NZ743851B2 - Ointment - Google Patents

Abstract

ointment is provided. The ointment stably comprises an oxazole compound that has specific inhibitory activity against PDE4 and that is represented by the following formula (11). The ointment can be efficiently absorbed into the skin.

Description

Description Title of Invention: OINTMENT Technical Field The present invention relates to an ointment sing an oxazole nd.

Background Art PTL 1 and 2 report an oxazole compound having specific inhibitory activity against phosphodiesterase 4 (PDE4) and a method for ing the oxazole compound. PDE4 is predominant in inflammatory cells. Inhibition of PDE4 increases intracellular CAMP levels, and increased CAMP levels down—regulate inflammatory se through ex— pression regulation of TNF—or, IL—23, or other inflammatory cytokines. Increases in CAMP levels also se anti—inflammatory cytokines, such as IL—10. Thus, the oxazole compound is thought to be suitable for use as an anti-inflammatory agent. For example, the oxazole compound is thought to be useful to reduce or eliminate eczema or dermatitis, including atopic dermatitis.

However, so far there has been no ointment that stably contains an e compound having ic inhibitory activity against PDE4 and that can be efficiently absorbed into the skin.

Citation List Patent Literature [PTL 1] W02007/058338 et 9—5 15872A) [PTL 2] W02014/034958 Pamphlet (JP20 1 5-528433A) Summary of Invention cal m An object of the present invention is to provide an ointment that stably comprises an oxazole compound having specific inhibitory activity against PDE4 and that can be ef— ficiently absorbed into the skin.

Solution to Problem The present inventors found that dissolving a specific oxazole compound, among oxazole nds having specific inhibitory activity against PDE4, in a specific solvent and dissolving or dispersing the resulting solution in a base material can provide an ointment that stably contains the specific oxazole nd and that can be efficiently absorbed into the skin. The inventors further made modification and completed the present invention.

Specifically, the present invention encompasses, for example, the following subject matters.

Item 1. An ointment comprising an oxazole compound ented by the following formula (1 1): [Chem. 1] o F>—F %;er (11) Item 2. The ointment according to Item 1, sing the oxazole compound dissolved in a base component.

Item 3. The ointment according to Item 2, n the base ent comprises a solvent for dissolving the oxazole compound in the solvent, and an ointment base for dispersing or dissolving the solvent in the nt base.

Item 4. The ointment according to Item 3, wherein the ointment base ses a hy- bon (preferably, at least one hydrocarbon selected from the group consisting of petrolatum, paraffin, wax, and x).

Item 5. The ointment according to Item 3 or 4, wherein the solvent comprises a polar compound that is a liquid at room temperature (preferably, at least one member selected from the group consisting of ne carbonate, propylene carbonate, benzyl alcohol, triacetin, N—methylpyrrolidone, l sebacate, diisopropyl sebacate, diethyl adipate, diisopropyl e, aryl alcohol, and isopropyl myristate).

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

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

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

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

Item 10. An ointment comprising: (I) an oxazole compound represented by formula (1 1), (II) a solvent comprising at least one member selected from the group consisting of ethylene carbonate, propylene carbonate, benzyl alcohol, and triacetin, and (III) beeswax, wherein component (II) in the form of droplets, in which component (I) is dissolved, is dispersed in component (III), and the droplets have a mean particle size of 100 um or less.

Item A. A method for producing a compound represented by formula (3) [Chem.2] *Q" XICFZCOOR1 Oxidation O >—F —>H o —»so? 2 o< wherein X1 represents n, and R1 represents an alkali metal or lower alkyl, the method comprising: (a) reacting a compound represented by formula (1a) with a compound represented by formula XlCFzCOOR1 to e a compound ented by a (2); and (b) oxidizing the compound represented by formula (2) to produce a compound rep— resented by formula (3).

Item B. A method for producing a compound represented by formula (3) [Chem.3] >_ F Oxidation o F)—F XZY 0 HQO HFQZ< Elia—2%o n X2 represents n, the method sing: (a) reacting a compound represented by formula (1b) with a compound represented by formula XZCH(CH3)2 to produce a nd represented by formula (2), and (b) oxidizing the compound represented by formula (2) to produce a compound rep— resented by formula (3).

Advantageous Effects of ion The ointment according to the present invention stably contains an oxazole compound having ic tory activity against PDE4, and the ointment can be efficiently absorbed into the skin. ption of Embodiments The ointment according to the present invention comprises a specific oxazole compound, which is preferably dissolved in a base component. The oxazole compound can be contained in an ointment as an active component. The base component as used here encompasses a solvent for dissolving the oxazole nd in the 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.

In other words, the ointment according to the present invention comprises (I) a specific oxazole compound, which is preferably dissolved in a base component, and the base component includes (II) a solvent for dissolving the oxazole compound in the solvent and (111) an ointment base.

More preferably, the ointment according to the present invention is an ointment wherein ent (II) in the form of droplets, in which component (I) is dissolved, is dissolved or sed in component (III).

Examples of oxazole compound (I) include compounds represented by the following ae (11) and (11a) to (11s). In particular, the compound represented by formula (1 1) is preferable.

[Chem.4] ENNJFCE.C: 2H [Table 1] Formula Number Structural Formula o >‘F 11a QwNilf—Q.‘‘F 11b H I O \/O O OH F H O>—F 110 NVEhl>——Q:‘F 11d Qwflflfi‘Q’o HO/\/0 O ov< lle QKHVEK—QOo HO/\/O o O'\ o >‘F 11f /V'QO HO/\/0 O /O o >4 11g anlfifl‘o Ho’\/0 0 >__/O o >‘F 11h Hi3"Q° Ho/VO O <>_/O 111 HVEO/ 0 HO N OH 0 o‘< HO F>—-F 0 11]. \©\I(NV[NI>—Q"‘F 11k "J 0 OH O O’< OH o 111 qu/[N’Q’O.< 11m 0 HO "\iN’ lln "DYE" 0 O 04 o >‘F Ho NfQ’O o 0% OH oyF 11p "it? Q \ \o/ O>7 llq l/ ,H\ N 115 O O o o —< "’OH These oxazole compounds can be used singly or in a 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 formulae (11) and (11a) to (11s).

Although there is no particular tion, e compound (I) is present in the ointment in an amount of preferably 0.01 to 10 parts by , more ably 0.05 to 7.5 parts by weight, still more preferably 0.1 to 5 parts by , per 100 parts by weight of the ointment.

As stated above, the e compound is preferably dissolved in solvent (11). The solvent is preferably a polar nd that is a liquid at room temperature. Specific examples of the t include ethylene carbonate, propylene carbonate, benzyl l, triacetin, diethyl sebacate, diisopropyl sebacate, diethyl adipate, diisopropyl adipate, isostearic acid, olive oil, hexyldodecanol, decyl oleate, isostearyl alcohol, and isopropyl myristate. Ethylene carbonate, propylene carbonate, benzyl alcohol, and triacetin are more preferable, and propylene carbonate and triacetin are still more preferable. Of these, propylene carbonate is preferable. These solvents can be used singly or in a combination of two or more. In particular, it is preferable to use ethylene carbonate or propylene carbonate alone, or a combination of ethylene carbonate or ene carbonate with benzyl alcohol and/or triacetin.

Solvent (II) is t in the ointment in an amount of preferably more than 2 parts by weight, more ably 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 (11) is not particularly limited, as long as the effect of the present invention is produced. 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.

Solvent (II) is present in the ointment in an amount of preferably 0.1 to 50 parts by , 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 the ointment.

A solution of the oxazole compound in the solvent is ably dissolved or dispersed in the form of droplets in ointment base (III), and more preferably dispersed in the form of droplets in ointment base (111).

Known ointment bases for use in the production of ointments can be used as ointment base (111). Examples of ointment bases include hydrocarbons, and more specific examples include grease bases, particularly natural wax, petroleum wax, and other hydrocarbons. Examples of natural wax include beeswax (e.g., unbleached beeswax, non—chemically bleached beeswax, and chemically bleached x), and carnauba wax. Examples of petroleum wax include paraffin 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 singly or in a combination of two or more.

WO 15780 Ointment base (III) is present in the ointment in an amount of preferably 5 to 5000 parts by weight, more preferably 10 to 2500 parts by , and still more preferably to 1000 parts by weight, per part by weight of oxazole compound (I).

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

Ointment base (III) preferably comprises at least beeswax. The beeswax for use is preferably beeswax that is not chemically bleached, including, for example, beeswax that is non- chemically bleached hemically bleached beeswax) and beeswax that is not bleached (unbleached beeswax).

The beeswax is present in the ointment in an amount of preferably 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, per part by weight of oxazole compound (I).

The beeswax is t in the ointment in an amount of preferably 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 still more preferably 0.5 to 7.5 parts by weight, and particularly preferably 1 to 5 parts by weight, per 100 parts by weight of the ointment.

When other ointment bases are combined with beeswax, the combination is not par— ticularly limited. However, for example, the combination ably comprises at least one member selected from the group consisting of petrolatum (preferably white petrolatum), liquid paraffin, and paraffin and beeswax.

In addition to the nt base, the ointment may comprise other ves for use in ointments (in particular, pharmaceutical additives), such as aroma components, colorants, preservatives, absorption promoters including higher alkene acids (e.g., oleic acid), or medicaments ive for treating other skin es.

As stated above, the ointment of the t ion is preferably an ointment wherein solvent (II), in which oxazole compound (I) is dissolved, is dissolved or dispersed in the form of droplets in ointment base (III). Examples of the method for producing this ointment e a method comprising preparing a solution of component (I) in component (II), and mixing the on with component (III) with stirring. Mixing with stirring can be performed with, for example, a homomixer, a paddle mixer, or a combination of these mixers.

In the use of multiple types of ointment bases (component (111)), it is preferable to mix the multiple ointment bases beforehand. In the ation of component (III) containing multiple types of ointment bases, it is preferable to mix the ointment bases with heating to melt the solids, such as beeswax. For example, when beeswax and other ointment bases are used in combination, beeswax and other ointment bases are ably mixed beforehand, preferably with heating. 2016/088843 In the case of an ointment wherein component (II), in which component (I) is dissolved, is dispersed in the form of droplets in component (III), the particle size of the droplets observed with a polarizing microscope is 100 pm or less, preferably about 40 um or less, more preferably about 25 um or less, and still more preferably about 20 um or less. In particular, there exist preferably no droplets having a particle size of more than 100 um, more ably no droplets having a particle size of more than 40 um, still more preferably no droplets having a particle size of more than 25 um, and even still more preferably no droplets having a particle size of more than 20 um. A desired mean particle size of the ts is achieved by adjusting the stirring rate at which the solution is mixed with component (III) with stirring.

The oxazole compound represented by formula (1 l) is a known nd disclosed in PTL l and 2, and can be produced in accordance with the procedure described in PTL l or 2.

The oxazole compound represented by formula (1 1) can also be produced as described below. The nds used as starting materials below are known or easily produced from known compounds.

Specifically, compound (3) is first synthesized, and then nd (7) is synthesized from nd (3). Subsequently, compound (1 l) is synthesized from compound (7).

In this specification, a compound represented by formula A may be indicated as compound A or compound (A).

F F kg?» miij "33‘3""quo F 3 7 Production of Compound 13) Compound (3) can be produced, for example, through the reaction steps illustrated in the following reaction scheme.

[Chem.6] F F X1CFZCOOR1 O >—F Oxidation 0 >—F —>H 0 —> 0 O-< HO 2 3 o_< Compound 1 la] + Compound XlCF_2COOR'——> Compound (2] nd (2) can be produced by reacting compound (la) with nd XICFZ COOR1 in the presence of a base.

In compound XICFZCOORI, X1 represents halogen, and the halogen includes fluorine, chlorine, bromine, and iodine, with chlorine, bromine, and iodine being preferable, and chlorine being more preferable.

R1 represents an alkali metal or lower alkyl. The alkali metal includes lithium, sodium, and potassium, with sodium being preferable. The lower alkyl includes C1—C6 (in particular, C1-C4) linear or branched alkyl. Specific examples include methyl, ethyl, n—propyl, isopropyl, l, isobutyl, sec—butyl, tert—butyl, l—ethyl propyl, n— pentyl, neopentyl, n—hexyl, yl, and 3—methyl pentyl, with methyl and ethyl being preferable.

The reaction can be performed in the presence of a common t. The solvent can be any solvent that does not adversely affect the reaction. Examples of the solvent include ketone solvents (e.g., acetone and methyl ethyl ), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, and diglyme), ester solvents (e.g., methyl acetate and ethyl acetate), aprotic polar solvents (e.g., acetonitrile, N,N—dimethylformamide, and dimethyl sulfoxide), nated hydrocarbon solvents (e.g., methylene chloride and ethylene chloride), and combinations of these solvents.

The solvent is preferably N,N—dimethylformamide.

The base for use can be known nic bases or c bases. es of inorganic bases include alkali metals (e.g., sodium and potassium), alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate), 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), alkali metal lower (Cl—C3) alkoxides (e.g., sodium methoxide and sodium ethoxide), and alkali metal hydrides (e.g., sodium hydride and potassium hydride). Examples of c bases include trialkyl amines (e.g., hylamine, tri— ethylamine, and N,N—diisopropylethylamine), pyridine, quinoline, piperidine, imidazole, picoline, 4—dimethylaminopyridine, N,N—dimethylaniline, N— methylmorpholine, l,5—diazabicyclo[4.3.0]non—5—ene (DBN), l,4—diazabicyclo[2.2.2]octane (DABCO), and l,8—diazabicyclo[5.4.0]undec—7—ene (DBU). When these bases are a liquid, these bases can also be used as a solvent. These bases are used singly or in a combination of two or more. The base is preferably an alkali metal carbonate (in particular, sodium carbonate or potassium ate).

The amount of the base for use is typically 1 to 10 moles, and ably 1 to 6 moles, per mole of compound (1a).

The on can be performed by optionally adding an alkali metal iodide, such as potassium iodide or sodium , as a reaction accelerator to the reaction system.

When a reaction rator is used, the amount of the reaction rator is typically at least 0.01 moles, and preferably about 0.1 to 2 moles, per mole of XICFZ COORI. [005 1] The proportion of compound (1a) and compound XICFZCOOR1 is typically at least 1 mole, preferably about 1 to 5 moles of compound XICFZCOORl, per mole of compound (1a).

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

Compound (2) —> nd 13] Compound (3) can be produced by oxidizing compound (2). Specifically, for e, compound (3) is produced by subjecting compound (2) to reaction in a solvent in the presence of an oxidant.

When compound (2) is reacted in a solvent in the presence of an oxidant, examples of the solvent for use include water; alcohols, such as ol, ethanol, ol, isopropyl alcohol, n—butanol, tert—butanol, and ethylene glycol; nated hy— drocarbons, such as dichloromethane, chloroform, and carbon tetrachloride; ethers, such as diethyl ether, ydrofuran, dioxane, monoglyme, and diglyme; ketones, such as acetone and methyl ethyl ketone; aromatic hydrocarbons, such as benzene, o— robenzene, e, and xylene; esters, such as methyl acetate, ethyl acetate, and butyl acetate; aprotic polar solvents, such as acetonitrile, N,N—dimethylformamide, and hexamethylphosphoric triamide; and combinations of these solvents.

Oxidants include halous acids, such as chlorous acid, iodous acid, and bromous acid; alkali metal salts of halous acids, such as sodium chlorite, sodium iodite, sodium bromite, potassium chlorite, potassium iodite, and potassium bromite; alkali metal salts of permanganic acid, such as potassium permanganate; chromic acid or alkali metal salts thereof, such as chromium oxide (VI), sodium mate, and potassium dichromate; and nitric acid. When using an alkali metal salt of permanganic acid, it is preferable to perform reaction in the presence of an nic base, such as potassium hydroxide, sodium hydroxide, sodium carbonate, or potassium carbonate. When using chromic acid or an alkali metal salt thereof, it is preferable to perform reaction in the ce of a mineral acid such as ic acid, or an c acid such as acetic acid.

Of these, in particular, halous acids, and alkali metal salts of halous acids are par— ticularly preferable.

The amount of the oxidant for use is lly 0.5 to 1 mole or more, and preferably 1 to 10 moles, per mole of compound (2).

The reaction temperature is typically about —20 to 50°C, and preferably about —20°C to room temperature (25°C). The reaction time is about 1 to 30 hours.

Compound (3) can be produced through the reaction steps illustrated in the following reaction .

[Chem.7] F F Oxidation 0 >‘F XZY 09 F>—F H o >_F , < 2 O —> o H \>‘0 H OH 0 1b 2 Compound 1 lb] + nd XZCH] CH3 )2 —> Compound 12] Compound (2) can also be produced by reacting compound (la) with compound X2 )2 in the presence of a base.

In compound XZCH(CH3)2, X2 represents halogen, and the halogen includes fluorine, chlorine, e, and iodine, with chlorine, bromine, and iodine being preferable, and bromine being more able.

The reaction can be performed in the presence of a common solvent. The solvent can be any solvent that does not adversely effect the reaction. Examples of the solvent include ketone solvents (e.g., acetone and methyl ethyl ketone), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, and diglyme), ester solvents (e.g., methyl acetate and ethyl acetate), aprotic polar solvents (e. g., acetonitrile, N,N—dimethylformamide, and dimethyl sulfoxide), nated hydrocarbon solvents (e.g., methylene chloride and ethylene chloride), and ations of these solvents.

The solvent is preferably methylformamide.

The base for use can be known inorganic bases or organic bases. Examples of inorganic bases include alkali metals (e.g., sodium and potassium), alkali metal hydrogen carbonates (e.g., lithium hydrogen ate, sodium hydrogen carbonate, and ium hydrogen carbonate), 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 ate), alkali metal lower (Cl—C3) alkoxides (e.g., sodium methoxide and sodium ethoxide), and alkali metal hydrides (e.g., sodium hydride and potassium hydride). Organic bases include trialkyl amines (e.g., trimethylamine, triethylamine, and N,N-diisopropylethylamine), pyridine, quinoline, piperidine, imidazole, picoline, 4—dimethylaminopyridine, N,N—dimethylaniline, N—methylmorpholine, l,5-diazabicyclo[4.3.0]non—5—ene (DBN), l,4—diazabicyclo[2.2.2]octane ), and l,8—diazabicyclo[5.4.0]undec—7—ene (DBU). When these bases are a liquid, these bases can also be used as a solvent. These bases are used singly or in a combination of two or more. The base is preferably an alkali metal ate (in particular, sodium carbonate or potassium carbonate).

The amount of the base for use is typically 1 to 10 moles, and preferably 1 to 6 moles, per mole of nd (lb).

The reaction can be performed by optionally adding an alkali metal iodide, such as potassium iodide or sodium iodide, as a on accelerator to the reaction system.

When a reaction accelerator is used, the amount of the reaction accelerator is typically at least 0.01 moles, and preferably about 0.1 to 2 moles, per mole of X2 The proportion of compound (1b) and compound XZCH(CH3)2 for use may be typically at least 1 mole, and preferably about 1 to 5 moles of compound XZCH(CH3)2, per mole of compound (lb).

The reaction temperature is not particularly limited, and the reaction can be typically performed under any of the following conditions: with cooling, at room temperature, or with heating. The reaction is preferably performed at a temperature within the range of around room temperature to about 85°C for l to 30 hours.

The method for producing compound (3) from compound (2) is as bed above.

Production of Compound 17) Compound (7) can be produced, for example, through the reaction steps illustrated in the following reaction scheme.

[Chem. 8] Amidation F o )—F o a )—F Xi)»x3 o )—F O O _> 3‘): , o HO H2N N O —< O —< o _< 3 4 5 Hydrolysrs F O >— F Com ound 3 —> Com ound 4 Compound (4) can be produced by subjecting compound (3) to condensation on with ammonia (amidation reaction). The reaction can be typically performed by reacting compound (3) with ammonia in a solvent in the presence of a condensation agent.

The t can be any solvent that does not ely effect the reaction. Examples of the solvent e halogenated aliphatic hydrocarbon solvents (e.g., methylene chloride, chloroform, and ethylene chloride), ketone solvents (e.g., acetone and methyl ethyl ketone), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, and diglyme), aromatic hydrocarbons (e.g., e and xylene), aprotic polar solvents (e.g., itrile, N,N-dimethylformamide, N- methylpyrrolidone, and dimethyl sulfoxide), and combinations of these solvents. The solvent is preferably acetonitrile.

Examples of the condensation agent include l,1’-carbonyl diimidazole (CDI), dicy- clohexyl carbodiimide (DCC), diisopropyl carbodiimide (DIC), 1-ethy1(3-dimethy1aminopropyl)carbodiimide hydrochloride (EDC or WSC), diphenylphosphoryl azide (DPPA), benzotriazol— 1—yloxy—tris(dimethylamino)phosphonium salts (e.g., benzotriazol—l- yloxy- tris(dimethylamino)phosphonium hexafluorophosphate), and 2—chloro—4,6—dimethoxytriazine (CDMT). The condensation agent is ably CDI.

The amount of the sation agent for use is typically at least 1 mole, and preferably about 1 to 5 moles, per mole of compound (3).

Together with the condensation agent, an additive ator), such as l—hydroxy ben— zotriazole (HOBt) and N—hydroxy succinimide (HOSu), may optionally be used.

When the additive is used, the amount of the additive is lly at least 1 mole, and preferably about 1 to 5 moles, per mole of the condensation agent.

The reaction can also be performed by optionally adding a base. Examples of the base e tertiary amines, such as triethylamine and N,N—diisopropylethylamine; and nitrogen—containing aromatic compounds, such as pyridine and 4—dimethylaminopyridine.

When a base is used, the amount of the base is typically at least 1 mole, and preferably about 1 to 5 moles, per mole of compound (5).

Ammonia is typically used as ammonia water. The amount of ammonia for use is typically at least 1 mole, and preferably about 1 to 10 moles, per mole of compound (3).

The reaction is typically med by reacting nd (3) with a condensation agent, optionally with an additive, to prepare an activated ester, and reacting the activated ester with ammonia.

The reaction temperature for the preparation of the activated ester and uent reaction with ammonia is not particularly limited. The preparation and the on can be typically med under any of the ing conditions: with cooling, at room temperature, or with heating. The reaction is preferably performed at a temperature within the range of ice cooling temperature to about room temperature for l to 30 hours.

Compound (4) —> Compound 15) Compound (5) can be produced by reacting compound (4) with compound CO(CH2X 3)2.

In compound CO(CH2X3)2, X3 represents halogen. The halogen represented by X3 includes fluorine, chlorine, e, and iodine, with chlorine, bromine, and iodine being preferable.

The reaction can be performed in the presence of a common solvent. The solvent can be any solvent that does not adversely effect the reaction. Examples of the solvent include halogenated aliphatic hydrocarbon solvents (e.g., methylene chloride, chloroform, and ethylene chloride), ketone solvents (e.g., acetone and methyl ethyl ketone), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, and e), 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., e and xylene).

The proportion of compound (4) and compound CO(CH2X3)2 for use is typically at least 1 mole, preferably about 1 to 5 moles of compound X3)2, per mole of compound (4).

Optionally, a dehydrating agent may be used. Examples of the ating agent include synthetic e, which specifically includes lar sieves (MS)3A, MS4A, and other similar zeolite with fine pores.

The on temperature is not particularly limited, and the reaction can be typically med under any of the following conditions: with cooling, at room ature, or with heating. The on is preferably performed at a temperature within the range of around room temperature to about 200°C for l to 30 hours. The use of this method enables the oxazole ring to form at a high yield.

Compound 15] —> Compound 16) Compound (6) can be produced by reacting compound (5) with compound RZOMl. In compound RZOMI, R2 represents alkanoyl, and M1 represents an alkali metal.

The alkanoyl represented by R2 includes Cl—C6 (in particular, Cl—C4) linear or branched alkanoyl. Specific examples of the alkanoyl e formyl, acetyl, n— propionyl, isopropionyl, ryl, isobutyryl, sec—butyryl, tert—butyryl, and yl, with formyl, acetyl, n—propionyl, and isopropionyl being preferable, and acetyl being more preferable.

The alkali metal represented by M1 includes lithium, sodium, and potassium, with sodium and potassium being preferable.

Specific examples of compound RZOM1 include sodium acetate and potassium acetate.

The reaction can be performed in the presence of a common solvent. The t can be any solvent that does not adversely affect the reaction. Examples of the solvent include ketone solvents (e.g., acetone and methyl ethyl ketone), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, and diglyme), ester solvents (e.g., methyl acetate and ethyl acetate), aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide), halogenated hydrocarbon solvents (e.g., methylene chloride and ethylene chloride), and combinations of these solvents.

The solvent is preferably N,N—dimethylformamide.

The proportion of compound (5) and compound ROM1 for use is typically at least 1 mole, and preferably about 1 to 5 moles of compound RZOMI, per mole of compound (5).

The on temperature is not particularly limited, and the reaction can be typically performed under any of the following conditions: with cooling, at room temperature, or with heating. The reaction may be preferably performed at a temperature within the range of around room temperature to about 120°C for 1 to 30 hours.

Compound 16) —> Compound 17] Compound (7) can be ed by hydrolyzing compound (6). The ysis of nd (6) can be typically med in a solvent in the presence of a base.

The solvent can be any solvent that does not adversely affect the reaction. Examples of the solvent e water, alcohol solvents (e.g., methanol, l, isopropanol, and n-butanol), ketone ts (e.g., acetone and methyl ethyl ketone), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, and diglyme), and ace— ile. Preferable examples of the solvent include a combination t of water and an alcohol t (methanol or ethanol). Alcohol solvents (in particular, methanol and ethanol) are preferable.

Examples of the base include alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, ium hydroxide, and cesium hydroxide). Typically, alkali metal hydroxides can be used in the form of an aqueous solution. Examples of the aqueous solution include sodium hydroxide aqueous on.

The amount of the base for use is typically at least 1 mole, and preferably about 1 to moles, per mole of compound (6).

The reaction temperature is not particularly limited, and the on can be typically performed under any of the following conditions: with cooling, at room temperature, or with heating. The reaction is preferably performed at a temperature within the range of around room temperature to about 85°C for 1 to 30 hours.

Production of Compound 1 11) Compound (11) can be produced, for example, through the reaction steps illustrated in the following reaction scheme.

WWO F F 0 )_ F H2 o o )_ F / I / O MeOH/H20 I I o _0> N N —>H2N N O—< conc. HCl DMF HCI 9 CPME 1o O—< 2-EBA, WSC Pm‘ficauon. . o )—F Eth,EtOAc —> —, Qt"fllf—Q-o V0 o 11 o-< Compound 17) —> Compound 18] Compound (8) can be ed by converting the hydroxy group of compound (7) into leaving group (X4).

Examples of the leaving group represented by X4 include halogen (e.g., fluorine, ne, bromine, and ) and organic yloxy (e.g., p—toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, and o—nitrobenzolsulfonyloxy). Halogen is preferable, and bromine is more preferable.

Compound (8’), n the leaving group represented by X4 is an organic sul— fonyloxy, can be produced by reacting compound (7) with an organic sulfonyl halide or organic sulfonic acid anhydride containing the organic sulfonyl group in a solvent in the presence of a base.

The solvent can be any solvent that does not adversely affect the reaction. Examples of the solvent include ketone solvents (e.g., e and methyl ethyl ketone), ether solvents (e. g., tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, and diglyme), ester solvents (e.g., methyl acetate and ethyl acetate), aprotic polar solvents (e.g., ace— tonitrile, methylformamide, and dimethyl sulfoxide), halogenated hydrocarbon solvents (e. g., methylene chloride and ethylene chloride), and combinations of these solvents. The solvent is preferably ester solvents (in ular, ethyl acetate etc.).

The base for use can be known inorganic bases or organic bases. Examples of the inorganic bases include alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium en carbonate), alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium ide), alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate), and alkali metal hydrides (e.g., WO 15780 sodium hydride and potassium hydride). The organic bases include trialkyl amines (e.g., trimethylamine, triethylamine, and N,N-diisopropylethylamine), pyridine, quinoline, piperidine, imidazole, picoline, 4-dimethy1aminopyridine, N,N—dimethylaniline, N—methylmorpholine, azabicyclo[4.3.0]non—5—ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), and 1,8-diazabicyclo[5.4.0]undecene (DBU). When these bases are a liquid, these bases can also be used as a solvent. These bases can be used singly or in a combination of two or more. The base is preferably N,N—diisopropylethylamine, and triethylamine, and more ably N,N—diisopropylethylamine. In particular, N,N—diisopropylethylamine is preferable because the use of N,N—diisopropylethylamine can significantly increase the yield. es of the organic sulfonyl halide include p—toluenesulfonyl halide, methane— sulfonyl halide, trifluoromethanesulfonyl halide, nonafluorobutanesulfonyl halide, and o—nitrobenzolsulfonyl halide. Examples of the halide include chloride and bromide, with chloride being preferable. Particularly preferable organic sulfonyl halide includes esulfonyl chloride.

Examples of the organic sulfonic acid anhydride include p—toluenesulfonic acid anhydride, methanesulfonic acid anhydride, trifluorosulfonic acid anhydride, nonafluo— robutanesulfonic acid anhydride, and o—nitrobenzenesulfonic acid anhydride.

The amount of the base for use is typically 1 to 10 moles, and preferably 1 to 6 moles, per mole of nd (7).

The amount of the organic sulfonyl halide or organic sulfonic acid anhydride for use is typically 1 to 5 moles, and preferably 1 to 2 moles, per mole of compound (7).

The reaction temperature is not particularly limited, and the reaction can be typically performed under any of the following conditions: with cooling, at room temperature, or with heating. The reaction is preferably performed at a ature of about 0 to 60°C for 1 to 30 hours.

The reaction described above produces compound (8’), n the leaving group represented by X4 is an organic sulfonyloxy.

Compound (8"), wherein the g group represented by X4 is halogen, can be ed by reacting compound (8’) with a halogenating agent in a t. When the leaving group represented by X4 is halogen, the halogen includes fluorine, chlorine, bromine, and iodine, with chlorine, bromine, and iodine being preferable and chlorine being more preferable.

The solvent can be any solvent that does not adversely affect the reaction. Examples of the solvent include ketone ts (e.g., acetone and methyl ethyl ketone), ether solvents (e. g., tetrahydrofuran, dioxane, l ether, oxyethane, and e), ester solvents (e.g., methyl acetate and ethyl acetate), aprotic polar solvents (e.g., ace— tonitrile, N,N-dimethylformamide, and dimethyl sulfoxide), halogenated hydrocarbon solvents (e.g., methylene de and ethylene de), and combinations of these solvents.

Examples of the halogenating agent e alkali metal halides (e.g., lithium chloride, lithium bromide, and lithium iodide), and quaternary ammonium halides (e.g., tetrabutylammonium chloride and utylammonium e). The halo- genating agent is preferably an alkali metal halide (in particular, lithium bromide).

The amount of the halogenating agent for use is typically 1 to 5 moles, and preferably 1 to 3 moles, per mole of compound (8’).

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

The step of producing compound (8’) from compound (7) and the step of producing compound (8") from compound (8’) are each independently performed. Alternatively, both steps can be performed in one pot.

The obtained compound (8) (including compounds (8’) and (8’ ’)) is subjected to the following reaction step.

Compound 18] —> Compound 19) nd (9) can be produced by reacting nd (8) with a compound rep- resented by the following formula: [Chem. 10] wherein M2 represents an alkali metal (which may be hereinafter referred to as "phthalimide M2 compound"). Examples of the alkali metal ented by M2 include m, sodium, and potassium, with potassium being preferable.

The reaction can be performed in a common solvent. The solvent can be any solvent that does not adversely affect the reaction. Examples of the solvent e ketone solvents (e.g., acetone and methyl ethyl ketone), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, and diglyme), ester solvents (e.g., methyl acetate and ethyl acetate), aprotic polar solvents (e.g., acetonitrile, methylformamide, and dimethyl sulfoxide), halogenated hydrocarbon solvents (e.g., methylene chloride and ethylene chloride), and combinations of these solvents.

The t is more preferably N,N—dimethylformamide.

The proportion of compound (8) and imide M2 compound is typically at least 1 mole, and preferably about 1 to 5 moles of phthalimide M2 compound, per mole of compound (8).

The reaction temperature is not particularly limited, and the reaction can be typically performed under any of the ing conditions: with cooling, at room temperature, or with heating. The reaction is performed at a ature of about 0 to 100°C for 1 to hours.

Compound 19] —> Compound 1 10) Compound (10) can be produced by reacting compound (9) with methylamine.

The reaction can be performed in a common solvent. The solvent can be any solvent that does not adversely affect the reaction. Examples of the solvent include water, alcohol solvents (e.g., methanol, ethanol, isopropanol, n—butanol, trifluoroethanol, and ethylene glycol), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, and diglyme), aprotic polar solvents (e.g., itrile, N,N—dimethylformamide, and dimethyl sulfoxide), and combinations of these solvents.

The solvent is preferably a combination solvent of water and an alcohol solvent (in particular, methanol or ethanol).

Methylamine can be typically used in the form of a methylamine aqueous solution.

The amount of methylamine for use is typically 1 to 10 moles, and preferably 1 to 5 moles, per mole of compound (9).

The reaction ature is not particularly limited, and the reaction can be typically performed under any of the following conditions: with g, at room temperature, or with heating. The reaction is preferably performed at a temperature within the range of around room temperature to about 100°C for 10 minutes to 30 hours.

Obtained compound (10) is a primary amine compound. Compound (10) can op- tionally be converted into a salt formed with an acid from the standpoint of han— dleability. The salt can be formed in accordance with a known method. The acid can be ed from a wide range of organic acids or inorganic acids. The 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, toluene— sulfonic acid, and naphthalenesulfonic acid. Examples of the inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.

The solvent for use in forming the salt can be any t that does not adversely affect the on. Examples of the solvent include alcohol solvents (e.g., methanol, l, isopropanol, n—butanol, trifluoroethanol, and ethylene ), ketone solvents (e.g., acetone and methyl ethyl ketone), ether ts (e.g., cyclopentyl methyl ether (CPME), tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, and e), ester solvents (e. g., methyl acetate and ethyl acetate), aprotic polar solvents (e.g., ace— tonitrile, N,N—dimethylformamide, and yl sulfoxide), and ations of these ts. The solvent is preferably ether solvents (in particular, CPME).

Compound 1 10) —> Compound 1 11 z Compound (1 1) can be produced by subjecting compound (10) to condensation reaction with 2-ethoxybenzoic acid.

The condensation reaction is typically performed in a solvent in the presence of a condensation agent. When compound (10) is a salt formed with an acid, compound (10) may be converted into a free primary amine by removing the acid from the salt using a base (e.g., inorganic bases, such as sodium hydroxide, potassium ide, sodium carbonate, and sodium en carbonate; and organic bases, such as tri— mine and N,N—diisopropylethylamine) before performing the reaction.

The t can be any solvent that does not adversely affect the reaction. Examples of the solvent include halogenated aliphatic hydrocarbon solvents (e.g., methylene chloride, chloroform, and ethylene chloride), ketone solvents (e.g., acetone and methyl ethyl ), ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, and diglyme), ester solvents (e.g., methyl acetate and ethyl e), aromatic hydrocarbons (e.g., toluene and xylene), aprotic polar solvents (e.g., ace- tonitrile, N,N—dimethylformamide, N—methylpyrrolidone, and dimethyl ide), and combinations of these solvents. The t is preferably ketone solvents (in particular, acetone and methyl ethyl ketone), ether solvents (in particular, tetrahydrofuran, dioxane, diethyl ether, and dimethoxyethane), and ester solvents (e.g., methyl e and ethyl acetate).

Examples of the condensation agent include arbonyl diimidazole (CDI), dicy— clohexyl carbodiimide (DCC), diisopropyl carbodiimide (DIC), l—ethyl—3-(3—dimethylaminopropyl) iimide hydrochloride (EDC or WSC), ylphosphoryl azide , benzotriazol— l—yloxy—tris(dimethylamino)phosphonium salts (e.g., benzotriazol— 1—yloxy—tris(dimethylamino)phosphonium hexafluorophosphate), and 2—chloro—4,6—dimethoxytriazine (CDMT). The condensation agent is preferably CD1 or WSC.

The amount of the condensation agent for use is typically at least 0.5 moles, and preferably about 1 to 5 moles, per mole of 2—ethoxybenzoic acid.

Together with the condensation agent, an additive (activator), such as l—hydroxy ben— zotriazole (HOBt) or N—hydroxy succinimide (HOSu), can optionally be used.

The amount of the additive for use is typically at least 1 mole, and preferably about 1 to 5 moles, per mole of the condensation agent.

The reaction can be performed by optionally adding a base. Examples of the base include tertiary amines, such as triethylamine and N,N—diisopropylethylamine; and nitrogen—containing aromatic compounds, such as pyridine and 4-dimethylaminopyridine.

When a base is used, the amount of the base may be typically at least 0.5 moles, and preferably about 1 to 5 moles, per mole of the condensation agent.

The proportion of compound (10) and 2-ethoxybenzoic acid is typically at least 1 mole, and preferably about 1 to 2 moles of 2—ethoxybenzoic acid, per mole of compound (10).

The reaction ature is not particularly limited, and the reaction can be typically performed under any of the following conditions: with cooling, at room temperature, or with heating. The reaction is preferably performed at a temperature of about 0 to 100°C for l to 30 hours.

In this specification, the term "comprising" includes "consisting essentially of’ and sting of." The present ion covers all combinations of the elements described in this specification.

Examples The following describes the present invention in detail. However, the present invention is not limited to the Examples.

Production Exam le 1: Production 1 of Com ound 3 Compound (3) was produced in accordance with the following reaction .

[Chem. 11] 1:30;? ClCF2CO2Na o F)—F Ofidation K2co3 H MF 20% 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 exotherm subsided. 16.92 g (111 mmol) of sodium chlorodi— fluoroacetate was added thereto, and the mixture was d at 95 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 ioned. 80 m1 of water was added again to the organic layer, followed by partitioning. 3 ml of concentrated hydrochloric acid was added to the organic layer, and the mixture was stirred at 60 to 70°C for 30 minutes. 40 ml of water and 10 ml of a 25% sodium hydroxide aqueous solution were added to the on solution, and the mixture 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 s solution was added dropwise thereto at a temperature of 20°C or below. The mixture was reacted at 20°C or below for 15 minutes, and 10 ml of a 25% sodium hydroxide aqueous solution was added dropwise thereto at a temperature of °C or below, ed by pouring in 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 m1 of methanol, 80 ml of water, and 10 ml of a 25% sodium ide s solution were added to the concentrated residue to dissolve the residue, and 5 ml of concentrated hydrochloric acid was added dropwise thereto to pre- cipitate crystals. The precipitated crystals were ted by filtration and dried at 80°C, thereby obtaining 11.81 g (yield: 86.4%) of compound (3) as a white powder. lH—NMR(CDC13) a: 7.70 (2H,dd,J = 6.4 Hz,2.0 Hz),7.22 (1H,d,J = 9.2 Hz),6.66 (1H,t,J = 74.8 Hz),4.66(lH,sept,J = 6.0 Hz),1.39 (6H,d,J = 6.0 Hz).

Production Exam le 2: Production 2 of Com ound 3 Compound (3) was produced in accordance with the following reaction scheme.

[Chem.12] F B'Y F o>_F _ . F o o o)_.: Ox1dat10n Hy—Q— o >_F K2CO3 —>Hey—Q70 H o_< 1b 2 3 O_< 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 isopropyl bromide were added to 40 m1 of N,N—dimethylformamide, and the mixture was reacted at 75 to 85°C for 2 hours. 80 ml of butyl acetate and 80 ml of water were added to the on solution, and the mixture was partitioned. 5.68 g (58.5 mmol) of ic acid and 10 ml of water were added to the organic layer, and 21.15 g (58.5 mmol) of a 25% sodium chlorite aqueous solution was added dropwise thereto at 20°C or below, followed by reaction for 15 minutes. 10 ml of a 25% sodium ide s solution was added thereto at °C or below, and subsequently 80.41 g (63.8 mmol) of a 10% sodium sulfite aqueous solution was poured in. onally, 2 ml of concentrated hydrochloric acid was added, and the mixture was partitioned, ed 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 trated residue, and the residue was dissolved, followed by dropwise addition of 5 ml of concentrated hy— drochloric acid to precipitate crystals. The precipitated crystals were collected by tion and dried at 80°C, thereby obtaining 12.09 g (yield: 92.4%) of compound (3) as a white powder.

Production e 3: Production of Compound 17) Compound (7) was produced in accordance with the following reaction scheme.

WO 15780 [Chem. 13] F)—I= CH3CN H:y_<3):? o )—F cuxxm |o )—F o o %NH3 ’ H2" —>c,\): C6H5CH3 N 0 F T]ydm]ysrs F CH3COOK , 0)— o )_ F _>AcO —> N I 0 H0\JI Synthesis of Compound 14) .00 g (40.6 mmol) of nd (3) was added to 25 ml of itrile at room temperature and stirred. 7.90 g (48.7 mmol) of carbonyl diimidazole was gradually added, and the mixture was reacted at room temperature for 1 hour. 10 ml (134 mmol) of 25% ammonia water was added to 120 ml of water and cooled to 10°C or below, followed by se addition of the on solution thereto. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 9.25 g (yield: 92.9%) of nd (4) as a white powder. lH—NMR (CDC13) a: 7.54 (1H,d,J = 1.6 Hz),7.25 (1H,dd,J = 8.4 Hz,2.0 Hz),7.17 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).

Synthesis of Compound 15) .00 g (40.8 mmol) of nd (4) and 6.21 g (48.9 mmol) of 1,3—dichloroacetone were added to 10 ml of toluene at room temperature, and the mixture was reacted under reflux for 3 hours. 60 ml of toluene, 20 m1 of water, and 2 ml of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the mixture was partitioned. The organic layer was concentrated under reduced pressure, thereby obtaining compound (5) as a brownish solid (after recrystallization: fine yellow powder). lH—NMR (CDC13) a: 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 J = 6.0 HZ).

Synthesis of Compound 17) ml of N,N—dimethylformamide and 4.80 g (48.9 mmol) of potassium acetate were added to the crude product of compound (5 ) ed in the section above, and the mixture was reacted at 90 to 100°C for 3 hours. 20 ml of methanol, 20 m1 of water, and ml of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and reacted under reflux for 1 hour. 35 m1 of water was added to the on solution, and the precipitated crystals were collected by filtration, followed by drying at 80°C, thereby obtaining 10.33 g (yield: 84.6%) of compound (7) as a pale brownish powder. lH-NMR (CDC13) a: 7.65-7.63 ,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 = 6.0 Hz).

Production Exam 1e 4: tion of Com ound 11 Compound (11) was produced in accordance with the following reaction scheme.

[Chem 14] 1) DIPEA 0 )\ MeSOZCl o >—F F I o EtOAc Ho\J: N —>BrJb—QON o_< 2) LiBr 7 8 o—< C33; F>_F 1) 40A)MeNH20 F o )_F OM):MIT’CZZZ MeOH/HZO \J: I 0 —>H2N N 2) cone. HCl HCI CPME 1° O-< Purification F Z-EBA, wsc o )-F N_0A, _,Et0WH20 HNJN’FQO 11 o< Synthesis of Compound 19] .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 poured in and stirred at to 30°C for 1 hour. 17.41 g (200 mmol) of lithium e was added thereto and reacted at 20 to 35°C for 1 hour. 100 ml of water was added to the reaction solution, and the mixture was partitioned, followed by tration of the organic layer under reduced pressure. 300 ml of ethyl acetate was added to the concentrated residue to dissolve the residue, and the solution was again concentrated under reduced pressure. 200 ml of N,N—dimethylformamide and 17.33 g (93.6 mmol) of potassium phthalimide were added to the trated residue and reacted at 75 to 85°C for 1 hour. 200 ml of water was added to the reaction on to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 25.90 g (yield: 90.5%) of compound (9) as a white . lH-NMR (DMSO-d6) 6: 8.22 (1H,s),7.94-7.86 ,7.58 (1H,d,J = 2.0 52 (1H,dd,J = 8.8 Hz,2.4 Hz),7.30 (1H,d,J = 8.4 14 (1H,t,J = 74.2 Hz),4.78-4.69 (3H,m),1.30 (6H,d,J = 6.0 Hz).

Synthesis of Compound 1 10] .00 g (35.0 mmol) of compound (9) was mixed with 30 ml of a 40% methylamine aqueous solution, 30 m1 of methanol, and 75 ml of water, and reacted under reflux for minutes. 150 ml of cyclopentyl methyl ether (CPME) and 15 ml of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the temperature was ed to 65 to 75°C, followed by partitioning. A mixture of 150 m1 of water and 7.50 g of sodium chloride was added to the c layer, and the temperature was adjusted to 65 to 75°C again, followed by partitioning. 3.75 ml of concentrated hy- drochloric acid was added to the organic layer to precipitate crystals. The precipitated crystals were collected by filtration and dried at 60°C, thereby obtaining 11.95 g (yield: quant.) of compound (10) as a white powder. lH-NMR (DMSO-d6) 6: 8.51 (3H,br—s),8.29 ,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 = 74.0 Hz),4.72 (1H,sept,J = 6.1 Hz),4.03 (2H,s),l.33 (6H,d,J = 6.4 Hz).

Synthesis of Compound 1 11] 13.30 g (39.7 mmol) of compound (10) was mixed with 3.83 g (37.8 mmol) of tri— ethylamine and 108 ml of ethyl acetate, and stirred at 20 to 30°C for 1 hour. 9.78 g (58.9 mmol) of 2-ethoxybenzoic acid and 11.28 g (58.8 mmol) of 1—ethyl—3—(3—dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added to the reaction solution, and reacted at 20 to 30°C for 1 hour. 54 ml of water and 5.4 ml of concentrated hydrochloric acid were added to the on solution, and the tem— perature was adjusted to 40 to 50°C, followed by partitioning. 54 ml of water and 5 .4 ml of a 25% sodium ide aqueous solution were added to the organic layer, and the ature was adjusted to 40 to 50°C again. The mixture was partitioned, and the c layer was concentrated under reduced pressure. 45 ml of ethanol, 18 ml of water, 5 .4 ml of a 25% sodium hydroxide aqueous on, 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 a seed crystal was added thereto to precipitate crystals. The precipitated crystals were collected by filtration and dried at °C, thereby obtaining 12.88 g (72.6%) of compound (11) as a white powder. lH-NMR ) a: 8.56 (1H,br-s),8.23 ,J = 7.6 Hz,1.6 Hz),7.66 (1H,s),7.63 (1H,d,J = 2.0 Hz),7.58 ,J = 8.4 Hz,2.0 Hz),7.44—7.39 ,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 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).

Production Example 5: Production of Compounds ii) to [ix] 2016/088843 The compounds shown in the following Table 2 were produced as described below.

The 1H—NMR of the produced compounds is also shown below. Compound (ii) is the same as compound (9).

[Table 2] Formula Number Structural Formula 0 o %F 1 Win ° 0 O F}F o 0% O O>_F "1 l H2N N’ Crépwuiwoi" Synthesis of Compound 1i) 13.1 g of 2—[2—(3—benzyloxy—4—difluoromethoxyphenyl)oxazol—4—ylmethyl]isoindoline— 1 ,3—dione( 2-((2-(3-(benzyloxy)(difluoromethoxy)phenyl)oxazolyl)methyl)isoindoline-1,3-d ione) synthesized in accordance with the synthesis procedure described in PTL 2 (W02014/034958 pamphlet) was dissolved in a mixture of 260 ml of ethanol and 140 m1 of DMF, and 1.3 g of a 10% palladium carbon powder was added thereto, followed by stirring in a hydrogen here at 40°C for 1 hour. 100 ml of methylene chloride was added to the reaction solution and stirred, followed by removal of the catalyst by filtration. The crude crystals obtained by concentrating the filtrate were recrystallized from ethyl e, thereby obtaining 8.8 g of 2—[2—(4—difluoromethoxy-3—hydroxyphenyl)oxazol—4—ylmethyl]isoindoline— 1,3—dione (2—((2—(4—(dif1uoromethoxy)—3—hydroxyphenyl)oxazol—4—yl)methyl)isoindoline— 1 ,3—dion e: compound (i)) as a white powder. lH—NMR (CDC13) a: 8.18 (1H, br-s) 7.85-8.17 (5H, m) 6.89-7.51 (4H, m) 4.74 (2H, Synthesis of Compound [ii] 2 g of compound (i) and 3.9 ml of 1,8-diazabicyclo[5,4,0]undec—7-ene (DBU) were dissolved in 20 ml of ethanol, and 3.18 g of isopropyl bromide was added thereto, followed by heating under reflux overnight. Subsequently, 1 m1 of a 10% sodium hydroxide aqueous solution was added to the on solution, and the e 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 with water twice, and concentrated under d pressure, thereby obtaining [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—d ione: compound (ii)). lH-NMR (CDC13) 6: .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).

Synthesis of Compound [iii] 1.58 g of compound (ii) was dissolved in 16 ml of methanol, and 3.2 ml of a methylamine aqueous solution (40%) was added thereto, ed by heating under reflux for 1 hour. The reaction solution was concentrated, and the reaction t was dissolved in ethyl acetate, followed by g of the organic layer with a 10% sodium hydroxide aqueous solution and water. The c layer was separated and concentrated under reduced pressure, thereby obtaining 1.17 g of [2—(4—difluoromethoxy—3—isopropoxyphenyl)oxazol—4—yl]methylamine ((2—(4—(difluoromethoxy)—3—isopropoxyphenyl)oxazol—4—y1)methanamine: compound (iii)) as a brownish solid. lH-NMR (CDC13) a: 7.65 (1H, d, J :18 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).

Synthesis of Compound giv) 0.24 g of 5—benzyloxy—2—ethoxybenzoic acid and 0.44 g of compound (iii) were suspended in 20 m1 of acetone, and 0.27 g of 1-hydroxy benzotriazole (HOBt) and 0.38 g of l—ethyl—3—(3—dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added thereto, followed by heating under reflux for 1 hour. The reaction solution was cooled, and acetone was evaporated under reduced pressure, followed by addition of water to the residue and extraction with ethyl acetate. The organic layer was washed with water twice and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n—hexanezethyl acetate 2 3:1). The obtained crude crystals were recrystallized from n—hexanezethyl acetate, thereby obtaining 0.28 g of N— [2—(4—difluoromethoxy—3—isopropoxyphenyl)oxazol—4—ylmethyl]—5—benzyloxy—2—ethoxy benzamide (5—(benzyloxy)—N—((2—(4— (difluoromethoxy)—3—isopropoxyphenyl)oxazol—4—yl)methyl)—2—ethoxybenzamide: compound (iv)) as a white powder. lH-NMR (CDCl3) a; 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).

Synthesis of Compound 1v] .5 g of [2-(3—benzyloxy—4—difluoromethoxyphenyl)oxazol—4—yl]methylamine(2—(3—(benzyloxy) fluoromethoxy)phenyl)oxazol—4—yl)methanamine (MAP—15211) synthesized in accordance with the synthesis procedure described in PTL 2 4/03495 8 pamphlet) and 3.4 g of acetylsalicylic acid were suspended in 150 ml of acetone. 3.4 g of l—hydroxy riazole (HOBt) and 4.8 g of 1—ethyl—3—(3—dimethylaminopropyl)carbodiimide hloride (WSC) were added thereto, followed by g under reflux for 1 hour. uently, 10 ml of a 10% sodium hydroxide aqueous solution was added thereto, and the mixture was heated under reflux for 30 minutes. The reaction solution was then cooled, and acetone was ated under reduced pressure. Water was added to the residue and tion was performed with ethyl e. The organic layer was washed with water twice and con— centrated under reduced pressure, thereby obtaining 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-hydroxybenz amide: compound (v)) as a white powder. lH-NMR (CDCl3) a: 12.19 (1H, s) 7.70-7.72 (2H, m), 7.63 (1H, dd, J = 8.4, 1.8 Hz), 2016/088843 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).

Synthesis of Compound gvi) 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 thereto, followed by heating with stirring at 80°C for 1 hour. Ice water was added to the on solution, and extraction was performed with ethyl acetate. The organic layer was washed with water twice and concentrated under d pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetatezn—hexane = 1:1), y obtaining 3.6 g of N— [2-(3—benzyloxy—4—difluoromethoxyphenyl)oxazol—4—ylmethyl]—2—[(2-acetoxy)ethoxy]b enzamide ((2—(3—(benzyloxy)-4—(difluoromethoxy)phenyl)oxazol-4—yl)methylcarbamoyl)ph enoxy)ethyl acetate: compound (vi)) as a white . lH-NMR(CDC13) 6: 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), .32 (2H, m), 2.03 (3H, s).

Synthesis of Compound gvii) 3.5 g of compound (vi) was suspended in 100 ml of ethanol, and 0.4 g of a 10% palladium carbon powder was added thereto, followed by stirring in a hydrogen at- mosphere at room temperature for 4 hours. The catalyst was removed by filtration, and the crude crystals obtained by concentrating the filtrate were recrystallized from ethanol—n—hexane, thereby obtaining 2.1 g of N— [2-(3—hydroxy—4—difluoromethoxyphenyl)oxazol—4—ylmethyl]—2—[(2—acetoxy)ethoxy]ben zamide (2-(2—((2—(4—(difluoromethoxy)-3—hydroxyphenyl)oxazol—4—yl)methylcarbamoyl)pheno xy)ethyl e: compound (Vii)) as a white powder. lH-NMR(CDC13) 6: 8.45 (1H, br-s), 8.25 (1H, d, J = 8.4 Hz), 7.76 (1H, s), 7.66 (1H, s), 7.42-7.53 (2H, m), 7.09-7.26 (3H, m), 6.95 (1H, d, J = 7.8 Hz), 6.78 (1H, br-s), 6.64 (1H, t, J = 74.1 Hz), 4.58-4.65 (4H, m), 4.31-4.34 (2H, m), 2.11 (2H, s).

Synthesis of Compound gviii) .1 g of methyl pyruvate and 0.8 ml of e were dissolved in 15 ml of 1,2—dimethoxyethane, and the solution was heated with stirring at 50°C for 1 hour. The reaction solution was concentrated, and the residue was dissolved in 45 ml of 2—methoxy l. 3 g of 3—benzyloxy—4—difluoromethoxybenzamjde (3—(benzyloxy)—4—(difluoromethoxy)benzamide) synthesized in accordance with the synthesis procedure described in PTL 1 (WO2007/058338 pamphlet) was added thereto and heated under reflux for 4 hours. 25 ml of water was added to the reaction solution and stirred at room temperature overnight. The precipitated crystals were collected by filtration and dried under reduced pressure at room temperature, thereby obtaining 0.73 g of methyl 2-(3-benzyloxydifluoromethoxyphenyl)oxazolecarboxylate l 2—(3—(benzyloxy)—4—(difluoromethoxy)pheny1)oxazole—4—carboxylate: compound (viii)) as white crystals. lH-NMR ) a: 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).

Synthesis of Compound [ix] 0.28 g of compound (viii) was dissolved in 5 m1 of ethanol, 1 m1 of tetrahydrofuran, and 0.5 m1 of N,N—dimethylformamide, and 0.03 g of a 10% palladium carbon powder was added o, followed by stirring in a hydrogen atmosphere at room temperature for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and extraction was performed with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution one time and concentrated under reduced pressure, thereby obtaining 0.18 g of methyl 2—(3—hydroxy—4—difluoromethoxyphenyl)oxazole—4—carboxylate (methyl 2—(4—(difluoromethoxy)—3—hydroxyphenyl)oxazole—4—carboxylate: compound (ix)) as white ls. lH-NMR (CDC13) a: 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).

Production Example 6: tion of Compounds 111a] to 1 11s] The nds shown in the following Table 3 were produced as described below.

The 1H—NMR of the produced compounds is also shown below.

[Table 3] a Number Structural Formula 11a QYHVE b—QONo O OH 0 4 o %F 11b : H I fQO HO NVEN V0 0 o~< OH F o o>7F 110 "in? \/O O K o >‘F 11d Qwflflg‘Qo HO/\/0 O O—< o >4 He QYHVEK’QO Ho/VO 0 O'\ 11f QWHVEK’QOo HONO O V0 o >‘F 11g QWHVQ‘QO Ho/VO 0 >40 o >‘F 11h "in? HO/\’0 O <>_/o )-—F HO N OH O 0<< HO 0 >‘F OWEN/{QOH 0 O W0 15780 2016/088843 OH F o >‘F 11k "ME a—Q’ON OH 0 O'< OH 0 >‘F 111 HJ 0 N N OH 0 ‘< lln "YEN/ 0 o 04 o >‘F 110 HOW/E@0N o 0’< OH"JEN HO o>¥F uq 13%}an QfivNflNH I / O 111. o >—F QWHJ@0N N 11$ O 0 o o —< "’OH Synthesis of Compound 1 11a: 3 g of compound (iii) and 1.5 g of salicylic acid were suspended in 60 m1 of acetone, and 1.8 g of 1-hydroxy benzotriazole (HOBt) and 2.6 g of l—ethyl—3—(3—dimethylan1inopropyl)carbodiimide hydrochloride (WSC) were added thereto, followed by heating under reflux for 1 hour. The reaction solution was cooled, and acetone was evaporated under reduced re. Water was added to the residue, and extraction was performed with ethyl acetate. The organic layer was washed with water twice and concentrated under reduced pressure. The obtained crude ls were recrystallized from ethyl acetate—n—hexane, thereby obtaining 1.47 g of N— [2-(3-isopropoxydifluoromethoxypheny1)oxazolylmethyl]hydroxybenzamide (N—((2—(4—(difluoromethoxy)—3-isopropoxyphenyl)oxazol—4—yl)methyl)—2—hydroxybenz amide: compound (11a)) as a white powder. lH-NMR (CDCl3) a: 12.19 (1H, s), 7.70 (1H, s), 7.50-7.64 (2H, m), .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).

Synthesis of Compound (11b) The procedure in "Synthesis of Compound (11a)" above was repeated using 0.44 g of compound (iii) and 0.24 g of 2—ethoxy-3—hydroxy benzoic acid, thereby ing 0.28 g of N— [2-(3—isopropoxy-4—difluoromethoxyphenyl)oxazol—4—ylmethyl]—2—ethoxy—3-hydroxybe nzamide (N-((2—(4—(difluoromethoxy)—3—isopropoxyphenyl)oxazol—4—yl)methyl)—2—ethoxy—3-hyd roxybenzamide: compound (11b)) as a white powder. lH-NMR(CDC13) 6: 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).

Synthesis of Compound 1 11c] The procedure in "Synthesis of Compound (11a)" above was repeated using compound (iv), thereby obtaining 5 mg of N— [2—(3—isopropoxy—4—difluoromethoxyphenyl)oxazol—4—ylmethyl]—2—ethoxy—5—hydroxybe nzamide (N—((2—(4—(difluoromethoxy)—3—isopropoxyphenyl)oxazol—4—yl)methyl)—2—ethoxy-5—hyd roxybenzamide: compound (11c)) as a white powder. lH-NMR(CDC13) a: 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 = 5.1Hz),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, Synthesis of Compound 1 11d] 0.1 g of compound (11a) was dissolved in 3 ml of N,N—dimethylformamide, and 0.12 g of 2—bromoethyl acetate and 0.14 g of potassium carbonate were added thereto, followed by heating with stirring at 80°C for 2 hours. uently, 1 ml of ol and 0.3 ml of a 25% sodium hydroxide aqueous 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 tion was performed with ethyl acetate. The organic layer was washed with water twice and concentrated under reduced pressure. The ed residue was recrystallized from ethyl acetate—n—hexane, y obtaining 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—hydroxyet hoxy)benzamide: nd (11d)) as a white powder. lH—NMR (CDC13) a: 8.67 (1H, br—s) 8.16 (1H, dd, J = 7.8, 1.8 Hz), .74 (2H, m), 7.62 (1H, dd, J = 8.4, 1.8 Hz), 7.40-7.46 (1H, m), 7.24—7.26 (1H, m), 7.06—7.12 (1H, m), 6.94—6.97 (1H, m), 6.65 (1H, t, J = 75.0 Hz), 5.43 (1H, t, J = 6.6 Hz), 4.69—4.77 (1H, m), 4.62 (2H, d, J = 5.4 Hz), 4.18—4.21 (2H, m), 3.94-3.99 (2H, m), 1.42 (6H, d, J = 6.3 Hz).

Synthesis of Compound 111e1 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 ethyl iodide was added thereto, followed by heating under reflux overnight. Subsequently, 1 ml of a 10% sodium hydroxide aqueous solution was added to the reaction solution, and heated under reflux for 30 minutes. Thereafter, ice water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with water twice and concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethanol—n—hexane, thereby ing 95 mg of N— [2—(3—ethoxy—4—difluoromethoxyphenyl)oxazol—4—ylmethyl]—2—(2—hydroxyethoxy)benza mide N— ((2—(4—(difluoromethoxy)—3—ethoxyphenyl)oxazol—4—yl)methyl)—2—(2—hydroxyethoxy)be nzamide (CPA—15566) as a white powder. lH—NMR (CDC13) a: 8.86 (1H, br—s) 8.15 (1H, dd, J = 81,18 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 = 45,42 Hz), 3.97 (2H, dd, J = 4.5, 4.2 Hz), 1.50 (3H, t, J = 6.9 Hz) Synthesis of Compound 1 11f) 0.3 g of compound (vii) and 0.3 ml of azabicyclo[5,4,0]undec—7—ene (DBU) were dissolved in ethanol, and 0.27 g of (bromomethyl)cyclopropane was added thereto, followed by heating under reflux ght. Subsequently, 1 ml of a 10% sodium hydroxide aqueous solution was added to the reaction solution, and heated under reflux for 30 minutes. Ice water was then added to the reaction solution, and ex- traction was performed with ethyl acetate. The organic layer was washed with water twice and concentrated under reduced pressure. The obtained e was purified by silica gel column chromatography (methylene chloride). The obtained crude crystals were tallized from ethyl acetate—n—hexane, thereby obtaining 0.26 g of N— [2-(3-cyclopropyl methoxy- 4—difluoromethoxyphenyl)oxazol—4—ylmethyl]—2—(2—hydroxyethoxy)benzamide (N-((2—(3-(cyclopropylmethoxy)-4—(difluoromethoxy)phenyl)oxazol-4—y1)methy1)—2-(2— hydroxyethoxy)benzamide: compound (11f)) as a white powder. lH-NMR (CDC13) a: 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), .37-5.42 (1H, m), 4.18-4.21 (2H, m), .01 (4H, m),1.32-1.37 (1H, 5—O.71 (2H, m), 0.37-042 (2H, m).

Synthesis of Compound 111g) 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 yl bromide was added thereto, followed by heating under reflux overnight. Subsequently, 1 ml of a 10% sodium ide aqueous solution was added to the reaction solution and heated under reflux for 30 minutes. Ice water was then added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with water twice and con— centrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride). The obtained crude ls were re— llized from ethyl acetate—n—hexane, thereby obtaining 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—hydroxyeth oxy)benzamide: nd (11g)) as a white powder. lH—NMR (CDC13) a: 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).

Synthesis of Compound 1 11h] 0.3 g of compound (vii) and 0.3 m1 of 1,8—diazabicyclo[5,4,0]undec—7—ene (DBU) were ved in ethanol, and 0.3 g of (bromomethyl)cyclobutane was added thereto, followed by heating under reflux overnight. Subsequently, 1 ml of a 10% sodium hydroxide aqueous solution was added to the reaction solution and heated under reflux for 30 minutes. Ice water was then added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with water twice and con— centrated under reduced pressure. The ed residue was purified by silica gel column tography lene chloride). The obtained crude crystals were re- crystallized from ethyl e—n—hexane, thereby obtaining 0.24 g of N— [2-(3-cyclobutylmethoxydifluoromethoxyphenyl)oxazolylmethyl](2-hydroxye thoxy) benzamide (N-((2-(3-(cyclobutylmethoxy)(difluorornethoxy)phenyl)oxazolyl)methy1)(2-h ydroxyethoxy) ide: compound (11h)) as a white powder. lH-NMR (CDC13) a: 8.86 (1H, br—s) 8.16 (1H, dd, J = 7.8, 1.8 Hz), 7.63 (1H, dd, J = 8.4, 2.1 Hz), 7.70-7.74 (2H, m), 7.40-7.46 (1H, m), 7.23-7.26 (1H, m), 7.07-7.12 (1H, m), 6.95 (1H, d, J = 7.8 Hz), 6.65 (1H, t, J = 75.3 Hz), 5.41 (1H, t, J = 6.6 Hz), 4.62 (2H, d, J = 5.4 Hz), 4.20 (2H, dd, J = 4.5, 4.2 Hz), 4.11 (2H, d, J = 6.6 Hz), 3.96—4.01 (2H, m), 2.80-2.90 (1H, m), .20 (2H, m), 1.88—2.02 (4H, m).

Synthesis of Compound 1 Hi] 0.28 g of compound (iii) and 0.17 g of 2,3—dihydroxy benzoic acid were ded in 3 ml of acetone, and 0.17 g of l—hydroxy benzotriazole (HOBt) and 0.23 g of 1—ethyl—3-(3—dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added thereto, followed by heating under reflux for 3 hours. The reaction solution was cooled, and acetone was evaporated under reduced pressure. Water was added to the residue, and extraction was performed with ethyl acetate. The organic layer was washed with water twice and concentrated under reduced pressure. The obtained residue was partially purified by silica gel column chromatography (dichloromethanezmethanol = 50: 1). The obtained crude crystals were recrystallized from n—hexane—acetone, thereby obtaining 0.2 g of N— [2-(4—difluoromethoxy—3—isopropoxypheny1)oxazol—4-ylmethyl]—2,3-dihydroxybenzami —(4—(difluoromethoxy)—3—isopropoxyphenyl)oxazol—4—yl)methyl)—2,3—dihydroxyb enzamide: compound (11i)) as a white powder. lH-NMR (DMSO) 6: 12.54 (1H, s), 9.30 (1H, br-t, J = 5.4 Hz), 9.23 (1H, s), 8.12 (1H, s), 7.61 (1H, d, J = 1.8 Hz), 7.55 (1H, dd, J = 8.4, 1.8 Hz), 7.38—7.28 (2H, m), 7.15 (1H, t, J = 74.1 Hz), 6.95—6.89 (1H, m), 6.69 (1H, t, J = 8.1 Hz), 4.74 (1H, sept., J = 6.0 Hz), 4.45 (2H, d, J = 5.4 Hz), 1.32 (6H, d, J = 6.0 Hz).

Synthesis of Compound 1 111') The procedure in "Synthesis of Compound (11i)" above was repeated using 0.28 g of compound (iii) and 0.17 g of hydroxybenzoic acid, thereby obtaining 0.17 g of N—[2—(3—isopropoxy—4—difluoromethoxyphenyl)oxazol—4—ylmethyl]—2,4—dihydroxybenza mide (N—((2-(4—(difluoromethoxy)—3—isopropoxyphenyl)oxazol—4—yl)methyl)—2,4—dihydroxyb enzamide: compound (11j)) as a white powder. lH-NMR (DMSO) (3: 12.75 (1H, s), 1011 (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).

Synthesis of Compound 111k) The procedure in "Synthesis of Compound (11i)" above was repeated using 0.28 g of compound (iii) and 0.17 g of 2,5-dihydroxybenzoic acid, thereby obtaining 0.16 g of N—[2—(3—isopropoxy—4—difluoromethoxyphenyl)oxazol—4—ylmethyl]—2,5—dihydroxybenza mide (N—((2—(4—(difluoromethoxy)—3—isopropoxyphenyl)oxazol—4—yl)methyl)—2,5—dihydroxyb enzamide: compound (11k)) as a white . lH-NMR (DMSO) 6; 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 21.8 Hz), 7.55 (1H, dd, J = 8.4, 1.8 Hz), 7.31 (1H, d, J = 8.4 Hz), 7.29 (1H, d, J = 3.0 Hz), 7.14 (1H, t, J = 74.1 Hz), 6.86 (1H, dd, J = 8.7 Hz), 6.74 (1H, d, J = 8.7 Hz), 4.74 (1H, sept., J = 6.0 Hz), 4.44 (2H, d, J = 5.1 Hz), 1.31 (6H, d, J = 6.0 HZ).

Synthesis of Compound 1111) The procedure in "Synthesis of Compound (11i)" above was repeated using 0.28 g of compound (iii) and 0.17 g of 2,6—dihydroxybenzoic acid, thereby obtaining 0.2 g of N— [2—(3—isopropoxy—4—difluoromethoxyphenyl)oxazol—4—ylmethyl]—2,6—dihydroxybenzami (N—((2—(4—(difluoromethoxy)—3—isopropoxyphenyl)oxazol—4—yl)methyl)—2,6—dihydroxyb de: compound (1 11)) as a white powder. lH-NMR (DMSO) 6: 12.51 (1H, s), 9.32 (1H, br-t, J = 5.4 Hz), 8.11 (1H, s), 7.62 (1H, d, J 21.8 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).

Synthesis of Compound 1 11m) 0.2 g of compound (11a) was dissolved in 2 ml of acetonitrile. 0.23 g of sodium iodide, 0.27 g of potassium ate, and 98 mg of 3—chloropropyl acetate were added thereto, ed by heating under reflux overnight. 2 ml of a 10% sodium ide aqueous solution was further added thereto, and the mixture was heated under reflux until the reaction was completed. After cooling, water was added to the reaction on, and extraction was performed with ethyl acetate. The c layer was washed with water twice and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n—hexanezethyl acetate = 3:1), and the obtained crude crystals were recrystallized from ethanol—n—hexane, thereby obtaining 0.15 g of N- [2-(3-isopropoxydifluoromethoxyphenyl)oxazolylmethyl](3-hydr0xypropoxyy )benzamide (N-((2-(4-(difluoromethoxy)isopropoxyphenyl)oxazolyl)methyl)(3-hydroxypr opoxy)benzamide: compound (11m)) as a white powder. lH-NMR (CDC13) a: 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 21.8 Hz), 7.57 (1H, dd, J = 8.4, 1.8 Hz), 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).

Synthesis of Compound 1 Mn] 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 isopropyl bromide were added thereto, followed by stirring at room temperature for 16 hours and at 45°C for 4 hours. Water was added thereto with ice cooling, and extraction was med with ethyl acetate.

The organic layer was washed with a saturated sodium chloride solution one time and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n—hexanezethyl acetate 2 2:1), thereby obtaining 0.16 g of methyl 2—(3—isopropoxy—4—difluoromethoxyphenyl)oxazole—4—carboxylate (methyl difluoromethoxy)—3—isopropoxyphenyl)oxazole—4—carboxylate: compound (11n)) as a white powder. lH-NMR (CDC13) a; 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).

Synthesis of Compound 1 1101 0.7 g of nd (1 1n) was dissolved in 7 ml of methanol, and 1.4 ml of a 25% sodium ide s solution was added thereto, followed by g under reflux at room temperature for 30 minutes. The reaction solution was stirred with ice cooling, and concentrated hydrochloric acid was added thereto to give a pH of 3, followed by collection of the precipitated crystals by filtration. The obtained crystals were dried under reduced pressure, thereby obtaining 2—(3—isopropoxy-4—dif1uoromethoxyphenyl)oxazole—4—carboxylic acid (2—(4—(difluoromethoxy)—3—isopropoxyphenyl)oxazole—4—carboxylic acid: nd (1 10)). lH-NMR (CDC13) a: 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). sis of Compound 1 11p] The procedure in "Synthesis of Compound (111)" above was repeated using compound (iii) and 2-ethoxyhydroxy benzoic acid, thereby obtaining N- [2—(3—isopropoxy—4—difluoromethoxyphenyl)oxazol—4—ylmethyl]—2—ethoxy—6—hydroxybe (N—((2—(4—(difluoromethoxy)—3-isopropoxyphenyl)oxazol—4—yl)methyl)—2—ethoxy—6—hyd roxybenzamide: compound (11p)). lH-NMR (CDCl3) a: 13.81 (1H, s), 9.00 (1H, brs), .62 (2H, m), 7.60 (1H, dd, J = 8.4 Hz, 2.1 Hz), 7.30—7.18 (2H, m), 6.63 (1H, t, J = 75 Hz), 6.61 (1H, d, J = 8.4 Hz), 6.37 (1H, d, J = 8.1 Hz), 4.69 (1H, sept, J = 6.0 Hz), 4.60 (2H, dd, J = 5.1 Hz, 0.9 Hz), 4.15 (2H, dd, J = 14.1 Hz, 6.9 Hz), 1.48 (3H, t, J = 6.9 Hz), 1.40 (6H, d, J = 6.3 Hz).

Synthesis of Compound 1 11g] The ure in "Synthesis of Compound (11i)" above was repeated using compound (iii) and xy—3,4—dihydroxybenzoic acid, y obtaining N— [2-(3—isopropoxy-4—difluoromethoxyphenyl)oxazol—4—ylmethyl]—2—ethoxy—3,4—dihydrox ybenzamide (N-((2—(4—(difluoromethoxy)—3—isopropoxyphenyl)oxazol—4—yl)methyl)—2—ethoxy—3,4—di hydroxybenzamide: compound (11q)). lH-NMR (d6—DMSO) 6: 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).

Synthesis of Compound 1 Hr] A typical synthesis procedure was performed using 0.1 g of compound (1 la) and chlorosulfuric acid, thereby ing N— —isopropoxy—4—difluoromethoxyphenyl)oxazol—4—yl)methylcarbamoyl]—2—phenyl ammonium sulfate (ammonium 2—((2—(4—(difluoromethoxy)—3—isopropoxyphenyl)oxazol—4—yl)methylcarbamoyl)phenyl sulfate (compound (11r)) as a white powder. The melting point was 162.0°C.

Synthesis of Compound 1 11s] A typical synthesis procedure was performed using 0.1 g of compound (1 la), 1—bromo—2,3,4—tri—O—acetyl—a—D—glucuronic acid methyl, and silver oxide, thereby obtaining (2S,3S,4S,5R,6S)—6—(2—((2—(3—isopropoxy—4—difluoromethoxyphenyl)oxazol—4—yl)methy lcarbamoyl)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)met hylcarbamoyl) phenoxy)—3,4,5—trihydroxytetrahydro-2H—pyran—2—carboxylic acid: compound (11s)) as a white powder. The melting point was 163.6°C.

Production Example 7: Production of Formulations Study of Solvent To select a solvent for dis solving compound (1 l) in preparing an ointment containing compound (11), the solubility of compound (11) in various solvents was studied. Even a solvent having a high solubility of compound (1 l) ts reduced lity of compound (11) if it has compatibility with a base al (ointment base), such as atum or paraffin, and is mixed with the base material. Such a case may result in precipitation of compound (11). Thus, a solvent that has a high solubility of compound (1 l) but that has no or low miscibility (compatibility) with petrolatum or in is relatively preferable for use. Table 4 shows the results of the study.

[Table 4] Solvent Miscibility of nd Solubility (W/W%) (l l) Solvent Solution with Petrolatum Triarxetine lmmiscible 32.5 Propylene carbonate Immiscible 56.9 Diethyl sebacate Miscible 42.6 ropyl adipate Miscible 40.3 Isosteanc acid Miscible 19.8 Olive oil Miscible 6.1 Isopropyl myristate Miscible 6.0 Hexyldodecanol Miscible 5.4 Isosbearyl alcohol Miscible 5.1 Decyl oleate Miscible 2.6 Liquid Paraffin Miscible 0.1 Table 4 indicates that tin and ene carbonate have low miscibility with atum, and also indicates that triacetin and propylene carbonate have a relatively high solubility of compound (1 l).

Formulation of Ointment Ointments (Examples 1 to 10 and Comparative Examples 1 to 8) were ed as bed below. As noted above, solvents that dissolve compound (1 l) were found.

Thus, the present invention encompasses all of the ointments prepared by dissolving compound (1 l) in a solvent. However, of these, the following describes particularly preferable examples as Examples, and others as Comparative Examples for con— venience. The particle size of droplets is measured by placing a suitable amount of a prepared ointment on a glass slide and observing the droplet size with a polarizing mi— croscope.

Example 1 73.0 g of white petrolatum, 10.0 g of liquid paraffin, 3.0 g of paraffin, and 1.0 g of beeswax (non—chemically bleached beeswax) were heated and dissolved at 70°C in an agi—homomixer. Thereafter, a solution of 3.0 g of compound (1 l) in 10.0 g of WO 15780 propylene ate was further added thereto, and the mixture was stirred with a homomixer at 5000 rpm and with a paddle at 30 rpm. The xer was then turned off at 45°C, and the paddle and cooling were turned off at 40°C to give a droplet size of 20 um or less. Thereafter, the resulting product was inserted into um tubes, 5 g in each tube, with a YS-7 filling machine, and the tubes were sealed, thereby obtaining ointments.

Example 2 The procedure of Example 1 was repeated except that 72.0 g of white petrolatum and 2.0 g of beeswax were used, thereby obtaining ointments.

Example 3 The procedure of Example 1 was repeated except that 70.5 g of white petrolatum and 3.5 g of beeswax were used, thereby ing ointments.

Example 4 The ure of e 1 was repeated except that 81.0 g of white petrolatum, 1.0 g of compound (11), and 4.0 g of propylene carbonate were used, thereby obtaining ointments.

Example 5 The procedure of Example 4 was repeated except that 80.0 g of white petrolatum and 2.0 g of beeswax were used, thereby obtaining ointments.

Example 6 The ure of Example 4 was repeated except that 78.5 g of white petrolatum and 3.5 g of beeswax were used, thereby obtaining ointments.

Example 7 The procedure of Example 6 was repeated except that 79.2 g of white petrolatum and 0.3 g of compound (11) were used, thereby obtaining ointments.

Example 8 The procedure of Example 6 was repeated except that 79.4 g of white petrolatum and 0.1 g of compound (11) were used, thereby obtaining ointments.

Example 9 70.5 g of white petrolatum, 10.0 g of liquid paraffin, 3.0 g of in, and 3.5 g of beeswax (chemically ed beeswax) were heated and dissolved at 70°C in an agi— homomixer. Thereafter, a solution of 3.0 g of compound (11) in 10.0 g of propylene carbonate was further added thereto, and the mixture was stirred with a homomixer at 5000 rpm and with a paddle at 30 rpm. The homomixer was then turned off at 45°C, and the paddle and cooling were turned off at 40°C to give a droplet size of 20 um or less. Thereafter, resulting product was inserted into aluminum tubes, 5 g in each tube, with a YS—7 filling machine, and the tubes were sealed, thereby obtaining ointments.

Example 10 2016/088843 The procedure of Example 3 was repeated except that 73.5 g of white petrolatum and 7.0 g of propylene carbonate were used, thereby obtaining ointments.

Comparative Example 1 The procedure of Example 4 was repeated except that 82.0 g of white petrolatum was used, and that beeswax was not added, y obtaining ointments. ative e 2 58.5 g of white petrolatum, 6.0 g of paraffin, 6.0 g of x, and 5.0 g of diethyl sebacate were heated and dissolved at 70°C by hand stirring in a 200—mL beaker. After cooling to 50°C, 17 g of liquid paraffin was added thereto, and the mixture was heated to 50°C. 13 g of a paste containing 10 g of liquid paraffin and 3 g of micronized compound (1 l) was added thereto and mixed well by hand stirring, with the tem— perature maintained at 50°C. The mixture was cooled to room temperature with ice water. Thereafter, the mixture was inserted into aluminum tubes, 5 g in each tube, with a YS—7 filling e, thereby obtaining ointments.

Micronized compound (1 l) was obtained by adding compound (1 l) to liquid paraffin and pulverizing the mixture with a DYNO—MILL (bead mill). Thus—obtained paste was used in the operation above.

Comparative Example 3 The procedure of Example 3 was repeated except that 75.5 g of white petrolatum and .0 g of propylene carbonate were used, y ing ointments.

Comparative Example 4 The procedure of e 6 was repeated except that 80.5 g of white petrolatum and 2.0 g of propylene carbonate were used, thereby obtaining ointments. ative Example 5 The procedure of Example 6 was repeated except that 79.5 g of white petrolatum was used, and that nd (1 l) was not added, thereby obtaining ointments.

Comparative Example 6 The procedure of Example 3 was repeated except that the mixture was stirred with a homomixer at 1500 rpm and with a paddle at 15 rpm, thereby preparing an ointment having a droplet size of about 50 um.

Comparative Example 7 The procedure of Example 6 was repeated except that the mixture was stirred with a homomixer at 1500 rpm and with a paddle at 15 rpm, thereby preparing an ointment having a droplet size of about 50 um.

Comparative Example 8 The ure of Example 7 was repeated except that the mixture was stirred with a homomixer at 1500 rpm and with a paddle at 15 rpm, thereby preparing an nt having a droplet size of about 50 um.

Table 5 shows the compositions of formulations described above.

[Table 5] $wa :3 81 E: mmm7V isi om. 0m om. . $385 305.5% $2 H $2 mmfl $2 _ £2 £2 £2 mmfl mmfl mmfl A355 52: :5 .S .5 .8 a (E a a a .8 .8 .8 a o fig a; S; a:. :1 :1 cl a: a: :2 :1 :1 8; 85 ow ON on ON om on1 ow om om ON ON ON efizmamba 22.5%.; . I , 85: E 852 coszEhi Limos—o 233.5 .3183. Eosfifio Leia—o ESE: LEASE 32550 36396 £5835 beach. aces—Ego $28.6 SEES .4313: BEES $23.6 gage .3396 use—5:5 $390.6 30.590 335:6 88 "525:6, wCOEaEta, o asofipfio 1 :9 w £933 . t. 50¢ .95 Cows i 35m mnevamoEoI €535 msceuwmcacm amzo maconwmofiom Basie mSOonmoSoE cBWHmeQ oSoE Engage maggomofiom EoflwHoawfio mSommmmoSom8%an gov—532:3: Sesame mdoogmofiom Sigma maewfiwmofiom wromqmwmofioww Edfioamzo :oflmwwafl gonwmofiom comtoawzo mdooqemofiom. VDOOCPEOEO: mdomqwmofiom829.89% £033 E0 :5 newiawwmfimm msownuwgwoaumHwamuawmflwmcII mzomquwofiosfisoawwnmfiwwwhmmm EJHMQm38m . . . . . . . . . . . m . I . . I .

SaginawEgg S S 3 w a v v a 9 w w , m. N v 8 v v Ao\o>>\>>v xmameemt mm ._1. L3 mm mm mum m. m m mm m H m H m . m . . . .. . r. A m. m mV m Wm afiwfio E00 m m m m m r. m m m m m m. m m r, m m m .HO ibmumm DEBOE WWEELE 0 o o o 0 c 0 o 0 0 0 5 o O C o o 0 USN «.8 HEQEOn ECO 83 «M55 m? Lc. . mu. m m m mp or1 #w cm s r 2 i mp NE E DE @mn mm mam 3,3 an 0%i E. m? w» NE 3339350 m m m H a — no _.o m m a n m — . m H md :0.EE:E&Z H N m w m c p w m CH mhpnwaafiow "5535289.". N m w c v w smegma a c a H _ 9:3 gamma m. waafim 29:me .233 iafim magnum 3E5? r; masfim wEEmmm r magnum PEEwQEoU Safimxm flQaOU maafim m>meaQEoww983 Peflgmafioo éEEé cifiaaaficc EQESE map—fiasco aEwam Stud into ation Stabilit 1 The nts prepared in Comparative Example 1 and Examples 4, 5, and 6 were allowed to stand at 40°C for 2 months. Thereafter, the sion state of the propylene carbonate on in each formulation was examined. Table 6 shows the results. Table 6 reveals that beeswax maintains the homogeneous dispersion state, and thus improves stability.

[Table 6] ation Amount ofBeeswax Dispersion State Comparative Example 1 0 The particle size was increased Example 4 10 Excellent Example 5 2.0 Excellent Example 6 3.5 Excellent [025 1] Study into Formulation Stability 2 The ointments prepared in Comparative Example 1 and Examples 1 to 6 are different in the amount of x added. These formulations were subjected to a stability test at 50°C for 2 weeks, 4 weeks, or 6 weeks. To examine the degree of decomposition of nd (11), the amount of generated 3—(2—propoxy oromethoxy)benzamide, which is one of the decomposed s, was measured by erformance liquid chromatography. Table 7 shows the results. The values in Table 7 indicate the con— centration (wt%) of compound (11), beeswax, and the osed matter in each for- mulation. While Comparative Example 1, to which beeswax was not added, generated about 1% of the decomposed matter, the formulations made by adding beeswax exhibited reduced generation of the decomposed matter.

[Table 7] Concentration of Amount of Formulation nd (1 1) BeeswaxAdded Afbeiz Aft/i4 (%) (%) Wee S Wee S AfieigWee S COmparatNe 1'0 0 0.90 0.99 0. 97 0.00 <0.05 <0.05 <0.05 0.23 Study into Formulation Stability 3 The formulation of the formulation of Example 3 was prepared using beeswax that was not bleached (unbleached beeswax), beeswax bleached by non—chemical pu— rification (non—chemically bleached beeswax), or beeswax that was chemically bleached (chemically bleached beeswax) as beeswax, and the formulation was ed into aluminum tubes, and sealed, followed by storage at 50°C for 2 weeks, 4 weeks, or 8 weeks. In the same manner as above, with the generated decomposed matter of compound (11) (3—(2—propoxy 3—difluoromethoxy)benzamide) as an index, the ity of compound (11) was ed. Table 8 shows the results. While the use of chemically bleached beeswax generated a high amount of the decomposed matter, the use of non-chemically bleached beeswax and ched x exhibited reduced generation of the decomposed .

[Table 8] After 2 After 4 After 8 Type Of Beeswax Weeks weeks weeks Chemically Bleached Beeswax Produced by Company A 0.19 0.20 0.16 Non-Chemically Bleached Beeswax ed by CompanyA 0.00 0.00 0. 00 Unbleached Beeswax Produced by Company A 0.00 0.00 0.00 Non-Chemically Bleached Beeswax Produced by y C 0.00 0. 00 0. 00 Chemically Bleached Beeswax Produced by Company D 0.18 0. 16 025 [0255 ] Study into Formulation Stability 4 Ointments containing compound (11) and different s of beeswax were prepared. A predetermined amount of each ointment was placed on a glass slide, and the droplet size of each nt was confirmed with a polarizing microscope to search for the amount of beeswax necessary to obtain an ointment in which droplets are ex— cellently dispersed. The ointments (Examples 11 to 19 and Comparative Examples 9 to 11) were prepared as described below. The present invention encompasses all of the ointments containing beeswax. However, of these, the following describes particularly able examples as Examples, and others as Comparative Examples for con— venience.

Example 11 141.0 g of white petrolatum, 20.0 g of liquid paraffin, 6.0 g of paraffin, and 7.0 g of beeswax (non—chemically bleached beeswax) were heated and dissolved at 70°C in an agi—homomixer. Thereafter, a solution of 6.0 g of compound (11) in 20.0 g of propylene carbonate was further added thereto, and the mixture was stirred with a homomixer at 5000 rpm and with a paddle at 30 rpm, followed by g. The homomixer was turned off at 45°C and the paddle and cooling were turned off at 40°C.

The resulting product was inserted into aluminum tubes, 5 g in each tube, with a YS—7 filling machine, and the tubes were sealed, thereby obtaining ointments.

Example 12 The procedure of Example 11 was repeated except that 146.0 g of white petrolatum and 2.0 g of beeswax were used, y obtaining ointments.

Example 13 The procedure of e 11 was repeated except that 146.4 g of white petrolatum and 1.6 g of beeswax were used, thereby obtaining ointments.

Example 14 The ure of e 11 was repeated except that 146.8 g of white petrolatum and 1.2 g of beeswax were used, thereby obtaining ointments.

Comparative Example 9 The procedure of Example 11 was repeated except that 147.2 g of white petrolatum and 0.8 g of beeswax were used, thereby obtaining ointments.

Comparative Example 10 The procedure of Example 11 was repeated except that 147.6 g of white petrolatum and 0.4 g of beeswax were used, thereby obtaining ointments.

Example 15 157.0 g of white atum, 20.0 g of liquid paraffin, 6.0 g of paraffin, and 7.0 g of beeswax (non—chemically bleached x) were heated and dissolved at 70°C in an agi-homomixer. Thereafter, a solution of 2.0 g of compound (11) in 8.0 g of propylene carbonate was further added thereto, and the mixture was stirred with a homomixer at 5000 rpm and with a paddle at 30 rpm, followed by cooling. The homomixer was turned off at 45 OC, and the paddle and cooling were turned off at 40°C. The resulting product was inserted into aluminum tubes, 5 g in each tube, with a YS—7 filling e, and the tubes were sealed, thereby obtaining ointments.

Example 16 The procedure of Example 15 was repeated except that 162.0 g of white petrolatum and 2.0 g of beeswax were used, thereby obtaining ointments.

Example 17 The ure of e 15 was repeated except that 162.4 g of white petrolatum and 1.6 g of beeswax were used, thereby obtaining ointments.

Example 18 The procedure of e 15 was repeated except that 162.8 g of white petrolatum and 1.2 g of beeswax were used, thereby obtaining ointments.

Example 19 The procedure of Example 15 was ed except that 163.2 g of white petrolatum and 0.8 g of beeswax were used, thereby obtaining ointments. ative Example 11 The procedure of Example 15 was repeated except that 163.6 g of white petrolatum and 0.4 g of beeswax were used, thereby ing ointments.

Table 9 shows the formulations and the state of the dispersion of droplets of the ointments. The unit is wt%. Table 9 reveals that when an ointment containing 3 parts by weight of component (11) contains 0.6 parts by weight or more of beeswax, the ointment exhibits particularly excellent dispersion of the droplets, and that when an nt ning 1 part by weight of compound (11) contains 0.4 parts by weight or more of x, the ointment exhibits particularly excellent dispersion of the droplets.

[Table 9] qofimHonBLQESQ m. :oflmwvamflwbflaem a a a w. m mat/m: war/m: ON gmflwbflggfl a966: ON :oflmamamflwbflmgm ON WERE ON mo :oflfldqiom mo we we newmawammzflaem magma E: mo we wfim wflw aim mfim aim sewmmwgmflwbflggm magma om wfizmz ONwe 83m 35 $6 Human—c6 mmfl $2 flowing $2 mg. $2 .3 .8 923 cmfi .5 Mo go 81 @5826 30332 81 fisfipfio €25:me 81 #59530 Sewing 81 Sagan mafia 968 £55950 Euflama 858 newmgwgmébflmgfl pcofipfio 28359 81 BMGOQEO @543th &5on Wm A9033 2359800 gash om Egg magma was 0.3 pSoQOQEoU BEE Espfiofiwm m‘wb Bits 5655350 0A EOMHNHSEMOHH S NH a 3 9/595 m 3555 3 5 magmxm mHQmem £98me magmxm @980 2%:wa 9:50 flagwxm £98me cofimaoamgbflggfl n m :Bmgwgmflwbwaem a a a war/w: 0N ammiflqgfl mat/m: 0m mgr/w: 0m 8: we we mo we 38 wfim mgr/w; ONwe aim aim mgr/m: wfim 225:6 mmfl mmfl $2 83% flowing Ho go .3 no E: ":55qu 81 @58in 232:3 £95.39 :3 :ofimeQmELwEEQ 295:6 28:59 E: coflmamgmwcbofigfl Emfiuflo @35th 858 04V 04V 0% 0% 0% 0A w.0 0.0 *0 N0 0.m 0.m oh 0.m 0.m 0.0H 0.0a 0.3 0.3 0.0a 040 mgw $40 040 040 0H 0A 04 0H 0A 0H 5 m: 3 35me 2 wadiwxm wEmem EQEMMH 298wa @800 29:8me DCC-12/08/2021

Claims (5)

Claims:

1. An ointment comprising an oxazole compound represented by the following formula (11): and a base component, wherein the base component comprises a solvent for dissolving the oxazole compound in the solvent, and an ointment base for dispersing or dissolving the t in the ointment base, n the e nd is dissolved in the solvent for dissolving the oxazole compound, and wherein the t for dissolving the oxazole compound is at least one member selected from the group consisting of ethylene carbonate, propylene carbonate, benzyl alcohol, and tin.

2. The ointment according to claim 1, wherein the solvent for dissolving the oxazole compound is (i) only ethylene carbonate, (ii) only propylene carbonate, (iii) ethylene carbonate with benzyl alcohol and/or triacetin, or (iv) propylene carbonate with benzyl alcohol and/or triacetin.

3. The ointment according to claim 1 or 2, wherein the base component comprises more than 2 parts by weight and 30 parts by weight or less of the solvent for ving the oxazole compound in the solvent, per part by weight of the oxazole compound, and 5 to 5000 parts by weight of the ointment base for sing or dissolving the solvent in the ointment base, per part by weight of the e compound.

4. The ointment according to any one of claims 1 to 3, wherein the ointment base comprises a hydrocarbon.

5. The ointment according to any one of claims 1 to 4, wherein the ointment base is an DCC-