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Preparation method of 6-fluorochroman-2-formic acid

A technology of formic acid and chroman, which is applied in the field of synthesis of chemical drug intermediates, can solve the problems of increased environmental protection costs, too long reaction steps, increased production costs, etc., and achieves the effect of low price, short reaction steps and mild reaction conditions

Inactive Publication Date: 2014-10-01
山东众诚生物医药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Method 2 and method 3 also use aluminum trichloride as a rearrangement reaction catalyst, which will also cause the problems of method 1, increase environmental protection costs, and easily cause environmental pollution, and method 3 The reaction steps are too long, and it is synthesized after five steps of reaction the final product, increasing the cost of product preparation

Method used

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  • Preparation method of 6-fluorochroman-2-formic acid
  • Preparation method of 6-fluorochroman-2-formic acid
  • Preparation method of 6-fluorochroman-2-formic acid

Examples

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Effect test

Embodiment 1

[0055] Embodiment 1: The preparation method of 6-fluorochroman-2-formic acid, the steps are as follows:

[0056] 1) Synthesis of 2-(p-fluorophenoxy)butenedioic acid

[0057] Add 44.8 g (0.4 mol) of p-fluorophenol into a four-necked flask, add 25 mL of methanol, and stir to dissolve. Weigh 56.8 g (0.4 mol) of butynedioic acid dimethyl ester and dissolve it in 15 mL of methanol, add it dropwise to the above-mentioned methanol solution of p-fluorophenol, stir well, there is no obvious heating phenomenon, and the solution appears light yellow. Weigh 2.0g (0.02mol) of triethylamine and slowly add it dropwise to the above reaction system, a large amount of heat will be generated. When dropping triethylamine, keep the temperature of the reaction system below 35°C, and the solution will gradually turn brown. After the addition of triethylamine is completed, keep the reaction system at 25-35°C for 1 hour. As the reaction progresses, a large amount of solids are gradually produced in t...

Embodiment 2

[0063] Embodiment 2: comparative example

[0064] The 2-(p-fluorophenoxy group) butenedioic acid dimethyl ester synthesized in the reaction process is separated, and the specific process is as follows

[0065] 1) Synthesis of 2-(p-fluorophenoxy)butenedioic acid dimethyl ester

[0066] Add 44.8g (0.4mol) of p-fluorophenol into a four-necked flask, add 25ml of methanol, and stir to dissolve. Weigh 56.8 g (0.4 mol) of dimethyl butynedate and dissolve it in 15 ml of methanol, add dropwise to the above-mentioned methanol solution of p-fluorophenol, stir well, there is no obvious temperature rise, and the solution appears light yellow. Weigh 2.0g (0.02mol) of triethylamine and slowly add it dropwise to the above reaction system, a large amount of heat will be generated. When dropping triethylamine, keep the temperature of the reaction system below 35°C, and the solution will gradually turn brown. After the triethylamine is added dropwise, keep the reaction system at 25-35°C for 1 ...

Embodiment 3

[0072] As described in Example 1, the difference is that in step 1) the concentrated hydrochloric acid used for acidification is used to prepare 6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid in the previous batch to obtain The sulfuric acid filtrate (the molar ratio of the hydrogen element in the alkali and the sulfuric acid solution is 1:1-1.5) replaces and carries out the acidification reaction, and the sulfuric acid aqueous solution obtained by filtering the extraction reaction as described in the embodiment 1 step 2 also obtains a good The effect of 2-(p-fluorophenoxy)butenedioic acid solid, the yield is 85.1%, and the purity is 98.7%.

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Abstract

The invention discloses a preparation method of 6- fluorochroman-2-formic acid. The method comprises the following steps: with p-fluorophenol and dimethyl acetylenedicarboxylate as initial raw materials, carrying out an addition reaction on p-fluorophenol and dimethyl acetylenedicarboxylate to generate dimethyl 2-(p-fluorophenoxy) acetylenedicarboxylate, hydrolyzing under an alkaline condition to generate 2-(p-fluorophenoxy) butenedioic acid, dissolving obtained 2-(p-fluorophenoxy) butenedioic acid in concentrated sulfuric acid to perform cyclization to generate 6-fluoro-4-oxo-4H-1-benzopyran-2-formic acid, and finally, carrying out pressurized hydrogenation catalytic reduction to obtain 6-fluorochroman-2-formic acid. The method disclosed by the invention has the advantages of simple operation, low cost and high product yield, and reactions in the steps are safe and environment-friendly, so that the method is especially suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of synthesis of chemical drug intermediates, and in particular relates to a preparation method of a drug intermediate 6-fluorochroman-2-carboxylic acid. Background technique [0002] The chroman structural unit of 6-fluorochroman-2-carboxylic acid (Formula I) is widely present in many molecular structures with biological activity, for example, vitamin E, many antihypertensive drugs that antagonize β receptors and inhibit aldehydes Sugar reductase drug for the treatment of diabetic complications. The derivatives have the effects of treating hypertension, angina pectoris and heart failure, and have anti-inflammatory, antibacterial and hypoglycemic activities. 6-Fluorochroman-2-carboxylic acid is one of the key intermediates for the synthesis of drugs with chroman structural units, and it has a very important application especially in the treatment of cardiovascular disease drugs and has a good application pro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/66
CPCC07D311/66
Inventor 沈乃涛李义李新山
Owner 山东众诚生物医药股份有限公司
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