Ointment

Abstract

The present invention relates to an ointment. The ointment contains an oxazole compound represented by the following formula (11). The ointment can be effectively absorbed into the skin.

Description

[0001] This application is a divisional application of international application PCT / JP2016 / 088843, which entered the Chinese national phase on June 27, 2018, with application number 201680076557.0 and invention title "Ointment". Technical Field

[0002] This invention relates to an ointment containing an oxazole compound. Background Technology

[0003] PTLs 1 and 2 report an oxazole compound with specific inhibitory activity against phosphodiesterase 4 (PDE4) and a method for producing the oxazole compound. PDE4 is predominant in inflammatory cells. Inhibition of PDE4 increases intracellular cAMP levels, and the increased cAMP levels downregulate the inflammatory response through the expression of TNF-α, IL-23, or other inflammatory cytokines. Increased cAMP levels also increase anti-inflammatory cytokines (e.g., IL-10). Therefore, this oxazole compound is considered suitable for use as an anti-inflammatory agent. For example, this oxazole compound is considered useful for reducing or eliminating eczema or dermatitis, including atopic dermatitis.

[0004] However, to date, there is no ointment that stably contains oxazole compounds with specific inhibitory activity against PDE4 and can be effectively absorbed into the skin.

[0005] List of cited references

[0006] Patent documents

[0007] [PTL 1] WO 2007 / 058338 booklet (JP 2009-515872 A)

[0008] [PTL 2] WO 2014 / 034958 Booklet (JP 2015-528433 A) Summary of the Invention

[0009] Technical issues

[0010] The object of the present invention is to provide an ointment that stably contains an oxazole compound having specific inhibitory activity against PDE4 and can be effectively absorbed into the skin.

[0011] Solution to the problem

[0012] The inventors discovered that dissolving a specific oxazole compound, which is an oxazole compound with specific inhibitory activity against PDE4, in a specific solvent and dissolving or dispersing it in a matrix material, provides a stable ointment containing that specific oxazole compound that can be effectively absorbed into the skin. The inventors further modified and perfected this invention.

[0013] Specifically, the present invention includes, for example, the following topics.

[0014] Item 1. An ointment comprising an oxazole compound represented by the following chemical formula (11): [Chemical Formula 1] .

[0015] Project 2. The ointment according to Project 1, comprising the oxazole compound dissolved in the base components.

[0016] Project 3. The ointment according to Project 2, wherein the base component comprises a solvent for dissolving the oxazole compound in the solvent, and an ointment base for dispersing or dissolving the solvent in the ointment base.

[0017] Item 4. The ointment according to Item 3, wherein the ointment base contains hydrocarbons (preferably at least one hydrocarbon selected from the group consisting of petrolatum, paraffin, wax and beeswax).

[0018] Item 5. The ointment according to Item 3 or 4, wherein the solvent comprises a polar compound that is liquid at room temperature (preferably, at least one member selected from the group consisting of: ethylene carbonate, propylene carbonate, benzyl alcohol, glyceryl triacetate, N-methylpyrrolidone, diethyl sebacate, diisopropyl sebacate, diethyl adipate, diisopropyl adipate, isostearyl alcohol, and isopropyl myristate).

[0019] Item 6. The ointment according to any one of Items 3 to 5, wherein the ointment base is an ointment base for dispersing the solvent in the ointment base, and the solvent containing the oxazole compound dissolved in droplets is dispersed in the ointment base.

[0020] Item 7. The ointment according to any one of Items 3 to 6, wherein the ointment base contains at least beeswax.

[0021] Item 8. The ointment according to Item 7, wherein the beeswax is not chemically bleached.

[0022] Item 9. An ointment according to any one of Items 1 to 8, for use in the treatment and / or prevention of eczema and dermatitis (preferably atopic dermatitis).

[0023] Item 10. An ointment comprising: (I) Oxazole compounds represented by chemical formula (11), (II) A solvent comprising at least one member selected from the group consisting of ethylene carbonate, propylene carbonate, benzyl alcohol, and glyceryl triacetate, and (III) Beeswax, Component (II) of component (I) is dissolved in droplets and dispersed in component (III), and these droplets have an average particle size of 100 μm or less.

[0024] Project A. A method for producing a compound represented by chemical formula (3).

[0025] [Chemical Formula 2]

[0026] Where X 1 Represents halogen, and R 1 Indicating alkali metals or lower alkyl groups, the method includes: (a) To make the compound represented by chemical formula (1a) react with the compound represented by chemical formula X 1 CF2COOR 1 The compound represented by it reacts to produce the compound represented by chemical formula (2); and (b) Oxidize the compound represented by chemical formula (2) to produce the compound represented by chemical formula (3).

[0027] Project B. A method for producing a compound represented by chemical formula (3).

[0028] [Chemical Formula 3]

[0029] Where X 2 The method for representing halogens includes: (a) To make the compound represented by chemical formula (1b) react with the compound represented by chemical formula X 2 The compound represented by CH(CH3)2 reacts to produce the compound represented by chemical formula (2), and (b) Oxidize the compound represented by chemical formula (2) to produce the compound represented by chemical formula (3).

[0030] Beneficial effects of the invention

[0031] The ointment according to the invention stably contains an oxazole compound with specific inhibitory activity against PDE4, and the ointment can be effectively absorbed into the skin. Detailed Implementation

[0032] The ointment according to the invention contains a specific oxazole compound, which is preferably dissolved in the base component. The oxazole compound may be included in the ointment as an active ingredient. The base component, as used herein, includes a solvent for dissolving the oxazole compound in a solvent and one or more other ointment bases. The ointment base is preferably an ointment base in which the solvent can be dispersed or dissolved.

[0033] In other words, the ointment according to the invention comprises (I) a specific oxazole compound, which is preferably dissolved in a matrix component, and the matrix component comprises (II) a solvent for dissolving the oxazole compound in a solvent and (III) an ointment matrix.

[0034] More preferably, the ointment according to the invention is an ointment in which component (II), which contains component (I) dissolved in droplets, is dissolved in or dispersed in component (III).

[0035] Examples of oxazole compounds (I) include compounds represented by the following chemical formulas (11) and (11a) to (11s). In particular, compounds represented by chemical formula (11) are preferred.

[0036] [Chemical Formula 4]

[0037] [Table 1]

[0038] These oxazole compounds can be used alone or in combination of two or more. Specifically, the ointment of the present invention comprises at least one oxazole compound selected from the group consisting of compounds represented by chemical formulas (11) and (11a) to (11s).

[0039] Although there are no particular limitations, the oxazole compound (I) is preferably present in the ointment in an amount of 0.01 to 10 parts by weight, more preferably 0.05 to 7.5 parts by weight, and still more preferably 0.1 to 5 parts by weight per 100 parts by weight of ointment.

[0040] As described above, the oxazole compound is preferably dissolved in solvent (II). Preferably, the solvent is a polar compound that is liquid at room temperature. Specific examples of such solvents include ethylene carbonate, propylene carbonate, benzyl alcohol, glyceryl triacetate, diethyl sebacate, diisopropyl sebacate, diethyl adipate, diisopropyl adipate, isostearic acid, olive oil, hexyldodecyl alcohol, decyl oleate, isostearyl alcohol, and isopropyl myristate. More preferably, ethylene carbonate, propylene carbonate, benzyl alcohol, and glyceryl triacetate are used, and still more preferably, propylene carbonate and glyceryl triacetate are used. Among these, propylene carbonate is preferred. These solvents can be used alone or in combination of two or more. In particular, it is preferred to use ethylene carbonate or propylene carbonate alone, or a combination of ethylene carbonate or propylene carbonate with benzyl alcohol and / or glyceryl triacetate.

[0041] Solvent (II) is preferably present in the ointment in an amount of more than 2 parts by weight, more preferably 2.1 parts by weight or more, and still more preferably 2.2 parts by weight or more per part by weight of oxazole compound (I). The upper limit of the amount of solvent (II) is not particularly limited as long as the effects of the present invention are achieved. For example, the upper limit is preferably 30 parts by weight or less, more preferably 20 parts by weight or less, and still more preferably 15 parts by weight or less.

[0042] Solvent (II) is preferably present in the ointment in an amount of 0.1 to 50 parts by weight, more preferably 0.2 to 25 parts by weight, and still more preferably 0.5 to 20 parts by weight per 100 parts by weight of ointment.

[0043] The solution of the oxazole compound in the solvent is preferably dissolved or dispersed in the ointment matrix (III) in droplet form, and more preferably dispersed in the ointment matrix (III) in droplet form.

[0044] Known ointment bases used in ointment production can be used as ointment bases (III). Examples of ointment bases include hydrocarbons, and more specifically, oil and fat bases, particularly natural waxes, petroleum waxes, and other hydrocarbons. Examples of natural waxes include beeswax (e.g., unbleached beeswax, non-chemically bleached beeswax, and chemically bleached beeswax) and carnauba wax. Examples of petroleum waxes include paraffin wax and microcrystalline wax. Examples of other hydrocarbons include liquid paraffin and petrolatum (e.g., white petrolatum and yellow petrolatum). These ointment bases can be used alone or in combination of two or more.

[0045] The ointment base (III) is preferably present in the ointment in an amount of 5 to 5000 parts by weight, more preferably 10 to 2500 parts by weight, and still more preferably 20 to 1000 parts by weight of oxazole compound (I).

[0046] The ointment base (III) is preferably present in the ointment in an amount of 50 to 99 parts by weight, more preferably 70 to 98 parts by weight, and still more preferably 80 to 97 parts by weight / 100 parts by weight.

[0047] The ointment base (III) preferably contains at least beeswax. The beeswax supplied for use is preferably unbleached beeswax, including, for example, non-bleached beeswax (non-chemically bleached beeswax) and unbleached beeswax (unbleached beeswax).

[0048] The beeswax in the ointment is preferably present in an amount of 0.05 to 50 parts by weight, more preferably 0.1 to 40 parts by weight, and still more preferably 0.2 to 35 parts by weight of oxazole compound (I).

[0049] Beeswax is preferably present in the ointment in an amount of 0.1 to 10 parts by weight, more preferably 0.2 to 9 parts by weight, still 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 ointment.

[0050] When other ointment bases are combined with beeswax, the combination is not particularly limited. However, for example, the combination preferably contains at least one member selected from the group consisting of: petrolatum (preferably white petrolatum), liquid paraffin, and paraffin and beeswax.

[0051] In addition to the ointment base, the ointment may also contain other additives (especially pharmaceutical additives) used in the ointment, such as fragrance ingredients, colorants, preservatives, absorption enhancers including higher olefinic acids (e.g., octadecenoic acid), or drugs effective in treating other skin conditions.

[0052] As described above, the ointment of the present invention is preferably an ointment in which a solvent (II) in which the oxazole compound (I) is dissolved is dissolved or dispersed in droplets in an ointment matrix (III). Examples of methods for producing such an ointment include a method comprising preparing a solution of component (I) in component (II) and mixing the solution with component (III) under stirring. The mixing under stirring can be performed using, for example, a homogenizer, a paddle mixer, or a combination of these mixers.

[0053] When using multiple types of ointment bases (component (III)), it is preferable to premix the multiple ointment bases. In formulations containing multiple types of ointment bases (component (III), it is preferable to mix the ointment bases under heating to melt solids (such as beeswax). For example, when beeswax is used in combination with other ointment bases, it is preferable to premix the beeswax and other ointment bases, preferably under heating.

[0054] In the case of an ointment in which component (II), containing dissolved component (I), is dispersed in component (III) as droplets, the droplet size observed under a polarizing microscope is 100 μm or smaller, preferably about 40 μm or smaller, more preferably about 25 μm or smaller, and still more preferably about 20 μm or smaller. In particular, it is preferable that there are no droplets with a diameter exceeding 100 μm, more preferably that there are no droplets with a diameter exceeding 40 μm, still more preferably that there are no droplets with a diameter exceeding 25 μm, and even more preferably that there are no droplets with a diameter exceeding 20 μm. The desired average droplet size is achieved by adjusting the stirring speed at which the solution and component (III) are mixed under stirring.

[0055] The oxazole compound represented by chemical formula (11) is a known compound disclosed in PTL 1 and 2 and can be produced according to the procedure described in PTL 1 or 2.

[0056] Oxazole compounds represented by chemical formula (11) can be generated as described below. Compounds used as starting materials are known or readily generated from known compounds.

[0057] Specifically, compound (3) is synthesized first, and then compound (7) is synthesized from compound (3). Subsequently, compound (11) is synthesized from compound (7). In this specification, a compound represented by chemical formula A may be represented as compound A or compound (A).

[0058] [Chemical Formula 5]

[0059] The generation of compound (3)

[0060] Compound (3) can be produced by reaction steps described, for example, in the following reaction scheme.

[0061] [Chemical Formula 6]

[0062] Compound (1a) + Compound X 1 CF2COOR 1 → Compound (2)

[0063] This can be achieved by reacting compound (1a) with compound X. 1 CF2COOR 1 The reaction takes place in the presence of a base to produce compound (2).

[0064] In compound X 1 CF2COOR 1 In the middle, X 1The term indicates a halogen, and the halogen includes fluorine, chlorine, bromine and iodine, preferably chlorine, bromine and iodine, and more preferably chlorine.

[0065] R 1 This indicates an alkali metal or a lower alkyl group. The alkali metal includes lithium, sodium, and potassium, with sodium being preferred. The lower alkyl group includes C1-C6 (especially C1-C4) straight-chain or branched alkyl groups. 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, with methyl and ethyl being preferred.

[0066] This reaction can be carried out in the presence of common solvents. The solvent can be any solvent that does not adversely affect the reaction. Examples of such solvents include ketone solvents (e.g., acetone and methyl ethyl ketone), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, and diethylene glycol dimethyl ether), ester solvents (e.g., methyl acetate and ethyl acetate), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide), halocarbon solvents (e.g., dichloromethane and vinyl chloride), and combinations of these solvents. The solvent is preferably N,N-dimethylformamide.

[0067] The base used can be a known inorganic or organic base. Examples of inorganic bases include alkali metals (e.g., sodium and potassium), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate), alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide), alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate), lower alkali metal (C1-C3) alkoxides (e.g., sodium methoxide and sodium ethoxide), and alkali metal hydrides (e.g., sodium hydride and potassium hydride). Examples of organic bases include trialkylamines (e.g., trimethylamine, triethylamine, and N,N-diisopropylethylamine), pyridine, quinoline, piperidine, imidazole, methylpyridine, 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), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). When these bases are liquids, they can also be used as solvents. These bases can be used alone or in combination of two or more. The base is preferably an alkali metal carbonate (particularly sodium carbonate or potassium carbonate).

[0068] The amount of base supplied for use is typically 1 to 10 moles, preferably 1 to 6 moles per mole of the compound (1a).

[0069] The reaction can be carried out by optionally adding an alkali metal iodide (such as potassium iodide or sodium iodide) as a reaction promoter to the reaction system.

[0070] When a reaction accelerator is used, the amount of the reaction accelerator is typically at least 0.01 mol, preferably about 0.1 to 2 mol / mol of X. 1 CF2COOR 1 .

[0071] Compound (1a) and Compound X 1 CF2COOR 1 The proportion is usually at least 1 mole, preferably about 1 to 5 moles of compound X 1 CF2COOR 1 / mole of compound (1a).

[0072] The reaction temperature is not particularly limited, and the reaction can generally be carried out under any of the following conditions: under cooling, at room temperature, or under heating. The reaction is preferably carried out at a temperature of about 80°C to 120°C for 1 to 30 hours.

[0073] Compound (2) → Compound (3)

[0074] Compound (3) can be generated by oxidizing compound (2). Specifically, for example, compound (3) can be generated by reacting compound (2) in a solvent in the presence of an oxidizing agent.

[0075] When compound (2) reacts in a solvent in the presence of an oxidizing agent, examples of solvents available for use include water; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, and ethylene glycol; halogenated hydrocarbons such as dichloromethane, trichloromethane, and carbon tetrachloride; ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether; 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 hexamethylphosphotriamide; and combinations of these solvents.

[0076] Oxidizing agents include halogenated acids, such as chlorite, iodinite, and bromine; alkali metal salts of halogenated acids, such as sodium chlorite, sodium iodite, sodium bromine, potassium chlorite, potassium iodite, and potassium bromine; alkali metal salts of permanganate, such as potassium permanganate; chromic acid or its alkali metal salts, such as chromium oxide (VI), sodium dichromate, and potassium dichromate; and nitric acid. When using alkali metal salts of permanganate, the reaction is preferably carried out in the presence of an inorganic base (such as potassium hydroxide, sodium hydroxide, sodium carbonate, or potassium carbonate). When using chromic acid or its alkali metal salts, the reaction is preferably carried out in the presence of an inorganic acid (such as sulfuric acid) or an organic acid (such as acetic acid). Particularly preferred are halogenated acids and their alkali metal salts.

[0077] The amount of oxidant used is typically 0.5 to 1 mole or more, preferably 1 to 10 moles of compound (2).

[0078] The reaction temperature is typically from about -20°C to 50°C, preferably from about -20°C to room temperature (25°C).

[0079] The reaction time is approximately 1 to 30 hours.

[0080] Compound (3) can be produced by the reaction steps described in the following reaction scheme.

[0081] [Chemical Formula 7]

[0082] Compound (1b) + Compound X 2 CH(CH3)2 → Compound (2)

[0083] It can also be achieved by reacting compound (1a) with compound X. 2 CH(CH3)2 reacts in the presence of a base to produce compound (2).

[0084] In compound X 2 In CH(CH3)2, X 2 The term indicates a halogen, and the halogen includes fluorine, chlorine, bromine and iodine, preferably chlorine, bromine and iodine, and more preferably bromine.

[0085] This reaction can be carried out in the presence of common solvents. The solvent can be any solvent that does not adversely affect the reaction. Examples of such solvents include ketone solvents (e.g., acetone and methyl ethyl ketone), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, and diethylene glycol dimethyl ether), ester solvents (e.g., methyl acetate and ethyl acetate), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide), halocarbon solvents (e.g., dichloromethane and vinyl chloride), and combinations of these solvents. The solvent is preferably N,N-dimethylformamide.

[0086] The base used can be a known inorganic or organic base. Examples of inorganic bases include alkali metals (e.g., sodium and potassium), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate), alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide), alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate), lower alkali metal (C1-C3) alkoxides (e.g., sodium methoxide and sodium ethoxide), and alkali metal hydrides (e.g., sodium hydride and potassium hydride). Organic bases include trialkylamines (e.g., trimethylamine, triethylamine, and N,N-diisopropylethylamine), pyridine, quinoline, piperidine, imidazole, methylpyridine, 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), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). When these bases are liquids, they can also be used as solvents. These bases can be used alone or in combination of two or more. The base is preferably an alkali metal carbonate (particularly sodium carbonate or potassium carbonate).

[0087] The amount of base supplied for use is typically 1 to 10 moles, preferably 1 to 6 moles per mole of the compound (1b).

[0088] The reaction can be carried out by optionally adding an alkali metal iodide (such as potassium iodide or sodium iodide) as a reaction promoter to the reaction system.

[0089] When a reaction accelerator is used, the amount of the reaction accelerator is typically at least 0.01 mol, preferably about 0.1 to 2 mol / mol of X. 2 CH(CH3)2.

[0090] Compound (1b) and compound X for use 2 The proportion of CH(CH3)2 can typically be at least 1 mole, preferably about 1 to 5 moles of compound X. 2 Compound (1b) with CH(CH3)2 / molar.

[0091] The reaction temperature is not particularly limited, and the reaction can generally be carried out under any of the following conditions: under cooling, at room temperature, or under heating. The reaction is preferably carried out at a temperature ranging from about room temperature to about 85°C for 1 to 30 hours.

[0092] The method for generating compound (3) from compound (2) is as described above.

[0093] The generation of compound (7)

[0094] Compound (7) can be produced by reaction steps described, for example, in the following reaction scheme.

[0095] [Chemical Formula 8]

[0096] Compound (3) → Compound (4)

[0097] Compound (4) can be produced by reacting compound (3) with ammonia in a condensation reaction (amidation). This reaction can usually be carried out by reacting compound (3) with ammonia in a solvent in the presence of a condensing agent.

[0098] The solvent can be any solvent that does not adversely affect the reaction. Examples of such solvents include halogenated aliphatic hydrocarbon solvents (e.g., dichloromethane, trichloromethane, and vinyl chloride), ketone solvents (e.g., acetone and methyl ethyl ketone), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether), aromatic hydrocarbons (e.g., toluene and xylene), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide), and combinations of these solvents. The solvent is preferably acetonitrile.

[0099] Examples of such condensing agents include 1,1'-carbonyldiimazole (CDI), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC or WSC), diphenyl azidophosphate (DPPA), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium salts (e.g., benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate), and 2-chloro-4,6-dimethoxytriazine (CDMT). CDI is preferred as the condensing agent.

[0100] The amount of condensing agent used is usually at least 1 mole, preferably about 1 to 5 moles of the compound (3).

[0101] Additives (activators), such as 1-hydroxybenzotriazole (HOBt) and N-hydroxysuccinimide (HOSu), may be used in conjunction with the condensing agent.

[0102] When additives are used, the amount of the additive is typically at least 1 mole, preferably about 1 to 5 moles of condensing agent.

[0103] The reaction can also be carried out by optionally adding a base. Examples of such bases include tertiary amines, such as triethylamine and N,N-diisopropylethylamine; and nitrogen-containing aromatic compounds, such as pyridine and 4-dimethylaminopyridine.

[0104] When using a base, the amount of the base is usually at least 1 mole, preferably about 1 to 5 moles of the compound (5).

[0105] Ammonia is commonly used as ammonia solution. The amount of ammonia supplied for use is usually at least 1 mole, preferably about 1 to 10 moles of the compound (3).

[0106] The reaction is typically carried out by reacting compound (3) with a condensing agent, optionally with an additive, to prepare an activated ester, and by reacting the activated ester with ammonia.

[0107] The reaction temperature for the preparation of the activated ester and subsequent reactions with ammonia is not particularly limited. Preparation and reaction can generally be carried out under any of the following conditions: cooling, at room temperature, or heating. The reaction is preferably carried out at a temperature ranging from freezing temperature to approximately room temperature for 1 to 30 hours.

[0108] Compound (4) → Compound (5)

[0109] This can be achieved by reacting compound (4) with compound CO(CH2X). 3 )2 reacts to produce compound (5).

[0110] In compound CO(CH2X) 3 In 2, X 3 Represents halogens. Derived from X 3 The halogens represented include fluorine, chlorine, bromine, and iodine, with chlorine, bromine, and iodine being preferred.

[0111] This reaction can be carried out in the presence of common solvents. The solvent can be any solvent that does not adversely affect the reaction. Examples of such solvents include halogenated aliphatic hydrocarbon solvents (e.g., dichloromethane, trichloromethane, and vinyl chloride), ketone solvents (e.g., acetone and methyl ethyl ketone), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether), aromatic hydrocarbons (e.g., toluene and xylene), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide), and combinations of these solvents. The solvent is preferably an aromatic hydrocarbon (e.g., toluene and xylene).

[0112] Compound (4) and compound CO(CH2X) are available for use. 3 The proportion of CO(CH2X) is usually at least 1 mole, preferably about 1 to 5 moles of the compound. 3 )2 / molar of compound (4).

[0113] Optionally, a dehydrating agent may be used. Examples of such dehydrating agents include synthetic zeolites, specifically molecular sieves (MS) 3A, MS4A, and other similar zeolites with fine pores.

[0114] The reaction temperature is not particularly limited, and the reaction can generally be carried out under any of the following conditions: cooling, at room temperature, or heating. The reaction is preferably carried out for 1 to 30 hours at a temperature ranging from about room temperature to about 200°C. This method enables the formation of oxazole rings in high yields.

[0115] Compound (5) → Compound (6)

[0116] This can be achieved by reacting compound (5) with compound R. 2 OM 1 A reaction is carried out to produce compound (6). In compound R 2 OM 1 In the middle, R 2 It represents an alkyl acyl group, and M 1 It represents alkali metals.

[0117] By R 2 The alkanoyl group represented includes C1-C6 (especially C1-C4) straight-chain or branched alkanoyl groups. Specific examples of this alkanoyl group include formyl, acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, sec-butyryl, tert-butyryl, and hexanoyl, with formyl, acetyl, n-propionyl, and isopropionyl being preferred, and acetyl being more preferred.

[0118] By M 1 The alkali metals represented include lithium, sodium, and potassium, with sodium and potassium being preferred. Compound R 2 OM 1 Specific examples include sodium acetate and potassium acetate.

[0119] This reaction can be carried out in the presence of common solvents. The solvent can be any solvent that does not adversely affect the reaction. Examples of such solvents include ketone solvents (e.g., acetone and methyl ethyl ketone), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, and diethylene glycol dimethyl ether), ester solvents (e.g., methyl acetate and ethyl acetate), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide), halocarbon solvents (e.g., dichloromethane and vinyl chloride), and combinations of these solvents. The solvent is preferably N,N-dimethylformamide.

[0120] Compound (5) and compound R are available for use. 2 OM 1 The proportion is usually at least 1 mole, preferably about 1 to 5 moles of compound R 2 OM 1 / mole of compound (5).

[0121] The reaction temperature is not particularly limited, and the reaction can generally be carried out under any of the following conditions: under cooling, at room temperature, or under heating. The reaction can preferably be carried out for 1 to 30 hours at a temperature ranging from about room temperature to about 120°C.

[0122] Compound (6) → Compound (7)

[0123] Compound (7) can be produced by hydrolyzing compound (6). The hydrolysis of compound (6) can usually be carried out in a solvent in the presence of a base.

[0124] The solvent can be any solvent that does not adversely affect the reaction. Examples of such solvents include water, alcohol solvents (e.g., methanol, ethanol, isopropanol, and n-butanol), ketone solvents (e.g., acetone and methyl ethyl ketone), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether), and acetonitrile. Preferred examples of such solvents include combinations of water and alcohol solvents (methanol or ethanol). Alcohol solvents (especially methanol and ethanol) are preferred.

[0125] Examples of such bases include alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide). Typically, alkali metal hydroxides can be used in aqueous solution form. Examples of such aqueous solutions include aqueous sodium hydroxide solutions.

[0126] The amount of base supplied for use is usually at least 1 mole, preferably about 1 to 5 moles of the compound (6).

[0127] The reaction temperature is not particularly limited, and the reaction can generally be carried out under any of the following conditions: under cooling, at room temperature, or under heating. The reaction is preferably carried out at a temperature ranging from about room temperature to about 85°C for 1 to 30 hours.

[0128] Production of compound (11)

[0129] Compound (11) can be produced by reaction steps described, for example, in the following reaction scheme.

[0130] [Chemical Formula 9]

[0131] Compound (7) → Compound (8)

[0132] This can be achieved by converting the hydroxyl group of compound (7) into a leaving group (X). 4 To produce compound (8).

[0133] By X 4Examples of leaving groups include halogens (e.g., fluorine, chlorine, bromine, and iodine) and organic sulfonyloxy groups (e.g., p-toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, and o-nitrobenzoylsulfonyloxy). Halogens are preferred, and bromine is more preferred.

[0134] Compound (8') can be produced by reacting compound (7) with an organic sulfonyl halide or organic sulfonic anhydride containing an organic sulfonyl group in a solvent in the presence of a base, wherein X 4 The leaving group indicated is an organic sulfonyloxy group.

[0135] The solvent can be any solvent that does not adversely affect the reaction. Examples of such solvents include ketone solvents (e.g., acetone and methyl ethyl ketone), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether), ester solvents (e.g., methyl acetate and ethyl acetate), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide), halocarbon solvents (e.g., dichloromethane and vinyl chloride), and combinations of these solvents. The solvent is preferably an ester solvent (especially ethyl acetate, etc.).

[0136] The bases available for use can be known inorganic or organic bases. Examples of such inorganic bases include alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate), alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide), alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate), and alkali metal hydrides (e.g., sodium hydride and potassium hydride). Examples of such organic bases include trialkylamines (e.g., trimethylamine, triethylamine, and N,N-diisopropylethylamine), pyridine, quinoline, piperidine, imidazole, methylpyridine, 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), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). When these bases are liquids, they can also be used as solvents. These bases can be used alone or in combination of two or more. The base is preferably N,N-diisopropylethylamine and triethylamine, more preferably N,N-diisopropylethylamine. In particular, N,N-diisopropylethylamine is preferred because its use can significantly increase the yield.

[0137] Examples of such organic sulfonyl halides include p-toluenesulfonyl halides, methanesulfonyl halides, trifluoromethanesulfonyl halides, nonafluorobutanesulfonyl halides, and o-nitrobenzoylsulfonyl halides. Examples of such halides include chlorides and bromides, with chlorides being preferred. Particularly preferred organic sulfonyl halides include methanesulfonyl chlorides.

[0138] Examples of such organic sulfonic anhydrides include p-toluenesulfonic anhydride, methanesulfonic anhydride, trifluorosulfonic anhydride, nonafluorobutanesulfonic anhydride, and o-nitrobenzenesulfonic anhydride.

[0139] The amount of base supplied for use is typically 1 to 10 moles, preferably 1 to 6 moles of the compound (7).

[0140] The amount of the organic sulfonyl halide or organic sulfonic anhydride used is typically 1 to 5 moles, preferably 1 to 2 moles per mole of the compound (7).

[0141] The reaction temperature is not particularly limited, and the reaction can generally be carried out under any of the following conditions: under cooling, at room temperature, or under heating. The reaction is preferably carried out at a temperature of about 0°C to 60°C for 1 to 30 hours.

[0142] The reaction described above produces compound (8'), wherein X... 4 The leaving group indicated is an organic sulfonyloxy group.

[0143] Compound (8”) can be produced by reacting compound (8’) with a halogenating agent in a solvent, wherein X 4 The leaving group represented is a halogen. When X 4 When the leaving group is a halogen, the halogen includes fluorine, chlorine, bromine and iodine, preferably chlorine, bromine and iodine, and more preferably chlorine.

[0144] The solvent can be any solvent that does not adversely affect the reaction. Examples of such solvents include ketone solvents (e.g., acetone and methyl ethyl ketone), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether), ester solvents (e.g., methyl acetate and ethyl acetate), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide), halocarbon solvents (e.g., dichloromethane and vinyl chloride), and combinations of these solvents.

[0145] Examples of such halogenating agents include alkali metal halides (e.g., lithium chloride, lithium bromide, and lithium iodide) and quaternary ammonium halides (e.g., tetrabutylammonium chloride and tetrabutylammonium bromide). The halogenating agent is preferably an alkali metal halide (particularly lithium bromide).

[0146] The amount of halogenating agent used is typically 1 to 5 moles, preferably 1 to 3 moles of the compound (8').

[0147] The reaction temperature is not particularly limited, and the reaction can generally be carried out under any of the following conditions: under cooling, at room temperature, or under heating. The reaction is preferably carried out at a temperature of about 0°C to 60°C for 1 to 30 hours.

[0148] The steps of generating compound (8') from compound (7) and generating compound (8'') from compound (8') are performed independently. Alternatively, the two steps can be performed in a one-pot process.

[0149] The resulting compound (8) (including compounds (8') and (8'')) undergoes the following reaction steps.

[0150] Compound (8) → Compound (9)

[0151] Compound (9) can be produced by reacting compound (8) with a compound represented by the following chemical formula: [Chemical Formula 10]

[0152] Where M 2 This indicates an alkali metal (which may be referred to below as "phthalimide M") 2 (Compound”). By M 2 Examples of alkali metals include lithium, sodium, and potassium, with potassium being preferred.

[0153] The reaction can be carried out in common solvents. The solvent can be any solvent that does not adversely affect the reaction. Examples of such solvents include ketone solvents (e.g., acetone and methyl ethyl ketone), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether), ester solvents (e.g., methyl acetate and ethyl acetate), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide), halocarbon solvents (e.g., dichloromethane and vinyl chloride), and combinations of these solvents. N,N-dimethylformamide is more preferably used as the solvent.

[0154] Compound (8) and phthalimide M 2 The proportion of the compound is typically at least 1 mole, preferably about 1 to 5 moles of phthalimide M. 2 Compounds per mole of compound (8).

[0155] The reaction temperature is not particularly limited, and the reaction can generally be carried out under any of the following conditions: cooling, at room temperature, or heating. The reaction is carried out at temperatures from about 0°C to 100°C for 1 to 30 hours.

[0156] Compound (9) → Compound (10)

[0157] Compound (10) can be produced by reacting compound (9) with methylamine.

[0158] This reaction can be carried out in common solvents. The solvent can be any solvent that does not adversely affect the reaction. Examples of such solvents include water, alcohol solvents (e.g., methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide), and combinations of these solvents. The solvent is preferably a combination of water and an alcohol solvent (particularly methanol or ethanol).

[0159] Methylamine can usually be used in the form of an aqueous solution.

[0160] The amount of methylamine used is typically 1 to 10 moles, preferably 1 to 5 moles per mole of the compound (9).

[0161] The reaction temperature is not particularly limited, and the reaction can generally be carried out under any of the following conditions: under cooling, at room temperature, or under heating. The reaction is preferably carried out at a temperature ranging from about room temperature to about 100°C for 10 minutes to 30 hours.

[0162] The resulting compound (10) is a primary amine compound. From a workability standpoint, compound (10) can optionally be converted into a salt to form with an acid. This salt can be formed according to known methods. The acid can be selected from a wide range of organic or inorganic acids. These 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 these inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.

[0163] The solvent used in salt formation can be any solvent that does not adversely affect the reaction. Examples of such solvents include alcohols (e.g., methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol), ketones (e.g., acetone and methyl ethyl ketone), ethers (e.g., cyclopentyl methyl ether (CPME), tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether), esters (e.g., methyl acetate and ethyl acetate), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide), and combinations of these solvents. The solvent is preferably an ether (especially CPME).

[0164] Compound (10) → Compound (11)

[0165] Compound (11) can be produced by condensing compound (10) with 2-ethoxybenzoic acid.

[0166] The condensation reaction is usually carried out in a solvent in the presence of a condensing agent. When compound (10) is a salt that forms with an acid, the acid can be removed from the salt by using a base (e.g., inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and sodium bicarbonate; and organic bases such as triethylamine and N,N-diisopropylethylamine) before the reaction proceeds.

[0167] The solvent can be any solvent that does not adversely affect the reaction. Examples of such solvents include halogenated aliphatic hydrocarbon solvents (e.g., dichloromethane, trichloromethane, and vinyl chloride), ketone solvents (e.g., acetone and methyl ethyl ketone), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether), ester solvents (e.g., methyl acetate and ethyl acetate), aromatic hydrocarbons (e.g., toluene and xylene), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide), and combinations thereof. The solvent is preferably a ketone solvent (especially acetone and methyl ethyl ketone), an ether solvent (especially tetrahydrofuran, dioxane, diethyl ether, and ethylene glycol dimethyl ether), and an ester solvent (e.g., methyl acetate and ethyl acetate).

[0168] Examples of such condensing agents include 1,1'-carbonyldiimazole (CDI), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC or WSC), diphenyl azidophosphate (DPPA), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium salts (e.g., benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate), and 2-chloro-4,6-dimethoxytriazine (CDMT). The condensing agent is preferably CDI or WSC.

[0169] The amount of condensing agent used is typically at least 0.5 mol, preferably about 1 to 5 mol / mol of 2-ethoxybenzoic acid.

[0170] Additives (activators), such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), may be used along with the condensing agent.

[0171] The amount of additives used is typically at least 1 mole, preferably about 1 to 5 moles of condensing agent.

[0172] The reaction can be carried out by optionally adding a base. Examples of such bases include tertiary amines, such as triethylamine and N,N-diisopropylethylamine; and nitrogen-containing aromatic compounds, such as pyridine and 4-dimethylaminopyridine.

[0173] When using an alkali, the amount of alkali is typically at least 0.5 mol, preferably about 1 to 5 mol / mol of condensing agent.

[0174] The ratio of compound (10) to 2-ethoxybenzoic acid is usually at least 1 mole, preferably about 1 to 2 moles of 2-ethoxybenzoic acid per mole of compound (10).

[0175] The reaction temperature is not particularly limited, and the reaction can generally be carried out under any of the following conditions: under cooling, at room temperature, or under heating. The reaction is preferably carried out at a temperature of about 0°C to 100°C for 1 to 30 hours.

[0176] In this specification, the term "comprising" includes both "consisting essentially of" and "consisting of". This invention covers all combinations of the elements described in this specification.

[0177] Example

[0178] The invention is described in detail below. However, the invention is not limited to these examples.

[0179] Example 1: Generation of compound (3)

[0180] Compound (3) is produced according to the following reaction scheme.

[0181] [Chemical Formula 11]

[0182] 10.00 g (55.5 mmol) of compound (1a) and 9.20 g (66.6 mmol) of potassium carbonate were added to 40 mL of N,N-dimethylformamide and 6 mL of water, and the mixture was stirred until the exothermic reaction ended. 16.92 g (111 mmol) of sodium difluorochloroacetate was added, and the mixture was reacted at 95°C to 110°C for 3 hours. 80 mL of butyl acetate and 80 mL of water were added to the reaction solution, and the solution was partitioned. After partitioning, another 80 mL of water was added to the organic layer. 3 mL of concentrated hydrochloric acid was added to the organic layer, and the mixture was stirred at 60°C to 70°C for 30 minutes. 40 mL of water and 10 mL of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the solution was partitioned. 5.93 g (61.1 mmol) of sulfamic acid and 10 ml of water were added to the organic layer, and 22.08 g (61.0 mmol) of a 25% sodium chlorite aqueous solution was added dropwise to it at 20°C or lower. The mixture was allowed to react at 20°C or lower for 15 minutes, and 10 ml of a 25% sodium hydroxide aqueous solution was added dropwise to it at 20°C or lower, followed by 83.95 g (66.6 mmol) of a 10% sodium sulfite aqueous solution. Additionally, 2 ml of concentrated hydrochloric acid was added, and the mixture was partitioned, followed by concentration of the organic layer under reduced pressure. 40 ml of methanol, 80 ml of water, and 10 ml of a 25% sodium hydroxide aqueous solution were added to the concentrated residue to dissolve it, and 5 ml of concentrated hydrochloric acid was added dropwise to it to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C to obtain 11.81 g (yield: 86.4%) of the compound as a white powder (3).

[0183] 1 H-NMR (CDCl3) δ: 7.70 (2H,dd,J = 6.4 Hz,2.0 Hz),7.22 (1H,d,J = 9.2Hz),6.66 (1H,t,J = 74.8 Hz),4.66(1H,sept,J = 6.0 Hz),1.39 (6H,d,J = 6.0 Hz).

[0184] Example 2: Generation of compound (3)

[0185] Compound (3) is produced according to the following reaction scheme.

[0186] [Chemical Formula 12]

[0187] 10.00 g (53.2 mmol) of compound (1b), 9.55 g (69.1 mmol) of potassium carbonate, and 8.50 g (69.1 mmol) of isopropane bromide were added to 40 mL of N,N-dimethylformamide, and the mixture was reacted at 75°C to 85°C for 2 hours. 80 mL of butyl acetate and 80 mL of water were added to the reaction solution, and the mixture was partitioned. 5.68 g (58.5 mmol) of sulfamic acid and 10 mL of water were added to the organic layer, and 21.15 g (58.5 mmol) of a 25% aqueous solution of sodium chlorite was added dropwise at 20°C or lower, followed by a reaction for 15 minutes. 10 mL of a 25% aqueous solution of sodium hydroxide was added at 20°C or lower, followed by 80.41 g (63.8 mmol) of a 10% aqueous solution of sodium sulfite. In addition, 2 ml of concentrated hydrochloric acid was added, and the mixture was partitioned, followed by concentration of the organic layer under reduced pressure. 40 ml of methanol, 80 ml of water, and 10 ml of 25% sodium hydroxide aqueous solution were added to the concentrated residue to dissolve it, followed by dropwise addition of 5 ml of concentrated hydrochloric acid to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C to give 12.09 g (yield: 92.4%) of the compound as a white powder (3).

[0188] Example 3: Generation of compound (7)

[0189] Compound (7) is produced according to the following reaction scheme.

[0190] [Chemical Formula 13]

[0191] Synthesis of compound (4)

[0192] At room temperature, 10.00 g (40.6 mmol) of compound (3) was added to 25 ml of acetonitrile and stirred. 7.90 g (48.7 mmol) of carbonyl diimidazole was added gradually, and the mixture was allowed to react at room temperature for 1 hour. 10 ml (134 mmol) of 25% ammonia solution was added to 120 ml of water and cooled to 10°C or lower, and the reaction solution was then added dropwise. The precipitated crystals were collected by filtration and dried at 80°C to give 9.25 g (yield: 92.9%) of compound (4) as a white powder.

[0193] 1H-NMR (CDCl3) δ: 7.54 (1H,d,J = 1.6 Hz),7.25 (1H,dd,J = 8.4 Hz,2.0Hz),7.17 (1H,d,J= 8.0 Hz),6.62 (1H,t,J = 75.0),5.96 (2H,br-d,J = 75.2 Hz), 4.66 (1H,sept,J = 6.13 Hz), 1.36 (6H,d,J = 6.0 Hz).

[0194] Synthesis of compound (5)

[0195] 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 the mixture was reacted under reflux for 3 hours. 60 ml of toluene, 20 ml of water, and 2 ml of 25% sodium hydroxide aqueous solution were added to the reaction solution, and the solution was partitioned. The organic layer was concentrated under reduced pressure to give compound (5) as a brown solid (after recrystallization: a yellow fine powder).

[0196] 1 H-NMR (CDCl3) δ: 7.69 (1H,d,J = 0.8 Hz), 7.64 (1H,d,J = 2.0 Hz), 7.58 (1H,dd,J = 8.0 Hz, 1.6 Hz), 7.21 (1H,d,J = 8.0 Hz), 6.61 (1H,t,J = 75.0 Hz), 4.69 (1H,sept,J = 6.1 Hz), 4.56 (2H,s), 1.38 (6H,d,J = 6.0 Hz).

[0197] Synthesis of compound (7)

[0198] 20 ml of N,N-dimethylformamide and 4.80 g (48.9 mmol) of potassium acetate were added to the crude product of compound (5) obtained in the above section, and the mixture was reacted at 90°C to 100°C for 3 hours. 20 ml of methanol, 20 ml of water, and 5 ml of 25% sodium hydroxide aqueous solution were added to the reaction solution, and the mixture was reacted under reflux for 1 hour. 35 ml of water was added to the reaction solution, and the precipitated crystals were collected by filtration and then dried at 80°C to give 10.33 g (yield: 84.6%) of compound (7) as a light brown powder.

[0199] 1H-NMR (CDCl3) δ: 7.65-7.63 (2H,m),7.57 (1H,dd,J = 8.4 Hz,2.0 Hz),7.21(1H,d,J = 8.0 Hz),6.61 (1H,t,J = 75.2 Hz),4.70-4.66 (3H,m),1.39 (6H,d,J = 6.0Hz).

[0200] Example 4: Generation of compound (11)

[0201] Compound (11) is produced according to the following reaction scheme.

[0202] [Chemical Formula 14]

[0203] Synthesis of compound (9)

[0204] 20.00 g (66.8 mmol) of compound (7) and 17.28 g (134 mmol) of N,N-diisopropylethylamine were added to 300 mL of ethyl acetate, and the mixture was cooled. 11.48 g (100 mmol) of methanesulfonyl chloride was added, and the mixture was stirred at 10°C to 30°C for 1 hour. 17.41 g (200 mmol) of lithium bromide was added, and the mixture was reacted at 20°C to 35°C for 1 hour. 100 mL of water was added to the reaction solution, and the mixture was partitioned, followed by concentration of the organic layer under reduced pressure. 300 mL of ethyl acetate was added to the concentrated residue to dissolve it, and the solution was concentrated again under reduced pressure. 200 mL of N,N-dimethylformamide and 17.33 g (93.6 mmol) of potassium phthalimide were added to the concentrated residue, and the mixture was reacted at 75°C to 85°C for 1 hour. 200 ml of water was added to the reaction solution to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C to give 25.90 g (yield: 90.5%) of the compound as a white powder (9).

[0205] 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 = 8.8 Hz,2.4 Hz),7.30 (1H,d,J = 8.4 Hz),7.14 (1H,t,J = 74.2Hz), 4.78-4.69 (3H,m), 1.30 (6H,d,J = 6.0 Hz).

[0206] Synthesis of compound (10)

[0207] 15.00 g (35.0 mmol) of compound (9) was mixed with 30 mL of 40% aqueous methylamine, 30 mL of methanol, and 75 mL of water, and reacted under reflux for 30 min. 150 mL of cyclopentyl methyl ether (CPME) and 15 mL of 25% aqueous sodium hydroxide solution were added to the reaction solution, and the temperature was adjusted to 65°C to 75°C, followed by partitioning. A mixture of 150 mL of water and 7.50 g of sodium chloride was added to the organic layer, and the temperature was again adjusted to 65°C to 75°C, followed by partitioning. 3.75 mL of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. The precipitated crystals were collected by filtration and dried at 60°C to give 11.95 g (yield: quantitative) of compound (10) as a white powder.

[0208] 1 H-NMR (DMSO-d6) δ: 8.51 (3H,br-s),8.29 (1H,s),7.64 (1H,d,J = 2 Hz),7.59 (1H,dd,J = 8.0 Hz,1.6 Hz),7.37 (1H,d,J = 8.4 Hz),7.18 (1H,t,J = 74.0Hz), 4.72 (1H,sept,J = 6.1 Hz), 4.03 (2H,s), 1.33 (6H,d,J = 6.4 Hz).

[0209] Synthesis of compound (11)

[0210] 13.30 g (39.7 mmol) of compound (10) was mixed with 3.83 g (37.8 mmol) of triethylamine and 108 ml of ethyl acetate and stirred at 20°C 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°C 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°C to 50°C, followed by partitioning. 54 ml of water and 5.4 ml of a 25% aqueous sodium hydroxide solution were added to the organic layer, and the temperature was again adjusted to 40°C to 50°C. The mixture was partitioned, and the organic layer was concentrated under reduced pressure. 45 ml of ethanol, 18 ml of water, 5.4 ml of 25% sodium hydroxide aqueous solution, and 0.54 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. The activated carbon was removed by filtration, and the filtrate was washed with 11 ml of ethanol. The filtrate was cooled, and seed crystals were added to precipitate crystals. The precipitated crystals were collected by filtration and dried at 35°C to give 12.88 g (72.6%) of the compound as a white powder (11).

[0211] 1 H-NMR (CDCl3) δ: 8.56 (1H,br-s),8.23 (1H,dd,J = 7.6 Hz,1.6 Hz),7.66(1H,s),7.63 (1H,d,J = 2.0 Hz),7.58 (1H,dd,J = 8.4 Hz,2.0 Hz),7.44-7.39 (1H,m),7.21 (1H,d,J = 8.0 Hz),7.08-7.04 (1H,mH),6.94 (1H,d,J = 8.0 Hz),6.61 (1H,t,J = 75.2 Hz),4.68 (1H,sept,J = 6.0 Hz),4.62 (2H,d,J = 6.0 Hz),4.17 (2H,q,J= 6.93), 1.48 (3H,t,J = 7.2 Hz), 1.39 (6H,d,J = 5.6 Hz).

[0212] Example 5: Generation of compounds (i) to (ix)

[0213] The compounds shown in Table 2 below are produced as described below. The resulting compounds... 1H-NMR is also shown below. Compound (ii) is the same as compound (9).

[0214] [Table 2]

[0215] Synthesis of compound (i)

[0216] 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 synthetic procedure described in PTL 2 (WO 2014 / 034958 brochure), was dissolved in a mixture of 260 ml ethanol and 140 ml DMF, and 1.3 g of 10% palladium powder on carbon was added. The mixture was then stirred at 40°C for 1 hour under a hydrogen atmosphere. 100 ml of dichloromethane was added to the reaction solution and stirred, followed by filtration to remove the catalyst. The crude crystals obtained by concentrating the filtrate were recrystallized from ethyl acetate to obtain 8.8 g of 2-[2-(4-difluoromethoxy-3-hydroxyphenyl)oxazol-4-ylmethyl]isoindoline-1,3-dione (2-((2-(4-(difluoromethoxy)-3-hydroxyphenyl)oxazol-4-ylmethyl)isoindoline-1,3-dione: compound (i)).

[0217] 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).

[0218] Synthesis of compound (ii)

[0219] 2 g of compound (i) and 3.9 ml of 1,8-diazabicyclo[5.4.0]undecyl-7-ene (DBU) were dissolved in 20 ml of ethanol, and 3.18 g of isopropane bromide was added. The mixture was then heated under reflux overnight. Subsequently, 1 ml of 10% aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was heated under reflux for 30 minutes. Ice water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed twice with water and concentrated under reduced pressure to give [2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]isoindoline-1,3-dione (2-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)isoindoline-1,3-dione: compound (ii)).

[0220] 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 = 2.1 Hz) 7.55 (1H, dd, J = 8.4 Hz, 2.1 Hz) 7.18 (1H, d, J =8.4 Hz) 6.60 (1H, t, J = 75 Hz) 4.86 (2H, d, J = 1.2 Hz) 4.68 (1H, sept, J =6.0 Hz) 1.38 (6H, d, J = 6.0 Hz).

[0221] Synthesis of compound (iii)

[0222] 1.58 g of compound (ii) was dissolved in 16 ml of methanol, and 3.2 ml of an aqueous solution of methylamine (40%) was added. The mixture was then heated under reflux for 1 hour. The reaction solution was concentrated, and the reaction product was dissolved in ethyl acetate. The organic layer was then washed with an aqueous solution of 10% sodium hydroxide and water. The organic layer was separated and concentrated under reduced pressure to give 1.17 g of brown solid [2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-yl]methylamine ((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methylamine: compound (iii)).

[0223] 1H-NMR (CDCl3) δ: 7.65 (1H, d, J = 1.8 Hz) 7.58 (1H, d, J = 8.4 Hz,1.8 Hz) 7.55 (1H, s) 7.22 (1H, d, J = 8.4 Hz) 6.62 (1H, t, J = 75 Hz) 4.70 (1H, sept, J = 6.3 Hz) 3.85 (2H, s) 1.40 (6H, d, J = 6.3 Hz).

[0224] Synthesis of compound (iv)

[0225] 0.24 g of 5-benzyloxy-2-ethoxybenzoic acid and 0.44 g of compound (iii) were suspended in 20 mL of acetone, and 0.27 g of 1-hydroxybenzotriazole (HOBt) and 0.38 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added. The mixture was then heated under reflux for 1 hour. The reaction solution was cooled, and the acetone was evaporated under reduced pressure. Water was then added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 3:1). The crude crystals were recrystallized from n-hexane:ethyl acetate to give 0.28 g of 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)).

[0226] 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).

[0227] Synthesis of compound (v)

[0228] 5.5 g of [2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-yl]methylamine (MAP-15211), synthesized according to the synthetic procedure described in PTL 2 (WO 2014 / 034958 brochure) 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, followed by heating under reflux for 1 hour. Subsequently, 10 mL of a 10% aqueous sodium hydroxide solution was added, and the mixture was heated under reflux for 30 minutes. The reaction solution was then cooled, and the acetone was evaporated 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 concentrated under reduced pressure to obtain 3.1 g of 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)).

[0229] 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).

[0230] Synthesis of compound (vi)

[0231] 3.1 g of compound (v) was dissolved in 45 ml of N,N-dimethylformamide, and 1.7 g of 2-bromoethyl acetate and 1.8 g of potassium carbonate were added. The mixture was then heated at 80°C with stirring 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 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:1) to give 3.6 g of 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)).

[0232] 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).

[0233] Synthesis of compound (vii)

[0234] 3.5 g of compound (vi) was suspended in 100 ml of ethanol, and 0.4 g of 10% palladium on carbon powder was added. The mixture was then stirred at room temperature for 4 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the crude crystals obtained by concentrating the filtrate were recrystallized from ethanol-n-hexane to give 2.1 g of 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)).

[0235] 1H-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 = 7.8Hz), 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).

[0236] Synthesis of compound (viii)

[0237] 5.1 g of methyl pyruvate and 0.8 ml of bromine were dissolved in 15 ml of 1,2-ethylene glycol dimethyl ether and heated with stirring at 50°C for 1 hour. The reaction solution was concentrated, and the residue was dissolved in 45 ml of 2-methoxyethanol. 3 g of 3-benzyloxy-4-difluoromethoxybenzamide (3-(benzyloxy)-4-(difluoromethoxy)benzamide), synthesized according to the synthetic procedure described in PTL 1 (WO 2007 / 058338 brochure), was added, and the mixture was heated under reflux for 4 hours. 25 ml of water was added to the reaction solution, and the mixture was stirred overnight at room temperature. The precipitated crystals were collected by filtration and dried under reduced pressure at room temperature to obtain 0.73 g of methyl 2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazole-4-carboxylate (methyl 2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxylate: compound (viii)).

[0238] 1 H-NMR (CDCl3) δ: 8.29 (1H, s) 7.84 (1H, d, J = 2.1 Hz) 7.71 (1H, dd,J = 8.4 Hz, 1.8 Hz) 7.35-7.48 (6H, m) 6.64 (1H, t, J = 75 Hz) 5.22 (2H, s)3.97 (3H, s).

[0239] Synthesis of compound (ix)

[0240] 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 powder on carbon was added. The mixture was then stirred at room temperature for 2 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and 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 a saturated sodium chloride solution and concentrated under reduced pressure to give 0.18 g of methyl 2-(3-hydroxy-4-difluoromethoxyphenyl)oxazole-4-carboxylate (methyl 2-(4-(difluoromethoxy)-3-hydroxyphenyl)oxazole-4-carboxylate: compound (ix)).

[0241] 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).

[0242] Example 6: Generation of compounds (11a) to (11s)

[0243] The compounds shown in Table 3 below are produced as described below. The resulting compounds... 1 H-NMR is also shown below.

[0244] [Table 3]

[0245] Synthesis of compound (11a)

[0246] 3 g of compound (iii) and 1.5 g of salicylic acid were suspended in 60 ml of acetone, and 1.8 g of 1-hydroxybenzotriazole (HOBt) and 2.6 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added. The mixture was then heated under reflux for 1 hour. The reaction solution was cooled, and the acetone was evaporated 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 concentrated under reduced pressure. The resulting crude crystals were recrystallized from ethyl acetate-n-hexane to give 1.47 g of N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-hydroxybenzamide (N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-hydroxybenzamide: compound (11a)) as a white powder.

[0247] 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).

[0248] Synthesis of compound (11b)

[0249] Using 0.44 g of compound (iii) and 0.24 g of 2-ethoxy-3-hydroxybenzoic acid, the procedure in “Synthesis of Compound (11a)” was repeated to obtain 0.28 g 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)) as a white powder.

[0250] 1H-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).

[0251] Synthesis of compound (11c)

[0252] Using compound (iv), the procedure in “Synthesis of compound (11a)” above was repeated to obtain 5 mg of N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy-5-hydroxybenzamide (N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-ethoxy-5-hydroxybenzamide: compound (11c)).

[0253] 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)

[0254] Synthesis of compound (11d)

[0255] 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. The mixture was then heated at 80°C with stirring for 2 hours. Subsequently, 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 under reflux 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 concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to give 70 mg of N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-(2-hydroxyethoxy)benzamide (N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-(2-hydroxyethoxy)benzamide: compound (11d)).

[0256] 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 = 75.0Hz), 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 = 6.3 Hz).

[0257] Synthesis of compound (11e)

[0258] 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, and 0.31 g of iodoethane was added. The mixture was then heated under reflux overnight. Subsequently, 1 ml of 10% sodium hydroxide aqueous solution was added to the reaction solution, and the mixture was heated under reflux 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 and concentrated under reduced pressure. The crude crystals were recrystallized from ethanol-n-hexane to obtain 95 mg of N-[2-(3-ethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-(2-hydroxyethoxy)benzamide (OPA-15566) as a white powder.

[0259] 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)

[0260] Synthesis of compound (11f)

[0261] 0.3 g of compound (vii) and 0.3 mL of 1,8-diazabicyclo[5.4.0]undec-7-(DBU) were dissolved in ethanol, and 0.27 g of (bromomethyl)cyclopropane was added, followed by heating under reflux overnight. Then, 1 mL of 10% aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was heated under reflux 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 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane). The crude crystals were recrystallized from ethyl acetate-n-hexane to obtain 0.26 g 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)).

[0262] 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).

[0263] Synthesis of compound (11g)

[0264] 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, and 0.28 g of bromoisobutane was added, followed by heating under reflux overnight. Then, 1 ml of 10% aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was heated under reflux 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 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane). The crude crystals were recrystallized from ethyl acetate-n-hexane to obtain 0.15 g of N-[2-(3-isobutoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-(2-hydroxyethoxy)benzamide (N-((2-(4-(difluoromethoxy)-3-isobutoxyphenyl)oxazol-4-yl)methyl)-2-(2-hydroxyethoxy)benzamide: compound (11 g)).

[0265] 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 = 6.9 Hz).

[0266] Synthesis of compound (11h)

[0267] 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, and 0.3 g of (bromomethyl)cyclobutane was added, followed by heating under reflux overnight. Then, 1 ml of 10% aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was heated under reflux 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 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane). The crude crystals were recrystallized from ethyl acetate-n-hexane to obtain 0.24 g 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)).

[0268] 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 = 75.3Hz), 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).

[0269] Synthesis of compound (11i)

[0270] 0.28 g of compound (iii) and 0.17 g of 2,3-dihydroxybenzoic acid were suspended in 3 mL of acetone, and 0.17 g of 1-hydroxybenzotriazole (HOBt) and 0.23 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added. The mixture was then heated under reflux for 3 hours. The reaction solution was cooled, and the acetone was evaporated 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 concentrated under reduced pressure. The residue was partially purified by silica gel column chromatography (dichloromethane:methanol = 50:1). The crude crystals were recrystallized from hexane-acetone to obtain 0.2 g of 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)).

[0271] 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, 1.8Hz), 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).

[0272] Synthesis of compound (11j)

[0273] Using 0.28 g of compound (iii) and 0.17 g of 2,4-dihydroxybenzoic acid, the procedure in “Synthesis of Compound (11i)” above was repeated to obtain 0.17 g of 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)) as a white powder.

[0274] 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).

[0275] Synthesis of compound (11k)

[0276] Using 0.28 g of compound (iii) and 0.17 g of 2,5-dihydroxybenzoic acid, the procedure in “Synthesis of Compound (11i)” above was repeated to obtain 0.16 g of 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)) as a white powder.

[0277] 1H-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, 1.8Hz), 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).

[0278] Synthesis of compound (11l)

[0279] Using 0.28 g of compound (iii) and 0.17 g of 2,6-dihydroxybenzoic acid, the procedure in “Synthesis of Compound (11i)” above was repeated to obtain 0.2 g of 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)) as a white powder.

[0280] 1 H-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).

[0281] Synthesis of compound (11m)

[0282] 0.2 g of compound (11a) was dissolved in 2 ml of acetonitrile. 0.23 g of sodium iodide, 0.27 g of potassium carbonate, and 98 mg of propyl 3-chloroacetate were added, followed by heating under reflux overnight. 2 ml of a 10% aqueous sodium hydroxide solution was then added, and the mixture was heated under reflux until the reaction was complete. After cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3:1), and the crude crystals were recrystallized from ethanol-n-hexane to give 0.15 g of N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-(3-hydroxypropoxy)benzamide (N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-(3-hydroxypropoxy)benzamide:compound(11m)).

[0283] 1 H-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 = 6.0 Hz).

[0284] Synthesis of compound (11n)

[0285] 0.18 g of compound (ix) was dissolved in 2 ml of N,N-dimethylformamide, and 0.18 g of potassium carbonate and 0.12 ml of isopropane bromide were added. The mixture was then 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 sodium chloride solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2:1) to give 0.16 g of methyl 2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazole-4-carboxylate as a white powder (methyl 2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazole-4-carboxylate: compound (11n)).

[0286] 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).

[0287] Synthesis of compound (11o)

[0288] 0.7 g of compound (11n) was dissolved in 7 ml of methanol, and 1.4 ml of 25% aqueous sodium hydroxide solution was added. The mixture was then heated under reflux at room temperature for 30 minutes. The reaction solution was stirred under ice cooling, and concentrated hydrochloric acid was added to give a pH of 3. The precipitated crystals were then collected by filtration. The crystals were dried under reduced pressure to give 2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-carboxylic acid (2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-carboxylic acid: compound (11o)).

[0289] 1H-NMR (CDCl3) δ: 8.38 (1H, s), 7.74 (1H, d, J = 1.8 Hz), 7.66 (1H,dd, J = 8.1 Hz, 1.8 Hz), 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).

[0290] Synthesis of compound (11p)

[0291] Using compound (iii) and 2-ethoxy-6-hydroxybenzoic acid, the procedure in “Synthesis of compound (11i)” above was repeated to obtain 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)).

[0292] 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 = 75Hz), 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, 6.9Hz), 1.48 (3H, t, J = 6.9 Hz), 1.40 (6H, d, J = 6.3 Hz).

[0293] Synthesis of compound (11q)

[0294] Using compound (iii) and 2-ethoxy-3,4-dihydroxybenzoic acid, the procedure in “Synthesis of compound (11i)” above was repeated to obtain 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)).

[0295] 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 =74 Hz), 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).

[0296] Synthesis of compound (11r)

[0297] A typical synthetic procedure is performed using 0.1 g of compound (11a) and chlorosulfonic acid to obtain N-[(2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-yl)methylcarbamoyl]-2-phenylammonium sulfate (2-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methylcarbamoyl)phenylammonium sulfate (compound (11r)) as a white powder. The melting point is 162.0°C.

[0298] Synthesis of compound (11s)

[0299] A typical synthetic procedure is performed using 0.1 g of compound (11a), methyl 1-bromo-2,3,4-tri-O-acetyl-α-D-glucuronic acid, and silver oxide to yield (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 is 163.6°C.

[0300] Example 7: Production of preparations

[0301] Solvent Research

[0302] To select a solvent for dissolving compound (11) in the preparation of ointments containing compound (11), the solubility of compound (11) in different solvents was investigated. Even solvents with high solubility for compound (11) showed reduced solubility even when the solvent was compatible with the base material (ointment base) (such as petrolatum or paraffin) and mixed with it. This could lead to precipitation of compound (11). Therefore, solvents with high solubility for compound (11) but low or no miscibility (compatibility) with petrolatum or paraffin were relatively preferred. Table 4 shows the results of the study.

[0303] [Table 4]

[0304] Table 4 shows that triacetin and propylene carbonate have low miscibility with petrolatum, and also shows that triacetin and propylene carbonate have relatively high solubility for compound (11).

[0305] Ointment formulations

[0306] The ointments (Examples 1 to 10 and Comparative Examples 1 to 8) were prepared as described below. As mentioned above, a solvent for dissolving compound (11) was found. Therefore, the present invention includes all ointments prepared by dissolving compound (11) in a solvent. However, for convenience, particularly preferred examples are described below as examples, while other examples are described as comparative examples. The droplet size was measured by placing an appropriate amount of the prepared ointment on a glass slide and observing the droplet size using a polarizing microscope.

[0307] Example 1

[0308] 73.0 g of white petrolatum, 10.0 g of liquid paraffin, 3.0 g of paraffin wax, and 1.0 g of beeswax (non-chemically bleached beeswax) were heated and dissolved in an AGI-homogenizer at 70°C. Subsequently, a solution of 3.0 g of compound (11) in 10.0 g of propylene carbonate was added, and the mixture was stirred at 5000 rpm using a homogenizer and at 30 rpm using a paddle mixer. The homogenizer was then turned off at 45°C, and the paddle mixer and cooling system were turned off at 40°C to produce droplet sizes of 20 μm or smaller. The resulting product was then inserted into aluminum tubes, 5 g per tube, using a YS-7 filling machine, and the tubes were sealed to obtain the ointment.

[0309] Example 2

[0310] Repeat the procedure of Example 1, except that 72.0 g of white petrolatum and 2.0 g of beeswax are used to obtain the ointment.

[0311] Example 3

[0312] Repeat the procedure of Example 1, except that 70.5 g of white petrolatum and 3.5 g of beeswax are used to obtain the ointment.

[0313] Example 4

[0314] Repeat the procedure of Example 1, except that 81.0 g of white petrolatum, 1.0 g of compound (11) and 4.0 g of propylene carbonate are used to obtain the ointment.

[0315] Example 5

[0316] Repeat the procedure of Example 4, except that 80.0 g of white petrolatum and 2.0 g of beeswax are used to obtain the ointment.

[0317] Example 6

[0318] Repeat the procedure of Example 4, except that 78.5 g of white petrolatum and 3.5 g of beeswax are used to obtain the ointment.

[0319] Example 7

[0320] Repeat the procedure of Example 6, except that 79.2 g of white petrolatum and 0.3 g of compound (11) are used to obtain the ointment.

[0321] Example 8

[0322] Repeat the procedure of Example 6, except that 79.4 g of white petrolatum and 0.1 g of compound (11) are used to obtain the ointment.

[0323] Example 9

[0324] 70.5 g of white petrolatum, 10.0 g of liquid paraffin, 3.0 g of paraffin wax, and 3.5 g of beeswax (chemically bleached beeswax) were heated and dissolved in an AGI-homogenizer at 70°C. Subsequently, a solution of 3.0 g of compound (11) in 10.0 g of propylene carbonate was added, and the mixture was stirred at 5000 rpm using a homogenizer and at 30 rpm using a paddle mixer. The homogenizer was then turned off at 45°C, and the paddle mixer and cooling system were turned off at 40°C to produce droplet sizes of 20 μm or smaller. The resulting product was then inserted into aluminum tubes, 5 g per tube, using a YS-7 filling machine, and the tubes were sealed to obtain the ointment.

[0325] Example 10

[0326] Repeat the procedure of Example 3, except that 73.5 g of white petrolatum and 7.0 g of propylene carbonate are used to obtain the ointment.

[0327] Comparison Example 1

[0328] Repeat the procedure of Example 4, except that 82.0 g of white petrolatum is used and no beeswax is added to obtain the ointment.

[0329] Comparison Example 2

[0330] 58.5 g of white petrolatum, 6.0 g of paraffin wax, 6.0 g of beeswax, and 5.0 g of diethyl sebacate were dissolved in a 200 mL beaker at 70°C by heating and stirring manually. After cooling to 50°C, 17 g of liquid paraffin wax was added, and the mixture was heated to 50°C. A paste containing 10 g of liquid paraffin wax and 3 g of micronized compound (11) was added and thoroughly mixed by stirring manually while maintaining the temperature at 50°C. The mixture was cooled to room temperature with ice water. Subsequently, the mixture was inserted into aluminum tubes, 5 g per tube, using a YS-7 filling machine to obtain an ointment.

[0331] Compound (11) was added to liquid paraffin and the mixture was ground using a DYNO-MILL (glass bead mill) to obtain micronized compound (11). The resulting paste was then used in the above operation.

[0332] Comparison Example 3

[0333] Repeat the procedure of Example 3, except that 75.5 g of white petrolatum and 5.0 g of propylene carbonate are used to obtain the ointment.

[0334] Comparison Example 4

[0335] Repeat the procedure of Example 6, except that 80.5 g of white petrolatum and 2.0 g of propylene carbonate are used to obtain the ointment.

[0336] Comparison Example 5

[0337] Repeat the procedure of Example 6, except that 79.5 g of white petrolatum is used and no compound (11) is added to obtain the ointment.

[0338] Comparison Example 6

[0339] Repeat the procedure of Example 3, except that: use a homogenizer to stir the mixture at 1500 rpm and use a paddle mixer to stir the mixture at 15 rpm to prepare an ointment with droplet size of approximately 50 μm.

[0340] Comparison Example 7

[0341] Repeat the procedure of Example 6, except that: use a homogenizer to stir the mixture at 1500 rpm and use a paddle mixer to stir the mixture at 15 rpm to prepare an ointment with droplet size of approximately 50 μm.

[0342] Comparison Example 8

[0343] Repeat the procedure of Example 7, except that: use a homogenizer to stir the mixture at 1500 rpm and use a paddle mixer to stir the mixture at 15 rpm to prepare an ointment with droplet size of approximately 50 μm.

[0344] Table 5 shows the composition of the preparations described above.

[0345] [Table 5]

[0346] Study on the stability of the formulation 1

[0347] The ointments prepared in Comparative Examples 1 and 4, 5 and 6 were allowed to stand at 40°C for 2 months. Subsequently, the dispersion of the propylene carbonate solution in each formulation was examined. Table 6 shows the results. Table 6 reveals that beeswax maintained a uniform dispersion, thus improving stability.

[0348] [Table 6]

[0349] Study on the stability of formulations 2

[0350] The amount of beeswax added differed between Comparative Example 1 and the ointments prepared in Examples 1 through 6. These formulations were subjected to stability tests at 50°C for 2, 4, or 6 weeks. To examine the extent of decomposition of compound (11), the amount of 3-(2-propoxy-3-difluoromethoxy)benzamide, one of the decomposition products, was measured by high-performance liquid chromatography. The results are shown in Table 7. The values ​​in Table 7 indicate the concentrations (wt%) of compound (11), beeswax, and decomposition products in each formulation. Comparative Example 1 (without added beeswax) produced approximately 1% decomposition product, while the formulations prepared with added beeswax showed a reduction in decomposition product production.

[0351] [Table 7]

[0352] Study the stability of the formulation 3

[0353] Unbleached beeswax (unbleached beeswax), non-chemically purified bleached beeswax (non-chemically bleached beeswax), or chemically bleached beeswax (chemically bleached beeswax) were used as formulations in beeswax preparation example 3. The formulations were inserted into aluminum tubes and sealed, and then stored at 50°C for 2, 4, or 8 weeks. The stability of compound (11) was examined using the decomposition products of compound (11) (3-(2-propoxy-3-difluoromethoxy)benzamide) as an indicator, in the same manner as above. Table 8 shows the results. Chemically bleached beeswax produced a large amount of decomposition products, while the use of non-chemically bleached and unbleached beeswax showed a reduction in decomposition product production.

[0354] [Table 8]

[0355] Study the stability of the formulation 4

[0356] Ointments containing compound (11) and varying amounts of beeswax were prepared. Predetermined amounts of each ointment were placed on a glass slide, and the droplet size of each ointment was determined using a polarizing microscope to determine the amount of beeswax necessary to obtain an ointment with well-dispersed droplets. The ointments (Examples 11 to 19 and Comparative Examples 9 to 11) were prepared as described below. This invention includes all ointments containing beeswax. However, for convenience, particularly preferred examples are described below as examples, while other examples are described as comparative examples.

[0357] Example 11

[0358] 141.0 g of white petrolatum, 20.0 g of liquid paraffin, 6.0 g of paraffin wax, and 7.0 g of beeswax (non-chemically bleached beeswax) were heated and dissolved in an AGI-homogenizer at 70°C. Subsequently, a solution of 6.0 g of compound (11) in 20.0 g of propylene carbonate was added, and the mixture was stirred at 5000 rpm using a homogenizer and at 30 rpm using a paddle mixer, followed by cooling. The homogenizer was shut off at 45°C, and the paddle mixer and cooling system were shut off at 40°C. The resulting product was inserted into aluminum tubes, 5 g per tube, using a YS-7 filling machine, and the tubes were sealed to obtain the ointment.

[0359] Example 12

[0360] Repeat the procedure of Example 11, except that 146.0 g of white petrolatum and 2.0 g of beeswax are used to obtain the ointment.

[0361] Example 13

[0362] Repeat the procedure of Example 11, except that 146.4 g of white petrolatum and 1.6 g of beeswax are used to obtain the ointment.

[0363] Example 14

[0364] Repeat the procedure of Example 11, except that 146.8 g of white petrolatum and 1.2 g of beeswax are used to obtain the ointment.

[0365] Comparison Example 9

[0366] Repeat the procedure of Example 11, except that 147.2 g of white petrolatum and 0.8 g of beeswax are used to obtain the ointment.

[0367] Comparison Example 10

[0368] Repeat the procedure of Example 11, except that 147.6 g of white petrolatum and 0.4 g of beeswax are used to obtain the ointment.

[0369] Example 15

[0370] 157.0 g of white petrolatum, 20.0 g of liquid paraffin, 6.0 g of paraffin wax, and 7.0 g of beeswax (non-chemically bleached beeswax) were heated and dissolved in an AGI-homogenizer at 70°C. Subsequently, a solution of compound (11) in 8.0 g of propylene carbonate was added, and the mixture was stirred at 5000 rpm using a homogenizer and at 30 rpm using a paddle mixer, followed by cooling. The homogenizer was shut off at 45°C, and the paddle mixer and cooling system were shut off at 40°C. The resulting product was inserted into aluminum tubes, 5 g per tube, using a YS-7 filling machine, and the tubes were sealed to obtain the ointment.

[0371] Example 16

[0372] Repeat the procedure of Example 15, except that 162.0 g of white petrolatum and 2.0 g of beeswax are used to obtain the ointment.

[0373] Example 17

[0374] Repeat the procedure of Example 15, except that 162.4 g of white petrolatum and 1.6 g of beeswax are used to obtain the ointment.

[0375] Example 18

[0376] Repeat the procedure of Example 15, except that 162.8 g of white petrolatum and 1.2 g of beeswax are used to obtain the ointment.

[0377] Example 19

[0378] Repeat the procedure of Example 15, except that 163.2 g of white petrolatum and 0.8 g of beeswax are used to obtain the ointment.

[0379] Comparison Example 11

[0380] Repeat the procedure of Example 15, except that 163.6 g of white petrolatum and 0.4 g of beeswax are used to obtain the ointment.

[0381] Table 9 shows the formulation and droplet dispersion of the ointment. The unit is wt%. Table 9 reveals that when the ointment containing 3 parts by weight of component (11) contains 0.6 parts by weight or more of beeswax, the ointment exhibits particularly excellent droplet dispersion, and when the ointment containing 1 part by weight of compound (11) contains 0.4 parts by weight or more of beeswax, the ointment exhibits particularly excellent droplet dispersion.

[0382] [Table 9]

Claims

1. An ointment comprising an oxazole compound represented by the following chemical formula (11): 。 2. The ointment according to claim 1, comprising the oxazole compound dissolved in the base component.

3. The ointment of claim 2, wherein the base component comprises a solvent for dissolving the oxazole compound in the solvent, and an ointment base for dispersing or dissolving the solvent in the ointment base.

4. The ointment of claim 3, wherein the ointment base comprises hydrocarbons.

5. The ointment according to claim 3 or 4, wherein the solvent comprises a polar compound that is a liquid at room temperature.

6. The ointment according to any one of claims 3 to 5, wherein the ointment base is an ointment base for dispersing the solvent in the ointment base, and the solvent containing the oxazole compound dissolved in droplets is dispersed in the ointment base.

7. The ointment according to any one of claims 3 to 6, wherein the ointment base comprises at least beeswax.

8. The ointment according to claim 7, wherein the beeswax is not chemically bleached.

9. The ointment according to any one of claims 1 to 8, for use in the treatment and / or prevention of eczema and dermatitis.

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