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Synthesis method of 4-chloroquinoline compound

A synthesis method and compound technology, which are applied in the field of 4-chloroquinoline compounds and synthesis, can solve the problems of unobtainable raw materials, long reaction time and steps, low total yield and the like, and achieve the effects of low price and shortening synthesis reaction time.

Pending Publication Date: 2021-12-31
LIAONING UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method is classic and reliable, but requires the use of high-boiling organic solvents (>200°C) and highly corrosive POCl 3 As a chlorination reagent, at least three steps are required from the raw material to the product, the reaction time and steps are long, the total yield of the product is about 50%, the total yield is low, and a large amount of phosphoric acid waste is produced
There are also reports on the one-step synthesis of 4-chloroquinoline compounds using various functionalized aromatic amines as raw materials (①Synthesis 2015, 47, 3139–3146②Org. Lett.2018, 10, 2657–2659③MendeleevCommun.2008,18,109–111④Tetrahedron 2001 ,57,3465–3469⑤J.Org.Chem.2013,78,10319–10328), but due to the difficulty of obtaining raw materials or the need to use noble metal palladium catalysts, these methods have not been widely used

Method used

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  • Synthesis method of 4-chloroquinoline compound
  • Synthesis method of 4-chloroquinoline compound
  • Synthesis method of 4-chloroquinoline compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1 Synthesis of 2-ethylthio-4-chloroquinoline-3-methyl formate

[0024] At room temperature, add 13mL chlorobenzene, 0.594g BTC (2.0mmol) to the 15mL thick-walled pressure bottle equipped with a magnetic stirrer, dissolve it at room temperature, add 0.590g substrate 1a (2.0mmol) therein, Seal the reaction system and heat it to 120°C to continue the magnetic stirring reaction for 2.5 hours. After the reaction, the reaction solution is concentrated under reduced pressure, and the obtained concentrate is separated by silica gel column chromatography. First, the volume ratio of petroleum ether and ethyl acetate is 50: The mixed solution of 1 is the eluent, collect the eluent containing the target product, evaporate the solvent and dry to obtain 0.506g light yellow solid product 2-ethylthio-4-chloroquinoline-3-methyl carboxylate 2a, producing The rate is 90%.

[0025] The above reaction formula is as follows:

[0026]

[0027] Product 2-Ethylthio-4-chloroquinolin...

Embodiment 2

[0029] Example 2 Synthesis of 6-methyl-2-ethylthio-4-chloroquinoline-3-formic acid methyl ester

[0030] At room temperature, add 14mL of toluene and 0.594g of BTC (2.0mmol) to a 38mL thick-walled pressure-resistant bottle equipped with a magnetic stirrer, dissolve them at room temperature, and add 0.618g of N,S-ketal ketal 1b (2.0mmol), the reaction system was sealed and heated to 120°C to continue the magnetic stirring reaction for 3h. After the reaction was over, the reaction solution was concentrated under reduced pressure, and the resulting concentrate was separated by silica gel column chromatography. A 50:1 mixture was used as the eluent, the eluate containing the target product was collected, the solvent was evaporated and dried to obtain 0.473g of a white solid product 6-methyl-2-ethylthio-4-chloroquinoline-3 - Methyl formate 2b in 80% yield.

[0031] The above reaction formula is as follows:

[0032]

[0033] Product 6-Methyl-2-ethylthio-4-chloroquinoline-3-carb...

Embodiment 3

[0035] Example 3 Synthesis of 6-methylthio-2-ethylthio-4-chloroquinoline-3-formic acid methyl ester

[0036] At room temperature, add 10 mL of xylene and 0.712 g of BTC (2.4 mmol) to a 15 mL thick-walled pressure-resistant bottle equipped with a magnetic stirrer, dissolve them at room temperature, and add 0.682 g of N,S-ketal 1c (2.0mmol), the reaction system was sealed and heated to 120°C to continue the magnetic stirring reaction for 3h. After the reaction was over, the reaction solution was concentrated under reduced pressure, and the resulting concentrate was separated by silica gel column chromatography. The mixture of 70:1 is the eluent, the eluate containing the target product is collected, the solvent is evaporated and dried to obtain 0.577g yellow solid product 6-methylthio-2-ethylthio-4-chloroquinoline- Methyl 3-carboxylate 2c, 88% yield.

[0037] The above reaction formula is as follows:

[0038]

[0039] Product 6-Methylthio-2-ethylthio-4-chloroquinoline-3-carbo...

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Abstract

The invention discloses a synthesis method of a 4-chloroquinoline compound, and belongs to the technical field of organic synthesis. The method comprises the following steps: dissolving triphosgene in an organic solvent at room temperature, adding an N,S-ketene acetal compound, sealing a reaction system, conducting heating to 90-140 DEG C, continuing stirring for reaction for 2-5 hours, and post-treating the obtained reaction liquid to obtain the 4-chloroquinoline compound. The method for synthesizing the 4-chloroquinoline compound has the advantages of few steps, high yield and safe and convenient operation.

Description

technical field [0001] The invention relates to a 4-chloroquinoline compound and a synthesis method, belonging to the technical field of organic synthesis. Background technique [0002] 4-Chloroquinoline compounds belong to a class of quinoline derivatives and are widely used as synthetic quinoline drug active molecules (ACS Omega 2021,6,12984-12994), catalysts (Angew.Chem.Int.Ed.2020,59 , 2735–2739), organic light-emitting materials (Chem.Commun.2015,51,15241-15244) and other raw materials or intermediates. [0003] The currently commonly used method for synthesizing 4-chloroquinoline compounds is to pre-construct 4-hydroxyquinoline intermediates through condensation reactions, and then 3 Under the action, it is converted into 4-chloroquinoline compounds (①J.Med.Chem.2020,63,11756-11785②Bioorg.Med.Chem.Lett.2013,23,1974-1977). This method is classic and reliable, but requires the use of high-boiling organic solvents (>200°C) and highly corrosive POCl 3 As a chlorinati...

Claims

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Application Information

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IPC IPC(8): C07D215/54
CPCC07D215/54
Inventor 黄鹏尹磊孙琪范宇馨
Owner LIAONING UNIVERSITY
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