WO2023027162A1 - ２－（４－エチルフェノキシ）－４'－メトキシ－３，３'－ビピリジンの結晶及びその製造方法 - Google Patents

２－（４－エチルフェノキシ）－４'－メトキシ－３，３'－ビピリジンの結晶及びその製造方法 Download PDF

Info

Publication number
WO2023027162A1
WO2023027162A1 PCT/JP2022/032144 JP2022032144W WO2023027162A1 WO 2023027162 A1 WO2023027162 A1 WO 2023027162A1 JP 2022032144 W JP2022032144 W JP 2022032144W WO 2023027162 A1 WO2023027162 A1 WO 2023027162A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
represented
content
purity
less
Prior art date
Application number
PCT/JP2022/032144
Other languages
English (en)
French (fr)
Japanese (ja)
Inventor
拓也 山田
剛志 金山
Original Assignee
科研製薬株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 科研製薬株式会社 filed Critical 科研製薬株式会社
Publication of WO2023027162A1 publication Critical patent/WO2023027162A1/ja

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4

Definitions

  • the present invention relates to crystals of 2-(4-ethylphenoxy)-4'-methoxy-3,3'-bipyridine, a production method, and intermediates for the production thereof.
  • compound (I) 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). ).
  • 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).
  • 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%).
  • 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.
  • 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.
  • 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.
  • PTSA p-toluenesulfonic acid
  • 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.
  • Form A Crystals of compound (I) produced by the above method are referred to as Form A.
  • Form C has 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.
  • the present invention was completed by discovering a manufacturing method with a high yield.
  • Step D Using compound (I) and a solvent containing 2-propanol, preparing a suspension of compound (I), stirring, and then filtering; Manufacturing method including.
  • 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.
  • R 1 is B(OH) 2 , B(OMe) 2 , B(OEt) 2 , B(Oi-Pr) 2 , BF 3 K, and The formula below:
  • 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.
  • 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).
  • 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.
  • 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.
  • a pharmaceutically acceptable carrier comprising mixing crystals of compound (I) according to any one of [01] to [13] with a pharmaceutically acceptable carrier.
  • 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 2 ⁇ in the powder X-ray diffraction spectrum
  • [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 2 ⁇ in the powder X-ray diffraction spectrum
  • 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.
  • 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.
  • 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.
  • step A 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:
  • step A is a cross-coupling reaction using a metal catalyst and a base.
  • 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 [17
  • 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).
  • 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].
  • 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 .
  • a pharmaceutical composition comprising a crystal of compound (I) according to any one of [01] to [13] and a pharmaceutically acceptable carrier.
  • 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;
  • Me represents methyl
  • Et represents ethyl
  • 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.
  • FIG. 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.
  • DSC differential scanning calorimetry
  • 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. 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.
  • 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).
  • crystals of low-molecular-weight compounds such as 2-(4-ethylphenoxy)-4'-methoxy-3,3'-bipyridine are often found near a specific diffraction angle (2 ⁇ ) 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.
  • DSC differential scanning calorimetry
  • absorption band at a specific wave number in infrared absorption spectrometry.
  • these instrumental analyzes may not be performed appropriately.
  • 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.
  • the diffraction angles (2 ⁇ ) of the same crystal match within the range of ⁇ 0.2° or ⁇ 0.1°.
  • the peak value of the diffraction angle 2 ⁇ means having at least the peak.
  • the diffraction angle represented by 2 ⁇ 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.
  • 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.
  • 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.
  • DSC differential scanning calorimetry
  • 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.
  • infrared absorption spectroscopy 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.
  • 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 .
  • 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.
  • Form A and Form C have excellent drug substance profiles.
  • 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.
  • 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.
  • “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.
  • solvent containing at least 2-propanol examples 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.
  • 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.
  • the mixed solvent of 2-propanol and water is also referred to as "IPA water mixed solvent".
  • 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
  • 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.
  • 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).
  • step D a suspension using a solvent containing compound (I) and 2-propanol is stirred in order to obtain crystals 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.
  • 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.
  • 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.
  • 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.
  • 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 (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
  • Step B and subsequent steps are steps for purifying the compound (I) obtained in the previous step.
  • 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.
  • 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.
  • 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.
  • step D 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.
  • step D includes steps similar to step D and steps similar to step D, for example, step D′ and the like, unless otherwise noted.
  • step B includes step B' and the like.
  • the production method of the present invention comprises Process A: Formula below:
  • 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.
  • 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 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.
  • compound (XIV) or compound (XV) is simply described in this specification, its salts and solvates are also included.
  • 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:
  • compound (II) 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:
  • 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].
  • the amount of metal catalyst used is not particularly limited as long as the reaction proceeds.
  • 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).
  • 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.
  • the amount of base used is not particularly limited as long as the reaction proceeds.
  • 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.
  • 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;
  • the amount of additive used is not particularly limited as long as the reaction proceeds.
  • 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.
  • 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.
  • 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.
  • 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.
  • step D' may be performed continuously without isolation, or the product may be isolated in any step.
  • the PTSA salt or phthalate salt of compound (I) is isolated as a solid.
  • step D' 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.
  • 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.
  • impurities can be used as an index in producing a highly pure compound (I) from the viewpoint of production amount and removability.
  • 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).
  • 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).
  • 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.
  • 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).
  • 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.
  • 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).
  • 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”).
  • 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;
  • 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.
  • the active ingredient may be in a suspended state in the above formulation.
  • 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.). .
  • the content of the compound (I) of the present invention 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%.
  • the active ingredient compound (I) of the present invention is generally used in a daily dose of about 1 ⁇ g/cm 2 to about 100000 ⁇ g/cm 2 , preferably about 10 ⁇ g/cm 2 to about 10000 ⁇ g/cm 2 . and can be administered once or more a day.
  • 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.
  • the pharmaceutical composition of the present invention is an external application preparation.
  • 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.
  • 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.
  • 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.
  • 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%.
  • sodium edetate hydrate and water may be included as long as the stability of the formulation can be guaranteed.
  • 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 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 Provide 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. .
  • 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.
  • 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.
  • 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).
  • 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)).
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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).
  • 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.
  • 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).
  • Example 6 Provide 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • PTSA salt compound (XIX)
  • phthalate compound (XX)
  • ⁇ -Alumina was used as a reference material.
  • 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).
  • 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.
  • Form C seed crystals
  • 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.
  • 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).
  • Compound (I) was gently added to a graduated cylinder (100 mL) and weighed when the volume reached 50 mL.
  • the volume was read by tapping 10 times, 20 times, 30 times, 40 times, and 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.
  • Form C 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.
  • Example 7 Provide 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/JP2022/032144 2021-08-27 2022-08-26 ２－（４－エチルフェノキシ）－４'－メトキシ－３，３'－ビピリジンの結晶及びその製造方法 WO2023027162A1 (ja)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2021-139132 2021-08-27
JP2021139132 2021-08-27

Publications (1)

Publication Number Publication Date
WO2023027162A1 true WO2023027162A1 (ja) 2023-03-02

Family

ID=85322954

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2022/032144 WO2023027162A1 (ja) 2021-08-27 2022-08-26 ２－（４－エチルフェノキシ）－４'－メトキシ－３，３'－ビピリジンの結晶及びその製造方法

Country Status (2)

Country Link
TW (1) TW202320764A (zh)
WO (1) WO2023027162A1 (zh)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006008553A (ja) * 2004-06-24 2006-01-12 Sankyo Co Ltd ピロロピリダジン化合物酸付加塩を含有する医薬
WO2017047602A1 (ja) * 2015-09-18 2017-03-23 科研製薬株式会社 ビアリール誘導体及びそれを含有する医薬
JP2018504414A (ja) * 2015-02-07 2018-02-15 サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． ジヒドロピリミジン誘導体の複合体及び塩並びにそれらの医薬品への応用
JP2018145180A (ja) * 2017-03-01 2018-09-20 科研製薬株式会社 ビアリール誘導体又はその塩からなる医薬
JP2019522015A (ja) * 2016-07-27 2019-08-08 サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． ２，６−ジメチルピリミドン誘導体の塩及びその使用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006008553A (ja) * 2004-06-24 2006-01-12 Sankyo Co Ltd ピロロピリダジン化合物酸付加塩を含有する医薬
JP2018504414A (ja) * 2015-02-07 2018-02-15 サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． ジヒドロピリミジン誘導体の複合体及び塩並びにそれらの医薬品への応用
WO2017047602A1 (ja) * 2015-09-18 2017-03-23 科研製薬株式会社 ビアリール誘導体及びそれを含有する医薬
JP2019522015A (ja) * 2016-07-27 2019-08-08 サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． ２，６−ジメチルピリミドン誘導体の塩及びその使用
JP2018145180A (ja) * 2017-03-01 2018-09-20 科研製薬株式会社 ビアリール誘導体又はその塩からなる医薬

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ASHIZAWA, KAZUHIDE: "IYAKUHIN NO TAKEI GENSHO TO SHOSEKI NO KAGAKU", 20 September 2002, MARUZEN CO., LTD. PUBLISHING DIVISION , JP , ISBN: 978-4-901689-06-9, article ASHIZAWA, KAZUHIDE: "Passage, Polymorphism and crystallization of the pharmaceutical drugs", pages: 305 - 317, XP009527171 *

Also Published As

Publication number Publication date
TW202320764A (zh) 2023-06-01

Similar Documents

Publication Publication Date Title
AU2013277429B2 (en) Preparation, uses and solid forms of obeticholic acid
CA2602968C (en) Crystals of morphinan derivative and process for producing the same
JP6632127B2 (ja) トロンボポエチン受容体アゴニスト作用を有する光学活性な化合物およびその中間体の製造方法
JP2019104760A (ja) ベンズイミダゾール誘導体の新規結晶形及びその製造方法
WO2014071772A1 (zh) 吡咯并喹啉醌的二钠盐结晶
JP2022071077A (ja) Ｂｃｌ－２タンパク質を阻害するためのＮ－ベンゼンスルホニルベンズアミド系化合物、その組成物および使用
JP2024069193A (ja) ブロモドメイン阻害剤の合成方法
WO2023027162A1 (ja) ２－（４－エチルフェノキシ）－４'－メトキシ－３，３'－ビピリジンの結晶及びその製造方法
US20120283274A1 (en) Crystalline forms of substituted pyrazolopyrimidines
JPWO2008093853A1 (ja) マクロライド系化合物の固体およびその製造法並びにその医薬組成物
TWI466872B (zh) 喹唑啉衍生物之製造方法
JP2014514274A (ja) マキサカルシトールの多形およびマキサカルシトールの調製方法
JP7068411B2 (ja) ヘキサデシルトレプロスチニル結晶及びその製造方法
TWI838531B (zh) 索吡銨溴化物的結晶形態及其製造方法
CN111233762B (zh) 一种乐伐替尼与对羟基苯甲酸共晶及其制备方法
CN110551065B (zh) 氘代Lucitanib化合物及其用途
TWI745764B (zh) 一種鴉片類物質受體激動劑的結晶形式及製備方法
CN109180564B (zh) 一种哌啶及其衍生物的制备方法
JP7450842B2 (ja) フェニルピリミドン化合物の塩、結晶多形並びにその医薬組成物及び使用
JP2022508864A (ja) チロシンキナーゼ阻害剤のマレイン酸塩の結晶形及びその調製方法
AU2016318700A1 (en) Crystalline form of androgen receptor inhibitor and preparation method thereof
CN111793027A (zh) 一种乐伐替尼与苯甲酸的共晶及其制备方法
EP3486241B1 (en) Method for producing crystal of uracil compound
EP3604284A1 (en) Crystalline eltrombopag monoethanolamine salt form d
JP2017523210A (ja) ６−アリールアミノピリドンカルボキサミド化合物の結晶、およびその製造方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22861450

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22861450

Country of ref document: EP

Kind code of ref document: A1