JPS62267282A - Crystal modification of 6-fluoro-4-chromanone and production thereof - Google Patents

Abstract

NEW MATERIAL:Crystal modification of 6-fluoro-4-chromonone characterized by X-ray diffraction pattern showing strong peaks at diffraction angles (2theta) of 13.5 deg., 15.4 deg., 19.2 deg., 26.2 deg. and 26.8 deg. and peak of middle intensity at 14.8 deg., 20.2 deg., 22.4 deg., 27.5 deg., 31.1 deg. and 33.9 deg. in X-ray diffraction method by Cu-Kalpha ray. USE:An intermediate for drugs such as remedy for diabetes as aldose reductase inhibitor. PREPARATION:6-Fluoro-4-chromanone is treated in an aqueous medium at 40-110 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to 6-fluoro-
The present invention relates to crystal modification of 4-chromanone and its production method.

BACKGROUND OF THE INVENTION 6-Fluoro-4-chromanone is an important compound, for example, as an intermediate for "Turvinyl" (trade name), which is used as an evaaldose reductase inhibitor in the treatment of diabetes.

6-Fluoro-4-chromanone can be obtained according to the prior art, for example in JP-A-53-53653 or JP-A-60-1.
3774, crude 6-fluoro-4-chromanone was obtained by reacting polyphosphoric acid with 3-(4-fluorophenoxy)-propionic acid, and purified 6-fluoro-4-chromanone was obtained by recrystallizing this from ethanol. -4-chromanone is obtained. In addition, these documents describe that purification methods such as sublimation may also be used in combination.

Moreover, according to Japanese Patent Publication No. 60-33433, it is suggested that sulfuric acid can be used in place of poly-1317 acid in the above method.

Problems to be Solved by the Invention Crude 6-fluoro-4- obtained by conventional techniques
Chromanone is easily colored, and in order to obtain 6-fluoro-4-10manone, which is less likely to be colored, it was necessary to recrystallize it using an organic solvent such as ethanol or purify it by sublimation, but such a process is not industrially possible. These methods are not only complicated but also economically disadvantageous, and from an industrial point of view, it is difficult to say that these methods are advantageous. It is desired to develop a method to do so.

Means for Solving the Problems The present inventors have conducted extensive research to solve the above-mentioned problems, and as a result they have arrived at the present invention. That is, the present invention is directed to the diffraction angle (
2ON3.5゜15.4.19.2.26.2 and 26
．． Strong peak at 8, 14.8°, 20°2°; 22.
4.27.5.3 Crystal modification of 6-fluoro-4-chromanone and 6-fluoro-4-characterized by an X-ray diffraction diagram showing intermediate intensity peaks at 1 and 33.9°
Provided is a method for producing a crystal modification of 6-fluoro-4-chromanone characterized by the X-ray diffraction pattern, characterized by treating the chromanone in an aqueous medium at 40 to 110°C.

The method for producing the crystal modification of the present invention will be explained in detail.

The most desirable aqueous medium used in the production method of the present invention is a medium consisting only of water, but a mixed solvent of water and a lower alcohol such as methanol, ethanol, or isopropyl alcohol, or a ketone such as acetone or methyl ethyl ketone is preferable. These water or mixed solvents often contain HL.
A nonionic surfactant having a B value of 8 to 15 or a water-insoluble organic solvent (benzene, toluene, chlorobenzene, methylene chloride, chloroform, ethyl acetate, etc.) may be contained in an amount not exceeding 5% (by weight). Also, the aqueous medium is salt,
Salts such as mirabilite, acids such as sulfuric acid and hydrochloric acid, and alkalis such as caustic soda, caustic potash, ammonia, and soda carbonate, about 4
There is no practical problem even if the content does not exceed 0% (by weight).

The amount of the aqueous medium used is usually 1 to 20 times (by weight) the amount of unconverted 6-fluoro-4-chromanone used as the raw material.

The treatment temperature is 40 to 110°C, preferably 55 to 90°C.
It is ℃.

The treatment time and treatment method are usually 10 to 180 minutes, preferably 3
The treatment is carried out under stirring for 0 to 60 minutes, and within the above-mentioned temperature range, when the treatment temperature is low, the treatment time is lengthened, and when the treatment temperature is high, the treatment time is shortened. Whether or not the desired crystal modification has been achieved is determined by sampling crystals from the treated solution and measuring their X-ray diffraction pattern.

When the treatment (crystal conversion) is completed, if the treatment liquid is not neutral, it is neutralized, and the target object is removed by filtration and dried, and it is characterized by the X-ray diffraction pattern as described above and has a crystal structure. 6-Fluoro-4-chromanone is obtained.

6-fluoro-4-chromano/
has a crystal modification that gives an X-ray diffraction pattern as shown in FIG. As is clear from Figure 2, the diffraction angle (2
October 3.5°.

It showed strong peaks at 15.4°, 19.2°, 26.2° and 26.8°, and 14.8.20.2.22.4.2
It shows moderate peaks at 7.5.31.1 and 33.9°. (Note that an error of about 0.2° in the display of the diffraction angle is allowed as a measurement error.) The crystal before crystal conversion is
Give a line diffraction diagram.

Since impurities contained in 6-fluoro-4-chromanone before crystal conversion are difficult to remove, it tends to become colored especially during the drying process after being removed from the oven. 6-Fluoro-4-chromanone, which has a crystal structure characterized by a specific X-ray diffraction pattern obtained by the production method of the present invention, is colored even when dried and stored, although it has to be purified. It can be used without any problems as a raw material for high purity 6-fluoro-4-chromanon tosite "Truvinyl". Although the degree of coloration can be clearly recognized with the naked eye, a method for more quantitative display is to dissolve the sample in an organic solvent such as ethanol and measure the optical density. .

In addition, in the production method of the present invention, 3-(4-fluorophenoxy)propionic acid is dehydrated and ring-closed in a solvent such as polyphosphoric acid or sulfuric acid, and then the crude 6-fluoro-4-chromanone (wet) obtained by pouring into water and removing E. It is convenient to use the raw material (cake) as a raw material, and excellent effects can be obtained.

Example The present invention will be explained in more detail with reference to Examples.

Example 1 21.5 g of 97% concentrated sulfuric acid was placed in a 50 ml flask and kept at 20°C. 5 g of 3-(4-fluorophenoxy)propionic acid was gradually added thereto over a period of 1 hour. After the reaction was heated to 25°C for 2 hours, the reaction mixture was heated to 5°C.
It was slowly poured into 0 g of ice water. The resulting precipitate was distributed door to door.

The moisture content of the wet cake was approximately 60%. When I sampled one part and measured the melting point, it was 108-110℃.
showed that.

This wet cake (crude 6-fluoro-4-chromanone) was made into 100 ml of beer, and 50 ml of hot water was added to loosen the crystals. Then adjust the pn to 7.8 with dilute NaOH water.
The mixture was stirred at 70-80°C for 30 minutes and cooled to 25°C. Separate the precipitated crystals in a furnace and dry them in an electric dryer (60℃)
Afterwards, 3.25 g of white crystals were obtained. The X-ray diffraction pattern of this crystal is shown in FIG.

The melting point of this product was 115 to 11°C, and analysis by liquid chromatography and gas chromatography showed that the purity was 99% or higher, confirming that it was a highly pure product. Further, when 1.2 g of this crystal was dissolved in 100 cc of ethanol and the transmittance at 470 nm (cell width: 1 cm) was measured, it was 96.1%.

Example 2 The same process as in Example 1 was carried out except that soda ash was added instead of NaOH and pn was set to 9. As in Example 1, a white 6-fluoro-4-chromanone was obtained which gave the X-ray diffraction pattern shown in FIG. The purity of this product as determined by liquid chromatography was the same as in Example 1. Further, the optical density measured in the same manner as in Example 1 was 95.7%.

Example 3 6-fluoro-4-chromanone obtained by carrying out the reaction in the same manner as in Example 1 was gradually poured into 50 g of ice water, and then heated at 60° C. for 1 hour without separating the precipitate. Thereafter, it was cooled to 25° C. and the precipitated crystals were separated from each other. The crystals were thoroughly washed with 15 ml of 0.5% NaOH water and 15 ml of cold water, and dried in a wet K# (1[1-fluoro-4-chromanone) laminated heat dryer.
6-Fluoro-4-chromanone (3,25 g) has a crystal structure characterized by the X-ray diffraction diagram in the figure.
Profitable.

The melting point was 114 to 116.5°C, and the appearance was grayish white with no coloration observed.

Analysis by liquid chromatography and gas chromatography showed that both had a purity of 99% or higher, confirming that they were highly pure products.

Example 4 A ring-closing reaction was carried out in the same manner as in Example 1 except that 20 g of polyphosphoric acid was used instead of concentrated sulfuric acid and the reaction was carried out at 70° C. for 3 hours. After the reaction was completed, the mixture was poured into 70 g of ice water to obtain a precipitate. After distributing this from door to door, 50% of the wet cake (crude 6-fluoro-4-chromanone) was
11 in water, and adjusted the pH to 7.1 with dilute Na 01-] water.
5 and then heat-treated at 75° C. for 1 hour. After cooling to 20°C, the formed precipitate was separated from each other and thoroughly washed with 15 ml of water. After drying in an electric dryer, 6-fluoro-4-chromanone (3.90 g) having a crystal structure characterized by the X-ray diffraction diagram shown in FIG. 2 was obtained.

The melting point was 1]3 to 116°C. Analysis by liquid chromatography and gas chromatography showed that it had a purity of 99% or more. The appearance of this crystal was a slightly pale skin color.

Comparative Example 1° Instead of heating at 70 to 80°C for 30 minutes in Example 1, stirring was performed at 25°C for 2 hours. Then cloth Na01
] Adjust the pH to 7 with water, remove the precipitated crystals from door to door, and boil for 20 minutes.
Wash thoroughly with 1 m of water and dry in an electric dryer (60°C)
3.31 g of 6-fluoro-4-chromanone was obtained as crystals. This product had a brick-colored appearance and was problematic for use as a raw material for manufacturing pharmaceuticals. Further, the optical density was measured in the same manner as in Example I and found to be 79.0%.

Effects of the invention High purity 6- that does not easily discolor during drying and storage
The crystal modification of fluoro-4-chromanone was changed.

4. Brief explanation of figures Figure 1 &'! Figure 2 shows the X-ray diffraction pattern of 6-fluoro-4-chromanone before crystal conversion.
An X-ray diffraction diagram of chromanone after crystal conversion is shown.

Claims (1)

[Claims] 1 Diffraction angle (2
θ) 13.5°, 15.4°, 19.2°, 26.2°
and strong peaks at 26.8°, 14.8°, 20.2°
, 22.4°, 27.5°, 31.1° and 33.9°
Crystal modification of 6-fluoro-4-chromanone characterized by an X-ray diffraction diagram showing a peak of intermediate intensity at
Diffraction angle (2θ) in X-ray diffraction method using Cu-Kα rays characterized by processing at 110°C: 13.5°, 15.
Strong peaks at 4°, 19.2°, 26.2° and 26.8°, 14.8°, 20.2°, 22.4°, 27.5
6-Fluoro-4-
Process for producing crystalline transformation of chromanone