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Method of preparing 3-cyano-quinolines and intermediates made thereby

A cyanoquinoline and aryl technology, applied in the field of preparation of substituted 3-cyanoquinolines, can solve problems such as no quinoline catalysis or elaboration of mild methods

Inactive Publication Date: 2008-05-14
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] To date, there is nothing in the art describing a catalytic or mild process for the preparation of quinolines that does not require high temperatures

Method used

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  • Method of preparing 3-cyano-quinolines and intermediates made thereby
  • Method of preparing 3-cyano-quinolines and intermediates made thereby
  • Method of preparing 3-cyano-quinolines and intermediates made thereby

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preparation example Construction

[0087] As mentioned above, the method for preparing 3-cyanoquinolines utilizes two separate routes. Both routes involve the reaction of arylamines, orthoformates, and reactive methylene groups and both lead to the production of N-aryl-2-propene derivatives. Since the method of the present invention does not involve heating to high temperature or use of microwave radiation, it avoids many obstacles of previous synthetic routes. Therefore, the present method can be easily adapted to large-scale preparation of 3-cyanoquinolines. Furthermore, the chlorination step used in previous synthetic methods is avoided. This is an improvement since chlorination of quinolines is known to form various tars and decomposition products, which lead to lower yields of the desired product and difficult to remove impurities. Therefore, syntheses involving quinoline chlorination are extremely unsuitable for large-scale synthesis of 3-cyanoquinolines. The method of the present invention is advantag...

example

[0154] The following examples are provided to illustrate the invention, not to limit the invention.

example 1

[0156] (E / Z)-3-(4-bromo-3-ethoxyanilino)-N-[3-chloro-4-(2-pyridyl-methoxy)phenyl]-2-cyano- Preparation of 2-acrylamide.

[0157]

[0158] A 3 neck 50ml flask was charged with cyanoacetamide (0.50g, 1.7mmol) in triethylorthoformate (2.45g, 2.75ml, d = 0.89g / ml). The mixture was heated to 50-60°C and acetic anhydride (0.42g, 0.39ml, 4.1mmol, 2.5eq, d=1.08g / ml) was added. The flask was heated to 100-105°C for a minimum of 4 hours and then cooled to 70-75°C. A solution of 3-ethoxy-4-bromoaniline hydrochloride (0.42 g, 1.67 mmol) in isopropanol (5 ml) was added. The mixture was stirred for 3 hours and cooled to room temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and stripped to dryness. The residue was dissolved in acetonitrile (10ml) and water (10ml) was added dropwise to precipitate the product. The product was filtered on a Buchner funnel to obtain 0.11 g of the title comp...

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Abstract

The present invention relates to methods for preparing substituted 3-cyanoquinolines and intermediates obtained by the methods of the present invention. The methods of the invention comprise reacting an N-aryl-2-propanimide with phosphoryl chloride to produce the substituted 3-cyanoquinolines. The methods further comprise reacting arylamines, orthoformates and active methylenes to produce the N-aryl-2-propenamide.

Description

technical field [0001] The present invention relates to a process for the preparation of substituted 3-cyanoquinolines. The 3-cyanoquinolines are prepared by two separate routes involving the reaction of arylamines, orthoformates and activated methylenes. Both routes lead to N-aryl-2-propene derivatives. Background technique [0002] Protein kinases are a class of enzymes that catalyze the transfer of the phosphate group of ATP to tyrosine, serine, threonine, or histidine residues on protein substrates, most of which play a role in normal cell growth. Accordingly, many growth factor receptor proteins act as protein tyrosine kinases (PTKs) to signal and are referred to as receptor tyrosine kinases (RTKs). [0003] The RTKs constitute a larger family of PTKs and possess various biological activities. Currently, at least nineteen distinct RTK subfamilies have been identified. One such subfamily is the "HER" family of RTKs, which includes EGFR (Epidermal Growth Factor Recept...

Claims

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Application Information

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IPC IPC(8): C07C251/50C07D209/48C07D213/30C07D215/54C07D401/12
CPCC07D401/14C07D401/12C07D213/30C07D413/02C07D209/48C07C217/84C07D215/54C07C255/30C07C257/06C07C255/23C07D215/38C07D403/02A61P35/00A61P43/00C07D215/00
Inventor 沃伦·丘玛丽亚·帕帕米谢拉基斯
Owner WYETH LLC
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