JP3256376B2 - Crystal of suplatast tosilate and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to crystals having good absorbability of suplatast tosilate useful as an antiallergic agent and a method for producing the same.

[0002]

2. Description of the Related Art Generally, the following chemical formula is used.

Embedded image Suplatast tosylate is known to be useful as an antiallergic agent, as shown in Japanese Patent Publication No. 3-70698. However, oral absorption of suplatast tosilate is low, and for example, it has been found that the bioavailability of rats and mice is about several percent (pharmacokinetics, 7,441 (1992)).

[0003] The inventors of the present invention have studied to improve the above-mentioned low absorbency of suplatast tosilate. As a result, the crystals of suplatast tosilate obtained by recrystallization by a certain method were orally and orally. The present inventors have found that they have excellent absorbability from the skin, and have completed the present invention.

[Means for Solving the Problems]

In view of such circumstances, the present inventors have conducted further intensive studies, and as a result, have found that crystals having good absorbability can be easily produced in high yield from a racemic form of suplatast tosylate in high yield, and completed the present invention. did. The present invention specifically relates to an X-ray diffraction pattern having a diffraction angle of 5.7 °, 1
2.0 ゜, 17.4１９, 19.8 ゜, 21.7 ゜, 2
That peaks are observed around 2.9 ゜ and 24.0 ゜
Characteristic optically inactive crystals of suplatast tosilate. A crystal obtained by dissolving a racemic form of suplatast tosilate in a solvent, adding an optically active form of suplatast tosilate as a seed crystal, and recrystallization.
Thus, as an X-ray diffraction pattern, a diffraction angle of 5.7 °, 1
2.0 ゜, 17.4１９, 19.8 ゜, 21.7 ゜, 2
A process for producing optically inactive suplatast tosylate, characterized in that peaks are observed at around 2.9 ° and 24.0 ° . Furthermore, after racemic suplatast tosilate dissolved in the solvent, obtained by cooling to about room temperature, to store or cooling Save recrystallized by adding an optically active substance crystals of suplatast tosilate as seed Crystal
Thus, as an X-ray diffraction pattern, a diffraction angle of 5.7 °, 1
2.0 ゜, 17.4１９, 19.8 ゜, 21.7 ゜, 2
A process for producing optically inactive suplatast tosylate, characterized in that peaks are observed at around 2.9 ° and 24.0 ° .

In practicing the present invention, the racemic form of suplatast tosilate, which is the starting material, is prepared as described in
It can be easily obtained by the production method described in JP-A-698. The optically active crystal of suplatast tosilate used as a seed crystal includes any one of a + body crystal and a − body crystal and a mixture thereof. These are known optical resolution methods, specifically, for example, It can be produced by synthesis from raw materials optically resolved by liquid chromatography or the like.

The solvent used in the present invention includes alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, dimethylethanol and 2-methylpropanol, and dichloromethane and chloroform. Halogenated hydrocarbons,
Acetone, alkyl ketones such as methyl ethyl Ji ketone,
An aprotic polar solvent such as N, N-dimethylformamide, acetonitrile, dimethylsulfoxide and the like, one kind of water and the like, or a mixed solvent of the above various organic solvents can be exemplified.

The amount of the solvent used is generally dissolved in a heated state,
The concentration may be within a range in which crystals are precipitated when left or cooled, and the concentration of suplatast tosilate at that time is usually 2%.
W / W% or more, preferably 10 to 50 W / W%. Suplatast tosylate crystals having good absorbability are prepared by adding a solvent to racemic form of suplatast tosilate, heating and sufficiently dissolving the crystals, returning the temperature to around room temperature, adding the seed crystals, and storing or cooling. Can be manufactured. The temperature for storage or cooling is usually from -50 ° C to
It is 40 degreeC, Preferably it is -30 degreeC-25 degreeC. Also, may be added to insoluble solvent instead of saving storage or cooling, as a solvent for the insoluble, ethers such as diethyl ether, diisopropyl ether, methyl acetate, acetic acid esters such as ethyl acetate, hexane, f flop data and solvents such as aliphatic hydrocarbons such as octane and octane.

[0008] The thus obtained crystals of suplatast tosylate having a good absorption effect are confirmed by X-ray diffraction patterns as shown in the examples described later. That is, as shown in FIG. 1, the X-ray diffraction pattern of the racemic body as a raw material
Diffraction angles 6.6 °, 13.3 °, 19.0 °, 20.0
ピ ー ク, 21.7 ゜ and 22.6 ゜, peaks were observed,
On the other hand, as shown in FIGS. 2 to 5, X-ray diffraction patterns of those manufactured according to the present invention have diffraction angles of 5.7 °, 12.
0 ゜, 17.4 ゜, 19.8 ゜, 21.7 ゜, 22.9
A peak is observed around {24.0}. Incidentally, the optically inactive crystals of suplatast tosylate obtained by carrying out the present invention are pulverized or in a solid state without pulverization, tablets, capsules, oral preparations such as granules, It can be provided in a clinical setting by processing into external preparations such as suppositories, inhalants, nasal drops, eye drops, ointments, plasters, aerosols and the like.

[0009]

According to the present invention, an optically inactive crystal of suplatast tosylate having a good absorption effect can be easily produced in a high yield from an ordinary racemate by this method.

[0010]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to some experimental examples and comparative examples, but the present invention is not limited thereto.

[Experimental Example 1] 4 ml of isopropanol was added to 1.0 g of racemic suplatast tosylate synthesized by the method described in the above-mentioned Japanese Patent Publication No. 3-70698, and the mixture was dissolved by heating to 70 ° C. The solution was cooled to 25 ° C and seeded with (-)-suplatast tosylate 2m
g, and stored at 25 ° C. for 7 days. The precipitated crystals were collected by filtration and dried under reduced pressure at room temperature for 1 day to obtain 0.929 g of optically inactive suplatast tosilate crystals (recovery rate: 92%). .9%). FIG. 2 shows the result of X-ray diffraction of the obtained crystal.

EXPERIMENTAL EXAMPLE 2 20 ml of 2-butanol was added to 5.0 g of racemic suplatast tosilate at 70 ° C.
After heating and dissolving in, the solution was cooled to 25 ° C. and inoculated with 3 mg of suplatast (-)-tosylate as a seed crystal,
After cooling and storing at 5 ° C for 3 days, the precipitated crystals were collected by filtration,
The crystals were dried at room temperature under reduced pressure for one day to obtain 4.82 g of optically inactive crystals of suplatast tosilate (recovery rate 96.4).
%). FIG. 3 shows an X-ray diffraction result of the obtained crystal.

Experimental Example 3 To 2.0 g of racemic suplatast tosylate was added 4 ml of ethanol and the mixture was heated to 70 ° C. and dissolved. 16 ml of isopropyl ether was added, and the solution was cooled to 25 ° C. to give seed crystals. After inoculating 3 mg of (+)-suplatast tosylate, cooling and storing at −30 ° C. for 10 days, the precipitated crystal was collected by filtration, dried under reduced pressure at room temperature for 1 day, and crystallized with optically inactive suplatast tosylate. 1.93 g was obtained (recovery rate 96.5%). FIG. 4 shows the result of X-ray diffraction of the obtained crystal.

Experimental Example 4 To 3.0 g of racemic suplatast tosylate was added 25 ml of acetone and dissolved by heating to 70 ° C., and the solution was cooled to 25 ° C. to obtain (−)-tosyl as a seed crystal. Inoculated with 3 mg of acid splatast, -30
After storage at 3 ° C. for 3 days, the precipitated crystals were collected by filtration and dried under reduced pressure at room temperature for 1 day to obtain 2.85 g of optically inactive suplatast tosilate crystals (recovery rate: 95.0%). FIG. 5 shows the obtained X-ray diffraction results.

EXPERIMENTAL EXAMPLE 5 100% each of the racemic crystals of suplatast tosilate and the crystals obtained in Experimental Example 1
mg in a mortar, 1.9 g of petrolatum was added and mixed well to obtain an ointment.
0 mg was applied to the abdominal skin of a hairless rat (application area: 5.31 cm ² ) and fixed in a vertical cell, and a permeation experiment was performed using 13 ml of water as a permeate, and the amount of permeation with time was measured by liquid chromatography. did. The results are shown in FIG. 6, which shows that the crystal obtained in Experimental Example 1 has a transmission amount that is approximately three times higher than that of a normal racemic crystal.

[Brief description of the drawings]

FIG. 1. Racemic X of normal suplatast tosilate
FIG.

FIG. 2 is an X-ray diffraction diagram of suplatast tosilate obtained in Experimental Example 1.

FIG. 3 is an X-ray diffraction diagram of suplatast tosilate obtained in Experimental Example 2.

FIG. 4 is an X-ray diffraction diagram of suplatast tosilate obtained in Experimental Example 3.

FIG. 5 is an X-ray diffraction diagram of suplatast tosilate obtained in Experimental Example 4.

6 is a transmission curve of a racemic crystal of suplatast tosylate and a crystal obtained in Experimental Example 1. FIG.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07C 381/12 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. A diffraction angle of 5.7 as an X-ray diffraction pattern.
{12.0}, 17.4}, 19.8, 21.7
ピ ー ク, peaks around 22.9 ゜ and 24.0 ゜
Optically inactive of suplatast tosylate, characterized in that
Crystal . 2. A crystal obtained by dissolving a racemic form of suplatast tosilate in a solvent, adding an optically active crystal of suplatast tosilate as a seed crystal and recrystallizing the solution.
Then, as an X-ray diffraction pattern, a diffraction angle of 5.7 °, 1
2.0 ゜, 17.4１９, 19.8 ゜, 21.7 ゜, 2
A process for producing optically inactive suplatast tosilate, wherein peaks are observed at around 2.9 ° and 24.0 ° . 3. After resolving a racemic form of suplatast tosylate in a solvent, cooling the mixture to around room temperature, adding an optically active crystal of suplatast tosilate as a seed crystal and preserving or preserving with cooling to recrystallize . The resulting crystals, X
As a line diffraction pattern, a diffraction angle of 5.7 °, 12.0 °,
17.4 ゜, 19.8 ゜, 21.7 ゜, 22.9 ゜, 2
Light having a peak around 4.0 °
Process for producing chemically inert suplatast tosilate.