JPH068288B2 - Method for producing 6-fluoro-4-chromanone - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing 6-fluoro-4-chromanone used as a raw material for medicines and the like. More details 3-
It relates to a method for producing 6-fluoro-4-chromanone by dehydration blocking of (4-fluorophenoxy) propionic acid.

Conventional technology The following formula (I) 6-fluoro-4-chromanone represented by is a useful substance as an aldose reductase inhibitor and as an intermediate of a drug (known as “sorbin”) used for the treatment of diabetes.

According to the prior art, 6-fluoro-4-chromanone is disclosed in, for example, JP-A-53-53653 or JP-A-60-
As described in 13774, by reacting 3- (4-fluorophenoxy) propionic acid with polyphosphoric acid, crude 6-fluoro-4-chromanone is obtained, and then recrystallized from ethanol. High purity 6-fluoro-4-chromanone is obtained. Further, the same document also describes a purification method by sublimation. It should be noted that Japanese Patent Publication 60-33
433 also suggests that sulfuric acid may be used in place of polyphosphoric acid in the above method.

It is also an easily presumable method that 3- (4-fluorophenoxy) propionic acid is subjected to Friedel-Craft type ring closure via an acid chloride.

Problems to be Solved by the Invention 6-Fluoro-4 is produced by the known production method as described above.
-Manufacturing chromanone has various problems. For example, the method using polyphosphoric acid, polyphosphoric acid is expensive,
Moreover, not only is waste treatment troublesome, but a highly pure product cannot be obtained by this method, and purification such as recrystallization or sublimation is required to obtain a highly pure target product.
Further, the method using sulfuric acid has a problem that it is troublesome to treat a large amount of sulfuric acid released after the reaction and the yield is rather low.

Means for Solving the Problems The present inventor has completed the present invention as a result of earnest research to solve the above-mentioned drawbacks of the conventional methods. That is, the present invention provides a method for producing 6-fluoro-4-chromanone, which comprises dehydrating and ring-closing 3- (4-fluorophenoxy) propionic acid with hydrofluoric acid.

In carrying out the present invention, anhydrous hydrofluoric acid is the best hydrofluoric acid used as a dehydration ring-closing agent.
% Or more, preferably 90% or more. The amount of hydrofluoric acid used is 0.2 to 30 times (weight) especially 3- (4-fluorophenoxy) propionic acid.
It is recommended to use 0.5 to 15 times the amount.

The reaction temperature is -20 ° C to + 150 ° C, particularly -10 ° C to 10 ° C.
It is advantageous to carry out at 0 ° C. The reaction time varies depending on the reaction temperature and the amount of hydrofluoric acid used, but usually 0.5 hours to 1
It's 0 hours.

The reaction solvent may not be used, but an inert organic solvent may be used.

As the inert organic solvent, aliphatic or aromatic halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, perkylene, chlorobenzene and dichlorobenzene, benzene, toluene, xylene, naphthalene, hexane, heptane, octane, etc. Aromatic and aliphatic hydrocarbons, nitroaromatic compounds such as nitrobenzene and nitrotoluene, and alkyl nitriles such as acetonitrile and propionitrile can be used.

The amount of these used is not particularly limited, but it is usually convenient to use 0.5 to 10 times (weight).

The reaction is a flask coated with polyethylene, polypropylene, or Teflon, or H of stainless steel, etc.
Take hydrofluoric acid or an aqueous solution thereof in a container resistant to F, add 3- (4-fluorophenoxy) propionic acid thereto, stir at a predetermined temperature, and then place in ice water, or 3 -(4-Fluorophenoxy) propionic acid and the solvent are stirred at a predetermined temperature while a gas of hydrofluoric acid is blown therein.

After completion of the reaction, the reaction solution can be neutralized with an alkaline agent such as NaOH, KOH, K ₂ CO ₃ to extract 6-fluorochromanone by an ordinary method such as an extraction method or an excess method. When the reaction is performed at a temperature of 19 ° C. or higher, a pressure vessel is used and the reaction is performed in the same manner as above. It is also possible to heat and vaporize the hydrofluoric acid after completion of the reaction to cool and trap the hydrofluoric acid.

The most efficient method is to recover the hydrofluoric acid sufficiently, then add water to neutralize the precipitated 6-fluoro-4-chromanone.

The 6-fluoro-4-chromanone thus obtained does not usually require a purification operation and has a melting point of 113-115.
It is a high-purity product with almost no coloring at ℃.

Example 1 In a Teflon container, 40 g of anhydrous hydrofluoric acid, 3- (4
-Fluorophenoxy) propionic acid 5g put 20 ℃
The reaction was allowed to stir for 2.5 hours. After the reaction was completed, the reaction solution was poured into ice water and then neutralized to pH 7.5 with an aqueous potassium hydroxide solution. At this time, the temperature rose to about 60 ° C., and it took 0.5 hours for neutralization. Then, it cooled to 30 degreeC and separated the white crystal which precipitated.

4.15 g of white, dry 6-fluoro-4-chromanone
Got

The yield was 92.0% and the melting point was 113-115 ° C.

Example 2 20 g of chloroform and 3 g of 3- (4-fluorophenoxy) -propionic acid were charged into a Teflon container, and 20 g of anhydrous hydrofluoric acid was added dropwise at room temperature with stirring. After completion of dropping, the reaction was carried out for 5 hours and the reaction mixture was poured into ice water. The chloroform layer was separated and washed with diluted alkaline water. When chloroform was distilled off from this chloroform layer, 2.40
g of white 6-fluoro-4-chromanone was obtained.
The yield was 88.6% and the melting point was 113 to 4 ° C.

Example 3 The reaction was carried out in the same manner as in Example 1. However, the amount of anhydrous hydrofluoric acid used was 15 g. After reacting for 4 hours, hydrofluoric acid which vaporized using a warm water bath was recovered by a Teflon trap, and 5.2 g was recovered. After pouring the residue into water and adjusting the pH to 7.5 using aqueous potassium hydroxide solution,
The white crystal precipitated at ℃ was separated and dried to obtain 4.05 g of 6-fluoro-4-chromanone. It was a white crystal and had a melting point of 113 to 115 ° C. The yield was 89.0%.

Example 4 In place of anhydrous hydrofluoric acid in Example 1, 60 g of 90% hydrofluoric acid was used. The reaction was carried out at 20 ° C. for 7 hours.

After the completion of the reaction, the same treatment as in Example 1 was carried out to obtain 3.69 g of white 6-fluoro-4-chromanone. The yield was 82.0% and the melting point was 113-115 ° C.

EFFECT OF THE INVENTION High-purity 6-fluoro-4-chromanone can be obtained in high yield without using an expensive reagent.

Claims (1)

[Claims] 1. A process for producing 6-fluoro-4-chromanone, which comprises dehydrating and ring-closing 3- (4-fluorophenoxy) propionic acid with hydrofluoric acid.