ointment

Abstract

To provide an ointment that stably comprises an oxazole compound having specific inhibitory activity against PDE4 and can be efficiently absorbed into the skin.SOLUTION: The present invention provides an ointment comprising an oxazole compound represented by the following formula (11), with the oxazole compound dissolved in a base component, and the base component comprising a solvent for dissolving the oxazole compound, and an ointment base for dispersing or dissolving the solvent.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an ointment containing an oxazole compound. [Background technology]

[0002] Patent Documents 1 and 2 report an oxazole compound having a specific inhibitory effect on phosphodiesterase 4 (PDE4) and a method for producing the same. PDE4 is the predominant PDE in inflammatory cells, and inhibition of PDE4 increases intracellular cAMP concentration, which in turn downregulates inflammatory responses through the regulation of the expression of TNF-α, IL-23, and other inflammatory cytokines. In addition, an increase in cAMP concentration increases anti-inflammatory cytokines such as IL-10. Therefore, the oxazole compound is considered to be suitable for use as an anti-inflammatory agent. For example, it is considered to be useful for suppressing skin eczema and dermatitis, including atopic dermatitis.

[0003] However, no ointment has been obtained to date which stably contains an oxazole compound having a specific inhibitory effect on PDE4 and can be efficiently absorbed into the skin. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2007 / 058338 Pamphlet (Patent Publication No. 2009-515872) [Patent Document 2] International Publication No. 2014 / 034958 Pamphlet (Patent Publication No. 2015-528433) Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide an ointment which stably contains an oxazole compound having a specific inhibitory effect on PDE4 and can be efficiently absorbed into the skin. [Means for solving the problem]

[0006] The present inventors have discovered that by dissolving a specific oxazole compound, among oxazole compounds having a specific inhibitory effect on PDE4, in a specific solvent and then dissolving or dispersing this in a base, an ointment can be obtained which stably contains the specific oxazole compound and can be efficiently absorbed into the skin. Through further improvements, the present inventors have completed the present invention.

[0007] That is, the present invention includes, for example, the subject matter described in the following paragraphs. Item 1. The following formula (11):

[0008] [ka]

[0009] An ointment comprising an oxazole compound represented by the formula: Item 2. The ointment according to Item 1, wherein the oxazole compound is dissolved in a base component. Item 3. The ointment according to Item 2, wherein the base component comprises a solvent for dissolving the oxazole compound and an ointment base for dispersing or dissolving the solvent. Item 4. The ointment according to Item 3, wherein the ointment base comprises a hydrocarbon (preferably at least one hydrocarbon selected from the group consisting of petrolatum, paraffin, wax, and beeswax). Item 5. The ointment according to Item 3 or 4, wherein the solvent contains a polar compound that is liquid at room temperature (preferably at least one selected from the group consisting of ethylene carbonate, propylene carbonate, benzyl alcohol, triacetin, N-methylpyrrolidone, diethyl sebacate, diisopropyl sebacate, diethyl adipate, diisopropyl adipate, isostearyl alcohol, and isopropyl myristate). Item 6. The ointment according to any one of Items 3 to 5, wherein the ointment base is an ointment base that disperses the solvent, and the solvent having the oxazole compound dissolved therein is dispersed in the ointment base as droplets. Item 7. The ointment according to any one of Items 3 to 6, wherein the ointment base contains at least beeswax. Item 8. The ointment according to Item 7, wherein the beeswax is not chemically bleached. Item 9. The ointment according to any one of Items 1 to 8, which is for treating and / or preventing skin eczema and dermatitis (preferably atopic dermatitis). Section 10. (I) an oxazole compound represented by formula (11), (II) a solvent comprising at least one selected from the group consisting of ethylene carbonate, propylene carbonate, benzyl alcohol, and triacetin; and (III) Ointment base containing beeswax Contains (I) is dissolved in (II) and dispersed as droplets in (III). The average particle size of the droplets is 100 μm or less. Ointment. Section A. A method for producing a compound represented by formula (3), comprising the steps of:

[0010] [ka]

[0011] (In the formula, X 1 represents a halogen atom, and R 1 represents an alkali metal atom or a lower alkyl group. (a) reacting a compound represented by formula (1a) with a compound represented by formula X 1 CF2COOR 1 to produce a compound represented by formula (2); and (b) oxidizing the compound represented by formula (2) to produce a compound represented by formula (3); A manufacturing method comprising: Section B. A method for producing a compound represented by formula (3), comprising the steps of:

[0012] [ka]

[0013] (In the formula, X 2 indicates a halogen atom.) (a) reacting a compound represented by formula (1b) with a compound represented by formula X 2 with a compound represented by formula (CH(CH3)2 to produce a compound represented by formula (2); and (b) oxidizing the compound represented by formula (2) to produce a compound represented by formula (3); A manufacturing method comprising: Effect of the Invention

[0014] The ointment according to the present invention stably contains an oxazole compound having a specific inhibitory effect on PDE4, and can be efficiently absorbed into the skin. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The ointment of the present invention contains a specific oxazole compound, and preferably the oxazole compound is dissolved in a base component. The oxazole compound can be contained in the ointment as an active ingredient. The base component here includes a solvent that dissolves the oxazole compound and other ointment bases. The ointment base is preferably an ointment base that disperses or dissolves the solvent.

[0016] In other words, the ointment of the present invention contains (I) a specific oxazole compound, and preferably the oxazole compound is dissolved in a base component, which includes (II) a solvent for dissolving the oxazole compound, and (III) an ointment base.

[0017] More preferably, the ointment according to the present invention is an ointment in which (II) in which (I) is dissolved is dissolved or dispersed as droplets in (III).

[0018] (I) Examples of the oxazole compound include compounds represented by the following formulas (11) and (11a) to (11s). In particular, the compound represented by formula (11) is preferred.

[0019] [ka]

[0020] [Table 1] TIFF2025024065000006.tif250169TIFF2025024065000007.tif133169

[0021] These oxazole compounds may be used alone or in combination of two or more. That is, the ointment of the present invention may contain at least one oxazole compound selected from the group consisting of the compounds represented by the above formulas (11) and (11a) to (11s).

[0022] Although there are no particular limitations, the ointment contains the (I) oxazole compound in an amount of preferably 0.01 to 10 parts by weight, more preferably 0.05 to 7.5 parts by weight, and even more preferably 0.1 to 5 parts by weight, per 100 parts by weight of the ointment.

[0023] As described above, the oxazole compound is preferably dissolved in the solvent (II). The solvent is preferably a polar compound that is liquid at room temperature, and more specifically, for example, ethylene carbonate, propylene carbonate, benzyl alcohol, triacetin, diethyl sebacate, diisopropyl sebacate, diethyl adipate, diisopropyl adipate, isostearic acid, olive oil, hexyldodecanol, decyl oleate, isostearyl alcohol, and isopropyl myristate are preferably mentioned. More preferably, ethylene carbonate, propylene carbonate, benzyl alcohol, and triacetin are mentioned, and even more preferably, propylene carbonate and triacetin are mentioned. Among them, propylene carbonate is preferable. The solvent can be used alone or in combination of two or more kinds. In particular, it is preferable to use only ethylene carbonate or propylene carbonate, or to use ethylene carbonate or propylene carbonate in combination with benzyl alcohol and / or triacetin.

[0024] The amount of the solvent (II) is preferably more than 2 parts by weight, more preferably 2.1 parts by weight or more, and even more preferably 2.2 parts by weight or more, per part by weight of the oxazole compound (I). The upper limit is not particularly limited as long as the effects of the present invention are obtained, but is, for example, preferably 30 parts by weight or less, more preferably 20 parts by weight or less, and even more preferably 15 parts by weight or less.

[0025] The ointment contains the (II) solvent in an amount of preferably 0.1 to 50 parts by weight, more preferably 0.2 to 25 parts by weight, and even more preferably 0.5 to 20 parts by weight, relative to 100 parts by weight of the ointment.

[0026] The solution in which the oxazole compound is dissolved in the solvent is preferably dissolved or dispersed as droplets in (III) an ointment base, and more preferably dispersed as droplets in (III) an ointment base.

[0027] (III) As the ointment base, a known ointment base used in the manufacture of ointments can be used, for example, a hydrocarbon, and more specifically, for example, an oleaginous base, particularly natural wax, petroleum wax, other hydrocarbons, etc. can be exemplified. Examples of natural waxes include beeswax (unbleached beeswax, non-chemically bleached white beeswax, chemically bleached white beeswax, etc.), carnauba wax, etc. Examples of petroleum waxes include paraffin, microcrystalline wax, etc. Examples of other hydrocarbons include liquid paraffin, petrolatum (white petrolatum, yellow petrolatum, etc.), etc. The ointment base can be used alone or in combination of two or more.

[0028] The ointment contains preferably 5 to 5,000 parts by weight, more preferably 10 to 2,500 parts by weight, and even more preferably 20 to 1,000 parts by weight of the ointment base (III) relative to 1 part by weight of the oxazole compound (I).

[0029] The ointment contains (III) an ointment base in an amount of preferably 50 to 99 parts by weight, more preferably 70 to 98 parts by weight, and even more preferably 80 to 97 parts by weight, per 100 parts by weight of the ointment.

[0030] The ointment base (III) preferably contains at least beeswax. As the beeswax, it is preferable to use beeswax that has not been chemically bleached, for example, non-chemically bleached beeswax (non-chemically bleached beeswax) or unbleached beeswax (unbleached beeswax).

[0031] The ointment contains beeswax in an amount of preferably 0.05 to 50 parts by weight, more preferably 0.1 to 40 parts by weight, and even more preferably 0.2 to 35 parts by weight, per part by weight of the oxazole compound (I).

[0032] Furthermore, the ointment contains beeswax in an amount of preferably 0.1 to 10 parts by weight, more preferably 0.2 to 9 parts by weight, even more preferably 0.4 to 8 parts by weight, even more preferably 0.5 to 7.5 parts by weight, and particularly preferably 1 to 5 parts by weight, per 100 parts by weight of the ointment.

[0033] When other ointment bases are used in combination with beeswax, there are no particular limitations, but it is preferable that they include, for example, beeswax and at least one selected from the group consisting of petrolatum (preferably white petrolatum), liquid paraffin, and paraffin.

[0034] In addition to the above ointment base, the ointment may contain other additives (particularly pharmaceutical additives) that can be used in ointments, such as fragrances, coloring agents, preservatives, and absorption enhancers such as higher alkenoic acids (e.g., oleic acid, etc.), as well as drugs that are effective against other skin diseases.

[0035] As described above, the ointment of the present invention preferably has a structure in which (I) the oxazole compound is dissolved in (II) the solvent, or is dispersed as droplets in (III) the ointment base. For example, a method for producing an ointment having such a structure includes a method of preparing a solution by dissolving (I) in (II), and stirring and mixing the solution with (III). For example, a homomixer, a paddle mixer, or a combination thereof can be used for stirring and mixing.

[0036] As for (III), when multiple ointment bases are used, it is preferable to mix them in advance. In the preparation, it is preferable to heat and mix in order to dissolve solids such as beeswax. For example, when beeswax and other ointment bases are used in combination, it is preferable to mix the beeswax and other ointment bases in advance, and it is preferable to heat and mix them when mixing.

[0037] In addition, when the ointment has a structure in which (I) is dissolved and (II) is dispersed as droplets in (III), the particle size of the droplets is 100 μm or less when observed with a polarizing microscope. It is preferably about 40 μm or less, more preferably about 25 μm or less, and even more preferably about 20 μm or less. In particular, it is preferable that there are no droplets larger than 100 μm, more preferably there are no droplets larger than 40 μm, even more preferably there are no droplets larger than 25 μm, and even more preferably there are no droplets larger than 20 μm. The particle size of the droplets can be adjusted to a desired average particle size by adjusting the stirring speed when stirring and mixing the dissolving solution and (III).

[0038] The oxazole compound represented by formula (11) is a known compound described in the above-mentioned Patent Documents 1 and 2, and can be produced according to the methods described in the above-mentioned Patent Documents 1 and 2.

[0039] Alternatively, it may be produced as follows: The compounds used as raw materials below are either known or can be easily produced from known compounds.

[0040] That is, first, compound (3) is synthesized, then compound (7) is synthesized from compound (3), and compound (11) can be synthesized from compound (7). In this specification, the compound represented by formula A may be referred to as compound A or compound (A).

[0041] [ka]

[0042] <Production of compound (3)> Compound (3) can be produced, for example, via the reaction steps shown in the following reaction scheme.

[0043] [ka]

[0044] Compound (1a) + Compound X 1 CF 2 COOR 1 →Compound (2) Compound (2) can be prepared by reacting compound (1a) with compound X in the presence of a base. 1 CF2COOR 1 It can be produced by reacting

[0045] Compound X 1 CF2COOR 1 X 1 represents a halogen atom, and examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, of which a chlorine atom, a bromine atom, and an iodine atom are preferred, and a chlorine atom is more preferred.

[0046] Also, R 1 represents an alkali metal atom or a lower alkyl group. Examples of the alkali metal atom include lithium, sodium, potassium, etc., and preferably sodium. Examples of the lower alkyl group include a C1-C6 (particularly C1-C4) linear or branched alkyl group. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl, neopentyl, n-hexyl, isohexyl, and 3-methylpentyl groups, and preferably methyl and ethyl groups.

[0047] The reaction can be carried out in the presence of a solvent. The solvent may be any solvent that does not adversely affect the reaction, and examples of the solvent include ketone solvents (e.g., acetone, methyl ethyl ketone, etc.), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, diglyme, etc.), ester solvents (e.g., methyl acetate, ethyl acetate, etc.), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, etc.), halogenated hydrocarbon solvents (e.g., methylene chloride, ethylene chloride, etc.), and mixtures thereof. N,N-dimethylformamide is preferred.

[0048] Known inorganic and organic bases can be used as the base. Examples of inorganic bases include alkali metals (e.g., sodium, potassium, etc.), alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.), alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal lower (C1-C3) alkoxides (e.g., sodium methoxide, sodium ethoxide, etc.), alkali metal hydrides (e.g., sodium hydride, potassium hydride, etc.), etc. Examples of organic bases include trialkylamines (e.g., trimethylamine, triethylamine, N,N-diisopropylethylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. In addition, when these bases are liquid, they can also be used as solvents. These bases are used alone or in combination of two or more. Preferably, they are alkali metal carbonates (particularly, sodium carbonate and potassium carbonate).

[0049] The amount of the base used is usually 1 to 10 mol, preferably 1 to 6 mol, per 1 mol of compound (1a).

[0050] The above reaction can be carried out, if necessary, by adding an alkali metal iodide such as potassium iodide or sodium iodide to the reaction system as a reaction accelerator.

[0051] When a reaction accelerator is used, the amount of the accelerator used is X 1 CF2COOR 1 It is usually at least 0.01 mol, and preferably about 0.1 to 2 mol, per mol of the solvent.

[0052] Compound (1a) and Compound X 1 CF2COOR 1 The ratio of the latter to the former is usually at least 1 mol, preferably about 1 to 5 mol.

[0053] The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, or under heating. The reaction is preferably carried out at a temperature of about 80 to 120° C. for 1 to 30 hours.

[0054] Compound (2) → Compound (3) Compound (3) can be produced by oxidizing compound (2). Specifically, for example, compound (2) can be reacted in a solvent in the presence of an oxidizing agent to produce compound (3).

[0055] Examples of the solvent to be used when reacting compound (2) in a solvent in the presence of an oxidizing agent include alcohols such as water, methanol, ethanol, propanol, isopropyl alcohol, n-butanol, tert-butanol, and ethylene glycol; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme; ketones such as acetone and methyl ethyl ketone; aromatic hydrocarbons such as benzene, o-dichlorobenzene, toluene, and xylene; esters such as methyl acetate, ethyl acetate, and butyl acetate; aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, and hexamethylphosphoric triamide; and mixtures thereof.

[0056] Examples of the oxidizing agent include halo acid such as chlorite, iodous acid, and bromous acid, alkali metal halo acid salts such as sodium chlorite, sodium iodite, sodium bromite, potassium chlorite, potassium iodite, and potassium bromite, alkali metal permanganate such as potassium permanganate, chromic acid or its alkali metal salts such as chromium (VI) oxide, sodium dichromate, and potassium dichromate, and nitric acid. When an alkali metal permanganate salt is used, it is preferable to react in the presence of an inorganic base such as potassium hydroxide, sodium hydroxide, sodium carbonate, or potassium carbonate. When chromic acid or its alkali metal salt is used, it is preferable to react in the presence of a mineral acid such as sulfuric acid, or an organic acid such as acetic acid. Among these, halo acid and alkali metal halo acid salts are particularly preferable.

[0057] The amount of the oxidizing agent used is usually 0.5 to 1 mole or more, and preferably 1 to 10 moles, per mole of compound (2).

[0058] The reaction temperature is usually about −20 to 50° C., and preferably about −20 to room temperature (25° C.) The reaction time may be about 1 to 30 hours.

[0059] Compound (3) can also be prepared by the reaction steps shown in the following reaction scheme.

[0060] [ka]

[0061] Compound (1b) + Compound X 2 CH(CH 3 ) 2 →Compound (2) Compound (2) can be prepared by reacting compound (1a) with compound X in the presence of a base. 2 It can also be prepared by reacting with CH(CH3)2.

[0062] Compound X 2 X in CH(CH3)2 2 represents a halogen atom, and examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, of which a chlorine atom, a bromine atom, and an iodine atom are preferred, and a bromine atom is more preferred.

[0063] The reaction can be carried out in the presence of a solvent. The solvent may be any solvent that does not adversely affect the reaction, and examples of the solvent include ketone solvents (e.g., acetone, methyl ethyl ketone, etc.), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, diglyme, etc.), ester solvents (e.g., methyl acetate, ethyl acetate, etc.), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, etc.), halogenated hydrocarbon solvents (e.g., methylene chloride, ethylene chloride, etc.), and mixtures thereof. N,N-dimethylformamide is preferred.

[0064] Known inorganic and organic bases can be used as the base. Examples of inorganic bases include alkali metals (e.g., sodium, potassium, etc.), alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.), alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal lower (C1-C3) alkoxides (e.g., sodium methoxide, sodium ethoxide, etc.), alkali metal hydrides (e.g., sodium hydride, potassium hydride, etc.), etc. Examples of organic bases include trialkylamines (e.g., trimethylamine, triethylamine, N,N-diisopropylethylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. In addition, when these bases are liquid, they can also be used as solvents. These bases are used alone or in combination of two or more. Preferably, they are alkali metal carbonates (particularly, sodium carbonate and potassium carbonate).

[0065] The amount of the base used is usually 1 to 10 mol, preferably 1 to 6 mol, per 1 mol of compound (1b).

[0066] The above reaction can be carried out, if necessary, by adding an alkali metal iodide such as potassium iodide or sodium iodide to the reaction system as a reaction accelerator.

[0067] When a reaction accelerator is used, the amount of the accelerator used is X 2 The amount is usually at least 0.01 mole, and preferably about 0.1 to 2 moles, relative to 1 mole of CH(CH3)2.

[0068] Compound (1b) and Compound X 2The ratio of the latter to CH(CH3)2 is usually at least 1 mole, preferably about 1 to 5 moles, per mole of the former.

[0069] The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, or under heating. The reaction is preferably carried out at a temperature of about room temperature to about 85° C. for 1 to 30 hours.

[0070] The method for producing compound (3) from compound (2) is the same as above.

[0071] <Production of compound (7)> Compound (7) can be produced, for example, via the reaction steps shown in the following reaction scheme.

[0072] [ka]

[0073] Compound (3) → Compound (4) Compound (4) can be produced by subjecting compound (3) to a condensation reaction (amidation reaction) with ammonia. The reaction can usually be carried out by reacting compound (3) with ammonia in a solvent in the presence of a condensing agent.

[0074] The solvent may be any solvent that does not adversely affect the reaction, and examples thereof include halogenated aliphatic hydrocarbon solvents (e.g., methylene chloride, chloroform, ethylene chloride, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone, etc.), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, diglyme, etc.), aromatic hydrocarbons (e.g., toluene, xylene, etc.), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, etc.), and mixed solvents thereof. Acetonitrile is preferred.

[0075] Examples of the condensing agent include 1,1'-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC or WSC), diphenylphosphoric acid azide (DPPA), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium salt (e.g., benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, etc.), 2-chloro-4,6-dimethoxytriazine (CDMT), etc. CDI is preferred.

[0076] The amount of the condensing agent used is usually at least 1 mole, and preferably about 1 to 5 moles, per mole of compound (3).

[0077] If necessary, 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu) or the like can be used as an additive (activator) together with the condensing agent.

[0078] When an additive is used, the amount used is usually at least 1 mol, and preferably about 1 to 5 mol, per mol of the condensing agent.

[0079] The reaction can be carried out by adding a base as necessary. For example, tertiary amines such as triethylamine and N,N-diisopropylethylamine, pyridine, 4-dimethylamino Nitrogen-containing aromatic compounds such as pyridine are also included.

[0080] When a base is used, the amount used is usually at least 1 mol, and preferably about 1 to 5 mol, per 1 mol of compound (5).

[0081] Ammonia can usually be used as aqueous ammonia. The amount of ammonia used is It is usually at least 1 mole, and preferably about 1 to 10 moles, per mole of compound (3).

[0082] The reaction can typically be carried out by reacting compound (3) with a condensing agent and, if necessary, an additive to prepare an activated ester, and then reacting this with ammonia.

[0083] The reaction temperature in the preparation of the active ester and the subsequent reaction with ammonia is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, or under heating. The reaction is preferably carried out for 1 to 30 hours under ice-cooling to room temperature.

[0084] Compound (4) → Compound (5) Compound (5) is the product of compound (4) and compound CO(CH2X 3 ) 2.

[0085] Compound CO(CH2X 3 )2X 3 X represents a halogen atom. 3 Examples of the halogen atom represented by the formula (I) include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and preferably a chlorine atom, a bromine atom, or an iodine atom.

[0086] The reaction can be carried out in the presence of a solvent. The solvent may be any solvent that does not adversely affect the reaction, and examples of the solvent include halogenated aliphatic hydrocarbon solvents (e.g., methylene chloride, chloroform, ethylene chloride, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone, etc.), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, diglyme, etc.), aromatic hydrocarbons (e.g., toluene, xylene, etc.), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, etc.), or mixed solvents thereof. Preferred are aromatic hydrocarbons (e.g., toluene, xylene, etc.).

[0087] Compound (4) and compound CO(CH2X 3The ratio of the latter to the former is usually at least 1 mole, preferably about 1 to 5 moles, of the latter per mole of the former.

[0088] If necessary, a dehydrating agent can be used, for example, synthetic zeolite, specifically, molecular sieves (MS) 3A, MS4A, or similar zeolites having fine pores.

[0089] The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, or under heating. The reaction is preferably carried out for 1 to 30 hours at a temperature of about room temperature to about 200° C. By using this method, the oxazole ring can be formed in high yield.

[0090] Compound (5) → Compound (6) Compound (6) is a mixture of compound (5) and compound R 2 O.M. 1 Compound R can be produced by reacting 2 O.M. 1 R 2 represents an alkanoyl group, M 1 represents an alkali metal atom.

[0091] R 2 Examples of the alkanoyl group represented by the formula (I) include linear or branched alkanoyl groups having C1-C6 (particularly C1-C4). Specific examples include formyl, acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, sec-butyryl, tert-butyryl, and hexanoyl groups, preferably formyl, acetyl, n-propionyl, and isopropionyl groups, and more preferably acetyl groups.

[0092] M 1 Examples of the alkali metal atom represented by the formula (I) include lithium, sodium, potassium, etc., and preferably sodium and potassium.

[0093] Compound R 2 O.M. 1Specific examples of the acetate include sodium acetate and potassium acetate.

[0094] The reaction can be carried out in the presence of a solvent. The solvent may be any solvent that does not adversely affect the reaction, and examples of the solvent include ketone solvents (e.g., acetone, methyl ethyl ketone, etc.), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, diglyme, etc.), ester solvents (e.g., methyl acetate, ethyl acetate, etc.), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, etc.), halogenated hydrocarbon solvents (e.g., methylene chloride, ethylene chloride, etc.), and mixtures thereof. N,N-dimethylformamide is preferred.

[0095] Compound (5) and Compound R 2 O.M. 1 The ratio of the latter to the former is usually at least 1 mol, preferably about 1 to 5 mol.

[0096] The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, or under heating. The reaction is preferably carried out at a temperature of about room temperature to about 120° C. for 1 to 30 hours.

[0097] Compound (6) → Compound (7) Compound (7) can be produced by hydrolyzing compound (6). The hydrolysis reaction of compound (6) can usually be carried out in a solvent in the presence of a base.

[0098] The solvent may be any solvent that does not adversely affect the reaction, and examples thereof include water, alcohol solvents (e.g., methanol, ethanol, isopropanol, n-butanol, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone, etc.), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, diglyme, etc.), acetonitrile, etc. Preferred is a mixed solvent of water and an alcohol solvent (methanol or ethanol). Preferred is an alcohol solvent (particularly, methanol, ethanol).

[0099] Examples of the base include alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.). Usually, the alkali metal hydroxide can be used in the form of an aqueous solution thereof. For example, an aqueous solution of sodium hydroxide can be used.

[0100] The amount of the base used is usually at least 1 mole, and preferably about 1 to 5 moles, per mole of compound (6).

[0101] The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, or under heating. The reaction is preferably carried out at a temperature of about room temperature to about 85° C. for 1 to 30 hours.

[0102] <Production of compound (11)> Compound (11) can be produced, for example, via the reaction steps shown in the following reaction scheme.

[0103] [ka]

[0104] Compound (7) → Compound (8) Compound (8) can be prepared by converting the hydroxyl group of compound (7) into a leaving group (X 4 ) can be produced by converting

[0105] X4 Examples of the leaving group represented by the formula (I) include a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), an organic sulfonyloxy group (e.g., a p-toluenesulfonyloxy, a methanesulfonyloxy, a trifluoromethanesulfonyloxy, a nonafluorobutanesulfonyloxy, an o-nitrobenzenesulfonyloxy group, etc.), etc. A halogen atom is preferable, and a bromine atom is more preferable.

[0106] X 4 In the case of compound (8') in which the leaving group represented by the formula: is an organic sulfonyloxy group, compound (8') can be produced by reacting compound (7) with an organic sulfonyl halide or organic sulfonic anhydride containing the organic sulfonyl group in a solvent in the presence of a base.

[0107] The solvent may be any solvent that does not adversely affect the reaction, and examples thereof include ketone solvents (e.g., acetone, methyl ethyl ketone, etc.), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, diglyme, etc.), ester solvents (e.g., methyl acetate, ethyl acetate, etc.), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, etc.), halogenated hydrocarbon solvents (e.g., methylene chloride, ethylene chloride, etc.), and mixed solvents thereof. Ester solvents (particularly, ethyl acetate, etc.) are preferred.

[0108] As the base, known inorganic bases and organic bases can be used. Examples of the inorganic base include Examples of the organic base include alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.), alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal hydrides (e.g., sodium hydride, potassium hydride, etc.), etc. Examples of the organic base include trialkylamines (e.g., trimethylamine, triethylamine, N,N-diisopropylethylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. In addition, when these bases are liquid, they can also be used as a solvent. These bases are used alone or in combination of two or more. N,N-diisopropylethylamine and triethylamine are preferred, and N,N-diisopropylethylamine is more preferred. In particular, the use of N,N-diisopropylethylamine is preferred because it can significantly improve the yield.

[0109] Examples of organic sulfonyl halides include p-toluenesulfonyl halide, methanesulfonyl halide, trifluoromethanesulfonyl halide, nonafluorobutanesulfonyl halide, and o-nitrobenzenesulfonyl halide. Examples of the above-mentioned halides include chloride and bromide, and chloride is preferred. Particularly preferred as the organic sulfonyl halide is methanesulfonyl chloride.

[0110] Examples of the organic sulfonic acid anhydride include p-toluenesulfonic acid anhydride, methanesulfonic acid anhydride, trifluorosulfonic acid anhydride, nonafluorobutanesulfonic acid anhydride, and o-nitrobenzenesulfonic acid anhydride.

[0111] The amount of the base used is usually 1 to 10 mol, preferably 1 to 6 mol, per 1 mol of compound (7).

[0112] The amount of the organic sulfonyl halide or organic sulfonic anhydride used is usually 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of compound (7).

[0113] The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, or under heating. The reaction is preferably carried out at a temperature of about 0 to 60° C. for 1 to 30 hours.

[0114] From the above reaction, X 4 In this case, the compound (8') is produced, in which the leaving group is an organic sulfonyloxy group.

[0115] X 4 Compound (8″) in which the leaving group represented by X is a halogen atom can be produced by reacting compound (8′) with a halogenating agent in a solvent. 4 When the leaving group represented by the formula: is a halogen atom, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and preferably a chlorine atom, a bromine atom, and an iodine atom, and more preferably a chlorine atom.

[0116] The solvent may be any solvent that does not adversely affect the reaction, and examples of the solvent include ketone solvents (e.g., acetone, methyl ethyl ketone, etc.), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, diglyme, etc.), ester solvents (e.g., methyl acetate, ethyl acetate, etc.), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, etc.), halogenated hydrocarbon solvents (e.g., methylene chloride, ethylene chloride, etc.), and mixtures of these solvents. can be done.

[0117] Examples of halogenating agents include alkali metal halides (e.g., lithium chloride, lithium bromide, lithium iodide, etc.), quaternary ammonium halides (e.g., tetrabutylammonium chloride, tetrabutylammonium bromide, etc.), etc. Preferred are alkali metal halides (particularly, lithium bromide).

[0118] The amount of the halogenating agent used is usually 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (8').

[0119] The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, or under heating. The reaction is preferably carried out at a temperature of about 0 to 60° C. for 1 to 30 hours.

[0120] The step of producing compound (8') from compound (7) and the step of producing compound (8'') from the obtained compound (8') can be carried out independently, or both steps can be carried out in one pot.

[0121] The resulting compound (8) (including compounds (8') and (8'')) is subjected to the next reaction step.

[0122] Compound (8) → Compound (9) Compound (9) is prepared by reacting compound (8) with the following formula:

[0123] [ka]

[0124] (wherein, M 2 represents an alkali metal atom) compound (hereinafter referred to as "phthalimide M 2 It can be produced by reacting M 2 Examples of the alkali metal atom represented by the formula (I) include lithium, sodium, potassium, etc., and potassium is preferred.

[0125] The above reaction can be carried out in a normal solvent. The solvent used may be any solvent that does not adversely affect the reaction, and examples thereof include ketone solvents (e.g., acetone, methyl ethyl ketone, etc.), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, diglyme, etc.), ester solvents (e.g., methyl acetate, ethyl acetate, etc.), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, etc.), halogenated hydrocarbon solvents (e.g., methylene chloride, ethylene chloride, etc.), or mixtures thereof. N,N-dimethylformamide is more preferred.

[0126] Compound (8) and phthalimide M 2 The ratio of the compound to be used is usually at least 1 mole, preferably about 1 to 5 moles, of the latter per mole of the former.

[0127] The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, or under heating. The reaction is preferably carried out at a temperature of about 0 to 100° C. for 1 to 30 hours.

[0128] Compound (9)→(10) Compound (10) can be produced by reacting compound (9) with methylamine.

[0129] The above reaction can be carried out in a normal solvent. The solvent used may be any solvent that does not adversely affect the reaction, and examples thereof include water, alcoholic solvents (e.g., methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, ethylene glycol, etc.), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, diglyme, etc.), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, etc.), and mixed solvents thereof. A mixed solvent of water and an alcoholic solvent (particularly methanol or ethanol) is preferred.

[0130] Methylamine can usually be used as an aqueous methylamine solution.

[0131] The amount of methylamine used is usually 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (9).

[0132] The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, or under heating. The reaction is preferably carried out at a temperature of about room temperature to about 100° C. for 10 minutes to 30 hours.

[0133] The resulting compound (10) is a primary amine compound. From the viewpoint of handling, compound (10) can be converted into a salt with an acid as necessary. The salt can be formed by a known method. A wide range of organic or inorganic acids can be selected as the acid. Examples of organic acids include organic carboxylic acids such as formic acid, acetic acid, lactic acid, tartaric acid, and succinic acid, and sulfonic acids such as methanesulfonic acid, toluenesulfonic acid, and naphthalenesulfonic acid. Examples of inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.

[0134] The solvent used in the salt formation reaction may be any solvent that does not adversely affect the reaction, and examples of such solvents include alcohol solvents (e.g., methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, ethylene glycol, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone, etc.), ether solvents (e.g., cyclopentyl methyl ether (CPME), tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, diglyme, etc.), ester solvents (e.g., methyl acetate, ethyl acetate, etc.), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, etc.), and mixtures of these solvents. Ether solvents (particularly, CPME, etc.) are preferred.

[0135] Compound (10)→(11) Compound (11) can be produced by subjecting compound (10) to a condensation reaction with 2-ethoxybenzoic acid.

[0136] The condensation reaction is usually carried out in a solvent in the presence of a condensing agent. When compound (10) forms a salt with an acid, the acid can be removed from the salt with a base (e.g., inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydrogen carbonate, and organic bases such as triethylamine and N,N-diisopropylethylamine) to convert the salt into compound (10), which is a free primary amine, before the reaction.

[0137] The solvent may be any solvent that does not adversely affect the reaction, such as halogenated fatty acids. Examples of the solvent include aromatic hydrocarbon solvents (e.g., methylene chloride, chloroform, ethylene chloride, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone, etc.), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, diglyme, etc.), ester solvents (e.g., methyl acetate, ethyl acetate, etc.), aromatic hydrocarbons (e.g., toluene, xylene, etc.), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc.), and mixed solvents thereof. Preferred are ketone solvents (particularly, acetone, methyl ethyl ketone, etc.), ether solvents (particularly, tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, etc.), and ester solvents (e.g., methyl acetate, ethyl acetate, etc.).

[0138] Examples of the condensing agent include 1,1'-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC or WSC), diphenylphosphoric acid azide (DPPA), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium salt (e.g., benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, etc.), 2-chloro-4,6-dimethoxytriazine (CDMT), etc. CDI and WSC are preferred.

[0139] The amount of the condensing agent used is usually at least 0.5 mol, and preferably about 1 to 5 mol, per mol of 2-ethoxybenzoic acid.

[0140] If necessary, 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu) or the like can be used as an additive (activator) together with the condensing agent.

[0141] The amount of the additive used is usually at least 1 mole, and preferably about 1 to 5 moles, per mole of the condensing agent.

[0142] The reaction can be carried out by adding a base as necessary. Examples of the base include tertiary amines such as triethylamine and N,N-diisopropylethylamine, and nitrogen-containing aromatic compounds such as pyridine and 4-dimethylaminopyridine.

[0143] When a base is used, the amount of the base used is usually at least 0.5 mol, and preferably about 1 to 5 mol, per mol of the condensing agent.

[0144] The ratio of compound (10) to 2-ethoxybenzoic acid used is usually 1 mole of the former and at least 1 mole, preferably about 1 to 2 moles, of the latter.

[0145] The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, or under heating. The reaction is preferably carried out at a temperature of about 0 to 100° C. for 1 to 30 hours.

[0146] In addition, in this specification, the term "comprising" includes "consisting essentially of" and "consisting of." In addition, the present invention includes all arbitrary combinations of the constituent elements described in this specification. EXAMPLES

[0147] The present invention will now be described in detail, but the present invention is not limited to the following examples.

[0148] Production Example 1 (Production of Compound (3) 1) Compound (3) was produced according to the following reaction scheme.

[0149] [ka]

[0150] Compound (1a) 10.00g (55.5mmol) and potassium carbonate 9.20g (66.6mmol) were added to N,N-dimethylformamide 40ml and water 6ml, and stirred until the heat generation subsided. Sodium chlorodifluoroacetate 16.92g (111mmol) was added and reacted at 95-110℃ for 3 hours. Butyl acetate 80ml and water 80ml were added to the reaction liquid and separated, and water 80ml was added to the organic layer again and separated. Concentrated hydrochloric acid 3ml was added to the organic layer and stirred at 60-70℃ for 30 minutes. Water 40ml and 25% sodium hydroxide aqueous solution 10ml were added to the reaction liquid and separated. Sulfamic acid 5.93g (61.1mmol) and water 10ml were added to the organic layer, and 25% sodium chlorite aqueous solution 22.08g (61.0mmol) was added dropwise at 20℃ or less. After reacting for 15 minutes at 20°C or less, 10ml of 25% aqueous sodium hydroxide solution was added dropwise at 20°C or less, followed by 83.95g (66.6mmol.) of 10% aqueous sodium sulfite solution. 2ml of concentrated hydrochloric acid was added and separated, and the organic layer was concentrated under reduced pressure. 40ml of methanol, 80ml of water, and 10ml of 25% aqueous sodium hydroxide solution were added to the concentrated residue to dissolve it, and 5ml of concentrated hydrochloric acid was added dropwise to precipitate crystals. The precipitated crystals were filtered and dried at 80°C to obtain 11.81g (yield 86.4%) of white powder of compound (3).

[0151] 1 H-NMR(CDCl3) δ: 7.70(2H,dd,J=6.4Hz,2.0Hz),7.22(1H,d,J=9.2Hz),6.66(1H,t,J=74.8Hz),4.66(1H,sept,J=6.0Hz),1.39(6H,d,J=6.0Hz).

[0152] Production Example 2 (Production 2 of Compound (3)) Compound (3) was produced according to the following reaction scheme.

[0153] [ka]

[0154] Compound (1b) 10.00g (53.2mmol), potassium carbonate 9.55g (69.1mmol), isopropyl bromide 8.50g (69.1mmol) were added to N,N-dimethylformamide 40ml and reacted at 75-85℃ for 2 hours. Butyl acetate 80ml and water 80ml were added to the reaction liquid and separated. Sulfamic acid 5.68g (58.5mmol) and water 10ml were added to the organic layer, 25% sodium chlorite aqueous solution 21.15g (58.5mmol) was added dropwise at 20℃ or less, and reacted for 15 minutes. 25% sodium hydroxide aqueous solution 10ml was added dropwise at 20℃ or less, followed by 10% sodium sulfite aqueous solution 80.41g (63.8mmol). Furthermore, concentrated hydrochloric acid 2ml was added, the liquid was separated, and the organic layer was concentrated under reduced pressure. The concentrated residue was dissolved in 40 ml of methanol, 80 ml of water, and 10 ml of 25% aqueous sodium hydroxide solution, and 5 ml of concentrated hydrochloric acid was added dropwise to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C. Compound (3) was obtained as a white powder in an amount of 12.09 g (yield 92.4%).

[0155] Production Example 3 (Production of Compound (7)) Compound (7) was produced according to the following reaction scheme.

[0156] [ka]

[0157] <Synthesis of compound (4)> At room temperature, 10.00 g (40.6 mmol) of compound (3) was added to 25 ml of acetonitrile and stirred, and 7.90 g (48.7 mmol) of carbonyldiimidazole was gradually added and reacted at room temperature for 1 hour. 10 ml (134 mmol) of 25% ammonia water was added to 120 ml of water, cooled to below 10°C, and the reaction liquid was added dropwise. The precipitated crystals were filtered and dried at 80°C to obtain 9.25 g (yield 92.9%) of white powder of compound (4).

[0158] 1H-NMR(CDCl3) δ: 7.54(1H,d,J=1.6Hz),7.25(1H,dd,J=8.4Hz,2.0Hz),7.17(1H,d,J=8.0Hz),6.62(1H,t ,J=75.0),5.96(2H,br-d,J=75.2Hz),4.66(1H,sept,J=6.13Hz),1.36(6H,d,J=6.0Hz).

[0159] <Synthesis of compound (5)> At room temperature, 10.00 g (40.8 mmol) of compound (4) and 6.21 g (48.9 mmol) of 1,3-dichloroacetone were added to 10 ml of toluene and reacted under reflux for 3 hours. To the reaction solution, 60 ml of toluene, 20 ml of water, and 2 ml of 25% aqueous sodium hydroxide solution were added and the mixture was separated. The organic layer was concentrated under reduced pressure to obtain a brown solid of compound (5). (After recrystallization: slightly yellow powder)

[0160] 1 H-NMR(CDCl3) δ: 7.69(1H,d,J=0.8Hz),7.64(1H,d,J=2.0Hz),7.58(1H,dd,J=8.0Hz,1.6Hz),7.21(1H,d,J=8 .0Hz),6.61(1H,t,J=75.0Hz),4.69(1H,sept,J=6.1Hz),4.56(2H,s),1.38(6H,d,J=6.0Hz).

[0161] <Synthesis of compound (7)> The crude compound (5) obtained in the previous section was added with 20 ml of N,N-dimethylformamide and 4.80 g (48.9 mmol) of potassium acetate and reacted at 90 to 100°C for 3 hours. 20 ml of methanol, 20 ml of water, and 5 ml of 25% aqueous sodium hydroxide solution were added to the reaction solution and reacted under reflux for 1 hour. 35 ml of water was added to the reaction solution, and the precipitated crystals were filtered and dried at 80°C. As a result, 10.33 g (yield 84.6%) of compound (7) was obtained as a light brown powder.

[0162] 1H-NMR(CDCl3) δ: 7.65-7.63(2H,m),7.57(1H,dd,J=8.4Hz,2.0Hz),7.21(1H,d,J=8.0Hz),6.61(1H,t,J=75.2Hz),4.70-4.66(3H,m),1.39(6H,d,J=6.0Hz).

[0163] Production Example 4 (Production of Compound (11)) Compound (11) was produced according to the following reaction scheme.

[0164] [ka]

[0165] <Synthesis of compound (9)> Compound (7) 20.00g (66.8mmol) and N,N-diisopropylethylamine 17.28g (134mmol) were added to ethyl acetate 300ml and cooled, methanesulfonyl chloride 11.48g (100mmol) was poured in and stirred at 10-30℃ for 1 hour. Lithium bromide 17.41g (200mmol) was added and reacted at 20-35℃ for 1 hour. Water 100ml was added to the reaction liquid, the liquid was separated, and the organic layer was concentrated under reduced pressure. Ethyl acetate 300ml was added to the concentrated residue to dissolve it, and it was concentrated under reduced pressure again. N,N-dimethylformamide 200ml and potassium phthalimide 17.33g (93.6mmol) were added to the concentrated residue, and it was reacted at 75-85℃ for 1 hour. Water 200ml was added to the reaction liquid to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80° C. to obtain 25.90 g (yield 90.5%) of compound (9) as a white powder.

[0166] 1 H-NMR(DMSO-d6) δ: 8.22(1H,s),7.94-7.86(4H,m),7.58(1H,d,J=2.0Hz),7.52(1H,dd,J=8.8Hz,2.4Hz),7 .30(1H,d,J=8.4Hz),7.14(1H,t,J=74.2Hz),4.78-4.69(3H,m),1.30(6H,d,J=6.0Hz).

[0167] <Synthesis of compound (10)> Compound (9) 15.00g (35.0mmol) was mixed with 40% methylamine aqueous solution 30ml, methanol 30ml, and water 75ml, and reacted under reflux for 30 minutes. Cyclopentyl methyl ether (CPME) 150ml and 25% sodium hydroxide aqueous solution 15ml were added to the reaction liquid, and the temperature was adjusted to 65-75℃ and the liquids were separated. A mixture of water 150ml and sodium chloride 7.50g was added to the organic layer, and the temperature was adjusted to 65-75℃ again and the liquids were separated. Concentrated hydrochloric acid 3.75ml was added to the organic layer to precipitate crystals. The precipitated crystals were filtered and dried at 60℃ to obtain compound (10) white powder 11.95g (yield quant.).

[0168] 1 H-NMR(DMSO-d6) δ: 8.51(3H,br-s),8.29(1H,s),7.64(1H,d,J=2Hz),7.59(1H,dd,J=8.0Hz,1.6Hz),7.37(1H,d,J =8.4Hz),7.18(1H,t,J=74.0Hz),4.72(1H,sept,J=6.1Hz),4.03(2H,s),1.33(6H,d,J=6.4Hz).

[0169] <Synthesis of compound (11)> 13.30 g (39.7 mmol) of compound (10), 3.83 g (37.8 mmol) of triethylamine, and 108 ml of ethyl acetate were mixed and stirred at 20 to 30 ° C. for 1 hour. 9.78 g (58.9 mmol) of 2-ethoxybenzoic acid and 11.28 g (58.8 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added to the reaction solution, and the mixture was reacted at 20 to 30 ° C. for 1 hour. 54 ml of water and 5.4 ml of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 to 50 ° C. and the mixture was separated. 54 ml of water and 5.4 ml of 25% aqueous sodium hydroxide solution were added to the organic layer, and the temperature was adjusted to 40 to 50 ° C. again and the mixture was separated, and the organic layer was concentrated under reduced pressure. To the concentrated residue, 45 ml of ethanol, 18 ml of water, 5.4 ml of 25% aqueous sodium hydroxide solution, and 0.54 g of activated carbon were added and refluxed for 30 minutes. The activated carbon was filtered off, washed with 11 ml of ethanol, and the filtrate was cooled and then seed crystals were added to precipitate crystals. The precipitated crystals were filtered off and dried at 35°C to obtain 12.88 g (72.6%) of white powder of compound (11).

[0170] 1 H-NMR(CDCl3) δ: 8.56(1H,br-s),8.23(1H,dd,J=7.6Hz,1.6Hz),7.66(1H,s),7.63(1H,d,J=2.0Hz),7 .58(1H,dd,J=8.4Hz,2.0Hz),7.44-7.39(1H,m),7.21(1H,d,J=8.0Hz),7.08-7.04(1 H,mH),6.94(1H,d,J=8.0Hz),6.61(1H,t,J=75.2Hz),4.68(1H,sept,J=6.0Hz),4.62 (2H,d,J=6.0Hz),4.17(2H,q,J=6.93),1.48(3H,t,J=7.2Hz),1.39(6H,d,J=5.6Hz).

[0171] Production Example 5 (Production of Compounds (i) to (ix)) Each compound shown in Table 2 was prepared as follows. 1 The H-NMR results are also shown. Compound (ii) is the same compound as compound (9).

[0172] [Table 2] TIFF2025024065000019.tif130170

[0173] <Synthesis of compound (i)> 13.1 g of 2-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]isoindoline-1,3-dione (2-((2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)oxazol-4-yl)methyl)isoindoline-1,3-dione) synthesized according to the synthesis method described in Patent Document 2 (International Publication No. 2014 / 034958) was dissolved in a mixture of 260 ml of ethanol and 140 ml of DMF, 1.3 g of 10% palladium carbon powder was added, and the mixture was stirred at 40°C under a hydrogen atmosphere for 1 hour. 100 ml of methylene chloride was added to the reaction solution and stirred, after which the catalyst was removed by filtration, and the crude crystals obtained by concentrating the filtrate were recrystallized from ethyl acetate to give 2-[2-(4-difluoromethoxy-3-hydroxyphenyl)oxazol-4-ylmethyl]isoindoline-1,3-dione (2-((2-(4-(d ifluoromethoxy-3-hydroxyphenyl)oxazol-4-yl)methyl)isoindoline-1,3-dione: 8.8 g of compound (i) was obtained as a white powder.

[0174] 1 H-NMR (CDCl3) δ: 8.18 ( 1H, br-s) 7.85-8.17 ( 5H, m ) 6.89-7.51 (4H, m ) 4.74 ( 2H, s ).

[0175] <Synthesis of compound (ii)> Compound (i) 2g and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) 3.9ml were dissolved in ethanol 20ml, and 3.18g of isopropyl bromide was added and the mixture was heated and refluxed overnight. Next, 1ml of 10% sodium hydroxide solution was added to the reaction solution, and the mixture was heated and refluxed for 30 minutes, after which ice water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and then concentrated under reduced pressure to obtain [2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-yl)methyl]isoindoline-1,3-dione (2-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)isoindoline-1,3-dione: compound (ii)).

[0176] 1 H-NMR (CDCl3) δ: 7.85-7.92 ( 2H, m ) 7.71-7.77 ( 2H, m ) 7.68 ( 1H, s ) 7.61 ( 1H, d, J = 2.1Hz ) 7.55 ( 1H, dd, J = 8.4Hz, 2.1Hz ) 7.18 ( 1H, d, J = 8.4Hz ) 6.60 ( 1H, t, J = 75Hz ) 4.86 ( 2H, d, J = 1.2Hz ) 4.68 ( 1H, sept, J = 6.0Hz) 1.38 ( 6H, d, J = 6.0Hz ).

[0177] <Synthesis of compound (iii)> 1.58 g of compound (ii) was dissolved in 16 ml of methanol, 3.2 ml of aqueous methylamine solution (40%) was added, and the mixture was heated under reflux for 1 hour. After concentrating the reaction solution, the reactant was dissolved in ethyl acetate, and the organic layer was washed with 10% aqueous sodium hydroxide solution and water. After separating the organic layer, it was concentrated under reduced pressure to obtain 1.17 g of a brown solid of [2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-yl]methylamine ((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methanamine: compound (iii)).

[0178] 1 H-NMR (CDCl3) δ: 7.65 ( 1H, d, J = 1.8Hz ) 7.58 ( 1H, d, J = 8.4Hz, 1.8Hz ) 7.55 ( 1H, s ) 7.22 ( 1H, d, J = 8.4Hz ) 6.62 ( 1H, t, J = 75Hz ) 4.70 ( 1H, sept, J = 6.3Hz ) 3.85 ( 2H, s ) 1.40 ( 6H, d, J = 6.3Hz ).

[0179] <Synthesis of compound (iv)> 0.24 g of 5-benzyloxy-2-ethoxybenzoic acid and 0.44 g of compound (iii) were suspended in 20 ml of acetone, 0.27 g of 1-hydroxybenzotriazole (HOBt) and 0.38 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added, and the mixture was heated to reflux for 1 hour. The reaction solution was cooled, and the acetone was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (normal hexane:ethyl acetate=3:1). The resulting crude crystals were recrystallized from normal hexane:ethyl acetate to obtain 0.28 g of white powder N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-5-benzyloxy-2-ethoxybenzamide (5-(benzyloxy)-N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-ethoxybenzamide: compound (iv)).

[0180] 1 H-NMR (CDCl3) δ: 8.68 (1H, br-s), 7.76 (1H, d, J = 3 Hz), 7.66-7.57 (3H, m ), 7.38-7.20 (6H, m), 6.97 (1H, dd, J = 3.3, 8.7 Hz), 6.62 (1H, t, J = 75 Hz), 4.71-4.61 (4H, m), 4.05 (2H, q, J = 6.9 Hz), 1.57-1.37 ( 9H, m).

[0181] <Synthesis of compound (v)> 5.5 g of [2-(3-benzyloxy)-4-(difluoromethoxy)phenyl)oxazol-4-yl]methanamine (MAP-15211) synthesized according to the synthesis method described in Patent Document 2 (International Publication No. 2014 / 034958 pamphlet) and 3.4 g of acetylsalicylic acid were suspended in 150 ml of acetone, 3.4 g of 1-hydroxybenzotriazole (HOBt) and 4.8 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added, and the mixture was heated and refluxed for 1 hour. Next, 10 ml of 10% aqueous sodium hydroxide solution was added, and the mixture was heated and refluxed for 30 minutes, after which the reaction solution was cooled and acetone was distilled off under reduced pressure, and water was added to the residue and extracted with ethyl acetate. The organic layer was washed twice with water and then concentrated under reduced pressure to obtain 3.1 g of a white powder, N-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-hydroxybenzamide (N-((2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)oxazol-4-yl)methyl)-2-hydroxybenzamide: compound (v)).

[0182] 1 H-NMR (CDCl3) δ: 12.19 (1H, s) 7.70-7.72 (2H, m), 7.63 (1H, dd, J = 8.4, 1.8 Hz), 7.28-7.51 (7H, m), 7.22-7.26 (2H, m), 6.98-7.01 (1H, m), 6.82-6.88 (2H, m), 6.63 (1H, t, J = 74.7 Hz), 5.22 (2H, s), 4.60(2H, dd, J = 5.4, 0.9 Hz).

[0183] <Synthesis of compound (vi)> 3.1 g of compound (v) was dissolved in 45 ml of N,N-dimethylformamide, 1.7 g of 2-bromoethyl acetate and 1.8 g of potassium carbonate were added, and the mixture was heated and stirred at 80° C. for 1 hour. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: normal hexane = 1:1) to obtain 3.6 g of white powder N-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-[(2-acetoxy)ethoxy]benzamide (2-(2-((2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)oxazol-4-yl)methylcarbamoyl)phenoxy)ethyl acetate: compound (vi).

[0184] 1H-NMR (CDCl3) δ: 8.43 (1H, br-s) 8.25 ( 1H, d, J = 8.4 Hz), 7.73 (1H, d, J = 1.8 Hz), 7.68 (1H, s), 7.62 (1H, dd, J = 5.4, 1.8 Hz), 7.34-7.49 (6H, m), 7.24-7.26 (1H, m), 7.09-7.15 (1H, m), 6.93 (1H, d, J = 7.8 Hz), 6.63 (1H, t, J = 74.4 Hz), 5.22(2H, s), 4.65(2H, d, J = 5.7 Hz), 4.50-4.53(2H, m), 4.27-4.32 (2H, m), 2.03 (3H, s).

[0185] <Synthesis of compound (vii)> 3.5 g of compound (vi) was suspended in 100 ml of ethanol, 0.4 g of 10% palladium carbon powder was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. The catalyst was removed by filtration, and the filtrate was concentrated to obtain crude crystals. The crude crystals were recrystallized from ethanol-normal hexane to obtain 2.1 g of white powder, N-[2-(3-hydroxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-[(2-acetoxy)ethoxy]benzamide (2-(2-((2-(4-(difluoromethoxy)-3-hydroxyphenyl)oxazol-4-yl)methylcarbamoyl)phenoxy)ethyl acetate: compound (vii) was obtained.

[0186] 1 H-NMR (CDCl3) δ: 8.45 (1H, br-s), 8.25 (1H, d, J = 8.4 Hz), 7.76(1H, s), 7.66(1H, s), 7.42-7.53 (2H, m), 7.09-7.26 (3H, m), 6.95 (1H, d, J = 7.8 Hz), 6.78 (1H, br-s), 6.64 (1H, t, J = 74.1 Hz), 4.58-4.65(4H, m), 4.31-4.34 (2H, m), 2.11 (2H, s).

[0187] <Synthesis of compound (viii)> 5.1 g of methyl pyruvate and 0.8 ml of bromine were dissolved in 15 ml of 1,2-dimethoxyethane and heated and stirred at 50° C. for 1 hour. After concentrating the reaction solution, the residue was dissolved in 45 ml of 2-methoxyethanol, and 3 g of 3-benzyloxy-4-difluoromethoxybenzamide (3-(benzyloxy)-4-(difluoromethoxy)benzamide) synthesized according to the synthesis method described in Patent Document 1 (International Publication No. 2007 / 058338 pamphlet) was added and heated under reflux for 4 hours. 25 ml of water was added to the reaction solution and stirred overnight at room temperature. The precipitated crystals were filtered and dried under reduced pressure at room temperature to obtain 0.73 g of white crystals of methyl 2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxylate (compound (viii)).

[0188] 1 H-NMR (CDCl3) δ: 8.29 ( 1H, s ) 7.84 ( 1H, d, J = 2.1Hz ) 7.71 ( 1H, dd, J = 8.4Hz, 1.8Hz ) 7.35-7.48 ( 6H, m ) 6.64 ( 1H, t, J = 75Hz ) 5.22 ( 2H, s ) 3.97 ( 3H, s ).

[0189] <Synthesis of compound (ix)> 0.28 g of compound (viii) was dissolved in 5 ml of ethanol, 1 ml of tetrahydrofuran, and 0.5 ml of N,N-dimethylformamide, and 0.03 g of 10% palladium carbon powder was added thereto, followed by stirring at room temperature for 2 hours under a hydrogen atmosphere. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed once with saturated saline and then concentrated under reduced pressure to obtain 0.18 g of white crystals of methyl 2-(4-(difluoromethoxy)-3-hydroxyphenyl)oxazole-4-carboxylate (compound (ix)).

[0190] 1 H-NMR (CDCl3) δ: 8.28 (1H, s), 7.77 (1H, d, J = 1.8 Hz), 7.68 (1H, dd, J = 8.4, 1.8 Hz), 7.21 (1H, d, J = 8.4 Hz), 6.61 (1H, t, J = 72.9 Hz), 5.57 (1H, s), 3.96 (3H, s).

[0191] Production Example 6 (Production of Compounds (11a) to (11s)) Each compound shown in Table 3 was prepared as follows. 1 H-NMR results may also be shown.

[0192] [Table 3] TIFF2025024065000021.tif255170 TIFF2025024065000022.tif37170

[0193] <Synthesis of compound (11a)> 3 g of compound (iii) and 1.5 g of salicylic acid were suspended in 60 ml of acetone, 1.8 g of 1-hydroxybenzotriazole (HOBt) and 2.6 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added, and the mixture was heated to reflux for 1 hour. The reaction solution was cooled, and acetone was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water, and the crude crystals obtained by concentrating under reduced pressure were recrystallized from ethyl acetate-normal hexane to obtain 1.47 g of white powder N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-yl)methyl]-2-hydroxybenzamide (N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-hydroxybenzamide: compound (11a)).

[0194] 1 H-NMR (CDCl3) δ: 12.19 (1H, s), 7.70 (1H, s), 7.50-7.64 (2H, m), 7.37-7.42 (2H, m), 7.23 (1H, d, J = 8.4 Hz), 6.81-7.01 (3H, m), 6.63 (1H, t, J = 75.0 Hz), 4.69 (1H, sept., J = 6.0 Hz), 4.59 (2H, d, J = 5.4 Hz), 1.40 (6H, d, J = 6.0 Hz).

[0195] <Synthesis of compound (11b)> Using 0.44 g of compound (iii) and 0.24 g of 2-ethoxy-3-hydroxybenzoic acid, 0.28 g of white powder of N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy-3-hydroxybenzamide (N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-ethoxy-3-hydroxybenzamide: compound (11b)) was obtained in the same manner as in the above “Synthesis of compound (11a)”.

[0196] 1 H-NMR (CDCl3) δ: 7.97 (1H, br-t, J = 5.1 Hz), 7.70 (1H, s), 7.64 (1H, d, J = 1.8 Hz), 7.52-7.60 (3H, m), 7.23 (1H, d, J = 8.4 Hz), 7.10 (1H, d, J = 2.4 Hz), 7.09 (1H, s), 6.63 (1H, t, J = 75.0 Hz), 4.64-4.72(1H, m), 4.61 (2H, d, J = 5.1 Hz), 4.00 (2H, q, J = 6.9 Hz), 1.38 (3H, t, J = 6.9 Hz).

[0197] <Synthesis of compound (11c)> Compound (iv) was used to synthesize N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy-5-hydroxybenzamide (N-((2-(4-(difluoro (methoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-ethoxy-5-hydroxybenzamide: 5 mg of compound (11c) was obtained as a white powder.

[0198] 1 H-NMR (CDCl3) δ: 8.83 (1H, br), 8.04 (1H, d, J = 3.3 Hz), 7.69 (1H, s), 7.64 (1H, d, J = 1.8 Hz), 7.58 (1H, dd, J = 1.8, 8.4 Hz), 7.21 (1H, d, J = 5.1 Hz), 6.87-6.99 (3H, m), 6.62 (1H, t, J = 75 Hz), 4.61-4.72 (3H, m), 4.12 (2H, q, J = 6.9 Hz), 1.38-1.47 (9H, m)

[0199] <Synthesis of compound (11d)> 0.1 g of compound (11a) was dissolved in 3 ml of N,N-dimethylformamide, and 0.12 g of 2-bromoethyl acetate and 0.14 g of potassium carbonate were added and the mixture was heated and stirred at 80°C for 2 hours. Next, 1 ml of methanol and 0.3 ml of 25% aqueous sodium hydroxide solution were added to the reaction solution and the mixture was heated and refluxed for 1 hour. Ice water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and then concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate-normal hexane to obtain 70 mg of white powder of N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-yl)methyl]-2-(2-hydroxyethoxy)benzamide (N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-(2-hydroxyethoxy)benzamide: compound (11d)).

[0200] 1 H-NMR (CDCl3) δ: 8.67 (1H, br-s) 8.16 (1H, dd, J = 7.8, 1.8 Hz), 7.70-7.74 (2H, m), 7.62 (1H, dd, J = 8.4, 1.8 Hz), 7.40-7.46 (1H, m), 7.24-7.26 (1H, m), 7.06-7.12 (1H, m), 6.94-6.97 (1H, m), 6.65 (1H, t, J = 75.0 Hz), 5.43 (1H, t, J = 6.6 Hz), 4.69-4.77(1H, m), 4.62 (2H, d, J = 5.4 Hz), 4.18-4.21 (2H, m), 3.94-3.99 (2H, m), 1.42 (6H, d, J = 6.3Hz).

[0201] <Synthesis of compound (11e)> 0.3 g of compound (vii) and 0.3 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) were dissolved in 4 ml of ethanol, 0.31 g of ethyl iodide was added, and the mixture was heated and refluxed overnight. Next, 1 ml of 10% aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was heated and refluxed for 30 minutes. Ice water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water, concentrated under reduced pressure, and the obtained crude crystals were recrystallized from ethanol-normal hexane to give N-[2-(3-ethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-(2-hydroxyethoxy)benzamide. 95 mg of a white powder of N-((2-(4-(difluoromethoxy)-3-ethoxyphenyl)oxazol-4-yl)methyl)-2-(2-hydroxyethoxy)benzamide (OPA-15566) was obtained.

[0202] 1 H-NMR (CDCl3) δ: 8.86 (1H, br-s) 8.15 (1H, dd, J = 8.1, 1.8 Hz), 7.74 (1H, d, J = 2.1 Hz),7.70 (1H, s), 7.63(1H, dd, J = 8.1, 2.1 Hz), 7.40-7.46 (2H, m), 7.06- 7.09 (1H, m), 6.90-6.96 (1H, m), 6.66 (1H, t, J = 74.7 Hz), 5.45(1H, brs), 4.62 (2H, d, J = 5.4 Hz), 4.22 (2H, q, J = 6.9 Hz), 4.19 (2H, dd, J = 4.5,4.2 Hz), 3.97 (2H, dd, J = 4.5,4.2 Hz), 1.50 (3H, t, J = 6.9 Hz)

[0203] <Synthesis of compound (11f)> 0.3g of compound (vii) and 0.3ml of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) were dissolved in ethanol, 0.27g of (bromomethyl)cyclopropane was added, and the mixture was heated and refluxed overnight. Next, 1ml of 10% aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was heated and refluxed for 30 minutes. Ice water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methylene chloride). The obtained crude crystals were recrystallized from ethyl acetate-normal hexane to obtain 0.26 g of a white powder of N-[2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-(2-hydroxyethoxy)benzamide (N-((2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-4-yl)methyl)-2-(2-hydroxyethoxy)benzamide: compound (11f)).

[0204] 1 H-NMR (CDCl3) δ: 8.85 (1H, br-s) 8.16 (1H, dd, J = 7.5, 1.8 Hz), 7.61-7.73 (2H, m), 7.40-7.46 (1H, m), 7.24-7.27 (1H, m), 7.06-7.12 (1H, m), 6.72 (1H, t, J = 74.7 Hz), 5.37-5.42(1H, m), 4.18-4.21(2H, m), 3.94-4.01(4H, m),1.32-1.37 (1H, m),0.65-0.71 (2H, m), 0.37-042 (2H, m).

[0205] <Synthesis of compound (11g)> 0.3 g of compound (vii) and 0.3 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) were dissolved in ethanol, 0.28 g of isobutyl bromide was added, and the mixture was heated and refluxed overnight. Next, 1 ml of 10% aqueous sodium hydroxide was added to the reaction solution, and the mixture was heated and refluxed for 30 minutes. After that, ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methylene chloride). The obtained crude crystals were recrystallized with ethyl acetate-normal hexane to obtain 0.15 g of white powder of N-[2-(3-isobutoxy-4-difluoromethoxyphenyl)oxazol-4-yl)methyl]-2-(2-hydroxyethoxy)benzamide (N-((2-(4-(difluoromethoxy)-3-isobutoxyphenyl)oxazol-4-yl)methyl)-2-(2-hydroxyethoxy)benzamide: compound (11g)).

[0206] 1 H-NMR (CDCl3) δ: 8.86 (1H, br-s) 8.16 (1H, dd, J = 7.8, 1.8 Hz), 7.70-7.74 (2H, m), 7.61-7.64 (1H, m), 7.40-7.46 (1H, m), 7.24-7.26 (1H, m), 6.97-6.90 (1H, m), 6.64 (1H, t, J = 75.0 Hz), 5.40 (1H, t, J = 6.6 Hz), 4.62 (2H, d, J = 5.4 Hz), 4.18-4.22(2H, m), 3.90-4.00(4H, m), 2.11-2.25(1H, m), 1.08(6H, d, J = 6.9Hz).

[0207] <Synthesis of compound (11h)> 0.3g of compound (vii) and 0.3ml of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) were dissolved in ethanol, 0.3g of (bromomethyl)cyclobutane was added, and the mixture was heated and refluxed overnight. Next, 1ml of 10% aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was heated and refluxed for 30 minutes. Ice water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methylene chloride). The obtained crude crystals were recrystallized from ethyl acetate-normal hexane to obtain 0.24 g of a white powder of N-[2-(3-cyclobutylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-(2-hydroxyethoxy)benzamide (N-((2-(3-(cyclobutylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-4-yl)methyl)-2-(2-hydroxyethoxy)benzamide: compound (11h)).

[0208] 1 H-NMR (CDCl3) δ: 8.86 (1H, br-s) 8.16 (1H, dd, J = 7.8, 1.8 Hz), 7.63 (1H, dd, J = 8.4, 2.1 Hz), 7.70-7.74 (2H, m), 7.40-7.46 (1H, m), 7.23-7.26 (1H, m), 7.07-7.12 (1H, m), 6.95 (1H, d, J = 7.8 Hz), 6.65 (1H, t, J = 75.3 Hz), 5.41 (1H, t, J = 6.6 Hz), 4.62 (2H, d, J = 5.4 Hz), 4.20 (2H, dd, J = 4.5, 4.2 Hz), 4.11(2H, d, J = 6.6 Hz), 3.96-4.01 (2H, m), 2.80-2.90(1H, m), 2.13-2.20(2H, m), 1.88-2.02 (4H, m).

[0209] <Synthesis of compound (11i)> 0.28 g of compound (iii) and 0.17 g of 2,3-dihydroxybenzoic acid were suspended in 3 ml of acetone, 0.17 g of 1-hydroxybenzotriazole (HOBt) and 0.23 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added, and the mixture was heated under reflux for 3 hours. The reaction solution was cooled, and acetone was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water, and then concentrated under reduced pressure. The resulting residue was crudely purified by silica gel column chromatography (dichloromethane:methanol=50:1). The obtained crude crystals were recrystallized from normal hexane-acetone to obtain 0.2 g of a white powder, N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2,3-dihydroxybenzamide (N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2,3-dihydroxybenzamide: compound (11i)).

[0210] 1 H-NMR (DMSO) δ: 12.54 (1H, s), 9.30 (1H, br-t, J = 5.4 Hz), 9.23 (1H, s), 8.12 (1H, s), 7.61 (1H, d, J = 1.8 Hz), 7.55 (1H, dd, J = 8.4, 1.8 Hz), 7.38-7.28 (2H, m), 7.15 (1H, t, J = 74.1 Hz), 6.95-6.89 (1H, m), 6.69 (1H, t, J = 8.1 Hz), 4.74 (1H, sept., J = 6.0 Hz), 4.45 (2H, d, J = 5.4 Hz), 1.32 (6H, d, J = 6.0 Hz).

[0211] <Synthesis of compound (11j)> Using 0.28 g of compound (iii) and 0.17 g of 2,4-dihydroxybenzoic acid, 0.17 g of a white powder, N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2,4-dihydroxybenzamide (N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2,4-dihydroxybenzamide: compound (11j)), was obtained in the same manner as in the above “Synthesis of compound (11i)”.

[0212] 1 H-NMR (DMSO) δ: 12.75 (1H, s), 10.11 (1H, s), 9.05 (1H, br-t, J = 5.4 Hz), 8.10 (1H, s), 7.74 (1H, d, J = 8.7 Hz), 7.61 (1H, d, J = 1.8 Hz), 7.55 (1H, dd, J = 8.4, 1.8 Hz), 7.32 (1H, d, J = 8.4 Hz), 7.16 (1H, t, J = 74.1 Hz), 6.29 (1H, dd, J = 8.7 Hz, 2.4 Hz), 6.24 (1H, d, J = 2.4 Hz), 4.74 (1H, sept., J = 6.0 Hz), 4.42 (2H, d, J = 5.7 Hz), 1.32 (6H, d, J = 6.0 Hz).

[0213] <Synthesis of compound (11k)> Using 0.28 g of compound (iii) and 0.17 g of 2,5-dihydroxybenzoic acid, 0.16 g of white powder N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2,5-dihydroxybenzamide (N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2,5-dihydroxybenzamide: compound (11k)) was obtained in the same manner as in the above "Synthesis of compound (11i)".

[0214] 1 H-NMR (DMSO) δ: 11.47 (1H, s), 9.14 (1H, br-t, J = 5.4 Hz), 8.98 (1H, s), 8.08 (1H, s), 7.61 (1H, d, J = 1.8 Hz), 7.55 (1H, dd, J = 8.4, 1.8 Hz), 7.31 (1H, d, J = 8.4 Hz), 7.29 (1H, d, J = 3.0 Hz), 7.14 (1H, t, J = 74.1 Hz), 6.86 (1H, dd, J = 8.7 Hz), 6.74 (1H, d, J = 8.7 Hz), 4.74 (1H, sept., J = 6.0 Hz), 4.44 (2H, d, J = 5.1 Hz), 1.31 (6H, d, J = 6.0 Hz).

[0215] <Synthesis of compound (11l)> Using 0.28 g of compound (iii) and 0.17 g of 2,6-dihydroxybenzoic acid, 0.2 g of white powder N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2,6-dihydroxybenzamide (N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2,6-dihydroxybenzamide: compound (11l)) was obtained in the same manner as in the above "Synthesis of compound (11i)".

[0216] 1H-NMR (DMSO) δ: 12.51 (1H, s), 9.32 (1H, br-t, J = 5.4 Hz), 8.11 (1H, s), 7.62 (1H, d, J = 1.8 Hz), 7.56 (1H, dd, J = 8.4, 1.8 Hz), 7.32 (1H, d, J = 8.4 Hz), 7.18 (1H, t, J = 8.1 Hz), 7.14 (1H, t, J = 74.1 Hz), 6.37 (2H, d, J = 8.1 Hz), 4.74 (1H, sept., J = 6.0 Hz), 4.52 (2H, d, J = 5.4 Hz), 1.32 (6H, d, J = 6.0 Hz).

[0217] <Synthesis of compound (11m)> 0.2 g of compound (11a) was dissolved in 2 ml of acetonitrile, and 0.23 g of sodium iodide, 0.27 g of potassium carbonate, and 98 mg of 3-chloropropyl acetate were added and the mixture was heated under reflux overnight. 2 ml of 10% aqueous sodium hydroxide solution was further added and the mixture was heated under reflux until the reaction was completed. After cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate and washed twice with water, and the organic layer was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (normal hexane: ethyl acetate = 3:1), and the obtained crude crystals were recrystallized from ethanol-normal hexane to obtain 0.15 g of white powder of N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-yl)methyl]-2-(3-hydroxypropoxy)benzamide (N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-(3-hydroxypropoxy)benzamide: compound (11m)).

[0218] 1H-NMR (CDCl3) δ: 9.11 (1H, br-t, J = 6.0 Hz), 8.21 (1H, dd, J = 8.4, 1.8 Hz), 7.72 (1H, s), 7.61 (1H, d, J = 1.8 Hz), 7.57 (1H, dd, J = 8.4, 1.8Hz), 7.38-7.44 (1H, m), 7.26-7.23 (1H, m), 7.03-7.08 (1H, m), 6.96 (1H, d, J = 8.4 Hz), 6.63 (1H, t, J = 75.0 Hz), 4.69 (1H, sept., J = 6.0 Hz), 4.59 (2H, d, J = 6.0 Hz), 4.29 (2H, t, J = 5.4 Hz), 3.89-3.94 (2H, m), 2.07-2.13 (2H, m), 1.41 (6H, d, J = 6.0Hz).

[0219] <Synthesis of compound (11n)> 0.18 g of compound (ix) was dissolved in 2 ml of N,N-dimethylformamide, 0.18 g of potassium carbonate and 0.12 ml of isopropyl bromide were added, and the mixture was stirred at room temperature for 16 hours and at 45°C for 4 hours. Water was added under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed once with saturated saline, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (normal hexane:ethyl acetate=2:1) ​​to obtain 0.16 g of white powder of methyl 2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazole-4-carboxylate (compound (11n)).

[0220] 1 H-NMR (CDCl3) δ: 8.28 (1H, s), 7.74 (1H, d, J = 1.8 Hz), 7.66 (1H, dd, J = 8.4, 1.8 Hz), 7.25 (1H, d, J = 8.4 Hz), 6.63 (1H, t, J = 74.7 Hz),4.71 (1H, sept., J = 6.0 Hz), 3.96 (3H, s), 1.39 (6H, d, J = 6.0 Hz).

[0221] <Synthesis of compound (11o)> 0.7 g of compound (11n) was dissolved in 7 ml of methanol, 1.4 ml of 25% aqueous sodium hydroxide solution was added, and the mixture was heated and refluxed at room temperature for 30 minutes. The reaction solution was cooled with ice and stirred until the pH became 3. Concentrated hydrochloric acid was added so as to obtain a precipitated crystal, which was then filtered off. The crystal was dried under reduced pressure to obtain 2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazole-4-carboxylic acid (compound (11o)).

[0222] 1 H-NMR (CDCl3) δ: 8.38 ( 1H, s ), 7.74 ( 1H, d, J = 1.8 Hz ), 7.66 ( 1H, dd, J = 8.1Hz, 1.8Hz ), 7.25 ( 1H, d, J = 8.1 Hz ), 6.64 ( 1H, t, J = 75 Hz ), 4.72 ( 1H, sept, J = 6.3 Hz ), 1.40 ( 6H, d, J = 6.3 Hz).

[0223] <Synthesis of compound (11p)> Using compound (iii) and 2-ethoxy-6-hydroxybenzoic acid, N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy-6-hydroxybenzamide (N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-ethoxy-6-hydroxybenzamide: compound (11p)) was obtained in the same manner as in the above "Synthesis of compound (11i)".

[0224] 1 H-NMR (CDCl3) δ: 13.81 ( 1H, s ), 9.00 ( 1H, brs ), 7.68-7.62 ( 2H, m ), 7.60 ( 1H, dd, J = 8.4 Hz, 2.1 Hz), 7.30-7.18 ( 2H, m ), 6.63 ( 1H, t, J = 75 Hz ), 6.61 ( 1H, d, J = 8.4 Hz ), 6.37 ( 1H, d, J = 8.1 Hz ), 4.69 ( 1H, sept, J = 6.0 Hz ), 4.60 ( 2H, dd, J = 5.1 Hz, 0.9 Hz ), 4.15 ( 2H, dd, J = 14.1 Hz, 6.9 Hz ), 1.48 ( 3H, t, J = 6.9 Hz ), 1.40 ( 6H, d, J = 6.3 Hz ).

[0225] <Synthesis of compound (11q)> Using compound (iii) and 2-ethoxy-3,4-dihydroxybenzoic acid, N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy-3,4-dihydroxybenzamide (N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-ethoxy-3,4-dihydroxybenzamide: compound (11q)) was obtained in the same manner as in the above "Synthesis of compound (11i)".

[0226] 1 H-NMR (d6-DMSO) δ: 9.83 ( 1H, brs ), 8.65 ( 1H, brs ), 8.54 ( 1H, t, J = 5.4 Hz ), 8.10 ( 1H, s ), 7.63 ( 1H, d, J = 1.8 Hz ), 7.56 ( 1H, dd, J = 8.4 Hz, 1.8 Hz ), 7.33 ( 1H, d, J = 8.4 Hz ), 7.21 ( 1H, d, J = 8.7 Hz ), 7.15 ( 1H, t, J = 74Hz ), 6.62 ( 1H, d, J = 8.4 Hz ), 4.73 ( 1H, sept, J = 6.0 Hz ), 4.45 ( 2H, d, J = 5.4 Hz ), 4.03 ( 2H, dd, J = 14.1 Hz, 7.2 Hz ), 1.32 ( 6H, d, J = 6.0 Hz ), 1.25 ( 3H, t, J = 7.2 Hz ).

[0227] <Synthesis of compound (11r)> Using 0.1 g of compound (11a) and chlorosulfuric acid, a white powder of ammonium 2-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methylcarbamoyl)phenyl sulfate (compound (11r)) was obtained by a conventional synthesis method. The melting point was 162.0°C.

[0228] <Synthesis of compound (11s)> A conventional synthesis method using 0.1 g of compound (11a), 1-bromo-2,3,4-tri-O-acetyl-α-D-methyl glucuronate and silver oxide gave a white powder of (2S,3S,4S,5R,6S)-6-(2-((2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-yl)methylcarbamoyl)phenyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid ((2S,3S,4S,5R,6S)-6-(2-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methylcarbamoyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid: compound (11s)). The melting point was 163.6°C.

[0229] Production Example 7 (Production of each formulation) <Solvent considerations> In preparing an ointment containing compound (11), the solubility of compound (11) in various solvents was examined in order to select a solvent capable of dissolving compound (11). Furthermore, even if the solubility is high, a solvent that is compatible with a base (ointment base) such as petrolatum or paraffin may reduce the solubility of compound (11) when mixed with the base, resulting in precipitation of compound (11). Therefore, it is relatively preferable that the solvent used is one in which compound (11) has high solubility and is not or has low miscibility (compatibility) with petrolatum, paraffin, etc. The results of the examination are shown in Table 4.

[0230] [Table 4]

[0231] From Table 4, it can be seen that triacetin and propylene carbonate have low miscibility with Vaseline. Furthermore, the solubility of compound (11) is relatively high in triacetin and propylene carbonate. It was discovered that...

[0232] <Preparation of ointment> Each ointment (Examples 1-10 and Comparative Examples 1-8) was prepared as follows. As mentioned above, a solvent that dissolves compound (11) was found this time. Therefore, all ointments prepared by dissolving compound (11) using a solvent are included in the present invention, but in the following, for convenience, particularly preferred examples among them are classified and labeled as Examples and other examples as Comparative Examples. In addition, the particle size of the droplets was measured by placing an appropriate amount of the prepared ointment on a slide glass and confirming the droplet size with a polarizing microscope.

[0233] Example 1 73.0 g of white petrolatum, 10.0 g of liquid paraffin, 3.0 g of paraffin, and 1.0 g of beeswax (non-chemically bleached white beeswax) were dissolved by heating in an Ajihomomixer at 70°C, and then a solution of 3.0 g of compound (11) dissolved in 10.0 g of propylene carbonate was further added, and the mixture was stirred at 5000 rpm with a paddle at 30 rpm, and then the homomixer was stopped at 45°C, and the paddle and cooling were stopped at 40°C, respectively, to reduce the droplet size to 20 μm or less. Then, 5 g of the mixture was filled into aluminum tubes using a filling machine YS-7, and the tubes were sealed to obtain ointments.

[0234] Example 2 An ointment was obtained in the same manner as in Example 1, except that the amount of white petrolatum was changed to 72.0 g and the amount of beeswax was changed to 2.0 g.

[0235] Example 3 An ointment was obtained in the same manner as in Example 1, except that the amount of white petrolatum was changed to 70.5 g and the amount of beeswax was changed to 3.5 g.

[0236] Example 4 An ointment was obtained in the same manner as in Example 1, except that the amount of white petrolatum was changed to 81.0 g, the amount of compound (11) was changed to 1.0 g, and the amount of propylene carbonate was changed to 4.0 g.

[0237] Example 5 An ointment was obtained in the same manner as in Example 4, except that the amount of white petrolatum was changed to 80.0 g and the amount of beeswax was changed to 2.0 g.

[0238] Example 6 An ointment was obtained in the same manner as in Example 4, except that the amount of white petrolatum was changed to 78.5 g and the amount of beeswax was changed to 3.5 g.

[0239] Example 7 An ointment was obtained in the same manner as in Example 6, except that the amount of white petrolatum was changed to 79.2 g and the amount of compound (11) was changed to 0.3 g.

[0240] Example 8 An ointment was obtained in the same manner as in Example 6, except that the amount of white petrolatum was changed to 79.4 g and the amount of compound (11) was changed to 0.1 g.

[0241] Example 9 70.5 g of white petrolatum, 10.0 g of liquid paraffin, 3.0 g of paraffin, and 3.5 g of beeswax (chemically bleached white beeswax) were dissolved by heating at 70°C in an ajihomomixer, and then a solution of 3.0 g of compound (11) dissolved in 10.0 g of propylene carbonate was added. After stirring at 5000 rpm with a homomixer and 30 rpm with a paddle, the homomixer was stopped at 45°C, the paddle was stopped at 40°C, and the cooling was stopped to reduce the droplet size to 20μm or less. After that, 5g of each was filled into aluminum tubes using a filling machine YS-7, and the tubes were sealed to obtain ointments.

[0242] Example 10 An ointment was obtained in the same manner as in Example 3, except that the amount of white petrolatum was changed to 73.5 g and the amount of propylene carbonate was changed to 7.0 g.

[0243] Comparative Example 1 An ointment was obtained in the same manner as in Example 4, except that the beeswax in Example 4 was not added and the amount of white petrolatum was changed to 82.0 g.

[0244] Comparative Example 2 58.5g of white petrolatum, 6.0g of paraffin, 6.0g of beeswax, and 5.0g of diethyl sebacate were heated and dissolved in a 200mL beaker at 70℃ by manual stirring. After cooling to 50℃, 17g of liquid paraffin was added and heated to 50℃. 13g of paste containing 10g of liquid paraffin and 3g of micronized compound (11) was added and mixed well by manual stirring at 50℃. The mixture was cooled to room temperature with ice water. Then, 5g of the mixture was filled into aluminum tubes using a filling machine YS-7 to obtain ointments.

[0245] The compound (11) was micronized by adding the compound (11) to liquid paraffin and pulverizing it with a Dyno Mill (beads mill). The paste obtained by this operation was used.

[0246] Comparative Example 3 An ointment was obtained in the same manner as in Example 3, except that the amount of white petrolatum was changed to 75.5 g and the amount of propylene carbonate was changed to 5.0 g.

[0247] Comparative Example 4 An ointment was obtained in the same manner as in Example 6, except that the amount of white petrolatum was changed to 80.5 g and the amount of propylene carbonate was changed to 2.0 g.

[0248] Comparative Example 5 An ointment was obtained in the same manner as in Example 6, except that the amount of white petrolatum in Example 6 was changed to 79.5 g and compound (11) was not added.

[0249] Comparative Example 6 An ointment having a droplet size of about 50 μm was prepared in the same manner as in Example 3, except that the homomixer was stirred at 1,500 rpm and the paddle was stirred at 15 rpm.

[0250] Comparative Example 7 An ointment having a droplet size of about 50 μm was prepared in the same manner as in Example 6, except that the homomixer was stirred at 1,500 rpm and the paddle was stirred at 15 rpm.

[0251] Comparative Example 8 An ointment having a droplet size of about 50 μm was prepared in the same manner as in Example 7, except that the homomixer was stirred at 1,500 rpm and the paddle was stirred at 15 rpm.

[0252] The formulations of the above preparations are shown in Table 5.

[0253] [Table 5]

[0254] Formulation stability study 1 The ointments prepared in Comparative Example 1, Example 4, Example 5, and Example 6 were left to stand at 40°C for 2 months, and the dispersion state of the propylene carbonate solution in each preparation was confirmed. The results are shown in Table 6. It was found from Table 6 that beeswax maintained a uniform dispersion state and improved stability.

[0255] [Table 6]

[0256] Formulation stability study 2 The ointments prepared in Comparative Example 1 and Examples 1 to 6 are preparations with different amounts of beeswax added. Stability tests were carried out on these preparations at 50°C for 2, 4 or 6 weeks. The degree of decomposition of compound (11) was measured by high performance liquid chromatography to measure the amount of 3-(2-propoxy 3-difluoromethoxy)benzamide, one of the decomposition products. The results are shown in Table 7. The values ​​in Table 7 are the concentrations (wt%) of compound (11), beeswax and the decomposition product in the preparation. Comparative Example 1, which does not contain beeswax, produced about 1% of the decomposition product, whereas the production was suppressed in the preparation containing beeswax.

[0257] [Table 7]

[0258] Formulation stability study 3 As beeswax, unbleached beeswax, bleached by non-chemical refining (non-chemically bleached) white beeswax, and chemically bleached (chemically bleached) white beeswax were used to prepare formulations according to the formula of Example 3, which were then filled into aluminum tubes, sealed, and stored at 50°C for 2, 4, or 8 weeks. The stability of compound (11) was examined in the same manner as above, using the generation of a decomposition product of compound (11) (3-(2-propoxy 3-difluoromethoxy)benzamide) as an indicator. The results are shown in Table 8. It was found that the use of chemically bleached white beeswax resulted in a large amount of the decomposition product, while non-chemically bleached white beeswax and unbleached beeswax suppressed the generation of the decomposition product.

[0259] [Table 8]

[0260] Formulation stability study 4 Ointment preparations containing compound (11) with different amounts of beeswax were prepared, and an appropriate amount of the ointment was placed on a slide glass, and the droplet size was confirmed under a polarizing microscope to determine the amount of beeswax required to obtain an ointment in which the droplets were well dispersed. Each ointment (Examples 11 to 19 and Comparative Examples 9 to 11) was prepared as follows. All ointments containing beeswax are included in the present invention, but in the following, particularly preferred examples are referred to as Examples, and other examples are referred to as Comparative Examples for convenience.

[0261] Example 11 141.0g of white petrolatum, 20.0g of liquid paraffin, 6.0g of paraffin, and 7.0g of beeswax (non-chemically bleached white beeswax) were dissolved in an Ajihomomixer at 70°C, and then a solution of 6.0g of compound (11) dissolved in 20.0g of propylene carbonate was added, and the mixture was stirred at 5000rpm with a paddle at 30rpm and cooled. After stopping the homomixer at 45°C and the paddle and cooling at 40°C, 5g of the mixture was filled into aluminum tubes using a filling machine YS-7 and sealed to obtain ointments.

[0262] Example 12 An ointment was obtained in the same manner as in Example 11, except that the amount of white petrolatum was changed to 146.0 g and the amount of beeswax was changed to 2.0 g.

[0263] Example 13 An ointment was obtained in the same manner as in Example 11, except that the amount of white petrolatum was changed to 146.4 g and the amount of beeswax was changed to 1.6 g.

[0264] Example 14 An ointment was obtained in the same manner as in Example 11, except that the amount of white petrolatum was changed to 146.8 g and the amount of beeswax was changed to 1.2 g.

[0265] Comparative Example 9 An ointment was obtained in the same manner as in Example 11, except that the amount of white petrolatum was changed to 147.2 g and the amount of beeswax was changed to 0.8 g.

[0266] Comparative Example 10 An ointment was obtained in the same manner as in Example 11, except that the amount of white petrolatum was changed to 147.6 g and the amount of beeswax was changed to 0.4 g.

[0267] Example 15 157.0g of white petrolatum, 20.0g of liquid paraffin, 6.0g of paraffin, and 7.0g of beeswax (non-chemically bleached white beeswax) were dissolved by heating in an Ajihomomixer at 70°C, and then a solution of 2.0g of compound (11) dissolved in 8.0g of propylene carbonate was further added, and the mixture was stirred at 5000rpm with a paddle at 30rpm with a homomixer, and then cooled. After stopping the homomixer at 45°C and the paddle and cooling at 40°C, 5g of the mixture was filled into aluminum tubes using a filling machine YS-7, and sealed to obtain ointments.

[0268] Example 16 An ointment was obtained in the same manner as in Example 15, except that the amount of white petrolatum was changed to 162.0 g and the amount of beeswax was changed to 2.0 g.

[0269] Example 17 An ointment was obtained in the same manner as in Example 15, except that the amount of white petrolatum was changed to 162.4 g and the amount of beeswax was changed to 1.6 g.

[0270] Example 18 An ointment was obtained in the same manner as in Example 15, except that the amount of white petrolatum was changed to 162.8 g and the amount of beeswax was changed to 1.2 g.

[0271] Example 19 The same procedure as in Example 15 was repeated except that the amount of white petrolatum was changed to 163.2 g and the amount of beeswax was changed to 0.8 g. An ointment was obtained in the same manner as in 15.

[0272] Comparative Example 11 An ointment was obtained in the same manner as in Example 15, except that the amount of white petrolatum was changed to 163.6 g and the amount of beeswax was changed to 0.4 g.

[0273] The formulations and the droplet dispersion state in each formulation are shown in Table 9. The units are % by weight. From Table 9, it was found that an ointment with a particularly good droplet dispersion state can be obtained when the ointment contains 3 parts by weight of compound (11) and 0.6 parts by weight or more of beeswax, and when the ointment contains 1 part by weight of compound (11) and 0.4 parts by weight or more of beeswax.

[0274] [Table 9]

Claims

[Claim 1] The following formula (11): 【Chemistry 1】 An ointment comprising an oxazole compound represented by the formula:

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