WO1998039305A1 - Crystalline form of a bis 1,2,4-triazole compound - Google Patents

Abstract

Form II crystals having a melting point of 127 °C ± 3 °C, of the compound represented by formula (I) are low in hygroscopicity and excellent in stability.

Description

DESCRIPTION CRYSTALLINE FORM OF A BIS 1,2,4-TRIAZOLE COMPOUND

TECHNICAL FIELD

This invention relates to stabilized crystals of an azole compound useful as therapeutic agent of mycosis [described on for example EP-0567982].

BACKGROUND ART

In, for example, EP-0567982, an azole compound such as ( 2- [( 1R,2R) -2- (2, 4-difluorophenyl ) -2-hydroxy-l- methyl-3- ( 1H-1 , 2 , 4-triazol-l-yl ) propyl ] -4- [ 4- ( 2 , 2 , 3 , 3- tetrafluoropropoxy)phenyl ] -3- ( 2H, 4H) -1 , 2 , 4-triazolone) (hereinafter simply called Compound A), which has an excellent antifungal activity, is disclosed.

And, In Working Example 5 of EP-0659751, the following method is disclosed: namely, an oxirane compound, i.e. ( 2R, 3S) -2- ( 2 , 4-difluorophenyl ) -3-methyl- 2-( 1H-1,2 ,4-triazol-l-yl)methyloxirane (hereinafter simply called Compound B) is allowed to react with a triazolone compound, i .e .4- [ 4-( 2 , 2 , 3 , 3- tetrafluoropropoxy)phenyl]-3-(2H, 4H) -1, 2 , 4-triazolone (hereinafter simply called Compound C) for 27 hours at 80°C in the presence of potassium carbonate, allowing the reaction to proceed for further 4 hours at 100 °C, washing the reaction mixture by shaking with water (once), with a IN aqueous solution of sodium hydroxide (three times), with IN HC1 (twice) and a saturated aqueous saline solution (once) (seven times in total), crystallizing three times including fractionation by means of a silica gel column chromatography and recrystallization to give a crystalline crude Compound A (crude yield 74%), followed by recrystallization from ethanol-water to afford crystals (Form I crystals), m.p.l54-155°C. The method disclosed in Working Example 5 of EP- 0659751 for producing Compound A, which is one of the useful azole compounds as excellent antifungal agents disclosed in the official gazette of the above- mentioned EP-0567982, requires as many as seven times shaking after diluting the reaction mixture in an organic solvent, and as many as four times in total of crystallization and recrystallization procedures including crystallization from diisopropyl ether, recrystallization from ethyl acetate - diisopropyl ether, subjecting the mother liquor to fractionation by means of a silica gel column chromatography, recrystallization from diisopropyl ether and further recrystallization from ethanol-water, thus requiring complicated procedures and a lot of hours.

And, the quality and yield of the crystalline Compound A, m.p.154-155°C, (Form I crystal) obtained in Working Example 5 of the above-mentioned EP-0659751 vary widely, because the reaction solvent (N,N- dimethylformamide) employed in the process for producing Compound A by subjecting the Compound B and the Compound C to coupling remains in the concentrate after the reaction, thus the maintenance of homogeneous quality being extremely difficult and further refining procedures by many times of recrystallization being inevitable .

Circumstances being such as above, highly pure and stable crystalline form of the said azole Compound A and establishment of a convenient method of it on an industrial scale have been ardently desired.

DISCLOSURE OF INVENTION In view of such circumstances as mentioned above, the present inventors have made an extensive study for establishing a method of producing the said azole Compound A in a highly pure and stable crystalline form, which is useful as the above-described agent for treatment of mycosis, conveniently on an industrially large scale. As a result, they found unexpectedly that crystals of higher purity and stability than those so far produced can be obtained by conducting dilution of the said reaction mixture in an organic solvent and shaking the solution three times, followed by crystallization once from a mixture of an organic solvent and a basic aqueous solution. Based on these findings, the present inventors have made further diligent investigation to complete the present invention. More specifically, the present invention relates to: (1) Form II crystals having a melting point of 127 °C plus/minus 3°C, of a compound represented by the formula:

(2) Form II crystals shown in (1) above, which have a peak near about 9° diffraction angle in spectrum of powder X-ray diffraction and have not a peak near 6 to 6.5°.

(3) Form II crystals shown in (1) above, which have an endothermic peak near 130 °C in spectrum of differential thermal analysis.

(4) A pharmaceutical composition which comprises Form II crystals shown in (1) above and pharmaceutically acceptable carrier, diluent or excipient. (5) A pharmaceutical composition described in (4) above, which is for the treatment of fungal infections. (6) A method for treating fungal infection which comprises administering an effective amount of Form II crystals shown in (1) above optionally together with a pharmaceutically acceptable carrier, diluent or excipient to a patient suffering from fungal infection.

(7) Use of Form II crystals shown in (1) above in the production of an pharmaceutical composition.

(8) Use of Form II crystals described in (7) above, which is for an antifungal composition. In the following, the present invention will be described in more detail.

Incidentally, Compound A represented by the formula (I) can be produced by the methods disclosed in, for example, the above-mentioned EP-0567982 and EP- 0659751 or analogous methods thereto.

Compound A represented by the formula (I) can be conveniently produced efficiently in a higher purity and yield by the following method. (1) The hydroxyl group of methyl (R)-lactate is protected with 3 , 4 , 5 , 6-tetrahydropyranyl (sometimes abbreviated as THP) group, then the ester group is amidated with morpholine, followed by allowing the resultant to react with a Grignard reagent obtained by allowing l-bromo-2 , -difluorobenzene to react with magnesium in an ether type organic solvent [preferably tetrahydrofuran (THF)] to give ( 2R) -2 ' , 4 ' -difluoro-2- (3,4,5, 6-tetrahydro-2H-pyran-2-yloxy) -propionphenone . While the amidation of the ester group is usually conducted in alcohol, it may optionally be conducted in an organic solvent other than ester type or ketone type ones . While the protection of the hydroxyl group is usually conducted in the absence of solvent, may optionally be conducted in an organic solvent other than alcohol type ones . (2) The compound produced above is allowed to react with a conventional reagent disclosed in, for example, Journal of American Chemical Society, Vol.87, p.1353 (1965) (for example, ylide derived from trimethylsulfoxonium iodide and a base) in an organic solvent [e.g. dimethyl sulfoxide (DMSO) or dimethylformamide (DMF)] to give 2- (2, 4- difluorophenyl ) -2- [ ( IR) -1- ( 3 , 4 , 5 , 6-tetrahydro-2H-pyran- 2-yloxy) ethyl ]oxirane .

(3) This product is subjected to condensation with 1H- 1,2,4-triazole to give ( 2R, 3R) -2- ( 2 , 4-difluorophenyl ) - 3- ( 3 , 4 , 5 , 6-tetrahydro-2H-pyran-2-yloxy) -1- ( 1H-1 , 2 , 4- triazol-l-yl)-2-butanol, then the THP group thereof is removed, followed by subjecting the resultant compound to mesylation (in an organic solvent such as ethyl acetate or dichloromethane other than alcohol type ones) and epoxidation (usually in methanol but, depending on cases, in other organic solvents) to produce Compound B. While the condensation is usually conducted in DMF, it may optionally be conducted in any other organic solvent. While the deprotection of THP is usually conducted in methanol, it may optionally be conducted in any other organic solvent.

(4) On the other hand, the nitro group of 4- (2, 2, 3, 3- tetrafluoropropoxy) nitrobenzene derived from p- nitrophenol is reduced to amino group, which is then led to an amidocarboxylic acid derivative with phenyl chlorocarbonate, which is then allowed to react with hydrazine to give 4-[ 4- ( 2 , 2 , 3 , 3- tetrafluoropropoxy) phenyl ] semicarbazide, which is then allowed to react with formamidine acetate to afford Compound C.

(5) Subsequently, in accordance with the method described in the official gazette of EP-0659751, Compound B, i.e. an oxirane compound, is allowed to react with Compound C, i.e. a triazolone compound, to produce the desired Compound A, i.e. an azole compound. Form II crystal of Compound A represented by the formula (I) can be produced by the following processes. Compound B is react with Compound C by the above- described method (concretely stating, the method to be described in the following Working Example); the reaction mixture is diluted in a mixture of an organic solvent and water, which is washed by shaking, then the organic layer was processed with activated charcoal, and the reaction mixture is concentrated, followed by subjecting the resultant to crystallization from a mixture of an organic solvent and a basic aqueous solution and, after processing with activated charcoal, subjecting the resultant to crystallization from a mixture of an organic solvent and water.

As the solvent for dilution, use is made of, usually, a mixture of a hardly water-soluble organic solvent and water in an appropriate ratio. Examples of the hardly water-soluble organic solvent include esters such as ethyl acetate, ketones such as methyl ethyl ketone, ethers such as diethyl ether and isopropyl ether, aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as dichloromethane, chloroform and 1 , 2-dichloroethane . As the solvent, mention is made of, preferably, esters such as ethyl acetate, ketones such as methyl ethyl ketone, and halogenated hydrocarbons such as dichloromethane, chloroform and 1, 2-dichloroethane, more preferably, esters such as ethyl acetate, and halogenated hydrocarbons such as dichloromethane, chloroform and 1, 2-dichloroethane, especially preferably ethyl acetate.

Volume of the solvent to be employed is as follows: a hardly water-soluble organic solvent of about 50 to about 500 times as much weight as Compound B, preferably about 70 to about 200 times as much, especially preferably about 100 to about 150 times as much, and water of about 5 to about 50 times as much weight as Compound B, preferably about 10 to about 50 times as much.

Washing is conducted by using an aqueous saline solution in accordance with a conventional method. Concentration of the aqueous solution of sodium chloride ranges from about 5 to about 50 weight %, preferably about 10 weight %. Volume of the aqueous saline solution to be employed ranges from about 10 to about 50 times by weight relative to Compound B, preferably about 30 times by weight.

The processing with activated charcoal is conducted by adding activated charcoal to the organic layer (or the organic solvent in which the reaction mixture is dissolved), or adding the organic layer (or the organic solvent in which the reaction mixture is dissolved) to activated charcoal, and by stirring the whole mixture. Amount of the activated charcoal to be employed ranges from about 0.001 to about 10 times by weight relative to Compound B, preferably from about 0.025 to about 1 times by weight, especially preferably from about 0.05 to about 1 times by weight. Temperatures of the processing with activated charcoal are not higher than the boiling point of the organic solvent employed, preferably about 10 to about 50°C. The processing with activated charcoal after concentration of the reaction mixture can be conducted substantially by the same manner. Removal of the activated charcoal after the processing can be conducted by a per se known method, for example, filtration and centrifugation.

Concentration of the organic layer after processing with activated charcoal can be conducted by a per se known method .

For crystallization from a mixture of an organic solvent and a basic aqueous solution, use is made of a mixture of (1) an organic solvent having the properties of dissolving the above-mentioned concentrate and also soluble in water and (2) a basic aqueous solution. Examples of the organic solvent capable of dissolving the concentrate mentioned in (1) above and also soluble in water include alcohols such as methyl alcohol, ethyl alcohol and denatured alcohol; ketones such as acetone; sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile; and amides such as dimethylformamide, acetamide, dimethylacetamide, l-methyl-2-pyrrolidone and 1, 3-dimethyl-2-imidazolidinone . Preferable examples of the organic solvent capable of dissolving the concentrate and also soluble in water include alcohols such as methyl alcohol, ethyl alcohol and denatured alcohol; sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile; and amides such as dimethylformamide, acetamide, dimethylacetamide, l-methyl-2-pyrrolidone and 1,3- dimethyl-2-indazolidinone . More preferably, are mentioned alcohols such as methyl alcohol, ethyl alcohol and denatured alcohol, especially preferably denatured alcohol . The solvents can be used singly or as a mixture of two or more of them in appropriate ratios .

As the basic aqueous solution of (2) above, mention is made of, for example, an aqueous solution of alkali metal hydroxide, alkali metal carbonate or alkali metal hydrogencarbonate, preferably alkali metal hydroxide. Examples of the alkali metal hydroxide include lithium hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide, and sodium hydroxide is especially preferable. Volume of the organic solvent of (1) to be employed for crystallization ranges from about 5 to about 50 times as much by weight, preferably from about 15 to about 35 times as much by weight relative to Compound B. Concentration of the basic aqueous solution of (2) ranges from about 0.05N to about 3N, preferably from about 0.5N to about 2N. Volume of the basic aqueous solution of (2) ranges from about 10 to about 100 times as much by weight, preferably from about 15 to about 50 times as much by weight relative to Compound B. The mixing ratio of the organic solvent and the basic aqueous solution ranges preferably from about 1 to about 100, more preferably from about 2 to about 20, using the latter in an excess volume to the former. Crystallization is preferably conducted by dissolving the concentrate in an organic solvent and by adding thereto dropwise a basic aqueous solution.

The crystallization is conducted at temperatures not higher than about 50 °C, preferably about 10 to about 30°C. Time for the crystallization ranges from about 30 minutes to about 3 hours, preferably from about 1 to about 2 hours. Aging of the crystals is conducted by stirring or leaving standing. Temperatures of the aging are not higher than those for crystallization. Time of the aging ranges from about

30 minutes to about 3 hours, preferably from about 1 to about 2 hours .

After being aged, the crystals are collected by a per se known means such as filtration and centrifugation, which are dried under reduced pressure to afford crystals of Compound A as a crude product.

It is preferable to further refine these crystals from a mixture of an organic solvent and water. In this case, it is preferable to use a mixture of water with an organic solvent having properties capable of dissolving crystals of the crude Compound A and also soluble in water. Examples of the organic solvent, which is capable of dissolving crystals of the crude Compound A and soluble in water, include alcohol such as methyl alcohol and ethyl alcohol and denatured alcohol; ketones such as acetone; sulfoxides such as methyl sulfoxide; nitriles such as acetonitrile; and amides such as dimethylformamide, acetamide, dimethylacetamide, l-methyl-2-pyrrolidone and 1,3- dimethyl-2-imidazolidinone . Preferable examples of the organic solvent capable of dissolving crystals of the crude Compound A and also soluble in water include alcohols such as methyl alcohol, ethyl alcohol and denatured alcohol; and ketones such as acetone, more preferably alcohols such as methyl alcohol, ethyl alcohol and denatured alcohol, especially preferable one being denatured alcohol . These solvents may optionally be used singly or as a mixture of two or more of them at an appropriate ratio. Volume of the organic solvent to be employed ranges from about 5 to about 50 times by weight, preferably from about 20 to about 35 times by weight, relative to the crystals of crude Compound A. Volume of water to be employed ranges from about 5 to about 100 times by weight, preferably from about 15 to about 50 times by weight, relative to crude Compound A.

Volume of water in the mixture of an organic solvent and water, relative to the organic solvent, is the same or an excess volume, preferably about 1 to about 10 times, more preferably about 1 to about 2 times .

The process for crystallization comprises dissolving the concentrate of the reaction mixture in an organic solvent, processing the solution with activated charcoal, removing the activated charcoal, and adding dropwise, to the solution, a basic aqueous solution to cause crystallization.

Temperatures for the crystallization are not higher than about 50 °C, preferably ranging from about 10 to about 30 °C. Time required for the crystallization ranges from about 30 minutes to about 3 hours, preferably from about 1 to about 2 hours. Aging of the crystals is conducted by stirring or leaving standing the reaction mixture containing the crystals. Temperatures of the aging are not higher than the crystallization temperature. Time for the aging ranges from about 30 minutes to about 3 hours, preferably from about 1 to about 2 hours .

The crystals, after being aged, are recovered by conventional means such as filtration and centrifugation, which are then dried under reduced pressure to afford the desired Form II crystals of Compound A.

As the solvent to be employed for the crystallization so as to form Form II crystals, a solvent in which Compound A is soluble is used singly or any mixture of a solvent capable of dissolving Compound A and a solvent in which Compound A is insoluble or hardly soluble can be used. For example, in the case of using singly a solvent in which Compound A is soluble, use is made of ethers such as diethyl ether and isopropyl ether; aromatic hydrocarbons such as benzene, toluene and xylene; preferably ethers such as diethyl ether and isopropyl ether; especially preferably isopropyl ether. In the case of using a mixture of two or more solvents, i.e. a solvent in which Compound A is soluble and a solvent in which

Compound A is insoluble or hardly soluble, use is made of, as the solvent in which Compound A is soluble, alcohols such as methyl alcohol, ethyl alcohol and denatured alcohol; ketones such as acetone; nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide; amides such as dimethylformamide, acetamide, dimethylacetamide, l-methyl-2-pyrrolidone and 1,3- dimethyl-2-imidazolidinone, preferably alcohols such as methyl alcohol ethyl alcohol and denatured alcohol; ketones such as acetone; nitriles such as acetonitrile; and esters such as ethyl acetate, more preferably alcohols such as methyl alcohol, ethyl alcohol and denatured alcohol .

Examples of the solvent, in which Compound A is insoluble or hardly soluble, include water and hydrocarbons such as hexane, preferably water.

While the kinds and numbers of these solvents to be mixed are not restricted, mention is made of a mixture of water and alcohols such as methyl alcohol, ethyl alcohol and denatured alcohol; ketones such as acetone; nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide; and amides such as dimethylformamide, acetamide, dimethylacetamide, 1- methyl-2-pyrrolidone and 1, 3-dimethyl-2- imidazolidinone; more preferably, water and alcohols such as methyl alcohol, ethyl alcohol and denatured alcohol .

Crystallization temperatures for obtaining preferentially Form II crystals, mention is made of those not higher than about 50 °C, preferably those not higher than about 40°C, more preferably those below about 30°C. As the lowest limit of crystallization temperatures, mention is made of any ones at which the solvent then used does not freeze (for example, not lower than about -10°C, preferably not lower than about 10 °C) . Accordingly, the crystallization temperatures in the method of producing crystals of this invention are in the range from about -10 to about 50 °C, preferably from about -10 to about 40°C, more preferably from about 10 to about 30 °C. In the present invention, Form II crystals of Compound A represented by the formula ( I ) are characterized by having the melting point ranging from about 115 to about 145°C, more concretely 127°C ± about 3°C. In this respect, they are entirely different from Form I crystals (m.p. 154-155°C) disclosed in the afore-mentioned official gazette of EP-0659751. Since melting point of Form II crystals of this invention is lower than that of Form I crystals by about 30 °C, Form I crystals are surmised to be thermodynamically stable, and, as is clear from results of the stability test described later, it was confirmed that Form II crystals were quite unexpectedly excellent in stability as compared with Form I crystals .

And, while Form I crystals are of needles under polarizing microscopic observation, Form II crystals of Compound A are of prisms which are entirely different from needles (cf. Working Examples to be described later) .

And, Form II crystals of Compound A show completely different spectrum from Form I crystals in powder X-ray diffraction. Namely, Form II crystals have a peak near about 9° diffraction angle in powder X-ray diffraction and have not a peak near 6 to 6.5°, which is a characteristic feature.

Furthermore, Form II crystals of Compound A show completely different spectrum from that of Form I crystals in differential thermal analysis as well. Namely, Form II crystals have a characteristic feature of having an endothermic peak near 130 °C, which is not observed in Form I crystals . Accordingly, Form II crystals of Compound A represented by the formula (I) in this invention are novel crystals, which are completely different from Form I crystals disclosed in the official gazette of EP-0659751. Form II crystals of Compound A produced by the present invention can be used as the antifungal agent.

Since the present compound (I) has strong antifungal activity to the genus Candida [e.g. Candida albicans _r Candida utilis, Candida graburata, etc.], genus Histoplasma [e.g. Histoplasma capsulatum, etc.], genus Aspergillus [e.g. Aspergillus niger, Aspergillus fumigatus , etc.], genus Cryptococcus [e.g. Cryptococcus neoformans , etc.], genus richophyton [e.g. Trichophyton rubrum. Trichophton mentagrophytes , etc.], genus Microsporum [e.g. Microsporum gypseum, etc.], genus Mallassezia [e.g. Mallassezia furfur, etc.] etc., it can be used for prevention or treatment of fungal infections [e.g. mucosal candidiasis (oral thrush, angular stomatitis, vulvovaginal candidiasis, Candida balanoposthitis and urethritis), dermal candidiasis ( interdigital candidiasis, intertriginous candidiasis, perianal candidiasis, blastomycosis cutis eczematosa, Candida onychia, Candida paronychia, auricular candidiasis, cutaneous lesion of Candida septicaemia, diffuse superficial candidiasis, Candida granuloma, congenital cutaneous candidiasis, candidids), chronic mucocutaneous candidiasis and systemic candidiasis (candidiasis of the respiratory tract, cnadidiasis of the gastrointestinal tract, Candida septicaemia, Candida endocarditis, candidiasis of the urinary tract, candidiasis of the eye, cnadidiasis of the central nervous system, articular and bone candidiasis, Candida peritonitis, candidiasis of the liver, intrauterine candidiasis, etc.) due to genus Candida: acute pulmonary histoplasmosis, chronic pulmonary histoplasmosis and disseminated histoplasmosis, etc. due to genus Histoplasma: aspergillosis of the respiratory tract (allergic aspergillosis, bronchial aspergillosis, aspergilloma, pulmonary aspergillosis (acute invasive pulmonary aspergillosis, chronic necrotizing pulmonary aspergillosis), aspergillary empyema) , disseminated aspergillosis, central nervous system aspergillosis, aspergillary endocarditis, aspergillary myocarditis, aspergillary pericarditis, aspergillary mycetoma, aspergillary otomycosis, aspergillary onychia, aspergillary paronychia, aspergillary keratitis, aspergillary endophthalmitis , cutaneous aspergillosis and nasal-orbital aspergillosis, etc. due to genus Aspergillus; pulmonary cryptococcosis , central nervous system cryptococcosis , cutaneous and mucocutaneous cryptococcosis, osseous cryptococcosis, cryptococcosis of lymphnodes, disseminated cryptococcosis and cryptococcosis of hematopoetic organs, etc. due to genus Cryptococcus ; tinea capitis, favus, kerion celsi, tinea barbae, trichophytia maculovesiculosa, trichophytia eczematosa marginata, tinea imbricata, trichophytia pompholyciformis , tinea unguium, trichophitid and gramuloma trychophyticum, etc. due to genus Trichophyton or genus Microsporum; tinea versicolor, etc. due to genus Mallassezia] in the mammals (e.g. human, domestic animal, fowl, etc.), and can be used for prevention or treatment of atopic dermatitis. Moreover, the compound (I) of the present invention can be used as an agricultural antifungal agent.

When the present Form II crystals are administered to human, it can be administered orally or parenterally in safety as a pharmaceutical composition such as oral administration (e.g. powder, granule, tablet, capsule, etc.), parenteral administration [e.g. injection, external preparation (e.g. nasal administration, percutaneous administration, etc.) and suppository

(e.g. rectal suppository, vaginal suppository, etc.)] alone or in combination with appropriate pharmaceutically acceptable carriers, excipients, diluents, etc. These preparations can be prepared by a per se known method which is usually used in the production process. The proportion of the present Form II crystals in the preparation varies depending on the form thereof, and can be in the range usually employed in the antifungal agent. For example, it is about 10 to about 95% by weight in case of the above oral administration and is about 0.001 to about 95% by weight in case of the above parenteral administration.

For example, the injection can be prepared by mixing the presnet Form II crystals with dispersants [e.g. Tween 80 (manufactured by Atlas Powder company, U.S.A.), HCO 60 (manufactured by Nikko Chemicals Co.), carboxymethylcellose, sodium aspartate, etc.], preservatives (e.g. methylparaben, propylparaben, benzyl alcohol, chlorobutanol, etc.) and isotonic agents (e.g. sodium chloride, glycerin, sorbitol, glucose, etc.) to form an aqueous injection, or by dissolving, suspending or emulsifying into vegetable oils (e.g. olive oil, sesame oil, peanut oil, cotton seed oil, corn oil, etc.), propyleneglycol , etc. to form an oily injection.

An oral administration preparation can be prepared by adding excipients (e.g. lactose, sucrose, starch, etc.), disintegrators (e.g. starch, calucium carbonate), binders (e.g. starch, arabic gum, carboxymethycellulose, polyvinyl pyrolidone, hydroxypropylcellulose, etc.) and lubricants (e.g. talc, magnesium stearate, polyethylene glycol 6000, etc.) to the present compound (I), subjecting the mixture to compress molding and optionally masking of taste or coating with a per se known method for the purpose of imparting enteric property or sustained- release property. As a coating agent, for example, hydroxypropylmethylcellulose , ethylcellulose , hydroxymethylcellulose , hydroxypropylcellulose , polyoxyethyleneglycol, Tween 80, Pulronick P68, cellulose acetate phtharate, hydroxypropylmethylcellulose phthalate , hydroxymethylcellulose acetate succinate, Oidora kid (manufactured by Rhome Co., West Germany, copolymer of methacrylic acid and acrylic acid) and pigment (e.g. titanium oxide, iron oxide red, etc.) can be used. The Form II crystals of the present invention can be used as a solid, semi-solid or liquid external preparation. For example, the solid external preparation can be prepared by using the present compound (I) as it is, or adding excipients (e.g. glycol, mannitol, starch, microcrystalline cellulose, etc.), thickeners (e.g. natural gums, cellulose derivatives, acrylic polymer, etc.), etc. to the present Form II crystals, followed by mixing to form a powdered composition. In case of the semi-solid external preparation, it is preferable to use as an aqueous or oily gel agent or an ointment. In case of the liquid external preparation, it can be prepared by forming into an oily or aqueous suspension in the nearly same manner as in case of the injection. To the solid, semi-solid or aqueous external preparation, pH adjustors (e.g. carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.) and preservatives (e.g. paraoxybenzoates , chlorobutanol, banzalkonium chloride, etc.) may be added.

Specifically, an ointment containing vaseline, lanoline, etc. as a base, and about 0.1 to about 100 mg of the present Form II crystals can be used for sterilization or disinfection of skin or mucosa. The present Form II crystals can be formed into an oily or aqueous solid, semi-solid or liquid suppository. In case of preparing the suppository, examples of the oily base include glyceride of higher fatty acid [e.g. cacao butter, witepsols (manufactured by Dynamite Novel Company), etc.], medium fatty acid [e.g. migriolic acid (manufactured by Dynamite Novel Company), etc.] and vegetable oil [e.g. sesame oil, soy bean oil, cotton seed oil]. Examples of the aqueous base include polyethylene glycols, propylene glycols, etc. and examples of the aqueous gel base include natural gums, cellulose derivative, vinyl polymer, acrylic polymer, etc.

The dose of the present Form II crystals varies depending on the infecting condition and administering route, etc. In case of administering orally to adult (weight 50 kg) patients for the purpose of treating Candidiasis, the dose is about 0.01 to about 100 mg/kg/day, preferably about 0.1 to about 50 mg/kg/day. More preferably, the dose is about 0.5 to about 10 mg/kg/day. The Form II crystals of the present invention is stable and especially solid composition can be stored with stable for a long term.

When the Form II crystals are used as an active component in an injectable preparation, the Form II crystals are stable for a long term if the Form II crystals are packed separately with the other liquid substances, which are capable to combine with each other to give an injectable solution.

The pharmaceutical composition of the present invention may contain one or more of known antifungal compound together with Form II crystals of the present invention.

Examples of the known antifungal compound include such as miconazole, ketoconazole, fluconazole, itraconazole, saperconazole, clotrimazole, D0870, voriconazole, econazole, isoconazole, sulconazole, butoconazole, tioconazole, bifonazole, croconazole, oxiconazole, terconazole, SSY-726, KP-103, Sch-56592, Sch-51048, UR-9746, MFB-1041, UR-9751, UR-9728, UR- 9825, ER-30346, T-8581, BAY-W-9279, fenticonazole, omoconazole, flutrimazole, eberconazole, lanoconazole, neticonazole, sertaconazole, genaconazole, etc., but are not limited to known antifungal agents .

When using the present Form II crystals as an agricultural antifungal agent, the present Form II crystals is dissolved or suspended into a suitable liquid carrier (e.g. solvent), or mixed with or adsorbed to a suitable solid carrier (e.g. diluent, bulking agnet, etc.) and, if necessary, emulsifiers, suspension, spreading agents, osmotic agents, wetting agents, mucilages, stabilizers, etc. are added to form an emulsion, hydrate, powder, granule, etc. These preparations can be prepared by a per se known method. In case of the control of rice blight, an amount of the Form II crystals of the present invention used is preferably from about 25 to about 150 g, more preferably from about 40 to about 80 g per are of the paddy field.

As the liquid carrier, for example, water, alcohols (e.g. methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, ethylene glycol, etc.), ethers (e.g. dioxane, tetrahydrofuran, etc.), aliphatic hydrocarbons (e.g. kerosene, kerosene oil, fuel oil, etc.), aromatic hydrocarbons (e.g. methylene chloride, chloroform, etc.), acid amides (e.g. dimethylformamide, dimethylacetoamide, etc.), esters (e.g. ethyl acetate, butyl acetate, etc.) and nitriles (e.g. acetonitrile, propionitrile, etc.) can be used, and these liquid carriers can be used alone or in combination thereof at a suitable proportion. As the solid carrier, for example, vegetable flours (e.g. soy bean flours, tabaco flours, wheat flours, etc.), mineral powders (e.g. kaolin, bentonite, etc.), alumina, sulfur powder, active carbon, etc. can be used, and these solid carriers can be used alone or in combination thereof at a suitable proportion.

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is hereinafter described in more detail by means of, for example, the following Working Examples and Reference Examples. It should be understood, however, that this invention is not restricted to them.

The analysis by means of high performance liquid chromatography in these Working Examples and Reference Examples was conducted under the following conditions : Detector UV absorptiometer 254 nm

Column YMC-pack ODS-A A-213 (manufactured by YMC)

6.0 mm i.d. x 150 mm Mobile phase Mixture of methanol, water and acetic acid (volume ratio =

700:300:1) Flow rate 0.8 mi/min. Column temperature 25 °C

H-spectrum was measured with Brucker 300 (300 MHz) spectrometer using tetramethylsilane as internal standard. All δ values were shown by ppm. Percent (%) means weight percent unless otherwise specified. In the following Working Examples and Comparative Examples, symbols have the following meanings. s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, dt: double triplet, tt: triple triplet, m: multiplet, quintet: quintet, septet: septet, br: broad, J: coupling constant

Differential thermal analysis was conducted by employing a differential scanning calorimeter (DSC 220C type, manufactured by SEIKO) under the following conditions:

Amount of sample 8.72 mg Temp, raising rate about 5°C/min. Temp, range 20 - 180°C

Powder X-ray diffractometry was conducted by employing a powder X-ray diffractometry apparatus (RU- 200BV type, manufactured by RIGAKU) under the following conditions for the measurement: Tube : Cu

Voltage : 40 kV Current : 50 mA Monochrometer : use Entrance slit : 0.60 mm

Goniometer : vertical goniometer monoaxial Sampling width : 0.020°

Scanning rate : 6.00°/min. Exit slit : 1° Dispersion slit : 1° Entrance slit : 0.30 mm Attachment : standard sample holder

[Examples]

Reference Example 1

Production of methyl ( 2R ) -2- ( 3 , 4 , 5 , 6-tetrahydro-2H- pyran-2-yloxy) propionate

A reaction vessel was charged with 50.0 g of methyl (R)-lactate and 0.2 g of p-toluenesulfonic acid monohydrate, and the pH of the mixture was confirmed to be not higher than 3. The mixture was cooled to 5°C, to which was then added dropwise, at temperatures not higher than 10 °C, 44.5 g of 3 , 4-dihydro-2H-pyran. Then, the mixture was stirred for one hour at room temperatures. After completion of the reaction, pH of the reaction mixture was adjusted to 7. The reaction was assumed to proceed quantitatively, and the amount of the starting material to be employed for the subsequent reaction step was calculated on the basis of its theoretical yield. Reference Example 2 Production of 4- ( 2R) -2-( 3 ,4 ,5 , 6-tetrahydro-2H-pyran-2- yloxy)propionyl ]morpholine

In 83.7 g of morpholine was dissolved 185.4 g of a 28% sodium methylate solution. Then, methanol was distilled off under reduced pressure. The concentrate was suspended in 180 ml? of diisopropyl ether. The suspension was cooled to -15 °C, to which was added dropwise, at temperatures around -15 °C, the whole amount of methyl ( 2R) -2- ( 3 , 4 , 5 , 6-tetrahydro-2H-pyran-2- yloxy)propionate produced in Reference Example 1. The mixture was stirred for 4 hours at the same temperature range. To the reaction mixture was added dropwise, at temperatures around -15 °C, 450 mβ of toluene. To the mixture was further added dropwise, at the same temperature range, 270 mH of water. The toluene layer was separated, and the aqueous layer was extracted twice with 450 mf each portion of toluene. Toluene layers were combined and concentrated under reduced pressure to give 104.9 g of 4 [ ( 2R) -2- ( 3 , 4 , 5 , 6- tetrahydro-2H-pyran-2-yloxy)propionyl ] morpholine as an oily product, (yield 89.8%, based on methyl (R)- lactate)

Reference Example 3

Production of (2R.-2 ',4 '-difluoro-2-( 3.4 , 5.6- tetrahydro-2H-pyran-2-yloxy)propiophenone

To 530 m{ of THF were added, in argon streams, 33.7 g of l-bromo-2 , 4-difluorobenzene and 12.7 g of magnesium (for Grignard reaction). The mixture was stirred for 20 minutes, while keeping the temperatures at not higher than 45 °C. To the reaction mixture was added dropwise gradually, at temperatures not higher than 45°C, 67.3 g of l-bromo-2 , 4-difluorobenzene . The mixture was stirred for one hour at temperatures ranging from 25 to 45°C. The reaction mixture was cooled to -5°C or below, to which was added dropwise a solution of 104.9 g of 4- [ ( 2R) -2- ( 3 , 4 , 5 , 6-tetrahydro- 2H-pyran-2-yloxy)propionyl] morpholine in THF (110 m ) while keeping the temperatures at not higher than 0°C. The mixture was then warmed to about 20°C, which was stirred for 90 minutes at the same temperature range. The reaction mixture was then cooled to -5°C, to which was added dropwise, at temperatures not higher than

25°C, 265 mi of cold water. The mixture was then added 6N HCl to adjust the pH to 7, to which was added 265 ml of water. The mixture was subjected to extraction with 530 mβ of ethyl acetate. To the aqueous layer was added 210 ml? of ethyl acetate, and the mixture was subjected to extraction. Organic layers were combined and washed with 320 ml] of a 5% aqueous solution of sodium chloride. The organic layer was concentrated under reduced pressure to give an oily substance. To the oily substance were added 850 ml? of ethanol and 10.6 g of activated charcoal. The mixture was warmed up to 60°C, which was stirred for 30 minutes at 60°C. The activated charcoal was then filtered off, which was washed with 210 ml? of ethanol. The solvent was distilled off under reduced pressure to give 118.8 g (yield 102%) of ( 2R) -2 ' , 4 ' -difluoro-2- ( 3 , 4 , 5 , 6- tetrahydro-2H-pyran-2-yloxy)propiophenone as yellow oily product. As the amount of ( 2R) -2 ' , 4 ' -difluoro-2- (3,4,5, 6-tetrahydro-2H-pyran-2-yloxy) propiophenone exceeded the theoretical yield, the reaction in this step was assumed to proceed quantitatively. The amount of the starting compound to be employed for the subsequent reaction step was calculated on the basis of the theoretical yield. IR(cm^_1, neat): 1695 (C=0) ¹H-NMR(CDCl₃)δ: 1.40-1.96 ( 9H,m) , 3.26-3.58 ( lH,m) , 3.65- 3.98(lH,m), 4.65 ( 1H, t , J=3.5Hz ) , 4.76 ( 1H, t , J=3.5Hz ) , 4.80-4.95(lH,m) , 5.02-5.18 ( lH,m) , 6.80-7.05 ( 2H,m) , 7.84-8.00(lH,m) Reference Example 4 Production of 2- ( 2 , -difluorophenyl . -2- [( IR) -1-

(3,4,5, 6-tetrahydro-2H-pyran-2-yloxy)ethyl]oxirane

To 700 mH of N,N-dimethylformamide was added, in argon streams, 49.8 g of sodium t-butoxide . The mixture was stirred for 20 minutes, to which was then gradually added, at 30°C, 113.8 g of trimethylsulfoxonium iodide, followed by stirring for 20 minutes. To the reaction mixture was gradually added dropwise, while keeping the temperatures at not exceeding 30°C, a solution of 118.8 g of (2R)-2',4'- difluoro-2- (3,4,5, 6-tetrahydro-2H-pyran-2- yloxy)propiophenone in 120 m(? of N,N-dimethylformamide . The reaction was allowed to proceed for one hour at room temperature. To the reaction mixture was added 820 ml? of water. The mixture was subjected to extraction twice with 820 m(> each portion of ethyl acetate. Ethyl acetate layers were combined, which was washed twice with 820 ml? each portion of water, followed by distilling off the solvent under reduced pressure to give 111.0 g of 2- ( 2 , 4-difluorophenyl ) -2- [ ( IR) -1- ( 3 , 4 , 5 , 6-tetrahydro-2H-pyran-2- yloxy) ethyl ]oxirane as a yellow oily product (yield

90.1%, based on 4- [ ( 2R) -2- ( 3 , 4 , 5 , 6-tetrahydro-2H-pyran- 2-yloxy)propionyl]morpholine) .

IR(cm^_1, neat): 2950, 1618, 1600, 1510, 1425, 1270, 1140, 1120, 1075, 1020 ¹H-NMR(CDCl₃)δ: 1.10-1.30 ( 3H,m) , 1.40-1.95 ( 6H,m) ,

2.83(lH,m), 3.05 ( lH,d, J=5.2Hz ) , 3.32 ( lH,d, J=5.2Hz ) , 3.42-3.60(lH,m), 3.76- .14 ( 2H,m) , 4.70-4.87 ( lH,m) , 4.88-4.97(lH,m), 6.72-6.95 ( 2H,m) , 7.32-7.60 ( lH,m) Reference Example 5 Production of (2R, 3R) -2- ( 2 , 4-difluorophenyl ) -3-

(3,4.5.6-tetrahydro-2H-pyran-2-yloxy) -1- ( 1H-1 , 2 , 4- triazol-1-yl ) -2-butanol

To 440 mi? of N,N-dimethylformamide were added 40.6 g of lH-l,2,4-triazole and 24.6 g of LiOH-H₂0. The mixture was warmed up to 60°C and stirred for 30 minutes, to which was added a solution of 110.0 g of 2- ( 2 , 4-difluorophenyl ) -2- [ ( IR) -1- ( 3 , 4 , 5 , 6-tetrahydro-2H- pyran-2-yloxy) ethyl ]oxirane in 110 mi of N,N- dimethylformamide. The reaction was allowed to proceed at 80°C for 4 hours. The reaction mixture was cooled to about 40 °C, to which was added 1100 mi of water, followed by extraction three times with 550 ml? each portion of ethyl acetate. Ethyl acetate layers were combined, which was washed with 550 f of a 5% aqueous solution of NaCl . Then, the solvent was distilled off under reduced pressure to give 146.9 g of (2R,3R)-2-

( 2 , 4-difluorophenyl ) -3- (3,4,5, 6-tetrahydro-2H-pyran-2- yloxy) -1- ( 1H-1 , 2 , 4-triazol-l-yl ) -2-butanol (yield 106%). As the amount of ( 2R, 3R) -2- ( 2 , 4- difluorophenyl) -3-( 3,4,5, 6-tetrahydro-2H-pyran-2- yloxy)-l-(lH-l,2,4-triazol-l-yl)-2-butanol thus produced exceeded the theoretical yield, this reaction step was assumed to proceed quantitatively, and the amount of the starting compound to be employed for the subsequent reaction step was calculated on the basis of the theoretical yield. IR(cm^"1, neat): 3420

¹H-NMR(CDCl₃)δ: 0.99 ( 3H, d, J=6.4Hz ) , 1.12 ( 3H,d, J=6.4Hz ) , 1.40-2.00(6H,m) , 3.40-3.65 ( lH,m) , 3.80-4.06 ( lH,m) , 4.25-4.45(lH,m) , 4.29(lH,s), 4.62 ( lH,d, J=14.2Hz ) , 4.62- 4.78(lH,m), 4.90 ( lH,d, J=1 .2Hz ) , 6.65-6.83 ( 2H,m) , 7.35- 7.50(lH,m), 7.71(lH,s), 7.72(lH,s), 7.91(lH,s), 7.94(lH,s) Reference Example 6 Production of ( 2R.3R) -2- ( 2 , 4-difluorophenyl ) -1- ( 1H- 1,2, 4-triazol-l-yl ) -2 _f 3-butanediol

In 690 mi? of methanol was dissolved 146.9 g of ( 2R, 3R) -2- ( 2 , 4-difluorophenyl ) -3- (3,4,5 , 6-tetrahydro- 2H-pyran-2-yloxy)-l-( 1H-1, 2 , 4-triazol-l-yl ) -2-butanol produced in Reference Example 5. To the solution was added 74.2 g of p-toluenesulfonic acid monohydrate. The mixture was stirred for 30 minutes at room temperature. After completion of the reaction, the reaction mixture was neutralized with a 8% aqueous solution of NaOH, followed by concentration under reduced pressure. To the concentrate was added 690 ml? of water. The mixture was subjected to extraction three times with 690 mi each portion of ethyl acetate. Ethyl acetate layers were combined, which was washed twice with 690 ml? each portion of water. The solvent was then distilled off. To the residue were added 410 mf of diisopropyl ether and 21 mf of ethyl acetate.

The mixture was stirred for 30 minutes at 70°C to cause crystallization, which was left standing for cooling, followed by aging for one hour. Crystals were collected by filtration and washed with 280 mi of a mixture of diisopropyl ether and ethyl acetate (100:5), followed by drying under reduced pressure at 40°C to give 50.9 g of ( 2R, 3R) -2- ( 2 , 4-difluorophenyl ) -1- ( 1H-1,2 , -triazol-l-yl) -2 , 3-butanediol as a slightly yellow crystalline product. (Yield 48.4%, based on 2- ( 2 , -difluorophenyl ) -2- [ ( IR) -1- ( 3 , 4 , 5 , 6-tetrahydro-2H- pyran-2-yloxy) ethyl ]oxirane) m.p.: 115-117°C [ ]_D -80.3° (c 1.0, MeOH) IR(cm^"1, KBr): 3550, 3420, 3150, 2990, 1615, 1600, 1500, 1420, 1265, 1130

¹H-NMR(CDCl₃)δ: 0.98 ( 3H, d, J=6.4Hz ) , 2.50(lH,br), 4.25- 4.40(lH,m), 4.70-4.93(3H,m) , 6.70-6.85 ( 2H,m) , 7.36- 7.48(lH,m), 7.84(lH,s), 7.85(lH,m) Anal.calcd for C₁₂H₁₃F₂N₃0₂ : C, 53.53; H, 4.87; N, 15.61. Found: C, 53.71; H, 4.87; N, 15.47.

Reference Example 7

Production of ( 2R, 3S) -2- ( 2 , 4-difluorophenyl ) -3-methyl- 2-( 1H-1 ,2 ,4-triazol-l-yl)methyl oxirane

To 240 mi? of ethyl acetate were added 30.0 g of ( 2R,3R) -2- (2, -difluorophenyl )-l-(lH-l, 2, 4-triazol-l- yl)-2 , 3-butanediol and 12.4 ml? of triethylamine. The mixture was cooled to 10 °C, to which was gradually added dropwise 14.0 ml? of methanesulfonyl chloride at about 20°C. The mixture was stirred for one hour at room temperature. After completion of the reaction, 240 M of water was added to the reaction mixture, which was then shaken and left standing. The organic layer was separated, to which was added 120 mi? of a 5% aqueous solution of NaCl . The mixture was shaken and left standing. The organic layer was separated, from which the solvent was distilled off under reduced pressure to leave an oily product. The oily product was dissolved in 60 mi of methanol. The solution was cooled to 10 °C, to which was gradually added dropwise, while keeping the temperature at 20°C or below, 23.6 g of a 28% solution of sodium methylate. The reaction was then allowed to proceed for 15 minutes at room temperature. To the reaction mixture was added dropwise 41 ml? of water to dissolve crystalline precipitate. To the solution was added 1.5 g of activated charcoal. The mixture was stirred for 10 minutes at room temperature. The activated charcoal was filtered off, which was washed with 23 mβ of ethanol. The filtrate and the washing were combined, to which was added dropwise 64 ml? of water under stirring at room temperature. To the mixture was added, at 25°C, seed crystals of (2R,3S)- 2- ( 2 , -difluorophenyl ) -3-methyl-2- ( 1H-1 , 2 , 4-triazol-l- yl )methyloxirane . The mixture was gradually cooled to cause crystallization, which was stirred for 30 minutes at 15°C. The mixture was cooled to 5°C, to which was then added 210 mi of water over 30 minutes at the same temperature. The mixture was cooled to 5°C and aged for one hour under stirring. Crystals were collected by filtration and washed with 90 mi of a cold mixture of methanol and water (1:3) to give wet crystals. To the wet crystals was added 20 mi of methanol, and the mixture was dissolved at 30 °C. The solution was cooled to 20°C, to which were added seed crystals, followed by stirring for 30 minutes to cause crystallization. The mixture was cooled to 5°C and aged for one hour under stirring. Crystals were collected by filtration and washed with 60 ml? of a cold mixture of methanol and water (1:5), followed by drying under reduced pressure at 40°C to give 18.7 g (yield 73.0%) of ( 2R, 3S ) -2- ( 2 , 4- difluorophenyl ) -3-methyl-2- ( 1H-1 , 2 , 4-triazol-l- yl) oxirane. m.p.: 89-90°C

[ ]_D -8.3° (c 1.02, MeOH)

IR(cm^_1, KBr): 3120, 1610, 1595, 1510, 1420, 1265

¹H-NMR(CDCl₃)δ: 1.65 ( 3H,d, J=5.8Hz ) , 3.20 ( 1H, q, J=5.8Hz ) , 4.33(lH,d,J=14.6Hz), 4.88 ( lH,d, J=14.6Hz ) , 6.68-

6.85(2H,m), 6.93-7.0 ( lH,m) , 7.82(lH,s), 7.96(lH,m) Anal.calcd for C₁₂H_nF₂N₃0 : C, 57.57; H, 4.41; N, 16.73.

Found: C, 57.27; H, 4.43; N, 16.83. Working Example 1 Production of Form II crystals of 2-f . IR.2R. -2-( 2. - difluorophenyl ) -2-hydroxy-l-methyl-3- ( 1H-1.2.4-triazol- l-yl)propyl]-4-[4-(2.2 _f 3.3-tetrafluoropropoxy) phenyl ]- 3-.2H. 4H.-l,2.4-triazolone

To N.N-dimethylformamide (14 (!) were added ( 2R, 3S ) -2- ( 2 , 4-difluorophenyl ) -3-methyl-2- ( 1H-1 , 2,4- triazol-l-yl)methyloxirane (700 g) , 4- [4- ( 2 , 2 , 3 , 3- tetrafluoropropoxy) phenyl ] -3- ( 2H, 4H) -1 , 2 , 4-triazolone (1014 g) and potassium carbonate (powdery: 1925 g) . The mixture was stirred for 45 hours at 80 to 85 °C. The reaction mixture was cooled, which was diluted with water (3.5 I? ) and ethyl acetate (89 d), followed by shaking and leaving standing to make two layers . The organic layer was separated and washed twice with a 10% aqueous NaCl solution (21 d ) . To the ethyl acetate layer was added activated charcoal (350 g) . The mixture was stirred for 30 minutes at room temperature, followed by filtering off the activated charcoal. The filtrate was concentrated under reduced pressure, which was dissolved in methanol-denatured ethanol (17.5 (> ). To the solution was added dropwise lN-NaOH (35 l? ) at

40°C, whereby a part of crystals was crystallized. The mixture was cooled to 5°C or below to yield the titled compound (1117 g, yield 73.8%) as a white crystalline product .

This product (1106 g) was dissolved in methanol- denatured ethanol (34 i ) at 45°C. To the solution was added activated charcoal (350 g) , and the mixture was stirred for 30 minutes at 40°C. The activated charcoal was filtered off. To the filtrate was added dropwise, at temperatures not exceeding 30°C, water (33 (? ) , whereby a part of the product was crystallized. The mixture was cooled to 5°C or below to yield the above- titled compound (crystal form: Form II, 943 g; yield 66.5%) as white crystals. The photograph of the crystals thus obtained in shown in [Fig. 1] and the corresponding powder X-ray diffraction spectrum is shown in [Fig. 2] . m.p.: 127°C

¹H-NMR(CDCl₃)δ: 1.30 ( 3H,d, J=7Hz ) , 4.36 ( IH, d, J=15Hz ) , 4.40(2H,tt,J=11.8Hz,1.4Hz) , 5.01 ( lH,d, J=15Hz ) , 5.09(lH,q,J=7Hz) , 5.47(lH,s), 6.07 ( IH, tt , J=53Hz , 4.8Hz ) , 6.75,6.88(2H,m) , 7.07 ( 2H,dt , J=9.0Hz , 2.2Hz ) , 7.48- 7.64(lH,m), 7.69(lH,s), 7.75(lH,s), 7.95(lH,s) Anal.calcd for C₂₃H₂₀F₆N₆O₃ : C, 50.93; H, 3.72; N, 15.49.

Found: C, 50.85; H, 3.59; N, 15.54. Working Example 2

Production of Form II crystals of 2- [ ( IR.2R. -2- ( 2.4- difluorophenyl ) -2-hydroxy-l-methyl-3- ( 1H-1.2.4-triazol- l-yl)propyl]-4-[4-(2 2 ,3 , 3-tetrafluoropropoxy)phenyl ] - 3- ( 2H .4H) -1 , 2 , 4-triazolene To N,N-dimethylformamide (54 ml? ) were added

( 2R, 3S ) -2- ( 2 , 4-difluorophenyl ) -3-methyl-2- ( 1H-1 , 2,4- triazol-l-yl)methyloxirane (18.0 g) , 4-[4-( 2 , 2 , 3, 3- tetrafluoropropoxy) phenyl ] -3- ( 2H, 4H) -1 , 2 , 4-triazolone (20.9 g) and potassium carbonate (49.5 g) . The mixture was stirred for 7 hours at 100 °C. The reaction mixture was cooled, which was diluted with IN aqueous solution of NaOH (90 mi ) and ethyl acetate (210 ml? ) , followed by shaking and leaving standing to make two layers . The organic layer was separated and washed twice with IN aqueous solution of NaOH (90 mi ) and a 10% solution of NaCl (90 ml? ) . The organic layer was concentrated to make the volume of 100 ml! .

To the resultant solution was added methanol- denatured ethanol (175 mi? ) and the mixture was concentrated to make the volume of 100 mi . To the resultant solution were added methanol-denatured ethanol (175 mi? ) and activated charcoal (0.9 g) . The mixture was stirred for 30 minutes at 40 °C, and then the activated charcoal was filtered off. The activated charcoal was washed with methanol-denatured ethanol (30 mi ) , and the washings is combined with mother liquor. To the mixed solution was dropwise added distilled water (300 mi ) at 40°C.

The mixture was left standing at not higher than 5°C to age. The resulting crystals were harvested by filtration and washed with a mixed solution (60 mi ) of methanol-denatured ethanol and distilled water (1:1). The crystals were dried under vacuum at 60°C to give a crude crystals as a white crystals (28.0 g, yield 72.0%). The crude crystals were dissolved in methanol-denatured ethanol (21 iri ) at 50°C. To the solution was added activated charcoal (90 mi ) . The mixture was stirred for 30 minutes at 50°C and the activated charcoal was filtered off. The activated charcoal was washed with methanol-denatured ethanol (6 mi ) and the washings were combined with mother liquor. To the mixed solution was added dropwise distilled water (27 mi ) at 30°C, whereby a part of the product was crystallized. The mixture was left standing at not higher than 5°C to age. The resulting crystals were collected by filtration and washed with a mixed solution (9 mi ) of methanol-denatured ethanol and distilled water (1:1). The crystals were subjected to dryness under vacuum for 12 hours at 40 °C, whereby the titled compound (Crystal form: Form II, 2.91 g, yield 97.0%) was obtained as white crystals. m.p.: 127°C

¹H-NMR(CDCl₃)δ: 1.30 ( 3H,d, J=7Hz ) , 4.36 ( lH,d, J=15Hz ) , 4.40(2H,tt,J=11.8,1.4Hz) , 01 ( lH,d, J=15Hz ) , 5.09(lH,q, J=7Hz) , 5.47(lH,s),

6.07(lH,tt,J=53,Hz,J=4.8Hz) , 6.75 , 6.88 ( 2H,m) , 7.07(2H,dt, J=9Hz,J=2.2Hz) , 7.48-7.64 ( lH,m) , 7.69(lH,s), 7.75(lH,s), 7.95(lH,s)

Anal . calcd for C₂₃H₂₀F₆N₆O₃ : C , 50 . 93 ; H , 3 . 72 ; N , 15 . 49 .

Found : C , 51 . 07 ; H , 3 . 70 ; N , 15 . 58 .

Comparative Example 1

Production of Form I crystals of 2- r ( IR, 2R1-2- ( 2.4- difluorophenyl ) -2-hydroxy-l-methyl-3- ( 1H-1 , 2 , 4-triazol- 1-yl ) propyl ]-4-[4-(2.2,3, 3-tetrafluoropropoxy)phenyl ] - 3-(2H.4H)-1.2,4-triazolone To N,N-dimethylformamide (20 mi ) were added

( 2R, 3S ) -2- ( 2 , 4-difluorophenyl ) -3-methyl-2- ( 1H-1 , 2 , - triazol-l-yl)methyloxirane (1.00 g) , 4- [ 4- ( 2 , 2 , 3 , 3- tetrafluoropropoxy) phenyl] -3 (2H,4H) -1,2 , 4-triazolone (1.45 g) and potassium carbonate (powdery: 2.75 g) . The mixture was stirred for 24 hours at 80-85 °C. The reaction mixture was cooled, which was then diluted with ethyl acetate (144 mi ) , followed by washing twice with water (30 mi? ) and a 10% aqueous NaCl solution (30 ml? ) . To the ethyl acetate layer was added activated charcoal (0.50 g) . The mixture was stirred for 30 minutes at room temperature. The activated charcoal was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was dissolved in ethanol (25 mi ) , to which was added dropwise IN-NaOH (50 mi ) at 40°C, whereby a part of the product was crystallized. The mixture was cooled to about 5°C to yield the titled compound (1.54 g, yield 71.3%) as a white crystalline product.

This product was subjected to recrystallization from a mixture of methanol-denatured ethanol and water (2:1) under reflux (80-84°C) to give the above-titled compound (crystal form: Form I) as white crystals. The photograph of the crystals thus obtained is shown in [Fig.3] and the corresponding powder X-ray diffraction spectrum is shown in [Fig.4]. m.p.: 154-155°C.

¹H-NMR(CDCl₃)δ: 1.30 ( 3H,d, J=7Hz ) , 4.36 ( lH,d, J=15Hz ) , 4.40(2H,tt,J=11.8Hz,1.4Hz) , 5.01 ( lH,d, J=15Hz ) , 5.09(lH,q,J=7Hz) , 5.47(lH,s), 6.07 ( IH, tt , J=53Hz , 4.8Hz ) , 6.75,6.88(2H,m) , 7.07 ( 2H,dt , J=9.0Hz , 2 .2Hz ) , 7.48- 7.64(lH,m), 7.69(lH,s), 7.75(lH,s), 7.95(lH,s)

Anal . calcd for C₂₃H₂₀F₆N₆O₃ : C , 50 . 93 ; H, 3 . 72 ; N, 15 . 49 .

Found: C, 50.90; H, 3.62; N, 15.55. Test Example 1. Stability test of crystals

Water/ethanol (1:1) suspensions respectively containing 20 mg/0.5 mi of Form I crystals and Form II crystals were prepared. To the suspension containing Form I crystals was added an infinitesimal volume of Form II crystals. To the suspension containing Form II crystals was added an infinitesimal volume of Form I crystals. The respective suspensions were slightly shaken at 24 °C, 35 °C and 50 °C, followed by leaving them standing at the respective temperatures . Powder X-ray diffraction spectra of the crystals obtained in 24 hours and 48 were measured to observe the crystal forms. [ Table 1 ]

As is clear from the above Table, no change from

Form II crystals to Form I crystals was observed at all temperatures, i.e. 25°C (around room temperatures), 35 °C and 50 °C was observed, while Form I crystals were all changed to Form II crystals. It has then become ascertained that Form II crystals are of more stable type as compared with Form I crystals [Table 1]. Working Example 3

A fluid granulator (FD-5S, manufactured by Paulek Co.) was charged with 525 g of Compound A, 2696 g of lactose and 630 g of corn starch. Onto the mixture was sprayed, while controlling the air-feeding temperature at about 70°C and controlling the temperature of the mixture at about 40°C, 2520 g of an aqueous solution containing 126 g of hydroxypropyl cellulose. After completion of the spraying, the resultant was dried for 3 minutes .

By using a Power Mill (P-3S, 1.5 mm φ punching screen, manufactured by Showa Chemical Machinary) , 3409 g of the powdery granule obtained above was crushed to obtain refined powdery granule. A tumbling mixer

(Tumbler Mixer, TM-15, manufactured by Showa Chemical Machinery) was charged with 3220 g of of the refined powdery granule, 170 g of Acdisol (cross carmellose sodium) and 10.2 g of magnesium stearate. The mixture was blended for one minute. Using a rotary tabletting machine (Collect 19K, punch 8 mm φ, plain tabletting pressure 1 ton/cm2 , manufactured by Kikusui Seisakusho), 3200 g of the blended powder was tabletted to obtain 16,000 tablets containing about 25 mg of Compound A in each tablet.

The tablet thus obtained has the following properties: Weight = about 200 mg; Thickness = about 3.1 mm; Hardness = about 8 kg; and Disintegration time = about 7 minutes . Composition per tablet is as follows:

Compound A 25.0 mg

Lactose 128.4 mg

Corn starch 30.0 mg

Cross carmellose sodium 10.0 mg Hydroxypropyl cellulose 6.0 mg

Magnesium stearate 0.6 mg

Total weight 200.0 mg

Working Example 4 In substantially the same procedure as in

Reference Example 1, tablets, having the following composition per tablet, are obtained.

Compound A 100.0 mg

Lactose 53.4 mg Corn starch 30.0 mg

Cross carmellose sodium 10.0 mg Hydroxypropyl cellulose 6.0 mg Magnesium stearate 0.6 mg

Total weight 200.0 mg

Working Example 5

In substantially the same procedure as in Reference Example 1, tablets, having the following composition per tablet, are obtained. Compound A 1.0 mg

Lactose 152.4 mg Corn starch 30.0 mg

Cross carmellose sodium 10.0 mg

Hydroxypropyl cellulose 6.0 mg

Magnesium stearate 0.6 mg

Total weight 200.0 mg

Working Example 6

In substantially the same procedure as in Working Example 3, tablets, having the following composition per tablet, are obtained.

Compound A 5.0 mg

Lactose 148.4 mg

Corn starch 30.0 mg Cross carmellose sodium 10.0 mg

Hydroxypropyl cellulose 6.0 mg

Magnesium stearate 0.6 mg

Total weight 200.0 mg

Working Example 7

Forty grams of tricaprylin (Panasate 800: manufactured by Nippon Oils & Fats Co., Ltd.) and 0.4 g of Compound A were mixed at 60 °C to dissolve the latter. To the resultant solution was added a solution of 2.4 g of egg yolk lecithin (manufactured by Asahi Chemical Industry Co., Ltd.) and 4.5 g of glycerin (special grade chemical: manufactured by Wako Pure Chemical Industries, Ltd.) in an appropriate volume of distilled water heated at 60 °C. The mixture was stirred in Polytron homogenizer (PT 10-35: manufactured by Kinematica Co.) to prepare a crude emulsion. To the crude emulsion was added distilled water to make the whole volume 200 ml? , which was then emulsified by using Nanomizer (PEN 02-15B: manufactured by Nanomizer Co.). The foregoing procedures were all conducted under nitrogen atmosphere. With IN NaOH (special grade chemical: manufactured by Wako Pure Chemical Industries, Ltd.), the pH of the solution was adjusted to 7.5, followed by subjecting to filtration with a filter having a pore size of 0.45 micrometer (Milipak 20: manufactured by Millipore Co.) to obtain an injectable solution in which fat particles of average particle size of 200 nm containing Compound A were dispersed.

INDUSTRIAL APPLICABILITY The Form II crystals of the present invention are remarkably low in hygroscopicity and are remarkably excellent in stability. When Compound A is crystallized as the Form II crystals from reaction mixture containing Compound A chemically synthesized, Compound A can be isolated by a simple and convenient procedure, on an industrially large scale, in a high purity and with a high yield. That is, by a purification procedure in which Form II crystals are crystallized, a remarkable decrease in working amount and a remarkable reduction of working hours can be realized, use of a large volume of organic solvents is unnecessary, and the procedure of silica gel chromatography can be saved, and, therefore, no problem is left on the treatment of waste silica gel, thus being remarkably preferable from the viewpoint of environmental problems .

[Brief Explanation of Figures]

[Fig. 1] shows a photograph of Form II crystals of

Compound A produced in Working Example 1 , under observation by a polarizing microscope.

[Fig. 2] shows powder X-ray diffraction spectrum (Cu, 40 kV, 50 mA) of Form II crystals of Compound A produced in Working Example 1. Transverse axis shows angle of diffraction (2 θ), and ordinate axis shows peak strength.

[Fig. 3] shows a photograph of Form I crystals of Compound A produced in Comparative Example 1, under observation by a polarizing microscope.

[Fig. 4] shows powder X-ray diffraction spectrum (Cu, 40 kV, 50 mA) of Form I crystals of Compound A produced in Comparative Example 1. Transverse axis shows angle of diffraction (2 θ), and ordinate axis shows peak strength.

Claims

1. Form II crystals having a melting point of 127┬░C┬▒3┬░C, of a compound represented by the formula:

2. Form II crystals as claimed in claim 1, which have a peak near about 9┬░ diffraction angle in spectrum of powder X-ray diffraction and have not a peak near 6 to 6.5┬░.

3. Form II crystals as claimed in claim 1, which have an endothermic peak near 130 ┬░C in spectrum of differential thermal analysis. 4. A pharmaceutical composition which comprises Form II crystals according to claim 1 and pharmaceutically acceptable carrier, diluent or excipient. 5. A pharmaceutical composition as claimed in claim

4. which is for the treatment of fungal infections. 6. A method for treating fungal infection which comprises administering an effective amount of Form II crystals according to claim 1 optionally together with a pharmaceutically acceptable carrier, diluent or excipient to a patient suffering from fungal infection. 7. Use of Form II crystals according to claim 1 in the production of an pharmaceutical composition. 8. Use of Form II crystals as claimed in claim 7, which is for an antifungal composition.