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Preparation method of 4-chloro-6-fluoroquinoline

A technology of fluoroquinoline and p-fluoroaniline, which is applied in the field of preparation of 4-chloro-6-fluoroquinoline, can solve the problem that the starting material diethyl malonate has limited sources, is not suitable for large-scale industrial production, and has a long synthesis route. and other problems, to achieve the effect of low production cost, short synthesis route and low price

Active Publication Date: 2017-04-19
CHANGZHOU SUNLIGHT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The disadvantages of this method are: (1) the synthetic route is long and the total yield is low; (2) the starting material 2-(ethoxymethylene)diethyl malonate has limited sources, is not easy to obtain, and is relatively expensive. (3) Both the condensation and ring formation temperatures are above 250°C, which requires special high-temperature equipment and is not suitable for large-scale industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1）

[0019] This example is the preparation method of the intermediate 3-(4-fluoroanilino)propionic acid.

[0020] Add 146.08g of p-fluoroaniline, 129.07g of acrylic acid, 240.8mL of deionized water and 1.2g of tetrabutylammonium bromide into a four-neck flask, heat to 45±2°C and stir for 12h, and control in HPLC until the raw materials disappear , stop the reaction, filter, wash the filter cake with water until neutral, and dry in vacuum to obtain 228.78 g of white solid 3-(4-fluorophenylamino)propionic acid, with a yield of 95.0%.

Embodiment 2～ Embodiment 3）

[0022] The preparation method of each embodiment is basically the same as that of Example 1, except for the phase transfer catalyst, see Table 1 for details.

[0023] Table 1

[0024] Example 1 Example 2 Example 3 phase transfer catalyst 1.2g of tetrabutylammonium bromide 1.2g of tetrabutylammonium chloride 1.2 g of trimethylbenzyl ammonium bromide 3-(4-Fluoroanilino)propionic acid 228.78g 219.14g 214.33g yield 95.0% 91.0% 89.0%

Embodiment 4）

[0026] This example is the preparation method of the intermediate 6-fluoro-2,3-dihydroquinolin-4(1H)-one.

[0027] Add 1143.0g of polyphosphoric acid in a four-neck flask, heat to 100±2°C, then add 228.78g of 3-(4-fluorophenylamino)propionic acid prepared in Example 1, and keep stirring at this temperature for 3h , controlled in HPLC until the raw materials disappeared, ended the reaction, stopped heating, cooled the material to room temperature, added 2000mL of ice-water mixture, stirred for 0.5h, filtered, washed the filter cake with water until neutral, and dried in vacuo to obtain 165.02g of a light yellow solid 6-Fluoro-2,3-dihydroquinolin-4(1H)-one, the yield is 80.0%.

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Abstract

The invention discloses a preparation method of 4-chloro-6-fluoroquinoline. The preparation method comprises the steps: with fluoroaniline as a starting material, firstly, carrying out Michael addition reaction with acrylic acid to obtain an intermediate 3-(4-fluoroanilino)propionic acid; followed by, carrying out a condensation cyclization reaction to obtain an intermediate 6-fluoro-2,3-dihydroquinoline-4(1H)-one; and finally, carrying out halogenation and dehydrogenation reaction to obtain 4-chloro-6-fluoroquinoline. The preparation method has the advantages of wide raw material sources and relatively low cost, thereby having relatively low production cost; at the same time, the preparation method has the advantages of relatively short synthesis route and relatively high yield, especially has mild reaction conditions, has no need of special high temperature equipment, and is suitable for industrialized mass production.

Description

technical field [0001] The invention belongs to the technical field of fine chemical synthesis, and in particular relates to a preparation method of 4-chloro-6-fluoroquinoline. Background technique [0002] 4-Chloro-6-fluoroquinoline is an important intermediate in the synthesis of quinoline-type tyrosine kinase inhibitors, and has very important uses in the synthesis of antitumor drugs. [0003] The preparation method of 4-chloro-6-fluoroquinoline disclosed in the prior art is to use p-fluoroaniline and 2-(ethoxymethylene) diethyl malonate as starting materials, through condensation, ring formation, It can be obtained by hydrolysis, decarboxylation and chlorination [Refer to literature: Indian Journal of Heterocyclic Chemistry, Volume 15, Issue 3, Pages 253-258, Journal, 2006]. [0004] The synthetic route of this method is as follows: [0005] . [0006] The disadvantages of this method are: (1) the synthetic route is long and the total yield is low; (2) the starting ...

Claims

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Application Information

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IPC IPC(8): C07D215/18
CPCC07D215/18
Inventor 胡国宜胡锦平郑建龙奚小金
Owner CHANGZHOU SUNLIGHT PHARMA
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