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Pyridine derivative and application thereof to mycobacterium resistance

A compound and hydrate technology, applied in antibacterial drugs, organic chemistry, etc., can solve the problems of low efficacy, high price, toxicity and so on

Active Publication Date: 2016-02-17
SHANGHAI JIA TAN PHARMATECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of these second-line drugs are toxic, expensive, and ineffective
Infectious, drug-resistant TB patients continue to spread disease due to lack of effective treatment

Method used

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  • Pyridine derivative and application thereof to mycobacterium resistance
  • Pyridine derivative and application thereof to mycobacterium resistance
  • Pyridine derivative and application thereof to mycobacterium resistance

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0265] Preparation of Intermediate A and Intermediate B

[0266]

[0267] step 1:

[0268] (5-Bromo-2-methoxypyridin-3-yl)(phenyl)methanol

[0269]

[0270] Under nitrogen protection, 3,5-dibromo-2-methoxypyridine (118g, 443mmol) was dissolved in 1.2L of anhydrous ether, and n-butyl lithium (2.5M n-hexane solution , 195mL, 487mmol), kept the temperature, stirred for 0.5 hours, dissolved benzaldehyde (47.0g, 443mmol) in 100mL of anhydrous ether, slowly added to the reaction system at -78°C, and slowly heated the mixture to 15- Stir for 1 hour at 25°C. Quench the reaction with 600mL of saturated ammonium chloride solution, extract 3 times with 200mL of ethyl acetate each time, combine the organic phases, wash with brine, dry over anhydrous sodium sulfate, concentrate in vacuo, and perform column chromatography (elution machine: petroleum ether / Ethyl acetate=50 / 1~10 / 1) isolated (5-bromo-2-methoxypyridin-3-yl)(phenyl)methanol (73.5 g, 56.0% yield) as a white solid. LC...

Embodiment 1

[0284] 2-(5-(4-(Dimethylamino)-2-hydroxy-2-(naphthalene-1-yl)-1-phenylbutyl)-3-(6-methoxypyridin-3-yl) ) benzonitrile

[0285]

[0286] Under nitrogen protection, intermediate A (1.00g, 1.98mmol), (2-cyanophenyl)boronic acid (349mg, 2.37mmol), potassium acetate (388mg, 3.96mmol) and Pd(dppf)Cl 2 (92mg, 0.1mmol) was added to the mixed solvent of dioxane / water (10mL / 2mL), and the reaction solution was heated to 80°C and stirred at this temperature for 5 hours under nitrogen protection. LCMS monitored that the reaction was complete. The reaction mixture was added to In water (30mL). Simultaneously extracted with ethyl acetate (10mL×3). The organic phases were combined, dried, and concentrated to obtain the crude compound, which was passed through preparative HPLC (GX-G; PhenomenexSynergiC18150*30mm*4um; acetonitrile15%-45%; water (0.225% fomicacid); 25mL / min) separated to obtain component A and component B. Component A was passed through chiral SFC (BergerMultiGramTMSFC, Me...

Embodiment 2

[0288] 1-(5-(2-bromophenyl)-2-methoxypyridin-3-yl)-4-(dimethylamino)-2-(naphthalene-1-yl)-1-phenylbutan-2 -alcohol

[0289]

[0290] Under nitrogen protection, intermediate B (2.00g, 3.62mmol), 1,2-dibromobenzene (1.02g, 4.34mmol), potassium acetate (710mg, 7.24mmol) and tetrakis (triphenylphosphine) palladium (209mg , 0.18mmol) was added to the mixed solution of dioxane / water (20mL / 4mL), the temperature was raised to 80°C, and the temperature was kept and stirred under nitrogen protection for 16 hours. LCMS monitored that the reaction was complete. The reaction mixture was added to water (40mL ), extracted with ethyl acetate (30mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude compound, which was passed through preparative HPLC (GX-G; PhenomenexSynergiC18150*30mm*4um; acetonitrile30%-60% water (0.225% fomicacid); 25mL / min) separated to obtain component A and component B. Component A was passed thr...

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Abstract

The invention discloses a preparation method and application of a series of novel pyridine derivatives. The derivatives can be used for the treatment of related diseases caused by mycobacterium species, especially for diseases caused by pathogenic mycobacterium, such as Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium avium and Mycobacterium marinum.

Description

technical field [0001] The present invention relates to a series of preparation methods and applications of novel pyridine derivatives. Such derivatives can be used to treat diseases caused by mycobacteria, especially diseases caused by pathogenic mycobacteria, such as Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium avium, and Mycobacterium marinum. technical background [0002] Mycobacterium tuberculosis is the causative agent of tuberculosis. As a globally widespread and fatal infectious disease, according to the World Health Organization, more than 8 million people are infected each year and 2 million people die from tuberculosis. Worldwide, tuberculosis cases have increased by 20% over the past decade, particularly in poorer regions. If this trend continues, TB cases are likely to continue growing at a rate of 41% over the next two decades. For fifty years after the initial introduction of chemotherapy, tuberculosis remained second only to AIDS as the l...

Claims

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Application Information

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IPC IPC(8): C07D213/64C07D401/04C07D405/04C07D409/04C07D417/04C07D213/74C07D401/06A61P31/06A61P31/04
Inventor 丁照中陈曙辉黄志刚罗微蔡哲王业鹏汤东东
Owner SHANGHAI JIA TAN PHARMATECH CO LTD
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