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A diazaspiro derivative containing 3-trifluoromethyl-phenyl substituent and its preparation method and application

A diazaspiro ring and phenyl substitution technology, applied in organic chemistry, antiviral agents, etc., can solve problems such as high adverse reactions, price restrictions, and shortened treatment cycles

Active Publication Date: 2020-04-17
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In 2011, newly diagnosed patients with HCV genotype 1 began to be treated with the first-generation protease inhibitor combined with interferon plus ribavirin, the treatment cycle was shortened, and the SVR rate could be increased to 70%, but the significant adverse reactions and high The price limit its application in patients

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  • A diazaspiro derivative containing 3-trifluoromethyl-phenyl substituent and its preparation method and application
  • A diazaspiro derivative containing 3-trifluoromethyl-phenyl substituent and its preparation method and application
  • A diazaspiro derivative containing 3-trifluoromethyl-phenyl substituent and its preparation method and application

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preparation example Construction

[0045] The present invention provides a preparation method for diazaspiro derivatives containing 3-trifluoromethyl-phenyl substituents described in the above technical scheme, comprising the following steps:

[0046] The compound containing 3-trifluoromethyl-phenyl substituent is subjected to substitution reaction with 8-methyl-2,8-diazaspiro[4.5]decane to obtain 3-trifluoromethyl-containing compound having the structure shown in formula I Diazaspiro derivatives of fluoromethyl-phenyl substituents;

[0047] The compound containing 3-trifluoromethyl-phenyl substituent has the structure shown in formula II:

[0048]

[0049] In formula II, R" is -Cl, -Br, -OH or

[0050] The present invention preferably selects the preparation method of the diazaspiro derivatives containing 3-trifluoromethyl-phenyl substituent according to R, specifically:

[0051] When R is -SO 2 -or-CH 2 -, in the presence of an organic solvent, compound 1 and 8-methyl-2,8-diazaspiro[4.5]decane are su...

Embodiment 1

[0104] Preparation of compound A, the reaction process is as follows:

[0105]

[0106] At 0°C, add ultra-dry solvent dichloromethane (DCM, 5 mL), compound A-a (131 mg, 0.5 mmol) and 8-methyl-2,8-diazaspiro[ 4.5] Decane (154 mg, 1 mmol), reacted for 2.5 h (TLC tracking); the pH value of the resulting system was adjusted to 10 with 1 mol / L sodium hydroxide solution, and then DCM (15 mL) extraction, water (10 mL) Washing, saturated sodium bicarbonate solution (10mL), saturated brine (10mL), collecting the organic phase, using anhydrous sodium sulfate to dry the organic phase, filtering, and the obtained filtrate was concentrated under reduced pressure and then subjected to silica gel column chromatography separation and purification (The eluent was dichloromethane:methanol=20:1, v / v) to obtain Compound A (59.4 mg, yield 31.26%) as a milky white solid.

[0107] HRMS: Anal.calcd for C 16 h 21 f 4 N 2 o 2 S 381.12544. Found: 381.12620. 1 H-NMR (500MHz, DMSO-d 6 )δ8.24(s,...

Embodiment 2

[0109] Preparation of compound B, the reaction process is as follows:

[0110]

[0111] At 0°C, add ultra-dry solvent dichloromethane (DCM, 5mL), compound B-b (234mg, 1mmol) and N,N'-carbonyldiimidazole (194.4mg, 1.2mmol) into a dry one-necked bottle protected by nitrogen , reaction 2h (TLC tracking);

[0112] Add 8-methyl-2,8-diazaspiro[4.5]decane (184.8mg, 1.2mmol) to the resulting system, react at 25°C for 12h (TLC tracking); Sodium solution adjusted the pH value of the resulting system to 10, and then carried out DCM (15mL) extraction, water (10mL) washing, saturated sodium bicarbonate solution (10mL) washing, and saturated brine (10mL) washing in sequence, and collected the organic phase. The organic phase was dried with sodium sulfate water, filtered, and the resulting filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: dichloromethane:methanol=5:1, v / v) to obtain milky white solid compound B ( 106.1mg, the yiel...

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Abstract

The invention relates to the technical field of medicine preparation, in particular to a diazaspiro derivative containing a 3-trifluoromethyl-phenyl substituent group as well as a preparation method and application thereof. A mother nucleus structure in the derivative provided by the invention contains the 3-trifluoromethyl-phenyl substituent group and diazaspiro, and has relatively high anti-HCVactivity.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a diazaspiro derivative containing a 3-trifluoromethyl-phenyl substituent and a preparation method and application thereof. Background technique [0002] Hepatitis C virus (HCV) is a type of RNA virus with a high mutation rate. Its onset is hidden, its transmission route is relatively clear, and it is easy to cause chronicity. According to the statistics of the World Health Organization, the global HCV infection rate is about 2.8%, about 185 million people are infected with HCV, and about 700,000 people die of HCV-related complications every year. Due to the low replication efficiency of HCV, the highly variable genome, and the lack of susceptible animal models, it is easy to escape the recognition of the body's immune system, which brings great difficulties to the research of HCV vaccines. At present, no exact and effective prevention of HCV infection has been devel...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/10A61P31/14
Inventor 陈晓芳洪斌杜郁马贝贝李健蕊卞聪
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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