WO2023027162A1 - 2-(4-ethylphenoxy)-4'-methoxy-3,3'-bipyridine crystal and production method therefor - Google Patents

Abstract

Provided is a 2-(4-ethylphenoxy)-4'-methoxy-3,3'-bipyridine (compound (I)) crystal that has superior stability and that is suitable as an active pharmaceutical ingredient of a drug. A suspension of the compound (I) is prepared by employing the compound (I) and a solvent containing 2-propanol, and the suspension is agitated and is subsequently filtered. An obtained compound (I) crystal (in particular, Form A) has a high purity and a high bulk density and is particularly superior as an active pharmaceutical ingredient of a drug.

Description

Crystal of 2-(4-ethylphenoxy)-4'-methoxy-3,3'-bipyridine and method for producing the same

The present invention relates to crystals of 2-(4-ethylphenoxy)-4'-methoxy-3,3'-bipyridine, a production method, and intermediates for the production thereof.

2-(4-ethylphenoxy)-4'-methoxy-3,3'-bipyridine has the following formula:

is a bipyridine compound represented by (hereinafter also referred to as compound (I)).
Since compound (I) has excellent nail permeability and potent antifungal activity, it has been reported that it is useful as a therapeutic agent for mycoses, particularly tinea unguium (Patent Documents 1 and 2). ).

In Patent Document 1, 3-bromo-2-(4-ethylphenoxy)pyridine is synthesized from 4-ethylphenol and 3-bromo-2-chloropyridine, and (4-methoxypyridin-3-yl) is synthesized. A method for producing compound (I) by coupling reaction with boronic acid is disclosed (see figure below).

However, this production method cannot be said to be an industrially suitable production method because it is purified using silica gel column chromatography and the yield is low (19%).

WO2017/047602 WO2019/088005

The drug substance of pharmaceuticals needs to be supplied by a simple and industrially applicable method, but it is also preferable to supply it in the form of stable crystals. The above prior art documents do not disclose any crystals of compound (I) nor suggest their existence. Therefore, it is unknown whether crystals of compound (I) exist, and if they do exist, what form they are in cannot be predicted at all.

In view of the above background, one of the problems to be solved by the present invention is to provide a compound (I) having an optimal profile as a drug substance for pharmaceuticals.
Another problem to be solved by the present invention is to provide a crystal of compound (I) having an optimum profile as a drug substance for pharmaceuticals.

Another problem to be solved by the present invention is to provide a highly pure compound (I), in particular, to provide a physicochemically stable and highly pure crystal of the compound (I).
Still another problem to be solved by the present invention is to provide an industrially applicable method for producing the compound (I) (including crystals thereof).

In view of the above problems, the present inventors have diligently studied to provide a crystal of compound (I) that has an optimal profile as a drug substance for pharmaceuticals. In the production method described in Patent Document 1, the reason for the low yield was that the coupling reaction did not proceed well. Therefore, the present inventors investigated various substrates and reaction conditions. As a result, we have surprisingly found that prior to the coupling reaction, 3-bromo-2-(4-ethylphenoxy)pyridine has the formula:

The compound (II) represented by or its derivative boronic ester, and then the following formula:

It was found that the compound (I) can be obtained in a good yield by performing a coupling reaction with the compound (III) represented by.
Furthermore, the present inventors once isolated the PTSA (p-toluenesulfonic acid) salt or phthalate of compound (I) as an intermediate in the purification step of the obtained compound (I), thereby obtaining a metal It was clarified that impurities and coloring components were efficiently removed.
Subsequently, the present inventors investigated a method for neutralizing the PTSA salt or phthalate of compound (I) and a method for crystallization. As a result, after neutralizing the PTSA salt or phthalate of compound (I), compound (I) can be crystallized from a solution containing IPA (2-propanol) in very good yields and high It was clarified that pure crystals of compound (I) can be produced.

Crystals of compound (I) produced by the above method are referred to as Form A. Separately, the present inventors have discovered Form C in addition to Form A as crystals of compound (I). Comparing Form A and Form C, Form A is superior as a drug substance in terms of bulk density. However, since Form C has lower solubility in IPA water mixed solvent, Form C is thermodynamically stable in the same solvent, and Form A transforms to Form C depending on the conditions. Therefore, a method for reproducibly manufacturing Form A, which is superior as a drug substance for pharmaceuticals, was sought.
The present inventors have made further extensive studies and found that when compound (I) is crystallized from a solution of IPA water mixed solvent, Form A is first generated, and the temperature during crystallization is set to 10 ° C. or less ( (preferably 5°C or less) or the stirring time is set to within 2 days, so that Form A does not substantially transition to Form C, and as a result, Robustness that can consistently obtain Form A The present invention was completed by discovering a manufacturing method with a high yield.

That is, the present inventors completed the following invention.
[01] Formula (I):

A crystal of compound (I) represented by

[02] Characterized by having peaks at 8.8 ± 0.2 °, 11.4 ± 0.2 °, 13.7 ± 0.2 °, 16.6 ± 0.2 ° and 17.5 ± 0.2 ° as diffraction angles represented by 2θ in the powder X-ray diffraction spectrum The crystal according to [01] (Form A).

[03] Characterized by having peaks at 7.5 ± 0.2 °, 10.3 ± 0.2 °, 10.8 ± 0.2 °, 15.5 ± 0.2 ° and 19.8 ± 0.2 ° as diffraction angles represented by 2θ in the powder X-ray diffraction spectrum The crystal according to [01] (Form C).

[04] The purity of compound (I) is 98.0% or more, and the content of compound (I) is represented by the following formula (IV):

The crystal according to any one of [01] to [03], wherein the content of compound (IV) represented by is 0.5% or less.

[05] The purity of compound (I) is 98.0% or more, and the content of compound (I) is represented by the following formula (V):

The crystal according to any one of [01] to [04], wherein the content of compound (V) represented by is 0.5% or less.

[06] The purity of compound (I) is 98.0% or more, and the content of compound (I) is represented by the following formula (VI):

The crystal according to any one of [01] to [05], wherein the content of compound (VI) represented by is 0.5% or less.

[07] The purity of compound (I) is 98.0% or more, and the content of compound (I) is represented by the following formula (VII):

The crystal according to any one of [01] to [06], wherein the content of compound (VII) represented by is 0.5% or less.

[08] The purity of compound (I) is 98.0% or more, and the content of compound (I) is represented by the following formula (VIII):

The crystal according to any one of [01] to [07], wherein the content of compound (VIII) represented by is 0.5% or less.

[09] The purity of compound (I) is 98.0% or more, and the content of compound (I) is represented by the following formula (IX):

The crystal according to any one of [01] to [08], wherein the content of compound (IX) represented by is 0.5% or less.

[10] The purity of compound (I) is 98.0% or more, and the content of compound (I) is represented by the following formula (X):

The crystal according to any one of [01] to [09], wherein the content of compound (X) represented by is 0.5% or less.

[11] The purity of compound (I) is 98.0% or more, and the content of compound (I) is represented by the following formula (XI):

The crystal according to any one of [01] to [10], wherein the content of compound (XI) represented by is 0.5% or less.

[12] The purity of compound (I) is 98.0% or more, and the content of compound (I) is represented by the following formula (XII):

The crystal according to any one of [01] to [11], wherein the content of compound (XII) represented by is 0.5% or less.

[13] The purity of compound (I) is 98.0% or more, and the content of compound (I) is represented by the following formula (XIII):

The crystal according to any one of [01] to [12], wherein the content of compound (XIII) represented by is 0.5% or less.

[14] A method for producing crystals of compound (I) according to any one of [01] to [13], comprising the following steps:
Step D: Using compound (I) and a solvent containing 2-propanol, preparing a suspension of compound (I), stirring, and then filtering;
Manufacturing method including.

[15] A method for producing a highly pure compound (I), comprising the following steps:
Step B: (i) compound (I), (ii) a solvent, and (iii) PTSA, PTSA hydrate, phthalic acid, or phthalic acid hydrate are mixed to obtain PTSA of compound (I) Precipitating the salt or phthalate followed by filtering;
Step C: a step of neutralizing the PTSA salt or phthalate of compound (I) and extracting compound (I) with an organic solvent;
Step D': A step of preparing a suspension of compound (I) using the compound (I) obtained in step C and a solvent containing 2-propanol, stirring, and then filtering;
Manufacturing method including.

[16] A method for producing compound (I), comprising the following steps:
Process A: Formula below:

(wherein R ₁ is B(OH) ₂ , B(OMe) ₂ , B(OEt) ₂ , B(Oi-Pr) ₂ , BF ₃ K, and
The formula below:

Any one selected from the group consisting of A wavy line drawn across lines in the structural formula indicates the position at which each group is attached to the pyridine ring in formula (XIV). ) and the following formula

Compound (XV) represented by (wherein X is selected from the group consisting of an iodine atom, a bromine atom, a chlorine atom, a fluorine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group a step of reacting the compound (I) to obtain a compound (I);
Step B′: (i) the compound (I) obtained in step A, (ii) a solvent, and (iii) PTSA, PTSA hydrate, phthalic acid, or phthalic acid hydrate are mixed. and precipitating the PTSA salt or phthalate of compound (I), followed by filtering;
Step C: a step of neutralizing the PTSA salt or phthalate of compound (I) and extracting compound (I) with an organic solvent;
Step D': A step of preparing a suspension of compound (I) using the compound (I) obtained in step C and a solvent containing 2-propanol, stirring, and then filtering;
Manufacturing method including.

[17] A method for producing compound (I), comprising the following steps:
Process A: Formula below:

The compound (XIV) represented by (wherein R ₁ is the same as in [16] above), and the following formula

A step of reacting compound (XV) represented by (wherein X is the same as in [16] above) to obtain compound (I),
Manufacturing method including.

[18] A method for producing compound (I),
The concentration of 2-propanol in the solvent in the suspension of step D (including step D') is from 20 vol% to 45 vol%,
And any one of (a) to (c) is satisfied {(a) the stirring time is within 2 days.
(b) The stirring time is 3 days or less, and the temperature of the suspension during stirring is 20°C or less.
(c) The temperature of the suspension during stirring is 10°C or less. },
The production method according to any one of [14] to [16].
[19] PTSA salt or phthalate of compound (I).

[20] Mycosis, superficial mycosis, produced by mixing crystals of compound (I) according to any one of [01] to [13] with a pharmaceutically acceptable carrier , or a pharmaceutical composition for the treatment or prevention of tinea unguium.

[21] a pharmaceutical composition produced by mixing the crystals of compound (I) according to any one of [01] to [13] and a pharmaceutically acceptable carrier; A method for treating or preventing mycosis, superficial mycosis, or tinea unguium, comprising the step of administering to an animal.
[22] A crystal of compound (I) according to any one of [01] to [13] for the manufacture of a pharmaceutical composition for the treatment of mycoses, superficial mycoses, or tinea unguium Use of.

[23] A method for producing a pharmaceutical composition, comprising mixing crystals of compound (I) according to any one of [01] to [13] with a pharmaceutically acceptable carrier.
[24] mycosis, superficial mycosis, or A method for producing a pharmaceutical composition for treating or preventing tinea unguium.

The present invention also includes the following inventions.
[02a] Characterized by having peaks at 8.8 ± 0.1 °, 11.4 ± 0.1 °, 13.7 ± 0.1 °, 16.6 ± 0.1 ° and 17.5 ± 0.1 ° as diffraction angles represented by 2θ in the powder X-ray diffraction spectrum The crystal according to [01] (Form A).
[03a] Characterized by having peaks at 7.5 ± 0.1 °, 10.3 ± 0.1 °, 10.8 ± 0.1 °, 15.5 ± 0.1 ° and 19.8 ± 0.1 ° as diffraction angles represented by 2θ in the powder X-ray diffraction spectrum The crystal according to [01] (Form C).

[04a] A compound (I) having a purity of 98.0% or more and a content of compound (IV) of 0.5% or less relative to the content of compound (I).

[05a] The compound according to [04a] (I ).

[06a] According to [04a] or [05a], wherein the purity of compound (I) is 98.0% or more and the content of compound (VI) is 0.5% or less relative to the content of compound (I) compound (I) of

[07a] Any of [04a] to [06a], wherein the purity of compound (I) is 98.0% or more and the content of compound (VII) is 0.5% or less relative to the content of compound (I) or compound (I) according to one of

[08a] Any of [04a] to [07a], wherein the purity of compound (I) is 98.0% or more and the content of compound (VIII) is 0.5% or less relative to the content of compound (I) or compound (I) according to one of

[09a] Any of [04a] to [08a], wherein the purity of compound (I) is 98.0% or more and the content of compound (IX) is 0.5% or less relative to the content of compound (I) or compound (I) according to one of

[10a] Any of [04a] to [09a], wherein the purity of compound (I) is 98.0% or more and the content of compound (X) is 0.5% or less relative to the content of compound (I) or compound (I) according to one of

[11a] Any of [04a] to [10a], wherein the purity of compound (I) is 98.0% or more and the content of compound (XI) is 0.5% or less relative to the content of compound (I) or compound (I) according to one of

[12a] Any of [04a] to [11a], wherein the purity of compound (I) is 98.0% or more and the content of compound (XII) is 0.5% or less relative to the content of compound (I) or compound (I) according to one of

[13a] Any of [04a] to [12a], wherein the purity of compound (I) is 98.0% or more and the content of compound (XIII) is 0.5% or less relative to the content of compound (I) or compound (I) according to one of

[13b] The content of compound (IV), compound (X), and compound (XI) is each 0.5% or less relative to the content of compound (I), and the purity of compound (I) is 98.0% Compound (I) which is above.

[15a] A method for producing crystals of compound (I) according to any one of [01] to [13], comprising the following steps:
Step B: (i) compound (I), (ii) a solvent, and (iii) PTSA, PTSA hydrate, phthalic acid, or phthalic acid hydrate are mixed to obtain PTSA of compound (I) Precipitating the salt or phthalate followed by filtering;
Step C: a step of neutralizing the PTSA salt or phthalate of compound (I) and extracting compound (I) with an organic solvent;
Step D': A step of preparing a suspension of compound (I) using the compound (I) obtained in step C and a solvent containing 2-propanol, stirring, and then filtering;
Manufacturing method including.

[16a] A method for producing crystals of compound (I) according to any one of [01] to [13], comprising the following steps:
Step A: a step of reacting compound (XIV) with compound (XV) to obtain compound (I);
Step B′: (i) the compound (I) obtained in step A, (ii) a solvent, and (iii) PTSA, PTSA hydrate, phthalic acid, or phthalic acid hydrate are mixed. and precipitating the PTSA salt or phthalate of compound (I), followed by filtering;
Step C: a step of neutralizing the PTSA salt or phthalate of compound (I) and extracting compound (I) with an organic solvent;
Step D': A step of preparing a suspension of compound (I) using the compound (I) obtained in step C and a solvent containing 2-propanol, stirring, and then filtering;
Manufacturing method including.

[17a] The compound (XIV) in step A is represented by the following formula:

Any one selected from the group consisting of compound (II), compound (XIV-1), compound (XIV-2), and compound (XIV-3) represented by
The compound (XV) in step A has the following formula:

The production method according to any one of [16], [17], and [16a], which is a compound (III) represented by

[17b] The production method according to any one of [16], [17], [16a] and [17a], wherein step A is a cross-coupling reaction using a metal catalyst and a base.

[17c] the metal catalyst is tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, palladium chloride, palladium acetate, palladium chloride-1,1′-bis(diphenylphosphino)ferrocene, tris(dibenzylidene) acetone)dipalladium, bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium, nickel nitrate hexahydrate, nickel acetate tetrahydrate, bis(1,5-cyclooctadiene)nickel, selected from the group consisting of bis(1,5-cyclooctadiene)(duroquinone)nickel and [(tetramethylenediamine)nickel(o-tolyl)chloride], 0.1% relative to the amount of compound (XV) to 10%, the production method of [17b].
[17d] the group wherein the base consists of tripotassium phosphate, potassium hexamethyldisilazane, potassium tert-butoxide, potassium hydroxide, lithium hydroxide, and 1,8-diazabicyclo[5.4.0]undec-7-ene; in an amount ranging from 1.1 equivalents to 4 equivalents relative to the amount of compound (XV).

[18a] A method for producing compound (I), comprising:
The concentration of 2-propanol in the solvent in the suspension of step D (including step D') is from 20 vol% to 45 vol%,
and satisfying any one of (a) to (c) {(a) the stirring time is within 2 days, and the temperature of the suspension during stirring is -10°C or higher and 25°C or lower;
(b) The stirring time is 3 days or less, and the temperature of the suspension during stirring is -10°C or higher and 20°C or lower.
(c) The stirring time is 7 days or less, and the temperature of the suspension during stirring is -10°C or higher and 10°C or lower. },
The production method according to any one of [14] to [16].

[18b] A method for producing compound (I), wherein the concentration of 2-propanol in the solvent in the suspension in step D (including step D') is from 30 vol% to 40 vol%, [18] or [ 18a].
[18c] A method for producing compound (I), wherein the solvent in step D (including step D') is an IPA water mixed solvent [14] to [16], [18], [18a], and the production method according to any one of [18b].

[19a] A PTSA salt crystal of Compound (I) having a DSC endothermic peak at 172±1°C, or a phthalate salt crystal of Compound (I) having a DSC endothermic peak of 163±1°C.
[19b] Crystals of compound (I) described in any one of [01] to [13], or production of compound (I) described in any one of [04a] to [13b] use of the PTSA salt or phthalate of Compound (I) for

[20a] A pharmaceutical composition for the treatment or prevention of mycosis, superficial mycosis, or tinea unguium, comprising the compound (I) of any one of [04a] to [13b] as an active ingredient thing.

[21a] A treatment of mycosis, superficial mycosis, or tinea unguium, comprising administering the compound (I) of any one of [04a] to [13b] to mammals including humans. A method of treatment or prevention.
[22a] Use of compound (I) according to any one of [04a] to [13b] for the manufacture of a pharmaceutical composition for treating mycoses, superficial mycoses, or tinea unguium .

[23a] A pharmaceutical composition comprising a crystal of compound (I) according to any one of [01] to [13] and a pharmaceutically acceptable carrier.
[24a] Treatment of mycosis, superficial mycosis, or tinea unguium, comprising crystals of compound (I) according to any one of [01] to [13] and a pharmaceutically acceptable carrier Or a pharmaceutical composition for prophylaxis.
[25a] A step of administering a pharmaceutical composition comprising crystals of compound (I) according to any one of [01] to [13] and a pharmaceutically acceptable carrier to mammals including humans; A method for treating or preventing mycoses, superficial mycoses, or tinea unguium, comprising:
In this specification, Me represents methyl, Et represents ethyl and i-Pr represents isopropyl.

The compound (I) of the present invention (for example, Form A crystals) is highly stable and can be used as a drug substance for pharmaceuticals.
The method for producing compound (I) of the present invention (for example, crystals of Form A) can be carried out by simple operations suitable for industrial scale, and high-purity crystals of compound (I) can be obtained in high yield. be able to.

1 is a powder X-ray diffraction spectrum of a crystal (Form A) of compound (I) produced in Example 1. FIG. 2 is a peak table of the powder X-ray diffraction spectrum of FIG. 1; 1 is a powder X-ray diffraction spectrum of a crystal (Form C) of compound (I) produced in Example 6. FIG. 4 is a peak table of the powder X-ray diffraction spectrum of FIG. 3; 1 is an infrared absorption spectrum of a crystal (Form A) of compound (I) produced in Example 1. FIG. 6 is a peak table of the infrared absorption spectrum of FIG. 5; 1 is an infrared absorption spectrum of a crystal (Form C) of compound (I) produced in Example 6. FIG. 8 is a peak table of the infrared absorption spectrum of FIG. 7; 1 is an infrared absorption spectrum of a PTSA salt of compound (I) (compound (XIX)) produced as an intermediate in Example 1. FIG. 2 is an infrared absorption spectrum of a phthalate salt of compound (I) (compound (XX)) produced as an intermediate in Example 3. FIG. 1 is a chart of differential scanning calorimetry (DSC) of crystals (Form A) of compound (I) produced in Example 1. FIG. 4 is a chart of differential scanning calorimetry (DSC) of crystals (Form C) of compound (I) produced in Example 6. FIG. 1 is a differential scanning calorimetry (DSC) chart of the PTSA salt of compound (I) (compound (XIX)) produced as an intermediate in Example 1. FIG. 3 is a differential scanning calorimetry (DSC) chart of the phthalate salt of compound (I) (compound (XX)) produced as an intermediate in Example 3. FIG.

The details of the present invention will be described below.

As used herein, the term "crystal" refers to solids in which constituents (molecules) form a three-dimensional repeating structure called a crystal lattice, and mixtures of these solids, which do not have such a repeating structure. It is distinguished from amorphous (amorphous solid).

In general, crystals of low-molecular-weight compounds such as 2-(4-ethylphenoxy)-4'-methoxy-3,3'-bipyridine are often found near a specific diffraction angle (2θ) in powder X-ray diffraction spectra. It has an endothermic peak at a specific temperature in differential scanning calorimetry (DSC), and an absorption band at a specific wave number in infrared absorption spectrometry. However, depending on the nature or quality of crystals, these instrumental analyzes may not be performed appropriately.

In the present specification, analysis by X-ray diffraction refers to a powder X-ray diffraction spectrum unless otherwise specified, for example, "Powder X-ray diffraction measurement method ” can be performed according to a conventional method. Generally, the diffraction angles (2θ) of the same crystal match within the range of ±0.2° or ±0.1°.
In this specification, the peak value of the diffraction angle 2θ means having at least the peak. For example, "in the powder X-ray diffraction spectrum, the diffraction angle represented by 2θ has peaks at 8.8 ± 0.2 °, 11.4 ± 0.2 °, 13.7 ± 0.2 °, 16.6 ± 0.2 ° and 17.5 ± 0.2 °" , at least at 8.8±0.2°, 11.4±0.2°, 13.7±0.2°, 16.6±0.2° and 17.5±0.2°; other peaks may be observed. Also, the peak intensities at 8.8±0.2°, 11.4±0.2°, 13.7±0.2°, 16.6±0.2° and 17.5±0.2° are not particularly limited as long as they can be distinguished from others.

　In the powder X-ray diffraction spectrum of this specification, the sample obtained by the manufacturing process was pulverized without pretreatment such as pulverization or sieving, and was directly measured. However, the sample may be pretreated if desired.

In this specification, analysis by differential scanning calorimetry (DSC) can be performed according to a conventional method such as the "thermal analysis method" described in the Japanese Pharmacopoeia (18th revision). As used herein, the term "endothermic peak" refers to the peak apex temperature, which may vary slightly depending on the measurement conditions. The range of measurement error that can occur varies somewhat depending on the measurement conditions and the substance to be tested. That is, for the same crystal, the "endothermic peaks" match within a range of ±2°C or ±1°C.

In the present specification, analysis by infrared absorption spectroscopy can be carried out according to conventional methods such as "infrared absorption spectroscopy" described in the Japanese Pharmacopoeia (18th revision). It should be noted that the wave number and intensity at which absorption is observed may vary somewhat depending on the measurement conditions and the like. Regarding the absorption band (cm ^-1 ), the possible range of measurement error is usually ±0.5% or ±5 cm ^-1 . In this case, if the crystal forms are the same, the absorption bands (cm ^-1 ) match within the range of ±0.5% or ±5 cm ^-1 .

Next, the details of the crystals of compound (I) in this specification will be explained. There are two types of crystals of compound (I), referred to herein as Form A and Form C.

Form A is one of the crystals of compound (I), and is a stable crystal that is thermally stable and shows no crystal transition below a certain temperature. Form A is a white solid, non-hygroscopic, has a high bulk density, and is particularly easy to handle, such as filtration from suspensions.
Form A is one of preferred crystals of compound (I) because of the above properties.

Form C is one of the crystals of compound (I), and is a stable crystal that is thermally stable and shows no crystal transition. Form C is a white solid, non-hygroscopic, and easy to handle such as filtration.
Form C is one of preferred crystals of compound (I) because of the above properties.

As noted above, Form A and Form C have excellent drug substance profiles.
In general, a drug substance with a high bulk density is less likely to scatter, and can contribute to simplification of the process and space saving in the preparation of a pharmaceutical composition, which is preferable. Therefore, since Form A has a high bulk density and is particularly easy to handle, it is a crystal that is particularly preferable as a drug substance for pharmaceuticals. Also, for oral formulations, crystals with high bulk density are particularly suitable for miniaturization of formulations.

Form A is manufactured by the manufacturing method of the present invention described above. Further, by applying the production method of the present invention, Form A with high purity can be produced on an industrial scale.

Next, crystals of the compound (I) of the present invention exemplified in [01] to [13] above, which are one embodiment of the present invention, and high-purity crystals of the present invention exemplified in [04a] to [13b] above A method for producing compound (I) (hereinafter simply referred to as "the compound (I) of the present invention" includes all of these) (hereinafter also simply referred to as "the production method of the present invention") will be described. .
Compound (I) of the present invention is produced through the steps described in [14] to [17] above. By applying the production method of the present invention, the compound of the present invention (for example, Form A crystals) can be obtained with high purity. Moreover, the production method of the present invention can be applied on an industrial scale.
The details of each step will be described below.

In one embodiment of the present invention, the production method of the present invention comprises
Step D: A step of preparing a suspension of compound (I) using compound (I) and a solvent containing 2-propanol, stirring, and then filtering.

As used herein, "suspension" refers to a dispersion of solid particles in a liquid. The “suspension of compound (I)” in step D is a liquid in which compound (I) is dispersed in a solvent containing at least 2-propanol.
The compound (I) used in this step is not limited, for example, an isolated compound (I) may be used, and the solution, concentrate, suspension of compound (I) obtained in the previous step A liquid, an extract, or the like may be used as it is.

Examples of the above "solvent containing at least 2-propanol" include a solvent containing only 2-propanol, a mixed solvent of 2-propanol and one or more other organic solvents, a mixed solvent of 2-propanol and water, Or a mixed solvent of 2-propanol, one or more other organic solvents, and water.

In step D, the preferred solvent is a solvent containing only 2-propanol, a mixed solvent of 2-propanol and ethyl acetate, a mixed solvent of 2-propanol and water, or a mixed solvent of 2-propanol, ethyl acetate and water. A more preferred solvent is a mixed solvent of 2-propanol and water, or a mixed solvent of 2-propanol, ethyl acetate and water. A particularly preferred solvent is a mixed solvent of 2-propanol and water. In this specification, the mixed solvent of 2-propanol and water is also referred to as "IPA water mixed solvent".

In the above "solvent containing at least 2-propanol", when using a mixed solvent of 2-propanol and other solvents, "concentration of 2-propanol" is 2-propanol to the solvent of the suspension in step D Although not particularly limited, it is preferably 20 vol% to 45 vol%, more preferably 30 vol% to 45 vol%, and particularly preferably 30 vol% to 40 vol%.
In one embodiment of the present invention, the solvent used in step D is preferably 20 vol% to 45 vol% IPA water mixed solvent, more preferably 30 vol% to 45 vol% IPA water mixed solvent, particularly preferably 30 vol% to 40 vol% IPA water mixed solvent.

In step D, the volume of the solvent used is not particularly limited, but the volume (L) of the solvent can be, for example, 2 to 50 times the weight (kg) of compound (I) used as a raw material. can. The volume (L) of the solvent is preferably 5 to 20 times, more preferably 10 to 15 times the weight (kg) of compound (I).

In step D, a suspension using a solvent containing compound (I) and 2-propanol is stirred in order to obtain crystals of compound (I). At this time, in order to obtain Form A of compound (I), compound (I) may be precipitated from a solution containing 2-propanol of compound (I).
The temperature in this case is not particularly limited, but the preferred temperature for obtaining crystals is -10°C or higher and 20°C or lower, the more preferred temperature is -10°C or higher and 15°C or lower, and the particularly preferred temperature is - The temperature is 10°C or higher and 10°C or lower, and a more preferable temperature is -5°C or higher and 10°C or lower.

When compound (I) is precipitated from a solution containing 2-propanol of compound (I), the stirring time should be set after solid particles of compound (I) are generated in the solution (or after seed crystals of compound (I) are formed. post addition), refers to the time until the end of stirring.
The stirring time in step D is not particularly limited as long as the temperature is 10°C or lower. When the temperature is 20°C or less, the stirring time is preferably 3 days or less, more preferably 24 hours or less. For temperatures above 20° C., stirring times of no more than 2 days are preferred, more preferably no more than 24 hours.
In step D, in order to obtain Form C of compound (I), the solution containing methyl tert-butyl ether (MTBE) of compound (I) was dried to obtain a solid of compound (I), followed by addition of 2-propanol. A suspension can be prepared with a solvent containing and suspension washed.

In another embodiment of the present invention, the production method of the present invention comprises
Step B: (i) Compound (I), (ii) a solvent, and (iii) PTSA (p-toluenesulfonic acid), PTSA hydrate, phthalic acid, or phthalic acid hydrate are mixed. , precipitating the PTSA salt or phthalate of compound (I) and then filtering;
Step C: a step of neutralizing the PTSA salt or phthalate of compound (I) and extracting compound (I) with an organic solvent;
Step D': A step of preparing a suspension of compound (I) using a solvent containing compound (I) obtained in step C and 2-propanol, stirring, and then filtering;
including.

Step B and subsequent steps are steps for purifying the compound (I) obtained in the previous step.
As used herein, "high-purity compound (I)" refers to compound (I) having a purity of 98.0% or more, for example, the compounds exemplified in [04a] to [13b] above ( I). Preferably, it refers to compound (I) having a purity of 99.0% or more.
In step B, the PTSA salt or phthalate of compound (I) is isolated, which effectively removes various impurities such as metal impurities and coloring components. Therefore, the PTSA salt or phthalate of compound (I) is a particularly useful intermediate compound in the manufacturing process of compound (I).
The PTSA salt or phthalate salt of compound (I) produced in this step is a crystal having DSC endothermic peaks at 172±1° C. and 163±1° C., respectively, and is a compound that is excellent in handling.

The "solvent" in step B above is not particularly limited as long as it can dissolve compound (I), but is preferably ethyl acetate, isopropyl acetate, tetrahydrofuran, cyclopentylmethyl ether, acetone, or a mixed solvent containing these, more preferably , isopropyl acetate, tetrahydrofuran, acetone, or a mixed solvent containing these, more preferably a solvent containing at least isopropyl acetate, particularly preferably isopropyl acetate.

The volume of the "solvent" in step B is not particularly limited, but for example, a volume (L) of 1 to 100 times the weight (kg) of compound (I) can be used. The volume (L) of the solvent is preferably 5 to 50 times, more preferably 15 to 30 times the weight (kg) of compound (I).

The reaction temperature in step B is not particularly limited as long as the reaction proceeds, but may be, for example, room temperature.
The reaction time in step B is not particularly limited as long as the reaction proceeds. For example, the reaction time in step B can be applied in the range of 1 hour to 24 hours.

Step C is a step of neutralizing the PTSA salt or phthalate of compound (I) with a base to release compound (I), and extracting the released compound (I) with an organic solvent.
The base used to neutralize the PTSA salt or phthalate of compound (I) is not particularly limited as long as it can release compound (I), but is preferably an inorganic base, particularly preferably sodium hydrogen carbonate. Or potassium hydrogen carbonate.
A solvent for extracting released compound (I) is not particularly limited as long as it can separate from water and extract compound (I). In one embodiment of the invention, it is ethyl acetate.

Compound (I) obtained in step C (including its solution, concentrate, suspension, or extract) is used in the following step D' (according to step D) to obtain a highly pure compound ( I) crystals (eg, Form A) can be obtained.
In the present specification, the term “step D” includes steps similar to step D and steps similar to step D, for example, step D′ and the like, unless otherwise noted. Hereinafter, similarly, step B includes step B' and the like.

In another embodiment of the present invention, the production method of the present invention comprises
Process A: Formula below:

The compound (XIV) represented by (wherein R ₁ is the same as in [16] above), and the following formula:

A step of reacting compound (XV) represented by (wherein X is the same as in [16] above) to obtain compound (I),
Step B′: (i) the compound (I) obtained in step A, (ii) a solvent, and (iii) PTSA, PTSA hydrate, phthalic acid, or phthalic acid hydrate are mixed. and precipitating the PTSA salt or phthalate of compound (I), followed by filtering;
Step C: a step of neutralizing the PTSA salt or phthalate of compound (I) and extracting compound (I) with an organic solvent;
Step D': A step of preparing a suspension of compound (I) using a solvent containing compound (I) obtained in step C and 2-propanol, stirring, and then filtering;
including.

The reaction in step A is not particularly limited as long as compound (XIV) and compound (XV) are reacted to produce compound (I). A typical embodiment of the invention is a cross-coupling reaction using a metal catalyst and a base. Here, when compound (XIV) or compound (XV) is simply described in this specification, its salts and solvates are also included.
Further, when compound (II) is used as compound (XIV), in the reaction system of step A, R ₁ of compound (XIV) is B(OMe)OH, B(OMe) ₂ , It may be converted to B(OEt)OH, B(OEt) ₂ , B(Oi-Pr)OH, B(Oi-Pr) ₂ and the like, followed by a coupling reaction.
A preferred compound (XIV) in step A has the formula:

is compound (II), compound (XIV-1), compound (XIV-2), or compound (XIV-3), more preferably compound (II) or compound (XIV-1), More preferred is compound (II). Here, in the present specification, when compound (II) is simply described, its salts and solvates are also included.
X in the formula of preferred compound (XV) in step A is an iodine atom, a bromine atom, or a chlorine atom, and more preferred compound (XV) has the following formula:

is a compound (III) represented by Here, in the present specification, when compound (III) is simply described, its salts and solvates are also included.

When using a metal catalyst in step A, the type is not particularly limited as long as the reaction proceeds. Examples of catalysts used in one embodiment of the present invention include: tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, palladium chloride, palladium acetate, palladium-1 chloride, 1′-bis(diphenylphosphino)ferrocene, tris(dibenzylideneacetone)dipalladium, bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium, nickel nitrate hexahydrate, nickel acetate tetrahydrate bis(1,5-cyclooctadiene)nickel, bis(1,5-cyclooctadiene)(duroquinone)nickel, and [(tetramethylenediamine)nickel(o-tolyl)chloride].

In the above case, the amount of metal catalyst used is not particularly limited as long as the reaction proceeds. For example, the amount of the metal catalyst used in one embodiment of the present invention ranges from 0.1% to 10% relative to the amount of compound (XV).

When using a base in step A, the type is not particularly limited as long as the reaction proceeds. Examples of bases used in one embodiment of the present invention include: tripotassium phosphate, potassium hexamethyldisilazane, potassium tert-butoxide, potassium hydroxide, lithium hydroxide, and 1, 8-diazabicyclo[5.4.0]undec-7-ene.

In the above case, the amount of base used is not particularly limited as long as the reaction proceeds. For example, the amount of the base used in one embodiment of the present invention ranges from 1.1 equivalents to 4 equivalents relative to the amount of compound (XV).

Additives may coexist in step A in order to allow the reaction to proceed smoothly. Examples of additives used in one embodiment of the present invention include triphenylphosphine, tri(p-tolyl)phosphine, tri(m-tolyl)phosphine, tris(4-methoxyphenyl)phosphine, tris(4- phosphine ligands such as fluorophenyl)phosphine and tris(4-trifluoromethylphenyl)phosphine;

In the above case, the amount of additive used is not particularly limited as long as the reaction proceeds. For example, the amount of the additive used in one embodiment of the present invention can be in the range of 1 to 5 equivalents relative to the amount of the metal catalyst.

When using a solvent in step A, the type is not particularly limited as long as the reaction proceeds. Preferred solvents are straight and branched chain alcohol solvents having 1 to 4 carbon atoms such as methanol, ethanol, 2-propanol, etc. Methanol is particularly preferred.

In the above case, the volume of the solvent used is not particularly limited, but the volume (L) of the solvent can be, for example, 1 to 10 times the weight (kg) of compound (XIV). The volume (L) of the solvent is preferably 2 to 7 times, more preferably 2 to 5 times the weight (kg) of compound (XIV).

The reaction temperature in step A is not particularly limited as long as the reaction proceeds. °C.
The reaction time in step A is not particularly limited as long as the reaction proceeds, but can be applied, for example, in the range of 1 hour to 24 hours.

Using the compound (I) obtained in step A as a raw material, step B' (according to step B), step C, and step D' (according to step D) are performed in order to obtain a highly pure compound of the present invention. Crystals of compound (I) (eg, Form A) can be obtained.

Each step from step A to step D' may be performed continuously without isolation, or the product may be isolated in any step. Preferably, in step B', the PTSA salt or phthalate salt of compound (I) is isolated as a solid. Also, preferably, after obtaining a solution of compound (I) in an organic solvent in step C, it is subjected to the next step (step D') as a concentrated solution without isolation.
By sequentially performing steps A to D', crystals of compound (I), which is preferable as a drug substance for pharmaceuticals, can be obtained.

Next, the purity and impurities of compound (I) of the present invention will be explained.
Depending on the method for producing compound (I), a wide variety of impurities are produced, resulting in an increased impurity content. However, the compound (I) produced by the production method of the present invention has very few impurities and is highly pure, and thus has appropriate quality as a drug substance for pharmaceuticals.
In the present specification, "impurity" is a general term for substances other than chemical substances defined as drug substances or excipients among substances contained in drug substances or drug products, and includes metal impurities, related substances, Including reaction by-products, decomposition products, etc.

As impurities in the process of manufacturing compound (I), the above compound (IV), compound (V), compound (VI), compound (VII), compound (VIII), compound (IX), compound (X), compound (XI), compound (XII), and compound (XIII). These impurities can be used as an index in producing a highly pure compound (I) from the viewpoint of production amount and removability. However, "impurities" in the present specification are not limited to these.

The content of each of the above impurities contained in compound (I) of the present invention is 0.5% or less relative to the content of compound (I). Therefore, the content of each impurity contained in the pharmaceutical composition using compound (I) of the present invention is 0.5% or less of the content of compound (I). In the present specification, the purity of compound (I) and the percentage (%) of the content of each impurity refer to area percentages in HPLC, unless otherwise specified.

The total content of each impurity contained in compound (I) of the present invention is 2.0% or less relative to the content of compound (I). Therefore, the total content of each impurity contained in the pharmaceutical composition using compound (I) of the present invention is 2.0% or less with respect to the content of compound (I).

In one of the embodiments of compound (I) of the present invention, the content of compound (IV), compound (X), and compound (XI) is each 0.5% or less with respect to the content of compound (I). and the purity of compound (I) is 98.0% or more. Therefore, one of the embodiments of the pharmaceutical composition using compound (I) of the present invention is the content of compound (IV), compound (X), and compound (XI) relative to the content of compound (I). A pharmaceutical composition comprising compound (I) in an amount of 0.5% or less and a purity of compound (I) of 98.0% or more.

One of the embodiments of compound (I) of the present invention is compound (IV), compound (V), compound (VI), compound (VII), compound (VIII) with respect to the content of compound (I) , compound (IX), compound (X), compound (XI), compound (XII), and compound (XIII) content is each 0.5% or less, and the purity of compound (I) is 98.0% or more A certain compound (I). Therefore, one of the embodiments of the pharmaceutical composition using compound (I) of the present invention is compound (IV), compound (V), compound (VI), compound ( VII), compound (VIII), compound (IX), compound (X), compound (XI), compound (XII), and compound (XIII) content is each 0.5% or less, and compound (I) A pharmaceutical composition containing compound (I) with a purity of 98.0% or more.

Among compounds (IV) to (XIII), which are impurities that can be contained in compound (I) of the present invention (including crystals of compound (I)), compound (IV), Compound (X) and compound (XI) are particularly useful compounds as indicators for producing highly pure compound (I).

Each impurity will be described in detail below.
<Compound (IV)>
In Step 3 of Example 1 described later, compound (IV) is obtained by oxidizing the benzyl position of compound (I).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.50 (3H, d, J = 6.4 Hz), 3.83 (3H, s), 4.90 (1H, q, J = 6.4 Hz), 6.88 (1H, d, J = 5.8Hz), 7.02 - 7.08 (2H, m), 7.09 (1H, dd, J = 4.9, 7.3Hz), 7.33 - 7.42 (2H, m), 7.68 (1H, dd, J = 2.0, 7.4Hz) ), 8.19 (1H, dd, J = 1.9, 5.0 Hz), 8.45 (1H, s), 8.51 (1H, d, J = 5.7 Hz).

<Compound (VII)>
Compound (VII) is obtained by reacting 2-ethylphenol in place of compound (XVI) in the series of reactions in Example 1 described below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.08 (3H, t, J = 7.6 Hz), 2.52 (2H, q, J = 7.6 Hz), 3.86 (3H, s), 6.90 (1H, d, J = 5.7 Hz), 7.01 (1H, dd, J = 1.4, 7.9 Hz), 7.05 (1H, dd, J = 5.0, 7.3 Hz), 7.12 (1H, dd, J = 1.4, 7.4, 7.4 Hz), 7.20 (1H, ddd, J = 1.9, 7.6, 7.7 Hz), 7.23 - 7.29 (1H, m), 7.66 (1H, dd, J = 2.0, 7.3 Hz), 8.16 (1H, dd, J = 1.9, 5.0 Hz), 8.47 (1H, s), 8.52 (1H, d, J = 5.7 Hz).

<Compound (X)>
In Step 2 of Example 1 described later, the by-product obtained by reacting the benzylic position of compound (XVIII) with isopropylmagnesium chloride lithium chloride complex is directly subjected to Step 3 to obtain compound (X).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.76 (3H, d, J = 6.7 Hz), 0.91 (3H, d, J = 6.7 Hz), 1.22 (3H, d, J = 7.0 Hz), 1.74 (1H, dq, J = 6.8, 13.7 Hz), 2.43 (1H, dq, J = 7.2, 13.7 Hz), 3.83 (3H, s), 6.88 (1H, d, J = 5.7 Hz), 6.94 - 7.03 ( 2H, m), 7.08 (1H, dd, J = 5.0, 7.3 Hz), 7.11 - 7.17 (2H, m), 7.67 (1H, dd, J = 2.0, 7.3 Hz), 8.21 (1H, dd, J = 2.0, 5.0 Hz), 8.46 (1H, s), 8.51 (1H, d, J = 5.8 Hz).

<Compound (XI)>
In Step 2 of Example 1 described later, the by-product obtained by reacting the 6-position of compound (XVIII) with isopropylmagnesium chloride lithium chloride complex is directly subjected to Step 3 to obtain compound (XI).
¹ H-NMR(400 MHz, CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.22 (3H, t, J = 7.6 Hz), 2.62 (2H, q, J = 7.6 Hz), 2.93 (1H, hept, J = 6.9 Hz), 3.78 (3H, s), 6.85 (1H, d, J = 5.7 Hz), 6.93 - 7.02 (3H, m), 7.07 - 7.16 (2H, m), 7.59 ( 1H, d, J = 7.5 Hz), 8.43 (1H, s), 8.47 (1H, d, J = 5.8 Hz).

<Compound (XIII)>
It is a by-product in Step 3 of Example 1 below.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.23 (6H, t, J = 7.6 Hz), 2.63 (4H, q, J = 7.6 Hz), 6.92 - 7.01 (4H, m), 7.07 (2H, dd, J = 4.9, 7.4 Hz), 7.12 - 7.20 (4H, m), 7.79 (2H, dd, J = 2.0, 7.4 Hz), 8.18 (2H, dd, J = 1.9, 4.9 Hz).

The present invention provides a pharmaceutical composition using the compound (I) of the present invention (including crystals of compound (I) and highly purified compound (I)) as an active ingredient (hereinafter also referred to as "pharmaceutical composition of the present invention"). say.). The present invention also includes a method for producing a pharmaceutical composition using the compound (I) of the present invention as a raw material (hereinafter also referred to as "a method for producing a pharmaceutical composition of the present invention").
The pharmaceutical composition of the present invention and its production method are described below.

The pharmaceutical composition of the present invention comprises compound (I) of the present invention (including crystals thereof) and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers include liquid or solid pharmaceutical carriers such as excipients, binders, diluents, fillers, disintegrants, stabilizers, preservatives, buffers, emulsifiers, flavoring agents, Colorants, sweeteners, thickening agents, flavoring agents, solubilizers, permeation enhancers, and other additives are included.
Examples of pharmaceutically acceptable carriers include volatile components such as ethanol, isopropanol; Medium-chain fatty acid triglycerides such as (caprylic/capric) glycerides; permeation enhancers such as methyl lactate, ethyl lactate, n-propyl lactate and n-butyl lactate;

Pharmaceutical compositions of the present invention include, for example, tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules, oral liquids, injections, suppositories, sustained-release preparations, lotions, liniments, and ointments. , patches, suspensions, emulsions, percutaneous absorption agents, external liquids, creams, aerosols, and the like.
In addition, other active ingredients may be contained as necessary.

The pharmaceutical compositions of the invention are preferably administered topically. The pharmaceutical composition for topical administration of the present invention is not particularly limited, but includes liquids, lotions, ointments, creams, gels, patches (e.g., tapes, poultices), nail lacquers, and the like. You can choose from a group. The bases for these preparations are not particularly limited as long as they are pharmaceutically acceptable, such as water-soluble bases, oleaginous bases or emulsifiable bases. In addition, the active ingredient may be in a suspended state in the above formulation.
Although the pharmaceutical composition of the present invention is not particularly limited, it is preferably an external application preparation.

The pharmaceutical composition of the present invention is not particularly limited, but is preferably used for the treatment (treatment or prevention) of mycosis, more preferably for the treatment of superficial mycosis, and even more preferably for tinea unguium. Used for treatment.
The pharmaceutical composition of the present invention can be administered orally or parenterally to mammals (eg, humans, monkeys, cows, horses, pigs, dogs, cats, rabbits, guinea pigs, rats, mice, etc.). .

When the pharmaceutical composition of the present invention is administered to the skin and nails as an external application preparation, the content of the compound (I) of the present invention, which is an active ingredient, is, for example, 0.01 w/w% to 30 w/w%, preferably. is 1 w/w% to 30 w/w%, more preferably 1 w/w% to 15 w/w%. In addition, the active ingredient compound (I) of the present invention is generally used in a daily dose of about 1 μg/cm ² to about 100000 μg/cm ² , preferably about 10 μg/cm ² to about 10000 μg/cm ^{2 .} and can be administered once or more a day.

Next, the method for producing the pharmaceutical composition of the present invention will be described.
The method for producing the pharmaceutical composition of the present invention comprises mixing compound (I) of the present invention and a pharmaceutically acceptable carrier. The mixing step can be performed by a conventional method in the technical field.
In one embodiment of the present invention, the pharmaceutical composition of the present invention is an external application preparation. For example, the manufacturing method includes mixing crystals of compound (I) of the present invention, volatile components, medium-chain fatty acid triglycerides, and ethyl lactate. The order of mixing each component is not particularly limited.
In one embodiment of the present invention, the crystals of compound (I) used in the method for producing a pharmaceutical composition of the present invention are preferably Form A, and particularly preferably highly pure Form A.

In the above method for producing the pharmaceutical composition of the present invention, the amount of the compound (I) of the present invention (including its crystals) used as a raw material is as long as the above pharmaceutical composition of the present invention can be produced. Although it is not particularly limited, it is preferably an amount that can produce the following pharmaceutical composition.
The content of compound (I) is 1 w/w% to 30 w/w%, more preferably 1 w/w% to 15 w/w%, even more preferably 5 w/w% to 15 w/w%. , particularly preferably 8 w/w % to 12 w/w %.
The pharmaceutical composition of the present invention, wherein the content of compound (I) is 1 w/w% to 12 w/w%, particularly preferably 2 w/w% to 12 w/w%.

The "volatile component" in the above embodiment is not particularly limited as long as it quickly evaporates at room temperature after applying the drug to human nails, but there is a clinical precedent for external use, Industrially available, odorless and nonirritating are preferred. Preferred are straight-chain or branched-chain lower alkyl alcohols having 1 to 4 carbon atoms such as ethanol and isopropanol, and more preferred is ethanol.
If ethanol is used as the "volatile component", absolute ethanol is more preferred.

The content of the "volatile component" is not particularly limited as long as it dissolves the compound (I) of the present invention (including its crystals) and other additives, but 35 w / w% to 85 w / w% It is preferably 35 w/w% to 65 w/w%, particularly preferably 45 w/w% to 65 w/w%.
In another aspect of the present invention, the content of the "volatile component" is preferably 35w/w% to 75w/w%, particularly preferably 45w/w% to 75w/w%.

The “medium-chain fatty acid triglyceride” in the above embodiment refers to a non-volatile component in which 3 molecules of fatty acid are ester-bonded to 1 molecule of glycerol, and the fatty acid is a saturated fatty acid having 6 to 14 carbon atoms. Fatty acids preferably have 8 to 12 carbon atoms, and for example, caprylic acid, capric acid, lauric acid and the like are selected. For example, Miglyol (registered trademark) 810 and 812 can be used.
Particularly preferred "medium chain fatty acid triglycerides" are tri(caprylic/capric) glycerides.

The content of medium-chain fatty acid triglycerides is not particularly limited, but is preferably 1 w/w% to 30 w/w%, more preferably 5 w/w% to 22 w/w%, and even more preferably 10 w/w%. to 22w/w%. A particularly preferred content is 18 w/w% to 22 w/w%, and an optimum content is about 20 w/w%.

"Ethyl lactate" in the above embodiment is ethyl ester of lactic acid. Lactic acid includes L-lactic acid, D-lactic acid or DL-lactic acid. A preferred ethyl lactate is the ethyl ester of DL-lactic acid.

The content of ethyl lactate is preferably 1 w/w% to 30 w/w%, more preferably 5 w/w% to 22 w/w%, and even more preferably 10 w/w% to 22 w/w%. . Especially preferred is 18w/w% to 22w/w%, and the optimum content is about 20w/w%.

In the above embodiments, sodium edetate hydrate and water may be included as long as the stability of the formulation can be guaranteed. For example, it may contain sodium edetate hydrate in an amount of about 0.00025 w/w% and water in an amount of about 1 w/w%.

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

For each crystal form in this specification, the characteristic diffraction angle by powder X-ray diffraction, the characteristic endothermic peak by DSC measurement, and the characteristic absorption band by IR measurement may vary depending on the measurement conditions. Therefore, errors may occur in the measured values of each crystal form in this specification.

Example 1 <Production method (1) of Form A of compound (I)>
Compound (I) was produced according to the following scheme.

Step 1
3-bromo-2-chloropyridine (XVII) (110.11 g, 572.21 mmol), 4-ethylphenol (XVI) (104.85 g, 858.30 mmol), dimethyl sulfoxide (572 mL) and potassium hydroxide (44.92 g, 800.58 mmol) ) and stirred at about 90° C. for 3 hours under a nitrogen gas stream. Cool to 30°C, add 1 mol/L sodium hydroxide solution [sodium hydroxide (22.94 g, 573.5 mmol) dissolved in water (572 mL)] and n-heptane (572 mL) and stir for 30 minutes. . The organic layer was separated, washed successively with water (twice) and sodium chloride solution, magnesium sulfate was added and stirred for 1 hour. Insolubles and magnesium sulfate were filtered, washed with n-heptane (22 mL), and compound (XVIII) (content: 148.72 g, yield: 93%, chemical purity: 97.72%) was obtained as pale yellow n-heptane. obtained as a solution.

Step 2
After decompressing the inside of the reaction vessel and purging with nitrogen gas, an isopropylmagnesium chloride lithium chloride complex tetrahydrofuran solution (1.3 mol/L, 800 mL, 1040 mmol) was added, and the solution was stirred at 10°C under nitrogen gas ventilation. An n-heptane solution of compound (XVIII) (content: 144.53 g, 519.63 mmol) was prepared in a separate vessel and added dropwise to the reaction vessel at 15±5° C. over 20 minutes. After washing the vessel with n-heptane (29 mL) and adding the washings to the reaction mixture, the reaction mixture was stirred at about 15°C for 1 hour and 45 minutes. After cooling the reaction solution to 0°C, trimethyl borate (81 mL, 724.95 mmol) was added dropwise over 1 hour and 40 minutes so that the temperature of the reaction solution did not exceed 5°C. The vessel was washed with n-heptane (14 mL), the washings were added to the reaction solution, and the reaction solution was stirred at 5°C or lower for 30 minutes. The reaction solution was added dropwise to about 2 mol/L hydrochloric acid (378 mL) over 30 minutes so as not to exceed 30°C. The vessel was washed with tetrahydrofuran (145 mL) and about 2 mol/L hydrochloric acid (200 mL), the washings were added to the reaction mixture, and the reaction mixture was stirred at 10°C to 30°C for 10 minutes. The organic layer was separated and washed with an aqueous sodium chloride solution. The obtained organic layer was concentrated under reduced pressure until the liquid volume became about 600 mL. Methanol (72 mL) was added, and the organic layer was concentrated under reduced pressure until the liquid volume was about 180 mL. Methanol (137 mL) was added again, and the organic layer was concentrated under reduced pressure until the liquid volume reached about 180 mL. Methanol (145 mL) was added to the obtained concentrate to obtain compound (II) (content: 116.68 g, yield: 92%, chemical purity: 96.17%) as a yellow methanol solution.

Step 3
3-bromo-4-methoxypyridine (III) (94.29 g, 501.49 mmol) and methanol (190 mL) were added to a methanol solution of compound (II) (content: 116.01 g, 477.27 mmol) and cooled to below 5°C. bottom. Potassium hydroxide (40.19 g, 716.27 mmol) was added so that the temperature of the reaction solution did not exceed 25°C, and then the inside of the reaction vessel was degassed under reduced pressure and replaced with nitrogen gas. Triphenylphosphine (6.27 g, 23.90 mmol) and palladium acetate (2.14 g, 9.53 mmol) were added at 25°C, and the reaction was stirred at 65°C for 3 hours under a stream of nitrogen gas. Cool the reaction solution to below 40°C and add 2.0 mol/L sodium hydroxide solution [sodium hydroxide (46.42 g, 1.16 mol) dissolved in water (534 mL)] until the liquid volume is about 500 mL. It was concentrated under reduced pressure to . Ice-cooled isopropyl acetate (464 mL) was added to dilute the obtained concentrate. Water (290 mL) and isopropyl acetate (696 mL) were added, the mixture was stirred at 20°C or lower for 30 minutes, and then the organic layer was separated. Activated carbon (11.64 g) and isopropyl acetate (116 mL) were added to the organic layer, and after stirring at about 20°C for 1 hour, the activated carbon was removed through celite and washed with isopropyl acetate (464 mL). After adding N-acetyl-L-cysteine (3 g) to the organic layer and stirring the organic layer at about 50° C. for about 1 hour, an aqueous potassium hydrogen carbonate solution was added. The mixture was stirred at 50°C for about 1 hour, and the organic layer was separated. After repeating the above operation twice, a potassium hydrogen carbonate solution [potassium hydrogen carbonate (12 g) dissolved in water (568 mL)] was added to the organic layer, and the mixture was stirred at 30°C for 1 hour. The organic layer was separated to obtain crude compound (I) (content: 132.68 g, yield: 91%, chemical purity: 93.97%) as a slightly yellow isopropyl acetate solution.

Step 4
An isopropyl acetate solution of crude compound (I) (content: 130.00 g, 424.34 mmol) was diluted with isopropyl acetate (1063 mL) and stirred at 25°C under nitrogen gas flow. p-Toluenesulfonic acid monohydrate (84.80 g, 445.80 mmol) was added and the reaction was stirred for 10 minutes, then seed crystals of compound (XIX) (0.13 g) were added and stirred at 25°C for 4 hours. . The solid was collected by filtration and washed with isopropyl acetate (650 mL). Isopropyl acetate (1300 mL) was added to the resulting solid, and the mixture was stirred at 25° C. for 2 hours. The solid was collected by filtration, washed with isopropyl acetate (650 mL), dried under reduced pressure at 40°C for 18 hours, and compound (XIX) [yield: 195.38 g, yield: 96%, chemical purity: 99.41% Numerical value excluding the sulfonic acid peak)] was obtained as a white powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.24 (3H, t, J = 7.6 Hz), 2.34 (3H, s), 2.65 (2H, q, J = 7.6 Hz), 4.07 (3H, s) , 6.92 - 7.01 (2H, m), 7.10 (1H, dd, J = 5.0, 7.4 Hz), 7.14 - 7.24 (4H, m), 7.51 (1H, d, J = 6.9 Hz), 7.68 (1H, dd , J = 1.9, 7.4 Hz), 7.79 - 7.86 (2H, m), 8.25 (1H, dd, J = 1.9, 5.0 Hz), 8.67 (1H, d, J = 1.1 Hz), 8.98 (1H, dd, J = 1.2, 6.8Hz).

Step 5
Compound (XIX) (175.00 g, 365.68 mmol) and ethyl acetate (1225 mL) were mixed and stirred at about 20°C. A potassium bicarbonate solution [potassium bicarbonate (40.27 g) dissolved in water (525 mL)] was added, the mixture was stirred for 30 minutes, and the organic layer was separated. The organic layer was washed with water (525 mL), activated carbon (11.26 g) and ethyl acetate (88 mL) were added to the obtained organic layer, and the mixture was stirred at about 20°C for about 1 hour. Activated carbon was removed through celite, washed twice with ethyl acetate (200 mL, 150 mL), and then the organic layer was concentrated under reduced pressure until the liquid volume was about 180 mL. 2-Propanol (175 mL) was added, and the organic layer was concentrated under reduced pressure until the liquid volume was about 180 mL. 2-Propanol (175 mL) was added again, and the organic layer was concentrated under reduced pressure until the liquid volume reached about 180 mL. 2-Propanol (123 mL) was added to obtain a concentrated solution of compound (I) (content: 108.29 g (LC quantitative value)). 2-Propanol (183 mL) and water (650 mL) were added to the concentrated solution of compound (I) and cooled to 5°C. Seed crystals of compound (I) (Form A: 0.11 g) were added, the mixture was stirred at about 0°C, and after crystal precipitation was confirmed, the mixture was stirred for 1 hour. After adding water (120 mL) dropwise over about 3 hours, the mixture was stirred for an additional 3 hours. The precipitate is collected by filtration, washed with an ice-cold 2-propanol solution [prepared from 2-propanol (63 mL) and water (112 mL)], and dried under reduced pressure at 40°C for 25 hours to obtain crystals of compound (I). (Yield: 100.98 g, Yield: 90%, Chemical Purity: 99.71%) was obtained as a white powder (Form A).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.23 (3H, t, J = 7.6 Hz), 2.64 (2H, q, J = 7.6 Hz), 3.84 (3H, s), 6.88 (1H, d, J = 5.7Hz), 6.95 - 7.04 (2H, m), 7.07 (1H, dd, J = 5.0, 7.3Hz), 7.14 - 7.23 (2H, m), 7.67 (1H, dd, J = 1.9, 7.3Hz) ), 8.19 (1H, dd, J = 1.9, 4.9 Hz), 8.46 (1H, s), 8.51 (1H, d, J = 5.8 Hz).

Example 2 <Another production method (2) of Form A of compound (I)>
Compound (XIX) (7.82 g, 16.34 mmol), potassium hydrogen carbonate (1.80 g, 17.98 mmol), ethyl acetate (55 mL) and water (24 mL) were mixed, stirred at about 25°C for 30 minutes, and the organic layer was was fractionated. The organic layer was washed with water (24 mL), activated carbon (0.5 g) was added to the obtained organic layer, and the mixture was stirred at about 25°C for 2 hours. Activated carbon was removed through celite, washed with ethyl acetate (15 mL), and the organic layer was concentrated under reduced pressure. The concentrate was dissolved in 2-propanol (5 mL), cooled to 5°C or below, n-heptane (45 mL) was added, and the mixture was stirred at 5°C or below for about 3 hours. The precipitate was collected by filtration, washed with n-heptane (10 mL), and dried under reduced pressure at 40°C for about 25 hours to obtain crystals of compound (I) (yield: 4.09 g, yield: 81.9%, chemical purity: 99.56 %) was obtained as a white powder (Form A).

Example 3 <Another Production Method (3) of Form A of Compound (I)>
Compound (I) was produced by following the scheme below instead of Step 4 and Step 5 of Example 1.

Step 4'
The isopropyl acetate solution of crude compound (I) obtained in Step 3 of Example 1 (compound (I) content: 6.82 g, 22.26 mmol) was diluted with isopropyl acetate (50 mL) and stirred at 25°C. Phthalic acid (3.93 g, 23.66 mmol) was added and the mixture was stirred at 25° C. for 6 hours and 30 minutes. The solid was collected by filtration, washed with isopropyl acetate (20 mL), dried under reduced pressure at 40°C for about 17 hours, and crystals of phthalate (XX) of compound (I) [yield: 10.13 g, yield: 96.3% , chemical purity: 98.53% (the value excluding the phthalic acid peak)] was obtained as a white powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.18 (3H, t, J = 7.5 Hz), 2.59 (2H, q, J = 7.6 Hz), 3.85 (3H, s), 6.92 - 7.00 ( 2H, m), 7.21 (4H, dd, J = 5.0, 7.2 Hz), 7.58 (2H, dd, J = 3.3, 5.7 Hz), 7.71 (2H, dd, J = 3.3, 5.7 Hz), 7.82 (1H , dd, J = 1.9, 7.4 Hz), 8.13 (1H, dd, J = 2.0, 5.0 Hz), 8.45 (1H, s), 8.52 (1H, d, J = 5.8 Hz), 13.49 (2H, s) .

Step 5'
Compound (XX) (7.83 g, 16.57 mmol), potassium hydrogen carbonate (3.67 g, 36.66 mmol), ethyl acetate (55 mL) and water (50 mL) are mixed, stirred at about 25°C for 30 minutes, and the organic layer is was fractionated. The organic layer was washed with water (25 mL), activated carbon (0.5 g) was added to the obtained organic layer, and the mixture was stirred at about 25°C for 1 hour. Activated carbon was removed through celite and the organic layer was washed with ethyl acetate (15 mL). The organic layer was concentrated under reduced pressure and diluted with 2-propanol (8 mL) to obtain a solution of compound (I) (content of compound (I): 5.03 g (LC quantitative value)). 2-Propanol (11.4 mL) and water (30.2 mL) were added to the solution of compound (I) and stirred at 0°C. Seed crystals of compound (I) (Form A: 5 mg) were added and the mixture was stirred at about 0° C. for 1 hour. After adding water (5.58 mL) dropwise over 3 hours, the mixture was stirred for about 3 hours. The precipitate is collected by filtration, washed with ice-cooled 2-propanol solution [prepared from 2-propanol (2.8 mL) and water (5.0 mL)], and dried under reduced pressure at 40°C for 16 hours to obtain crystals of compound (I). (Yield: 4.57 g, Yield: 90.0%, Chemical Purity: 99.44%) was obtained as a white solid (Form A).

Example 4 <Another Production Method (4) of Form A of Compound (I)>
Compound (I) was produced according to the following scheme.

Step 1
Compound (II) (15.00 g, 61.69 mmol) and 3-bromo-4-methoxypyridine (III) (12.19 g, 64.30 mmol) were dissolved in 2-propanol (150 mL). Stir for a minute. Tripotassium phosphate (39.33 g, 185.28 mmol), tri(p-tolyl)phosphine (1.88 g, 6.19 mmol) and nickel nitrate hexahydrate (0.91 g, 3.12 mmol) were added and the temperature was raised to 70°C. The reaction was stirred for 3 hours. The reaction solution was cooled to 20°C, water (75 mL) was added, and the mixture was stirred at 25°C for 10 minutes, and then the organic layer was separated. The organic layer was concentrated under reduced pressure, isopropyl acetate (150 mL) and aqueous ammonia [prepared from 28% aqueous ammonia (5 mL) and water (70 mL)] were added, the mixture was stirred at 25°C for 10 minutes, and then the organic The layers were separated. Furthermore, aqueous ammonia [prepared from 28% aqueous ammonia (5 mL) and water (70 mL)] was added to the organic layer, and the mixture was stirred at 25°C for 10 minutes, and then the organic layer was separated. After water (75 mL) was added to the organic layer and the mixture was stirred at 25°C for 10 minutes, the organic layer was separated. Activated carbon (1.51 g) was added to the organic layer, and the organic layer was stirred at 25°C for 1 hour. The activated carbon was removed through celite, washed with isopropyl acetate (50 mL), and crude compound (I) (compound (I) content: 14.54 g, yield: 77%, chemical purity: 83.59%) was obtained as a slightly yellow isopropyl acetate solution.

Step 2
An isopropyl acetate solution of the crude compound (I) (content of compound (I): 7.08 g, 23.11 mmol) was diluted with isopropyl acetate (40 mL) to give p-toluenesulfonic acid monohydrate (4.61 g, 24.23 mmol). ) was added and stirred at 25°C for about 4 hours. The solid was collected by filtration and washed with isopropyl acetate (30 mL). Isopropyl acetate (70 mL) was added to the resulting solid and the mixture was stirred at 25° C. for 2 hours. The solid was collected by filtration, washed with isopropyl acetate (30 mL), and dried under reduced pressure at 40°C for 15 hours. Numeric value excluding the peak of p-toluenesulfonic acid)] was obtained as a white powder.

Step 3
Compound (XIX) (7.85 g, 16.40 mmol), potassium hydrogen carbonate (1.82 g, 18.18 mmol), ethyl acetate (55 mL) and water (25 mL) were mixed, stirred at about 25°C for 30 minutes, and the organic layer was was fractionated. The organic layer was washed with water (25 mL), activated carbon (0.5 g) was added to the obtained organic layer, and the mixture was stirred at about 25°C for 1 hour. Activated charcoal was removed through celite and washed with ethyl acetate (15 mL). The organic layer was concentrated under reduced pressure to obtain a concentrate of compound (I) (content of compound (I): 4.88 g). 2-Propanol (11.3 mL) and water (29 mL) were added to the concentrated solution of compound (I), and the mixture was stirred at 0°C. Seed crystals of compound (I) (Form A: 5.3 mg) were added and the mixture was stirred at about 0° C. for 1 hour. After adding water (5.42 mL) dropwise over 3 hours, the mixture was stirred for 2 hours. The precipitate was collected by filtration, washed with ice-cooled 2-propanol solution [prepared from 2-propanol (2.8 mL) and water (5.0 mL)], and dried under reduced pressure at 40°C for 16.5 hours to obtain crystals of compound (I). (Yield: 4.13 g, Yield: 82.1%, Chemical purity: 99.48%) was obtained as a white solid (Form A).

Example 5 <Another Production Method (5) of Form A of Compound (I)>
Compound (I) was produced by performing Step 2' and Step 3' below instead of Step 2 and Step 3 of Example 4 using crude compound (I).

Step 2'
The isopropyl acetate solution of crude compound (I) obtained in Step 1 of Example 4 (compound (I) content: 7.44 g, 24.29 mmol) was diluted with isopropyl acetate (43 mL) and stirred at 25°C. . Phthalic acid (4.22 g, 25.40 mmol) was added and the mixture was stirred at 25° C. for 6 hours. The solid was collected by filtration and washed with isopropyl acetate (30 mL). Isopropyl acetate (70 mL) was added to the resulting solid and the mixture was stirred at 25° C. for 2 hours. The solid was collected by filtration, washed with isopropyl acetate (30 mL), and dried under reduced pressure at 40°C for 10 hours. , chemical purity: 98.64% (the value excluding the phthalic acid peak)] was obtained as a white powder.

Step 3'
Compound (XX) (7.85 g, 16.61 mmol), potassium hydrogen carbonate (3.68 g, 36.76 mmol), ethyl acetate (55 mL) and water (50 mL) were mixed, stirred at about 25°C for 30 minutes, and the organic layer was was fractionated. The organic layer was washed with water (25 mL), activated carbon (0.5 g) was added to the obtained organic layer, and the mixture was stirred at about 25°C for 1 hour. Activated charcoal was removed through celite and washed with ethyl acetate (15 mL). The organic layer was concentrated under reduced pressure and diluted with 2-propanol (8 mL) to obtain a solution of compound (I) (content of compound (I): 4.81 g). 2-Propanol (11.1 mL) and water (29 mL) were added to the solution of compound (I) and the mixture was stirred at 0°C. Seed crystals of compound (I) (Form A: 5.7 mg) were added and the mixture was stirred at about 0° C. for 1 hour. After adding water (5.34 mL) dropwise over 3 hours, the mixture was stirred for 2 hours. The precipitate was collected by filtration, washed with an ice-cooled 2-propanol solution [prepared from 2-propanol (2.8 mL) and water (5.0 mL)], and dried under reduced pressure at 40°C for 17 hours to obtain crystals of compound (I). (Yield: 4.25 g, Yield: 83.5%, Chemical Purity: 99.48%) was obtained as a white solid (Form A).

Example 6 <Production method (1) of Form C of compound (I)>
MTBE (550 mL) was added to compound (I) (100.09 g) and dissolved at 50°C. The mixture was stirred at 30°C for 1 hour, seed crystals of compound (I) (Form C: 180 mg) were added, and the mixture was further stirred to confirm the precipitation of crystals. The mixture was stirred at 30° C. for 112 hours in order to allow the MTBE to evaporate spontaneously. The residue was concentrated under reduced pressure at 30°C, and the obtained concentrated residue was dried under reduced pressure at 40°C for 12 hours to obtain compound (I) as a white solid. A 33 vol% IPA water mixed solvent (1000 mL) was added to the resulting compound (I), the mixture was stirred at 5°C for 5 hours, and then filtered. mL). The obtained solid was dried under reduced pressure at 40° C. for 12 hours to obtain a crystal of compound (I) (yield: 92.62 g, yield: 93%, chemical purity: 99.5%) as a white solid (Form C).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.23 (3H, t, J = 7.6 Hz), 2.64 (2H, q, J = 7.6 Hz), 3.84 (3H, s), 6.88 (1H, d, J = 5.7 Hz), 6.98 - 7.01 (2H, m,), 7.07 (1H, dd, J = 5.0 Hz, 7.3 Hz), 7.17 - 7.20 (2H, m), 7.67 (1H, dd, J = 2.0 Hz) , 7.3 Hz), 8.19 (1H, dd, J = 2.0 Hz, 5.0 Hz), 8.46 (1H, s), 8.51 (1H, d, J = 5.8 Hz).

Reference Example <Preparation of compound (XIII)>
Methanol solution of compound (II) (content 11.80 g, 48.546 mmol), compound (XVIII) (13.51 g, 48.573 mmol) and triphenylphosphine (0.5121 g, 1.925 mmol) were dissolved in methanol (38 mL) and decompressed under reduced pressure. After aeration, argon gas was passed through. Palladium acetate (0.219 g, 0.975 mmol) and potassium hydroxide (4.58 g, 90 wt%, 81.631 mmol) were added and the mixture was stirred at 70°C for 1.5 hours. A 2 mol/L sodium hydroxide solution (50 mL) was added to stop the reaction, and the reaction mixture was concentrated under reduced pressure. The concentrated residue was extracted with ethyl acetate (100 mL×2), filtered through celite to remove insolubles, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 12.16 g of solid. The resulting solid was suspended in n-hexane (60 mL), stirred at 70°C for 1 hour, and then stirred at room temperature for 3 hours while allowing to cool naturally. The resulting crystals were collected by filtration, washed with n-hexane (30 mL), dried under reduced pressure at 40°C overnight, and compound (XIII) (yield: 11.06 g, yield: 57%, chemical purity: 98.75 %) was obtained as white crystals.

Test Example 1 <Form A Purity Test (Related Substances)>
The purity of Form A obtained in Examples 1-5 above was measured using high performance liquid chromatography (HPLC) under the following conditions.

1) Analysis conditions Detector: UV spectrophotometer (measurement wavelength: 273 nm)
Column: Xselect® CSH ^TM C ₁₈ (inner diameter 4.6 mm, length 150 mm, grain size 3.5 μm)
Column temperature: Constant temperature around 40°C Flow rate: 1.0 mL/min
Injection volume: 10 μL
Mobile phase A: water/trifluoroacetic acid mixture (1000:1)
Mobile phase B: acetonitrile/trifluoroacetic acid mixture (1000:1)
Transfer of mobile phase: The concentration gradient was controlled by changing the mixing ratio of mobile phases A and B as follows.

2) Preparation of sample solution Approximately 10 mg of each sample was weighed, dissolved by adding a methanol solution of acetic acid (0.1 v/v%) to make exactly 10 mL, and used as a sample solution.

The retention times of compound (I) and each impurity when measured by the above analytical method, and the content of compound (I) and each impurity in Examples 1 to 5 were as follows (HPLC area percentage).

From these results, it was clarified that compound (I) produced in this example was of extremely high purity and had an appropriate profile as a drug substance for pharmaceuticals.

Test Example 2 <Powder X-ray diffraction pattern analysis of Form A and Form C>
About 0.1 g of each sample was loaded into a glass sample plate. This sample plate was attached to a standard sample holder, and a diffraction pattern was measured under the following conditions with a powder X-ray diffraction measurement device (Rigaku: RINT2200Ultima II/PC). Separately, an angular standard silicon powder was measured.

Figure 1 is the Form A diffraction pattern of compound (I), and Figure 2 is its peak table. The characteristic diffraction angles are shown in the table below.

Figure 3 is the Form C diffraction pattern of compound (I), and Figure 4 is its peak table. The characteristic diffraction angles are shown in the table below.

Test Example 3 <Infrared absorption spectrum (IR) measurement of Form A and Form C>
Each sample was analyzed according to the potassium bromide tablet method of infrared absorption spectrometry of the Japanese Pharmacopoeia (18th revision).

(1) Preparation of measurement sample Potassium bromide for IR was ground in an agate bowl to obtain a powder. An appropriate amount of powdered potassium bromide was weighed out, and a sample of about 2 wt% of potassium bromide was weighed out, added to the potassium bromide and ground in an agate bowl. The mixture was used to make potassium bromide tablets.
(2) Measurement method Using a Fourier transform infrared spectrophotometer (FTIR-8400), Compound (I) Form A, Form C, PTSA salt (compound (XIX)), and phthalate (compound (XX) ) was measured (Figs. 5 to 10).

Figure 5 is the Form A IR chart of compound (I), and Figure 6 is its peak table. Characteristic peaks are shown in the table below.

Figure 7 is the Form C IR chart of compound (I), and Figure 8 is its peak table. Characteristic peaks are shown in the table below.

Test Example 4 <Thermal Analysis (DSC) of Form A and Form C>
A sample was prepared by weighing an appropriate amount of this product into an aluminum autosampler sample container. The test substances are Form A, Form C, PTSA salt (compound (XIX)), and phthalate (compound (XX)) of compound (I). Using a thermal analysis system, measurements were made under a nitrogen stream (50 mL or 30 mL/min) at a heating rate of 2° C./min in the range of 30° C. to 100° C. (FIGS. 11 to 14). α-Alumina was used as a reference material.
Some of the results are shown in the table below.

From the DSC results, it was found that the stable form in the one-component system is Form A. However, the difference in the endothermic peak from Form C is slight, and it is not possible to predict which form will be the stable form when crystallized from a solution (multicomponent system).

Test Example 5 <Saturated solubility of Form A and Form C>
In a certain solution, at a given concentration and temperature, the less soluble crystal is the thermodynamically stable crystal form. Therefore, the stable form of a single-component system determined by DSC may differ from the stable form in solution (the stable form of a multi-component system). Therefore, it was investigated whether Form A of compound (I) produced in Example 1 is stable even in a mixed solvent of 2-propanol and water (IPA water mixed solvent).

(1) Add about 1 g of Form A or Form C of compound (I) to about 10 mL of a 36 vol% or 40 vol% IPA water mixed solvent and suspend it at a temperature of 5 ° C, 9 ° C, 14 ° C, 20 and 25°C respectively and stirred for 3 hours.
(2) After standing still, remove the supernatant, set the rotation speed to 2000 rpm in a centrifuge and centrifuge for 1 minute, then collect the supernatant (sample) and determine the content of compound (I) in the solution. amount was measured.
(3) Saturated solubility (g/g)* at each temperature was calculated from the content of compound (I).
*: Solubility (g/g) = content (mg) / (sample amount (mg) - content (mg))

Saturated solubility (g/g) of each crystal system in 36 vol% IPA water mixed solvent

Saturated solubility (g/g) of each crystal system in 40vol% IPA water mixed solvent

From the endothermic peak of DSC, it was not possible to predict which of Form A and Form C is more stable in a multi-component system containing a solvent, but the solubility of each crystal form in each IPA water mixed solvent was Form C was found to be lower in temperature than Form A. This indicates that Form C is stable in the IPA-water mixed solvent. Therefore, if compound (I) is crystallized from a solution of IPA water mixed solvent, Form C, which is a stable form, can be preferentially obtained, or even if Form A is generated in the system, Form C was expected to migrate to

Test Example 6 <Effect of stirring temperature and time on production of crystals of compound (I)>
About 1.0 g of Compound (I) Form A was weighed, 10 mL each of 36 vol% and 40 vol% IPA water mixed solvent was added and suspended, and about 1 mg of Form C seed crystals was added. The mixture was stirred at 5°C, 10°C, 15°C, 20°C and 25°C for 7 days, and a small amount was sampled every 24 hours to confirm the presence or absence of transition to Form C. Crystal determination was performed by DSC. The DSC measurement conditions are the same as in Test Example 4.

Results of temperature effect (when suspended in 36 vol% IPA water mixed solvent)

Results of temperature effect (when suspended in 40 vol% IPA water mixed solvent)

Surprisingly, despite the addition of Form C seed crystals, in 36 vol% IPA water mixture, 2 days at 25 °C, 4 days at 20 °C, 15 °C, 10 °C and 5 °C. Form A was maintained through day 7. Form A was maintained in a 40 vol% IPA water mixed solvent until day 2 at 25°C, day 3 at 20°C, day 4 at 15°C, and day 7 at 10°C and 5°C.
It was thought that Form A would quickly transition to Form C, which is a stable form in an IPA water mixed solvent, but 20 ° C. or less, preferably 15 ° C. or less, more preferably 10 ° C. or less, and even more preferably 8 The transition from Form A to Form C is suppressed under conditions from below ℃ to -5℃ or above, and the transition from Form A to Form C occurs with stirring for about 1 to 2 days regardless of the temperature. It became clear that no.
From the above results, it was found that even if Form A of compound (I) was generated in the IPA water mixed solvent, it would not transition to Form C under the above conditions.

Test Example 7 <Investigation of bulk density and tap density>
Bulk density and tapped density were investigated using Form A and Form C of compound (I). For bulk density, Compound (I) was gently added to a graduated cylinder (100 mL) and weighed when the volume reached 50 mL. As for the tap density, the volume was read by tapping 10 times, 20 times, 30 times, 40 times, and 50 times. However, since there was a case in which volume fluctuation was observed even after tapping 50 times, tapping was continued by tapping 80, 100, and 130 times until the volume fluctuation disappeared.
The results are shown in the table below.

The bulk density of Form C was 0.105 g/mL, while that of Form A was 0.320 g/mL, about three times that of Form C.
As for the tap density, Form C was 0.188 g/mL, while Form A had a tap density of 0.533 g/mL, about three times that of Form C.
From the above results, both Form A and Form C are crystals that can be used for commercial production, but Form A has higher bulk density and tap density than Form C, and is more suitable for commercial production. It became clear.

Example 7 <Production of external application preparation>
Medium-chain fatty acid triglycerides (200 g), ethyl lactate (200 g), and anhydrous ethanol (500 g) were stirred and mixed. Form A (100 g) of compound (I) was added thereto and dissolved with stirring to obtain an external application formulation (liquid formulation).

The compound (I) of the present invention (for example, Form A crystals) is physicochemically stable and has a suitable profile as a drug substance for pharmaceuticals.
Moreover, by applying the production method of the present invention, it is possible to produce compound (I) with high purity on a simple and industrial scale.

This application is based on Japanese Patent Application No. 2021-139132 (filing date: August 27, 2021) filed in Japan, the contents of which are hereby incorporated by reference.

Claims (24)

1. Formula (I):
   

   

   A crystal of compound (I) represented by
2. In the powder X-ray diffraction spectrum, the diffraction angle represented by 2θ has peaks at 8.8 ± 0.2 °, 11.4 ± 0.2 °, 13.7 ± 0.2 °, 16.6 ± 0.2 ° and 17.5 ± 0.2 °, Crystal according to claim 1 (Form A).
3. In the powder X-ray diffraction spectrum, the diffraction angle represented by 2θ has peaks at 7.5 ± 0.2 °, 10.3 ± 0.2 °, 10.8 ± 0.2 °, 15.5 ± 0.2 ° and 19.8 ± 0.2 °, Crystal according to claim 1 (Form C).
4. The purity of compound (I) is 98.0% or more, and the content of compound (I) is represented by the following formula (IV):
   

   

   4. The crystal according to any one of claims 1 to 3, wherein the content of compound (IV) represented by is 0.5% or less.
5. The purity of compound (I) is 98.0% or more, and the content of compound (I) is represented by the following formula (V):
   

   

   5. The crystal according to any one of claims 1 to 4, wherein the content of compound (V) represented by is 0.5% or less.
6. The purity of compound (I) is 98.0% or more, and the content of compound (I) is represented by the following formula (VI):
   

   

   6. The crystal according to any one of claims 1 to 5, wherein the content of compound (VI) represented by is 0.5% or less.
7. The purity of compound (I) is 98.0% or more, and the content of compound (I) is represented by the following formula (VII):
   

   

   7. The crystal according to any one of claims 1 to 6, wherein the content of compound (VII) represented by is 0.5% or less.
8. The purity of compound (I) is 98.0% or more, and the content of compound (I) is represented by the following formula (VIII):
   

   

   8. The crystal according to any one of claims 1 to 7, wherein the content of compound (VIII) represented by is 0.5% or less.
9. The purity of compound (I) is 98.0% or more, and the content of compound (I) is represented by the following formula (IX):
   

   

   9. The crystal according to any one of claims 1 to 8, wherein the content of compound (IX) represented by is 0.5% or less.
10. The purity of compound (I) is 98.0% or more, and the content of compound (I) is represented by the following formula (X):
    

    

    10. The crystal according to any one of claims 1 to 9, wherein the content of compound (X) represented by is 0.5% or less.
11. The purity of compound (I) is 98.0% or more, and the content of compound (I) is represented by the following formula (XI):
    

    

    11. The crystal according to any one of claims 1 to 10, wherein the content of compound (XI) represented by is 0.5% or less.
12. The purity of compound (I) is 98.0% or more, and the content of compound (I) is represented by the following formula (XII):
    

    

    12. The crystal according to any one of claims 1 to 11, wherein the content of compound (XII) represented by is 0.5% or less.
13. The purity of compound (I) is 98.0% or more, and the content of compound (I) is represented by the following formula (XIII):
    

    

    13. The crystal according to any one of claims 1 to 12, wherein the content of compound (XIII) represented by is 0.5% or less.
14. 14. A method for producing crystals of compound (I) according to any one of claims 1 to 13, comprising the following steps:
    Step D: Using compound (I) and a solvent containing 2-propanol, preparing a suspension of compound (I), stirring, and then filtering;
    Manufacturing method including.
15. High purity formula (I):
    

    

    A method for producing a compound (I) represented by the following steps:
    Step B: (i) Compound (I), (ii) a solvent, and (iii) p-toluenesulfonic acid (PTSA), PTSA hydrate, phthalic acid, or phthalic acid hydrate are mixed. , precipitating the PTSA salt or phthalate of compound (I) and then filtering;
    Step C: a step of neutralizing the PTSA salt or phthalate of compound (I) and extracting compound (I) with an organic solvent;
    Step D': A step of preparing a suspension of compound (I) using the compound (I) obtained in step C and a solvent containing 2-propanol, stirring, and then filtering;
    Manufacturing method including.
16. Formula (I):
    

    

    A method for producing a compound (I) represented by the following steps:
    Process A: Formula below:
    

    

    (wherein R ₁ is B(OH) ₂ , B(OMe) ₂ , B(OEt) ₂ , B(Oi-Pr) ₂ , BF ₃ K, and
    The formula below:
    

    

    Any one selected from the group consisting of A wavy line drawn across lines in the structural formula indicates the position at which each group is attached to the pyridine ring in formula (XIV). ) and the following formula
    

    

    Compound (XV) represented by (wherein X is selected from the group consisting of an iodine atom, a bromine atom, a chlorine atom, a fluorine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group is any one.) to obtain compound (I),
    Step B′: (i) the compound (I) obtained in step A, (ii) a solvent, and (iii) PTSA, PTSA hydrate, phthalic acid, or phthalic acid hydrate are mixed. and precipitating the PTSA salt or phthalate of compound (I), followed by filtering;
    Step C: a step of neutralizing the PTSA salt or phthalate of compound (I) and extracting compound (I) with an organic solvent;
    Step D': A step of preparing a suspension of compound (I) using the compound (I) obtained in step C and a solvent containing 2-propanol, stirring, and then filtering;
    Manufacturing method including.
17. Formula (I):
    

    

    A method for producing a compound (I) represented by the following steps:
    Process A: Formula below:
    

    

    The compound (XIV) represented by (wherein R ₁ is the same as in claim 16) and the following formula
    

    

    A step of reacting compound (XV) represented by (wherein X is the same as in claim 16) to obtain compound (I),
    Manufacturing method including.
18. A method for producing compound (I),
    The concentration of 2-propanol in the solvent in the suspension of step D (including step D') is from 20 vol% to 45 vol%,
    And any one of (a) to (c) is satisfied {(a) the stirring time is within 2 days.
    (b) The stirring time is 3 days or less, and the temperature of the suspension during stirring is 20°C or less.
    (c) The temperature of the suspension during stirring is 10°C or less. },
    17. The manufacturing method according to any one of claims 14-16.
19. Formula (I):
    

    

    PTSA salt or phthalate of compound (I) represented by.
20. Mycosis, superficial mycosis, or nail, produced by mixing crystals of compound (I) according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier A pharmaceutical composition for treating or preventing ringworm.
21. Administering a pharmaceutical composition produced by mixing the crystals of compound (I) according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier to mammals including humans A method for treating or preventing mycosis, superficial mycosis, or tinea unguium, comprising the step of
22. Use of crystals of compound (I) according to any one of claims 1 to 13 for the manufacture of a pharmaceutical composition for the treatment of mycoses, superficial mycoses, or tinea unguium.
23. A method for producing a pharmaceutical composition, comprising mixing crystals of compound (I) according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier.
24. A treatment for treating mycosis, superficial mycosis, or tinea unguium, comprising mixing crystals of compound (I) according to any one of claims 1 to 13 with a pharmaceutically acceptable carrier. A method for producing a pharmaceutical composition for treatment or prevention.

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