JP2001334102A - Method for desorbing solvent from clathrate crystal - Google Patents

Abstract

PROBLEM TO BE SOLVED: To remove solvent, which is contained in a clathrate crystal and is hardly desorbed, in a short time without causing transition of the crystal. SOLUTION: The solvent contained in the clathrate crystal is displaced with solvent to be more easily desorbed, which is then desorbed from the clathrate crystal.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for desorbing a solvent from a clathrate crystal. More specifically, the present invention provides a method for replacing a solvent contained in a clathrate crystal by replacing the solvent contained in the clathrate crystal with a more easily desorbable solvent, and then desorbing the more easily desorbed solvent from the clathrate crystal. It relates to a solvent desorption method.

[0002]

BACKGROUND OF THE INVENTION 8- [3- [N-[(E)-] having a bradykinin antagonism.
3- (6-acetamidopyridin-3-yl) acryloylglycyl] -N-methylamino] -2,6-dichlorobenzyloxy] -2-methylquinoline (hereinafter referred to as "F
R173657 ") is a compound having several crystal forms. Among these crystal forms, the A-form crystal obtained by crystallization from an acetone-water-based solvent has good solid stability and purity. It is reported to be high (JP-A-10-316677).

However, the type A crystal of FR173657 is
Contains a small amount of acetone used during crystallization.
Acetone is a substance harmful to the human body and needs to be removed, but it has been difficult to reduce the content of acetone to 0.5% or less only by ordinary vacuum drying.

[0004] Subsequent studies have shown that this FR17365
The A-type crystal of No. 7 was found to be a crystal having a clathrate structure (referred to as “clathrate crystal” in this specification). X-ray crystal structure analysis revealed that FR173657 formed a tunnel structure in this A-type crystal, and acetone and water were included in the tunnel.

[0005] The clathrate structure usually means that when two kinds of molecules are combined under appropriate conditions to form a crystal, one of the molecules forms a tunnel-like, layer-like or network-like structure (inclusion lattice), and the interstices are formed. Is understood to mean a structure in which the other molecule has entered. No strong intermolecular force acts between the molecule (host) that forms the inclusion lattice and the molecule (guest) that is included in it, and the size of the cavity matches the size of the molecule inside. Is said to affect the generation of the clathrate structure.

[0006] Therefore, the term "clathrate crystal" in the present invention means a crystal having a clathrate structure composed of an ordinary host and guest.

FR17365 having a clathrate structure
In the A-type crystal of No. 7, FR173657 itself serves as a host, and acetone or water used during crystallization is included as a guest in the clathrate structure of FR173657, and thus is desorbed by a method such as vacuum drying. It is considered difficult.

In general, as a method for removing acetone as a guest in a clathrate structure, a method is known in which a compound having a clathrate structure is retained in the presence of water vapor and acetone in the clathrate structure is replaced with water. I have. When this method is applied to type A crystal of FR173657, FR1
It is possible to reduce the acetone content of 73657 Form A crystals to 0.5% or less.

However, since FR173657 itself is hydrophobic, it takes a long time to replace acetone in the clathrate structure with water. In addition, FR173657
The A-type crystal has a property that the crystal form is liable to be transferred when excess water is present.
There is an inconvenience that different crystal forms are mixed into the A-type crystal of No. 657.

Therefore, without the transformation of the crystal form,
It has been desired to develop a method for efficiently desorbing the solvent from the type A crystal of FR173657.

[0011]

Means for Solving the Problems The present inventors have noticed that no intermolecular bond such as a hydrogen bond has been confirmed between the solvent contained in the crystal and FR173657. Attempts were made to replace the included guest solvent with another guest having a smaller molecular structure than the guest itself.
As a result, the present inventors have found that the replacement of the guest contained in the clathrate crystal with another guest proceeds in a short time under a mild condition that the guest is kept under the atmosphere of another guest. Then, other guests are quickly removed from the clathrate crystal by holding under vacuum which is a condition usually used for removing the solvent from the crystal, and as a result, the guest is removed from the clathrate crystal. Completed the invention.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The clathrate crystal in the present invention may be any crystal having the above-mentioned clathrate structure, for example, an A-type crystal of FR173657.

[0013] The solvent contained in the clathrate crystal is the solvent used for crystallizing the produced compound. The solvent contained in the clathrate crystal varies depending on the compound to be crystallized, and examples thereof include acetone, acetonitrile, ethanol, isopropyl alcohol, tetrahydrofuran, and ethyl acetate. Specifically, examples of the solvent contained in the clathrate structure of FR173657 include acetone and water used to form the A-type crystal of FR173657.

The solvent (hereinafter referred to as “solvent B”) to be replaced with the solvent in the clathrate structure as described above (hereinafter referred to as “solvent A”), which is easily desorbed from the solvent (hereinafter referred to as “solvent B”), generally has a molecular weight of Small organic solvents are preferred. That is, in general, those having a small molecular size are preferable.
This is considered to be because the clathrate structure usually does not have a strong intermolecular force between the guest and the host, so that the size of the cavity formed by the host depends on whether or not the guest can easily enter. For example, methanol, acetonitrile and the like can be mentioned, and among them, methanol is preferable.

The combination of the host of the clathrate crystal and the solvents A and B, which are the guests contained therein, depends on the relationship between the size of the cavity formed by the host having the clathrate structure and the size of the guest, And guest polarity. That is, another guest formed by the host having the clathrate structure and smaller than the size of the cavity in which the included guest enters is preferable because it is easily replaced.
Therefore, the solvent B is preferably a solvent smaller than the solvent A. On the other hand, when the polarity of the host is lipophilic, it is preferable that the guest to be replaced is also lipophilic. Specifically, acetone contained in the clathrate structure of the A-type crystal of FR173657 is preferably replaced with methanol.

FR17365 containing acetone as solvent
The A-type crystal of No. 7 can be produced, for example, according to the method of Example 1 described in JP-A-10-316677.

The replacement of the solvent A with the solvent B can be performed by maintaining the clathrate crystal in an atmosphere of a solvent from which the clathrate crystals are easily desorbed. Specifically, a method in which a clathrate crystal containing the solvent A is allowed to stand in a desiccator or a drying cabinet filled with the vapor of the solvent B can be adopted.

In the method using a desiccator, the desiccator is first filled with the vapor of the solvent B by sealing in a desiccator containing the solvent B at the bottom. In the desiccator, clathrate crystals containing the solvent A are added in a concentration of 10 to 5
The solvent A can be replaced with the solvent B by allowing to stand at 0 ° C., more preferably 20 to 35 ° C., and most preferably around room temperature for about 1 to 2 days.

The replacement of the solvent A contained in the clathrate crystals with the solvent B can be confirmed by gas chromatography.

Next, the desorption of the solvent B from the clathrate crystals can be performed using a shelf-type vacuum dryer. That is, the clathrate crystal is placed on a shelf in a shelf-type dryer, and the entire dryer is degassed by a vacuum pump or the like to be in a vacuum state, whereby the solvent B is desorbed from the clathrate crystal. The temperature in the dryer is preferably from room temperature to about 50 ° C.
A temperature of about 0 to 35 ° C. is more preferable. The time required for the elimination of the solvent B varies depending on the type of the solvent B, the amount of crystals, the thickness of the layer, and the like, but usually takes about 1 to 3 days.

After the solvent B is desorbed from the clathrate crystals, if necessary, the clathrate crystals may be left under a humidity-controlling condition so that desired moisture can be included. Inclusion of a desired amount of water can be performed by a conventional method using a desiccator, for example.

Next, the present invention will be described with reference to examples, but the present invention is not limited to these examples.

[0023]

EXAMPLES Production Example 1 8- [3- (N-glycyl-N-methylamino) -2,
6-Dichlorobenzyloxy] -2-methylquinoline (100 mg), (E) -3- (6-acetamidopyridin-3-yl) acrylic acid (56.1 mg) and N, N-dimethylformamide (2 ml) 1 in a mixture of
-Hydroxybenzotriazole (43.4 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (56.9 mg) in a nitrogen stream at 0 ° C.
And the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, water and brine,
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by preparative thin-layer chromatography (methanol: dichloromethane = 1: 10, v / v), solidified with diethyl ether and ethyl acetate, and treated with 8- [3- [N-
[(E) -3- (6-acetamidopyridin-3-yl) acryloylglycyl] -N-methylamino]-
2,6-Dichlorobenzyloxy] -2-methylquinoline (FR173657) (78.8 mg) was obtained as an off-white solid.

FR1736 in methanol (720 ml)
57 (7 g) was added at 60 ° C., and the mixture was stirred under reflux for 5 minutes. After cooling the mixture to 30 ° C or lower, the mixture was stirred at 20 to 30 ° C for 2 hours to be crystallized. The crystallized solution was filtered, and the crystallized product was washed with methanol (14 ml), dried at 40 ° C. under vacuum,
A crude anhydrous crystal of R173657 (6.3 g) (hereinafter, referred to as “crude FR173657 crystal”) was obtained. The crystals were crystals containing about 5% methanol.

Concentrated hydrochloric acid (28.1 ml) was added to a mixture of crude FR173657 crystals (100 g) and purified water (500 ml) while stirring at 10 ° C. or lower to dissolve the mixture. After adding activated carbon powder (5 g) and stirring for 2.5 hours, the activated carbon powder was filtered off, purified water (200 ml) and concentrated hydrochloric acid (1.
4 ml). The obtained filtrate is washed with acetone (70
0 ml) and triethylamine (35.87 g) were added at 55 ° C., and the mixture was stirred at the same temperature for 5 minutes and refluxed for 20 minutes. After cooling to 40 ° C., the precipitated crystals were collected by filtration. Wash with 50% acetone, vacuum dry, FR173
Crystals of 657 hydrate (Form A crystal) (88.7 g) were obtained. This crystal was a clathrate crystal containing acetone as a guest.

Reference Example 1 Each of the replacement solvents B, methanol, acetonitrile, ethanol, acetone, isopropyl alcohol, and ethyl acetate, was placed in a sealed desiccator at room temperature at room temperature.
The mixture was left for 2 hours, and the desiccator was filled with the vapor of the solvent B. 1.0 g of the A-type crystal of FR173657 prepared in Production Example 1 was allowed to stand at room temperature for 2 days in a desiccator filled with the vapor of the solvent B for substitution. After that, the clathrate crystal containing the solvent B taken out of the desiccator,
Dry overnight at 30 ° C. under a vacuum of 1-4 Torr. The content of the solvent B contained in the dried A-type crystal was measured by gas chromatography. The result is shown in FIG. In addition, in the graph of FIG. 1, each symbol of a to f means the following solvent, respectively. a: methanol, b: acetonitrile, c: ethanol, d: acetone, e: isopropyl alcohol, f: ethyl acetate.

As is clear from FIG. 1, the smaller the molecular weight of the solvent B, the lower the residual amount thereof in the clathrate crystal of FR173657, which is preferable.

Comparative Example 1 (Vacuum drying) A of FR173657 prepared in Production Example 1
5.0 g of the type crystal was vacuum-dried at 40 ° C. and 0.2 Torr for 9 days. Table 1 shows the acetone content and the water content in the crystals before and after vacuum drying.

[0029]

[Table 1]

Even after 9 days, acetone could not be removed to 0.5% or less.

Comparative Example 2 (substituted with water) A of FR173657 prepared in Production Example 1
50 g of the type crystals were allowed to stand at 40 ° C. for one week under reduced pressure in a closed vessel filled with steam in the same manner as in Reference Example 1. Table 2 shows the acetone content and the water content in the crystal.

[0032]

[Table 2]

It took one week to remove the acetone from the crystals to less than 0.5%.

Comparative Example 3 (substituted with water) A of FR173657 prepared in Production Example 1
14.0 kg of the type crystal was allowed to stand at 40 ° C. for 13 days under a reduced pressure of 30 to 100 Torr in a closed container filled with steam in the same manner as in Production Example 1. Table 3 shows the acetone content and the water content in the crystals.

[0035]

[Table 3]

Because of the large amount of crystals, it took 13 days to remove acetone to 0.5% or less in the crystals.

Example 1 A type crystal 13 of FR173657 prepared in Production Example 1
2.8 g was left at 30 ° C. for 1 day in a sealed desiccator filled with methanol vapor in the same manner as in Production Example 1,
Acetone in the crystals was replaced with methanol. The A-form crystal replaced with methanol was placed in a shelf-type vacuum dryer for 30 minutes.
The methanol was removed by vacuum drying at 1 to 4 Torr at 2 ° C. for 2 days. The A-type crystal from which methanol was removed was spread on a tray, and the humidity was adjusted in a room ventilated at 20 to 30 ° C. for 3 days to adjust the water content of the A-type crystal. Finally, FR17
132.64 g of type A crystal of 3657 was obtained. Table 4 shows the acetone content, methanol content, and water content in the crystals at each stage.

[0038]

[Table 4]

Acetone could be removed to 0.5% or less in a short time, and methanol could be removed to 0.5% or less. Powder X-ray analysis of the A-type crystal after humidity control revealed that the structure of the crystal in which the solvent was replaced by the method of the present invention was the same as the A-form before the replacement.

FIG. 2 shows the change over time of the acetone content in the crystals in Comparative Examples 1 to 3 and Example 1.

[0041]

According to the method of the present invention, the solvent contained in the clathrate crystal can be efficiently removed in a short time.

[Brief description of the drawings]

FIG. 1 is a graph showing the ease of solvent replacement in clathrate crystals.

FIG. 2 is a graph showing the change over time of the acetone content according to each method.

Continued on the front page (72) Inventor Shunsuke Goto 5-5-35-701, Nanko Naka, Suminoe-ku, Osaka-shi, Osaka (72) Inventor Satoshi Hirabayashi 6-7-4, Morikita-cho, Higashinada-ku, Kobe-shi, Hyogo 4C063 AA01 BB07 CC14 DD12 DD97 EE01 4D056 EA01 EA03 EA08

Claims (7)

[Claims] 1. A method for desorbing a solvent from a clathrate crystal, comprising replacing a solvent contained in the clathrate crystal with a solvent which is easily desorbed from the solvent, and desorbing the solvent from the clathrate crystal. . 2. The method according to claim 1, wherein the solvent contained in the clathrate crystals is acetone, ethanol, tetrahydrofuran, isopropyl alcohol or ethyl acetate, and the solvent which is easily desorbed from the solvent is methanol or acetonitrile. 3. The method according to claim 1, wherein the replacement of the solvent is carried out by maintaining the clathrate crystals in an atmosphere of a solvent that easily releases the clathrate crystals. 4. The method according to claim 1, wherein the replacement of the solvent is carried out at a temperature of from 20 to 35 ° C. 5. The method according to claim 1, wherein the elimination of the solvent is carried out by keeping the clathrate crystals under vacuum. 6. The method according to claim 1, wherein the elimination of the solvent is carried out at a temperature of from 20 to 35 ° C. 7. A clathrate crystal comprising 8- [3- [N-
[(E) -3- (6-acetamidopyridin-3-yl) acryloylglycyl] -N-methylamino]-
The method according to any one of claims 1 to 6, which is a type A crystal of 2,6-dichlorobenzyloxy] -2-methylquinoline.