiomer, or a diastereoisomer thereof,wherein R1, R2, R3, m, n and A are defined in the specification and claims. The invention also provides a preparation method of the compound shown in the formula (I) and medicinal application of the compound in treatment or prevention of hepatitis B virus infection.

Description

technical field [0001] The invention relates to a thiazolyl dihydropyrimidine compound and its application as medicine. The compound has the effect of treating and preventing hepatitis B, especially as a hepatitis B virus (HBV) inhibitor, and treats HBV infection by targeting the HBV capsid. The invention also relates to processes for the preparation of such compounds. Background technique [0002] Hepatitis B is a disease caused by hepatitis B virus (HBV), mainly characterized by liver inflammatory lesions, and can cause multiple organ damage. Hepatitis B virus, referred to as HBV, is a DNA virus belonging to the family Hepadnavividae. It can cause acute or persistent / progressive chronic disease. Hepatitis B is widely prevalent in countries around the world, with more than 400 million people, especially in the Asia-Pacific region. A small number of patients can be transformed into cirrhosis or liver cancer. Anti-HBV nucleoside (acid) drugs currently on the market inclu...

Claims

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Application Information

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IPC IPC(8): C07D417/14A61P1/16A61P31/20
CPCC07D417/14
Inventor 白骅季明哲龚永祥刘礼飞骆红英钟金清李译李云霞曹启雄周亚陈洋尹亚婷
Owner ZHEJIANG HISUN PHARMA CO LTD