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Method for preparing 2, 6-dichloro-5-fluorine nicotinoyl ethyl acetate

A technology of ethyl flunicotinyl acetate and acid hydrolysis, applied in the direction of organic chemistry, can solve the problems of low total yield, few preparation steps, large melting range, etc., achieve good process reproducibility, and avoid hydrolysis side reactions , the effect of improving the total yield

Active Publication Date: 2011-07-27
CHANGZHOU YINSHENG PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compared with the aforementioned several methods, this method has a relatively high yield; fewer preparation steps; no need to prepare acid chlorides, and less environmental pollution; however, it has been proved through repeated tests by the applicant according to the method disclosed in this patent that the total yield of this method is Very low, even can't get the product, there are many impurities in the product, and the melting range is very large (see comparative examples 1, 2); multiple tests have also found that the reproducibility is also extremely poor, and it is difficult to realize industrial production

Method used

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  • Method for preparing 2, 6-dichloro-5-fluorine nicotinoyl ethyl acetate
  • Method for preparing 2, 6-dichloro-5-fluorine nicotinoyl ethyl acetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1 Preparation of 2,6-dichloro-5-fluoronicotinoyl ethyl acetate (I)A

[0032] The specific operation steps are as follows:

[0033] ① Generate zinc salt intermediate 3-(2,6-dichloro-5-fluoro-3-pyridyl)-3-iminopropionic acid ethyl ester zinc bromide (III)

[0034] 4.12g (63.2mmol) of zinc powder was added to 60.0mL of tetrahydrofuran and 24.0mg of methanesulfonic acid solution, and the mixture was refluxed and stirred for 1 hour to activate the zinc powder, and 8.0g (41.9mmol) of 2,6 - Dichloro-5-fluoro-3-pyridinecarbonitrile (II), followed by the dropwise addition of 8.8 g (52.7 mmol) ethyl bromoacetate within 1 hour. After the addition, the reaction mixture continued to reflux and stir for 0.5 to 2 hours to generate the reaction solution containing the zinc salt intermediate (III), for subsequent use. The main chemical reactions involved are shown in the following formula:

[0035]

[0036] ②Acidification of zinc salt intermediate (III) to generate imidoest...

Embodiment 2

[0042] Example 2 Preparation of 2,6-dichloro-5-fluoronicotinoyl ethyl acetate (I) B

[0043] The specific operation steps are as follows:

[0044] Step 1. and step 2. are identical with embodiment 1;

[0045] Step ③ When preparing 2,6-dichloro-5-fluoronicotinoyl ethyl acetate (I), add 3-4 mL of concentrated sulfuric acid dropwise to carry out acid-catalyzed alcoholysis, instead of adding hydrogen chloride dropwise in step ③ in Example 1 6~7mL of dehydrated ethanol solution carried out acid-catalyzed alcoholysis, and the rest were all the same as step 3 in Example 1 to obtain 2,6-dichloro-5-fluoronicotinoyl acetate (I)B fine work, and its yield It is 95%, the purity is 99%, and the melting point mp is 68°C to 70°C (decomposition).

Embodiment 3

[0046] Example 3 Preparation of 2,6-dichloro-5-fluoronicotinoyl ethyl acetate (I)C

[0047] Step 1. When the zinc salt intermediate (III) is generated, activate the zinc powder by stirring the mixture for 0.5 hours under reflux, instead of 1. the mixture in step 1 of Example 2 activates the zinc powder by stirring the mixture under reflux for 1 hour, and the rest are all the same as in step 1 of Example 2. same;

[0048] Step ② and step ③ are all the same as in Example 2, and 2,6-dichloro-5-fluoronicotinoyl acetate (I)C fine product is obtained, the yield is 90%, the purity is 99%, and the melting point mp is 68℃~70℃ (decomposition).

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Abstract

The invention relates to a method for preparing 2, 6-dichloro-5-fluorine nicotinoyl ethyl acetate, which comprises the following steps: taking 2, 6-dichloro-5-fluorine-3-pyridine carbonitrile as a raw material, producing a zinc salt intermediate 3-(2, 6-dichloro-5-fluorine-3-pyridyl)-3-imino ethyl propionate zinc bromide, and then acidating the zinc salt intermediate into an imido ester intermediate 3- (2, 6-dichloro-5-fluorine-3-pyridyl)-3-imino ethyl propionate, thus obtaining the 2, 6-dichloro-5-fluorine nicotinoyl ethyl acetate through the acidolysis of the imido ester intermediate. The method is characterized in that the temperature for acidification of the zinc salt intermediate to the imido ester intermediate is 0-10 DEG C and the pH thereof is 2-3, the oily liquid of unhydrous imido ester intermediate can be separated through extracting and distilling the produced imido ester intermediate; the acidolysis of the imido ester intermediate is carried out in absolute ethyl alcohol solvent, and the acid catalyzed alcoholysis of the oily liquid of unhydrous imido ester intermediate is carried out with absolute ethyl alcohol solution of hydrogen chloride or concentrated sulfuric acid under the temperature of 20-30 DEG C. The total yield reaches 88-95 percent, the purity reaches 99 percent, and the invention has good reproducibility.

Description

technical field [0001] The invention relates to a method for preparing ethyl 2,6-dichloro-5-fluoronicotinoyl acetate. Background technique [0002] 2,6-Dichloro-5-fluoronicotinoyl ethyl acetate is an important intermediate of the fourth-generation fluoroquinolone oral antibacterial drug "Gemifloxacin" (Gemifloxacin), and it can also be used to synthesize other fluoroquinolones containing naphthyridine rings. Quinolones such as toloxacin, enoxacin, etc. 2,6-dichloro-5-fluoronicotinoyl ethyl acetate, also known as 2,6-dichloro-5-fluoro-pyridine-3-acetoacetic acid ethyl ester, fluchloronicotinate, (2,6-dichloro -5-fluoro-pyridine-3-carbonyl)-ethyl acetate), 3-(2,6-dichloro-5-fluoro-3-pyridyl)-3-oxopropionic acid ethyl ester. [0003] 2, the structural formula of 6-dichloro-5-fluoronicotinoyl ethyl acetate is as shown in (I): [0004] [0005] There are many methods for preparing 2,6-dichloro-5-fluoronicotinoyl acetate, and the disclosed methods are exemplified as follows:...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/61
Inventor 陈文华刘巧云陶鑫郭亮
Owner CHANGZHOU YINSHENG PHARMA
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