CN1223258A - Triazole derivative or salt thereof, preparation process thereof and pharmaceutical containing said compound as effective ingredient - Google Patents
Triazole derivative or salt thereof, preparation process thereof and pharmaceutical containing said compound as effective ingredient Download PDFInfo
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- CN1223258A CN1223258A CN 98126265 CN98126265A CN1223258A CN 1223258 A CN1223258 A CN 1223258A CN 98126265 CN98126265 CN 98126265 CN 98126265 A CN98126265 A CN 98126265A CN 1223258 A CN1223258 A CN 1223258A
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Abstract
The present invention describs a triazole derivative represented by the formula (1), wherein R1 represents a hydrogen atom, a lower alkyl group or an aralkyl group, X1 and X2 are the same or different and each independently represents a hydrogen atom, a halogen atom or a halogenoalkyl and n stands for an integer of 0 to 2, or salt thereof; a preparation process of said compound and a pharmaceutical comprising said compound as an effective ingredient.The compound as described above has high antimycotic activity and is useful for the prevention and treatment of mammalian mycotic infections.
Description
The present invention relates to have effect of excellent anti mould and higher-security triazole derivative or its salt, be used to prepare the intermediate of described compound and contain the medicine of described compound as effective constituent.
Mycosis can be divided into two types, promptly, with trichophytosis, marginality eczema, psoriasis, dermatocandidiasis or like that be representative the shallow-layer mycosis and with the fungal infection disease of fungal meningitis, respiratory organs, fungemia, urinary tract mycosis or like that be the mycosis that is positioned at the deep of representative.Wherein the mycosis that is positioned at the deep such as moniliosis or aspergillosis etc. has the trend of remarkable increase recently, this be since the frequent use of anti-cancer chemotherapeutic agents or immunosuppressor or HIV infect due to biological immunology reduce or like that causing.Therefore the medicine that needs these diseases due to a kind of effective opposing fungi.
As effective anti-Aspergillus and candidal medicine, amphotericin B and pyrroles's alkali cpd, normally known as fluconazole and itraconazole are commercial available but also there is not so many medicine.In addition, above-mentioned illustrative medicine involves the problem of security and antifungal effect.Therefore need effectively resist Aspergillus and candidal antimycotic agent.At present, more efficiently pyrroles's alkali cpd is just under development.For example, as compound, known as described in Japanese Patent Application Publication 163374/1984,163269/1993 and 227531/1996 with a difluoro methylene.As compound ring series with a tert-hydroxyl; known to Japanese Patent Application Publication 217778/1996 and 333367/1996 described compound ring series; Japanese Patent Application Publication 104676/1996 and 183769/1997 described acyl compounds; or the like, but they are not entirely satisfactory.
Therefore, an object of the present invention is to provide and a kind ofly have higher-security and have effective anti-Aspergillus and an active compound of candidal antifungal.
Consider above-mentioned situation, the inventor has synthesized a large amount of triazole derivatives and salt thereof, and its effective anti-Aspergillus and candidal antifungal activity are studied.Found that; by the triazole derivative that contains ethylmercapto group or ethylsulfonyl of following formula (1) representative and salt thereof on the antifungal activity of the anti-fungi that comprises Aspergillus and Candida and in security, be better than present known similar compound, thereby finished the present invention.
An aspect of of the present present invention provides a kind of triazole derivative or its salt by following formula (1) representative:
R wherein
1Represent hydrogen atom, low alkyl group or an aralkyl, X
1With X
2Identical or different, each represents a hydrogen atom, a halogen atom or a haloalkyl independently, and n represents one 0 to 2 integer; Be used to prepare the intermediate of described compound; Preparation method with these compounds.
Another aspect of the present invention also provides a kind of medicine that contains triazole derivative (1) or its salt as effective constituent.
Further aspect of the present invention also provides a kind of pharmaceutical composition that contains triazole derivative (1) or its salt and a kind of pharmaceutically acceptable carrier.
Further aspect of the present invention also provides triazole derivative (1) or its salt purposes as a kind of medicine.
Further aspect of the present invention also provides a kind of methods of treatment of fungal infection, and this method comprises to the patient takes triazole derivative (1) or its salt.
Have stronger antifungal activity according to triazole derivative of the present invention or its salt, contain this compound and can be used for preventing and treating the Mammals fungal infection that comprises the people as the antimycotic agent of effective constituent.
In the triazole derivative of the present invention, in the formula (1) by R
1The low alkyl group example of representative comprises straight or branched C
1-6Alkyl.Concrete example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl and n-hexyl.As by R
1The aralkyl of representative is preferably C
7-10Aralkyl, more preferably phenyl-C
1-4Alkyl.Concrete example comprises phenmethyl and styroyl and hydrocinnamyl.As R
1, be preferably methyl and phenmethyl.By X
1Or X
2The halogen atom example of representative comprises fluorine, chlorine, bromine and iodine atom, is preferably fluorine and chlorine atom especially.The haloalkyl example comprises the above-mentioned illustration C that is replaced by above-mentioned illustration halogen atom
1-6Alkyl.Wherein be preferably perfluoroalkyl, be preferably trifluoromethyl and pentafluoroethyl group especially, more preferably trifluoromethyl.The n number of Sauerstoffatom is represented one 0 to 2 integer, is preferably 0 and 2.
In the scope of pharmacy acceptable salt, the salt of triazole derivative of the present invention (1) is had no particular limits.Example comprises acid salt, as hydrogen chlorate, nitrate, hydrobromate, tosilate, mesylate, fumarate, succinate and lactic acid salt.
Has steric isomer according to triazole derivative of the present invention (1) or its salt based on its asymmetric carbon and sulfoxide.Therefore the present invention comprises this isomer and isomer mixture arbitrarily, as racemic modification.Triazole derivative (1) or its salt can with a kind of be that the solvate forms of representative exists with the hydrate.The present invention also comprises the solvate of these compounds.
Triazole derivative of the present invention (1) can be prepared by for example following reaction process:
R wherein
1, X
1And X
2Define the same, X
3Represent a halogen atom.
Specifically, ethylmercapto group is introduced known compound 2-halo-acetophenone derivative (5), make gained ethylmercapto group compound (4) difluoro turn to compound (2), directly triazole methyl is introduced compound (2) then, perhaps earlier the epoxy methylene radical is introduced compound (2), obtain compound (3), then triazolyl is introduced compound (3), can make compound (1a), just wherein n represents 0 formula (1) compound.As required, the R1 of gained compound (1a) can be by alkylation or aralkylization.By oxygenated compound (1a), can make compound (1b), just wherein n represents 1 formula (1) compound, or compound (1c), just wherein n represents 2 formula (1) compound.Alternative method is by oxygenated compound (1b) preparation compound (1c).
Among the above-mentioned preparation method, by 2 of formula (2) representative, 2-two fluoro-2-ethylmercapto group acetophenone derivatives and the epoxyethane derivative of being represented by formula (3) are by inventor's synthetic new compound, can be used as intermediate, are used for synthetic triazole derivative (1).
Below, according to above-mentioned steps, will more specifically describe the present invention.
Step (5-4):
By ethylmercapto group being introduced compound (5), can make compound (4).
As in the compound (5) of raw material, X in the formula (5)
3Example comprise fluorine, chlorine and bromine atoms.Wherein preferred chlorine and bromine atoms.Contain fluorine, chlorine or bromine atom as X
3, contain fluorine atom as X
1With X
2Compound (5) for example can obtain commercial from Aldrich chemical company.
In the presence of a kind of alkali, make compound (5) and sulfur alcohol reaction, can make compound (4).The example of reaction solvent comprises such as alcohol solvent, N such as methyl alcohol and ethanol, dinethylformamide, 1, and 4-diox and tetrahydrofuran (THF) are preferably the alcohol solvent, are preferably methyl alcohol especially.As alkali, can use yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride KH, sodium methylate, sodium ethylate, pyridine, triethylamine or like that.Wherein preferred salt of wormwood.
Step (4-2):
In a kind of solvent, make compound (4) and a kind of fluorizating agent reaction, can make compound (2).
The example of fluorizating agent comprises fluorine gas, perchloryl fluorine, Potassium monofluoride, spray-dired Potassium monofluoride, cryodesiccated Potassium monofluoride, fluoridizes tetra-allkylammonium, three (dimethylamino) sulfanilamide (SN) (three silyls) difluoro, N-fluorine pyridone, N-fluoro-N-alkyl-aryl sulfonic acid amides, N-fluorine rubane salt, N-fluorine perfluoroalkyl sulfimide, N-fluorosaltum, xenon fluoride, N-fluorine pyridinium salt and sulfonic acid N-fluorine pyridine.Commercial available fluorizating agent example comprises " Onoda fluorizating agent FP-T300, FP-T500, FP-T700, FP-B300, FP-B500, FP-B700 and FP-B800 " (trade(brand)name; Chichibu Onoda company limited product) and " MEC-01, MEC-02, MEC-03, MEC-04 and MEC-05 " (trade(brand)name; Daikin Industries company limited product).Every mole compound (4) preferably uses 2 to 20 normal fluorizating agents.
Illustrating of reaction solvent comprises 1,2-ethylene dichloride, vinyl trichloride, chloroform, methylene dichloride, diethyl ether, ethyl acetate and tetrahydrofuran (THF).Wherein preferred vinyl trichloride.Temperature of reaction is-78 ℃ of boiling points to solvent, is preferably 80 to 100 ℃.
In order to improve the productive rate of compound, can use a kind of Lewis acid or alkali.The Lewis acid example comprises aluminum chloride, zinc chloride and tin chloride, and the alkali example comprises sodium hydroxide, potassium hydroxide, hydrated barta, yellow soda ash, salt of wormwood, sodium hydride, potassium tert.-butoxide, diisopropyl amide lithium and hexamethyldisilazane base potassium.
Step (2-1a):
At-100 ℃ to room temperature or solvent boiling point, make 1 mole compound (2) and 1 to 5 mole of epoxy methylene radical (epoxymethylene) introduce agent and 1 to 4 mole 1,2,4-triazole or its an alkali metal salt reacted in a kind of solvent 1 to 30 hour, can be directly from compound (2) synthetic compound (1a).The example that the epoxy methylene radical is introduced agent comprises iodate trimethylammonium sulfoxonium and iodate trimethylsulfonium.The example of alkali comprises sodium hydroxide, potassium hydroxide, hydrated barta, sodium methylate, yellow soda ash, salt of wormwood and sodium hydride, is preferably potassium hydroxide especially.As solvent, be preferably methyl alcohol, ethanol, Virahol, propyl carbinol, sec-butyl alcohol, the trimethyl carbinol and like that.
Step (2-3):
Can prepare compound (1a) by compound (3).
In the presence of 1 to 5 normal a kind of alkali, make compound (2) and 1 to 2 normal a kind of epoxy methylene radical introduce agent, react as iodate trimethylammonium sulfoxonium or iodate trimethylsulfonium, can obtain compound (3).Dimethyl sulfoxide (DMSO), tetrahydrofuran (THF) or the solvent that is suitable as like that.The example of alkali comprises sodium hydroxide, potassium hydroxide, hydrated barta, sodium methylate, sodium ethylate, yellow soda ash, salt of wormwood and sodium hydride, is preferably sodium hydride and sodium methylate especially.Range of reaction temperature preferably from-100 ℃ to solvent boiling point, be preferably-40 to 50 ℃ especially.
Step (3-1a):
In the presence of a kind of alkali, make compound (3) and 1,2,4-triazole or its an alkali metal salt react in a kind of solvent, can make to contain a hydrogen atom as R
1Compound (1a).The preferred embodiment of solvent comprises N, dinethylformamide, acetonitrile, N,N-dimethylacetamide and dimethyl sulfoxide (DMSO).The example of alkali comprises sodium hydroxide, potassium hydroxide, hydrated barta, yellow soda ash, salt of wormwood and potassium tert.-butoxide.Range of reaction temperature preferably from 0 ℃ to solvent boiling point, be preferably 20 to 60 ℃ especially.
As required, in the presence of a kind of alkali,, can will contain a hydrogen atom as R by alkylation or aralkyl tert-hydroxyl
1Compound (1a) be converted into and contain a low alkyl group or aralkyl as R
1Compound (1a).The alkylogen example that is used for alkylated reaction comprises methyl-iodide, iodoethane, propyl iodide and phenmethyl chlorine.The example of alkali comprises sodium hydroxide, potassium hydroxide, hydrated barta, yellow soda ash, salt of wormwood and sodium hydride.The example of solvent comprises such as alcohol solvents such as methyl alcohol and ethanol, such as N, the polar solvent of dinethylformamide non-water such as (DMF) and such as 2, and 4-diox and tetrahydrofuran (THF) ether solvents such as (THF) is preferably DMF especially.Range of reaction temperature preferably from-40 ℃ to solvent boiling point, be preferably 0 to 20 ℃ especially.
Step (1a-1c):
By in compound (1a), adding at least 2 equivalents, being preferably 2.2 to 2.3 normal a kind of oxygenants, can make compound (1c).The example of oxygenant comprises metachloroperbenzoic acid, aqueous hydrogen peroxide, peracetic acid, crosses ruthenic acid tetrapropyl ammonium, perosmic anhydride, potassium permanganate and oxone.Illustrating of solvent comprises chloroform, methylene dichloride, acetate, methyl alcohol, water, acetonitrile and tetracol phenixin and their mixture.Temperature of reaction is preferably-40 ℃ to solvent boiling point, is preferably 0 to 50 ℃ especially.In order to improve productive rate, can use ruthenium trichloride, tin anhydride, sodium wolframate, Sodium orthomolybdate and vanadium oxide as catalyzer.
Step (1a-1b) and (1b-1c):
By in compound (1a), adding 1 to 2 equivalent, being preferably 1.2 normal a kind of oxygenants, can make compound (1b).The example of oxygenant comprises metachloroperbenzoic acid, aqueous hydrogen peroxide, peracetic acid, crosses ruthenic acid tetrapropyl ammonium, perosmic anhydride, potassium permanganate and oxone.Illustrating of solvent comprises chloroform, methylene dichloride, acetate, methyl alcohol, water, acetonitrile and tetracol phenixin and their mixture.Temperature of reaction is preferably-40 ℃ to solvent boiling point, is preferably 0 to 50 ℃ especially.In order to improve productive rate, can use ruthenium trichloride, tin anhydride, sodium wolframate, Sodium orthomolybdate and vanadium oxide as catalyzer.Can carry out step (1b-1c) similarly.
Compound (1a), (1b) and (1c) each all has the enantiomorph based on its unsymmetrical carbon.Separate with the optically active isomer separator column, can make this optically active material.The example of optically active stationary phase comprises synthetic optically active polymkeric substance, natural polymer and amino acids metal title complex.Wherein be preferably the silica gel that derivatived cellulose applies.Pillar as the silica gel that loads this derivatived cellulose coating can use commercial available product, (is trade(brand)name as CHIRALCEL OD and CHIRALPAK AS; Daicel chemical industry company limited product), be preferably CHIRALCEL OD especially.As chromatography, be preferably liquid phase chromatography.In this case, can use hexane-ethanol, hexane-Virahol as elutriant, as moving phase.
Also can get the optically active material by the optical resolution legal system.The example of optical resolution reagent comprises optically active camphorsulfonic acid or its salt that can be replaced by halogen atom.Specific examples comprises (+)-camphor-10-sulfonic acid, (-)-camphor-10-sulfonic acid, (+)-3-bromo-camphor-8-sulfonic acid, (-)-3-bromo-camphor-8-sulfonic acid, (+)-3-bromo-camphor-10-sulfonic acid, (-)-3-bromo-camphor-10-sulfonic acid, (+)-3-bromo-camphor-8-ammonium sulphonate and (-)-3-bromo-camphor-7-ammonium sulphonate.Wherein be preferably (+)-3-bromo-camphor-8-sulfonic acid, (-)-3-bromo-camphor-8-sulfonic acid, (+)-3-bromo-camphor-8-ammonium sulphonate and (-)-3-bromo-camphor-7-ammonium sulphonate especially.
Have no particular limits from the reaction mixture that derives from above-mentioned each step reaction, separating the method that obtains target product.For example by recrystallization method, various chromatography or like that can the separate targets product.And, target compound can be converted into a kind of required salt with ordinary method.
Can obtain the medicine of various formulations, particularly antimycotic agent from The compounds of this invention, formulation is tablet, granule, powder, capsule, suspension, injection, suppository and external preparation for example.In this case, by making this medicine to wherein adding pharmaceutically acceptable carrier.Specifically, in The compounds of this invention (1), add excipient according to a conventional method, if necessary add tackiness agent, disintegrating agent, weighting agent, Drug coating, sugar-coat agent and/or like that again, can make a kind of solid preparation.The preparation of injection can by The compounds of this invention (1) is dissolved, disperses or be emulsified in aqueous carrier, as in the distilled water for injection, form in advance to the injection of liquid or make powder injection, dissolve during use.The medication example of injection comprises intravenous administration, intra-arterial administration, intraperitoneal administration, subcutaneous administration and instillation.
The compounds of this invention or its salt are different because of various factors as the dosage of medicine, for example by administration patient's symptom, body weight, age or sex, or route of administration.When using as antimycotic agent, according to The compounds of this invention (1) or its salt, amount of drug is each grownup 0.1 to 1000mg/ day, is preferably 1 to 300mg/ day.Above-mentioned consumption can be used once or is divided into 2 to 4 parts every day every day and use.
Embodiment
By reference example and embodiment, below will describe the present invention.What but should remember is that the present invention will be not limited to the following example or be limit by it.Reference example 1
Synthesizing of 2 ', 4 '-two fluoro-2-(ethylmercapto group) phenyl methyl ketones [compound (4-1)]
Ice-cooled down, to 2-chloro-2 ', 4 '-difluoro phenyl methyl ketone (10g, 0.053mol) and sulfur alcohol (3.6g, (8.8g 0.064mol), at room temperature stirred 1.5 hours then to add salt of wormwood in methyl alcohol 0.058mol) (200ml) solution.After reaction was finished, underpressure distillation removed and desolvates.In resistates, add entry, use extracted with diethyl ether then.Continuous water of extraction liquid and saturated brine washing are through dried over mgso.Underpressure distillation removes and desolvates then.Gained oily matter carries out underpressure distillation (boiling point: 115 to 118 ℃, 2mmHg), obtain 2 ', 4 '-two fluoro-2-(ethylmercapto group) phenyl methyl ketones (11.4g, productive rate: 99.9%), be a colorless oil by this.
1H-NMR (CDCl
3, δ): 1.24 (J=7Hz), 2.51 (J=7Hz), 3.77 (J=2Hz), (2H, m), (1H, m) reference example 2 for 7.86-8.13 for 6.75-7.09 for 2H, d for 2H, q for 3H, t
Synthesizing of 2-ethylmercapto group-4 '-acetyl fluoride benzene [compound (4-2)]
Except with beyond 2-chloro-4 '-acetyl fluoride benzene replacement 2-chloro-2 ', 4 '-difluoro phenyl methyl ketone, according to the method that is similar to reference example 1, obtain 2-ethylmercapto group-4 '-acetyl fluoride benzene, be a colorless oil.
1H-NMR (CDCl
3, δ): 1.27 (J=7.2Hz), 2.58 (J=7.2Hz), 3.77 (2H, s), (2H, m), (2H, m) reference example 3 for 7.90-8.10 for 7.00-7.40 for 2H, q for 3H, t
Synthesizing of 2-ethylmercapto group-4 '-trifluoromethyl phenyl methyl ketone [compound (4-3)]
Except with beyond 2-bromo-4 '-trifluoromethyl phenyl methyl ketone replacement 2-chloro-2 ', 4 '-difluoro phenyl methyl ketone, according to the method that is similar to reference example 1, obtain 2-ethylmercapto group-4 '-trifluoromethyl phenyl methyl ketone, be a colorless oil.
1H-NMR (CDCl
3, δ): 1.27 (J=7.5Hz), 2.57 (J=7.5Hz), 3.80 (2H, s), 7.74 (J=8.4Hz), 8.10 (J=8.4Hz) reference example 4 for 2H, d for 2H, d for 2H, q for 3H, t
Synthesizing of 2 ', 4 '-two chloro-2-(ethylmercapto group) phenyl methyl ketones [compound (4-4)]
Except with 2, beyond 2 ', 4 '-tribromo-acetyl benzene replacement 2-chloro-, 2 ', 4 '-difluoro phenyl methyl ketone,, obtain 2 ', 4 '-two chloro-2-(ethylmercapto group) phenyl methyl ketones according to the method that is similar to reference example 1, be a colorless oil.
1H-NMR (CDCl
3, δ): 1.25 (J=7.3Hz), 2.55 (J=7.3Hz), 3.80 (2H, s), (3H, m) example 1 for 7.20-7.70 for 2H, q for 3H, t
2-ethylmercapto group-2,2,2 ', 4 '-tetrafluoro phenyl methyl ketone [compound (2-1)] synthetic
Under 95 ℃ of internal temperatures, to 2 ', 4 '-two fluoro-2-(ethylmercapto group) phenyl methyl ketones (11.4g, gradation adds N-fluoro-4-picoline-2-sulphonate (" MEC-02 ", trade(brand)name in vinyl trichloride 0.053mol) (100ml) solution; Daikin Industries company limited) (24g 0.127mol), stirred 1.5 hours under 95 to 100 ℃ of internal temperatures then.After reaction is finished, internal temperature is cooled to 50 ℃ or lower.In reaction mixture, add entry, extract with vinyl trichloride then.Continuous water of extraction liquid and saturated brine washing are through dried over mgso.Underpressure distillation removes and desolvates then.Gained oily matter carries out underpressure distillation (boiling point: 105 to 110 ℃, 3mmHg), obtain 2-ethylmercapto group-2,2 by this, 2 ', 4 '-tetrafluoro phenyl methyl ketone (4.6g, productive rate: 35%), be a colorless oil.
1H-NMR (CDCl
3, δ): 1.37 (J=7Hz), 2.92 (J=7Hz), (2H, m), (1H, m) example 2 for 7.85-8.11 for 6.81-7.12 for 2H, q for 3H, t
2-ethylmercapto group-2,2,4 '-trifluoroacetyl benzene [compound (2-2)] synthetic
Except replacing 2-ethylmercapto group-2 ' with 2-ethylmercapto group-4 '-acetyl fluoride benzene, beyond 4 '-difluoro phenyl methyl ketone,, obtain 2-ethylmercapto group-2,2 according to the method that is similar to example 1,4 '-trifluoroacetyl benzene is a colorless oil.
1H-NMR (CDCl
3, δ): 1.38 (J=7.5Hz), 2.93 (J=7.5Hz), 7.76 (J=8.6Hz), 8.24 (J=8.6Hz) example 3 for 2H, d for 2H, d for 2H, q for 3H, t
2-ethylmercapto group-2,2-two fluoro-4 '-(trifluoromethyl) phenyl methyl ketone [compound (2-3)] synthetic
Except replacing 2-ethylmercapto group-2 ' with 2-ethylmercapto group-4 '-trifluoromethyl phenyl methyl ketone, beyond 4 '-difluoro phenyl methyl ketone,, obtain 2-ethylmercapto group-2 according to the method that is similar to example 1,2-two fluoro-4 '-(trifluoromethyl) phenyl methyl ketone are a colorless oil.
1H-NMR (CDCl
3, δ): 1.38 (J=7.5Hz), 2.94 (J=7.5Hz), (2H, m), (2H, m) example 4 for 8.0-8.4 for 7.00-7.40 for 2H, q for 3H, t
2 ', 4 '-two chloro-2-ethylmercapto groups-2,2-difluoro phenyl methyl ketone [compound (2-4)] synthetic
Except replacing 2-ethylmercapto group-2 ' with 2 ', 4 '-two chloro-2-(ethylmercapto group) phenyl methyl ketones, beyond 4 '-difluoro phenyl methyl ketone,, obtain 2 ', 4 '-two chloro-2-ethylmercapto groups-2 according to the method that is similar to example 1,2-difluoro phenyl methyl ketone is a colorless oil.
1H-NMR (CDCl
3, δ): 1.37 (J=7.7Hz), 2.90 (J=7.7Hz), (2H, m), (2H, m) example 5 for 7.20-7.80 for 6.81-7.12 for 2H, q for 3H, t
2-(2, the 4-difluorophenyl)-and the 2-[(ethylmercapto group) (difluoro) methyl] oxyethane [compound (3-1)] synthetic with 60%NaH (876mg, 0.022mol) THF (30ml)-DMSO (50ml) suspension to be heated to outside temperature be 50 ℃, then gradation add iodate trimethylammonium sulfoxonium (4.8g, 0.022mol).Under uniform temp, stir after one hour, reaction mixture is cooled to-20 ℃, and drip 2-ethylmercapto group-2,2,2 ', 4 '-tetrafluoro phenyl methyl ketone (4.6g, THF 0.018mol) (20ml) solution.The gained mixture at room temperature stirred 2 hours.With in the reaction mixture impouring frozen water, use ethyl acetate extraction subsequently then.Continuous water of extraction liquid and saturated brine washing are through dried over mgso.Underpressure distillation removes and desolvates then, obtains 2-(2,4 difluorobenzene base)-2-[(ethylmercapto group by this) (difluoro) methyl] oxyethane (4.3g, productive rate: 90.0%), be a faint yellow oily thing.
1H-NMR (CDCl
3, δ): 1.30 (J=7Hz), 2.86 (J=7Hz), (1H, m), 3.48 (J=5Hz), (2H, m), (1H, m) example 6 for 7.40-7.66 for 6.71-7.02 for 1H, d for 2.95-2.98 for 2H, q for 3H, t
The 2-[(ethylmercapto group) [2-'s (4-fluorophenyl)-oxyethane [compound (3-2)] is synthetic for (difluoro) methyl
Except using 2-ethylmercapto group-2,2,4 '-trifluoroacetyl benzene replaces 2-ethylmercapto group-2,2, beyond 2 ', 4 '-tetrafluoro phenyl methyl ketone, according to the method that is similar to example 5, obtain the 2-[(ethylmercapto group) (difluoro) methyl]-2-(4-fluorophenyl)-oxyethane, be a faint yellow oily thing.
1H-NMR (CDCl
3, δ): 1.30 (J=7.5Hz), 2.86 (3H, m), 3.46 (J=5.5Hz), (2H, m), (2H, m) example 7 for 7.40-7.70 for 6.80-7.30 for 1H, d for 3H, t
The 2-[(ethylmercapto group) (difluoro) methyl]-2-(4-trifluoromethyl)-oxyethane [compound (3-3)] synthetic
Except using 2-ethylmercapto group-2,2-two fluoro-4 '-(trifluoromethyl) phenyl methyl ketone replaces 2-ethylmercapto group-2,2,2 ', beyond 4 '-tetrafluoro phenyl methyl ketone, according to the method that is similar to example 5, obtain the 2-[(ethylmercapto group) (difluoro) methyl]-2-(4-trifluoromethyl)-oxyethane, be a faint yellow oily thing.
1H-NMR (CDCl
3, δ): 1.31 (J=7.5Hz), (3H, m), 3.50 (J=5.5Hz), (2H, m), 7.66 (4H, br.s) example 8 for 6.80-7.30 for 1H, d for 2.60-3.00 for 3H, t
2-(2,4 dichloro benzene base)-2-[(ethylmercapto group) (difluoro) methyl] oxyethane [compound (3-4)] synthetic
Except using 2-ethylmercapto group-2 ', 4 '-two chloro-2,2-difluoro phenyl methyl ketone replacement 2-ethylmercapto group-2,2, beyond 2 ', 4 '-tetrafluoro phenyl methyl ketone, according to the method that is similar to example 5, obtain 2-(2,4 dichloro benzene base)-2-[(ethylmercapto group) (difluoro) methyl] oxyethane is a faint yellow oily thing.
1H-NMR (CDCl
3, δ): 1.30 (J=7.5Hz), (3H, m), 3.58 (J=5.1Hz), (2H, m), (3H, m) example 9 for 7.20-7.60 for 6.80-7.30 for 1H, d for 2.60-3.10 for 3H, t
2-(2,4 difluorobenzene base)-1-(ethylmercapto group)-1,1-two fluoro-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol [compound (1a-1)] synthetic
To 2-(2,4 difluorobenzene base)-2-[(ethylmercapto group) (difluoro) methyl] (4.3g adds 1 in DMSO 0.016mol) (50ml) solution to oxyethane, 2, and the 4-triazole (2.98g, 0.043mol) and salt of wormwood (5.96g, 0.043mol), stirred 2 hours down at 60 ℃ then.After reaction is finished, in reaction mixture, add entry.Gained mixture ethyl acetate extraction.Continuous water of extraction liquid and saturated brine washing are through dried over mgso.Underpressure distillation removes and desolvates then.With the resistates crystallization from isopropyl ether-ethyl acetate that so obtains, obtain 2-(2,4 difluorobenzene base)-1-(ethylmercapto group)-1 by this, 1-two fluoro-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol (1.5g, productive rate: 25%), be clear crystal.Fusing point: 109 to 110 ℃ of IR (KBr) ν
MaxCm
-1: 3136,1681,1499,1145MS (FAB): 336 (M+H)
1H-NMR (CDCl
3, δ): 1.29 (J=7Hz), 2.84 (J=7Hz), 4.79 (J=14Hz), 5.28 (J=14Hz), 5.74 (1H, s), (2H, m), (1H, m), 7.79 (1H, s), 8.09 (1H, s) example 10 for 7.60-7.87 for 6.60-6.95 for 1H, d for 1H, d for 2H, q for 3H, t
1-(ethylmercapto group)-1,1-two fluoro-2-(4-fluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol [compound (1a-2)] synthetic
Except using the 2-[(ethylmercapto group) (difluoro) methyl]-2-(4-fluorophenyl) oxyethane replacement 2-(2, the 4-difluorophenyl)-and the 2-[(ethylmercapto group) (difluoro) methyl] beyond the oxyethane, according to the method that is similar to example 9, obtain 1-(ethylmercapto group)-1,1-two fluoro-2-(4-fluorophenyl)-3-(1H-1,2, the 4-triazol-1-yl)-the 2-propyl alcohol, be clear crystal.Fusing point: 101 to 102 ℃ of IR (KBr) ν
MaxCm
-1: 3111,1584,1519,1144MS (FAB): 318 (M+H)
1H-NMR (CDCl
3, δ): 1.27 (3H, t, J=7.5Hz), 2.80 (2H, q, J=7.5Hz), 4.78 (1H, d, J=14.5Hz), 4.90 (1H, d, J=14.5Hz), 5.72 (1H, s), 6.85-7.10 (2H, m), (1H, m), 7.77 (1H, s), 7.93 (1H, s) example 11 for 7.40-7.70
1-(ethylmercapto group)-1,1-two fluoro-2-(4-trifluoromethyl)-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol [compound (1a-3)] synthetic
Except using the 2-[(ethylmercapto group) (difluoro) methyl]-2-(4-trifluoromethyl) oxyethane replacement 2-(2, the 4-difluorophenyl)-and the 2-[(ethylmercapto group) (difluoro) methyl] beyond the oxyethane, according to the method that is similar to example 9, obtain 1-(ethylmercapto group)-1,1-two fluoro-2-(4-trifluoromethyl)-3-(1H-1,2, the 4-triazol-1-yl)-the 2-propyl alcohol, be clear crystal.Fusing point: 122 to 123 ℃ of IR (KBr) ν
MaxCm
-1: 3207,1620,1514,1121MS (FAB): 368 (M+H)
1H-NMR (CDCl
3, δ): 1.27 (3H, t, J=7.5Hz), 2.81 (2H, q, J=7.5Hz), 4.72 (1H, d, J=14.5Hz), 4.95 (1H, d, J=14.5Hz), 5.41 (1H, s), 7.58 (2H, d, J=9.2Hz), 7.70 (J=9.2Hz), 7.87 (1H, s), 7.95 (1H, s) example 12 for 2H, d
2-(2,4 dichloro benzene base)-1-(ethylmercapto group)-1,1-two fluoro-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol [compound (1a-4)] synthetic
Except using 2-(2, the 4-dichlorophenyl)-and the 2-[(ethylmercapto group) (difluoro) methyl] oxyethane replacement 2-(2, the 4-difluorophenyl)-and the 2-[(ethylmercapto group) (difluoro) methyl] beyond the oxyethane, according to the method that is similar to example 9, obtain 2-(2,4 dichloro benzene base)-1-(ethylmercapto group)-1,1-two fluoro-3-(1H-1,2, the 4-triazol-1-yl)-the 2-propyl alcohol, be clear crystal.Fusing point: 98 to 100 ℃ of IR (KBr) ν
MaxCm
-1: 3112,1614,1519,1108MS (FAB): 368 (M+H)
1H-NMR (CDCl
3, δ): 1.30 (3H, t, J=7.5Hz), 2.85 (2H, q, J=7.5Hz), 4.85 (1H, d, J=14.3Hz), 5.82 (1H, d, J=14.5Hz), 5.91 (1H, s), 7.05-7.30 (2H, m), 7.82 (1H, s), 7.89 (J=8.6Hz), 8.20 (1H, s) example 13 for 1H, d
1-[2-(2,4 difluorobenzene base)-3-ethylmercapto group-3,3-difluoro-2-methoxyl propyl group]-1H-1,2,4-triazole [compound (1a-5)] synthetic
Under ice-cooled, to 60% sodium hydride (0.16g, 4.0mmol) N, drip 2-(2,4 difluorobenzene base)-1-(ethylmercapto group)-1 in dinethylformamide (50ml) solution, 1-two fluoro-3-(1H-1,2, the 4-triazol-1-yl)-(1.0g 3.0mmol), at room temperature stirred 30 minutes the 2-propyl alcohol then.(0.56g, 3.9mmol), the gained mixture at room temperature stirred 1 hour to drip methyl-iodide then in ice-cooled downhill reaction mixture.In reaction mixture, add entry, use extracted with diethyl ether then.Ethereal solution washes with water, through dried over mgso.Underpressure distillation removes and desolvates then.Make resistates pass through silicagel column, from chloroform wash-out part, obtain 1-[2-(2,4 difluorobenzene base)-3-ethylmercapto group-3,3-difluoro-2-methoxyl propyl group]-1H-1,2,4-triazole (0.81g, productive rate: 78%), be a colorless oil.MS (FAB): 350 (M+H)
1H-NMR (CDCl
3, δ): 1.29 (J=7.5Hz), 2.82 (J=7.5Hz), (3H, m), 5.10 (2H, br.s), (1H, m), (1H, m), 7.80 (1H, s), 8.00 (1H, s) example 14 for 7.4-7.7 for 6.6-6.9 for 3.70-3.74 for 2H, q for 3H, t
1-[2-(benzyloxy)-2-(2,4 difluorobenzene base)-3-(ethylmercapto group)-3,3-two fluoropropyls]-1H-1,2,4-triazole [compound (1a-6)] synthetic
Except replace methyl-iodide with the phenmethyl chloro,, obtain 1-[2-(benzyloxy)-2-(2,4 difluorobenzene base)-3-(ethylmercapto group)-3,3-two fluoropropyls according to the method that is similar to example 13]-1H-1,2, the 4-triazole is a colorless oil.MS (FAB): 426 (M+H)
1H-NMR (CDCl
3, δ): 1.31 (J=7.3Hz), 2.85 (J=7.3Hz), (4H, m), (2H, m), (6H, m), 7.78 (1H, s), 7.94 (1H, s) example 15 for 7.2-7.6 for 6.6-6.9 for 4.8-5.3 for 2H, q for 3H, t
2-(2,4 difluorobenzene base)-1-(ethylsulfonyl)-1,1-two fluoro-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol [compound (1c-1)] synthetic
At room temperature, to 2-(2, the 4-difluorophenyl)-1-(ethylmercapto group)-1,1-two fluoro-3-(1H-1,2, the 4-triazol-1-yl)-(850mg adds 85% metachloroperbenzoic acid (1.4g to the 2-propyl alcohol in methylene dichloride 2.39mmol) (100ml) solution, 5.75mmol), at room temperature stirred then 12 hours.After reaction is finished, add thiosulfuric acid saturated aqueous solution of sodium and saturated aqueous solution of sodium bicarbonate, stir the gained mixture.Separate dichloromethane solution and wash with water after, through dried over mgso.Underpressure distillation removes and desolvates then.With the resistates crystallization from isopropyl ether-ethyl acetate that so obtains, obtain 2-(2,4 difluorobenzene base)-1-(ethylsulfonyl)-1 by this, 1-two fluoro-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol (718mg, productive rate: 78%), be clear crystal.Fusing point: 117 to 118 ℃ of IR (KBr) ν
MaxCm
-1: 3136,1617,1503,1323MS (FAB): 368 (M+H)
1H-NMR (CDCl
3, δ): 1.48 (J=7Hz), 3.41 (J=7Hz), 5.14 (J=14Hz), 5.37 (J=14Hz), 6.11 (1H, s), (2H, m), (1H, m), 7.77 (1H, s), 8.07 (1H, s) example 16 for 7.55-7.82 for 6.64-6.96 for 1H, d for 1H, d for 2H, q for 3H, t
1-(ethylsulfonyl)-1,1-two fluoro-2-(4-fluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol [compound (1c-2)] synthetic
Except using 1-(ethylmercapto group)-1,1-two fluoro-2-(4-fluorophenyl)-3-(1H-1,2; the 4-triazol-1-yl)-and 2-propyl alcohol (220mg) replacement 2-(2,4 difluorobenzene base)-1-(ethylmercapto group)-1,1-two fluoro-3-(1H-1; 2; the 4-triazol-1-yl)-the 2-propyl alcohol beyond, according to the method that is similar to example 15, obtain 1-(ethylsulfonyl)-1 by elution order; 1-two fluoro-2-(4-fluorophenyl)-3-(1H-1; 2, the 4-triazol-1-yl)-the 2-propyl alcohol, be clear crystal.Fusing point: 82 to 84 ℃ of IR (KBr) ν
MaxCm
-1: 3110,1587,1518,1332MS (FAB): 350 (M+H)
1H-NMR (CDCl
3, δ): 1.46 (3H, t, J=7.5Hz), 3.35 (2H, q, J=7.5Hz), 4.83 (1H, d, J=14.5Hz), 5.27 (1H, d, J=14.5Hz), 5.81 (1H, br.s), 6.90-7.10 (2H, m), (2H, m), 7.80 (1H, s), 7.90 (1H, s) example 17 for 7.30-7.60
1-(ethylsulfonyl)-1,1-two fluoro-2-(4-trifluoromethyl)-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol [compound (1c-3)] synthetic
Except using 1-(ethylmercapto group)-1,1-two fluoro-2-(4-trifluoromethyl)-3-(1H-1,2; the 4-triazol-1-yl)-and 2-propyl alcohol replacement 2-(2,4 difluorobenzene base)-1-(ethylmercapto group)-1,1-two fluoro-3-(1H-1; 2; the 4-triazol-1-yl)-the 2-propyl alcohol beyond, according to the method that is similar to example 15, obtain 1-(ethylsulfonyl)-1; 1-two fluoro-2-(4-trifluoromethyl)-3-(1H-1; 2, the 4-triazol-1-yl)-the 2-propyl alcohol, be clear crystal.Fusing point: 155 to 157 ℃ of IR (KBr) ν
MaxCm
-1: 3207,1620,1514,1329MS (FAB): 400 (M+H)
1H-NMR (CDCl
3, δ): 1.47 (J=7.5Hz), 3.38 (J=7.5Hz), 4.88 (J=14.3Hz), 5.32 (J=14.3Hz), 6.09 (1H, br.s), 7.64 (4H, s), 7.78 (1H, s), 7.92 (1H, s) example 18 for 1H, d for 1H, d for 2H, q for 3H, t
2-(2,4 dichloro benzene base)-1-(ethylsulfonyl)-1,1-two fluoro-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol [compound (1c-4)] synthetic
Except using 2-(2,4 dichloro benzene base)-1-(ethylmercapto group)-1,1-two fluoro-3-(1H-1; 2, the 4-triazol-1-yl)-2-propyl alcohol replacement 2-(2,4 difluorobenzene base)-1-(ethylmercapto group)-1; beyond 1-two fluoro-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol; according to the method that is similar to example 15, obtain 2-(2,4 dichloro benzene base)-1-(ethylsulfonyl)-1; 1-two fluoro-3-(1H-1; 2, the 4-triazol-1-yl)-the 2-propyl alcohol, be clear crystal.Fusing point: 79 to 81 ℃ of IR (KBr) ν
MaxCm
-1: 3421,1617,1518,1331MS (FAB): 400 (M+H)
1H-NMR (CDCl
3, δ): 1.50 (3H, t, J=7.7Hz), 3.43 (2H, q, J=7.7Hz), 5.20 (1H, d, J=14.7Hz), 6.13 (1H, d, J=14.7Hz), 6.31 (1H, br.s), 7.10-7.40 (2H, m), 7.88 (1H, s), 7.74 (J=8.1Hz), 8.16 (1H, s) example 19 for 1H, d
1-[2-(2,4 difluorobenzene base)-3-ethylsulfonyl-3,3-difluoro-2-methoxyl propyl group]-1H-1,2,4-triazole [compound (1c-5)] synthetic
Except using 1-[2-(2,4 difluorobenzene base)-3-ethylmercapto group-3,3-difluoro-2-methoxyl propyl group]-1H-1; 2, the 4-triazole replaces 2-(2,4 difluorobenzene base)-1-(ethylmercapto group)-1; beyond 1-two fluoro-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol; according to the method that is similar to example 15, obtain 1-[2-(2,4 difluorobenzene base)-3-ethylsulfonyl-3; 3-difluoro-2-methoxyl propyl group]-1H-1; 2, the 4-triazole is a colorless oil.MS (FAB): 382 (M+H)
1H-NMR (CDCl
3, δ): 1.43 (J=7.5Hz), 3.20 (J=7.5Hz), 3.75 (3H, br.s), 5.15 (J=5.5Hz), 5.24 (J=5.5Hz), (2H, m), (1H, m), 7.78 (1H, s), 8.06 (1H, s) example 20 for 7.4-7.7 for 6.6-7.0 for 1H, d for 1H, d for 2H, q for 3H, t
1-[2-(benzyloxy)-2-(2,4 difluorobenzene base)-3-(ethylsulfonyl)-3,3-two fluoropropyls]-1H-1,2,4-triazole [compound (1c-6)] synthetic
Except using 1-[2-(benzyloxy)-2-(2,4 difluorobenzene base)-3-(ethylmercapto group)-3,3-two fluoropropyls]-1H-1; 2, the 4-triazole replaces 2-(2,4 difluorobenzene base)-1-(ethylmercapto group)-1; beyond 1-two fluoro-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol; according to the method that is similar to example 15, obtain 1-[2-(benzyloxy)-2-(2,4 difluorobenzene base)-3-(ethylsulfonyl)-3; 3-two fluoropropyls]-1H-1; 2, the 4-triazole is a colorless oil.MS (FAB): 458 (M+H)
1H-NMR (CDCl
3, δ): 1.41 (J=7.3Hz), 3.19 (J=7.3Hz), 5.07 (2H, s), 5.27 (J=15.8Hz), 5.50 (J=15.8Hz), (2H, m), (6H, m), 7.80 (1H, s), 8.03 (1H, s) example 21 for 7.2-7.7 for 6.6-7.0 for 1H, d for 1H, d for 2H, q for 3H, t
To 2-(2,4 difluorobenzene base)-1-(ethylsulfonyl)-1,1-two fluoro-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol [compound (1c-1)] carries out optical resolution with optically active separating substances post
Make (±)-2-(2,4 difluorobenzene base)-1-(ethylsulfonyl)-1,1-two fluoro-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol (40mg) is by CHIRALCEL OD (trade(brand)name; Diacel chemical industry company limited product), the pillar that just is used for the optically active separating substances.From the elutriant part of 4: 1 hexane-isopropanol mixtures by elution order obtain 17mg (optical purity: 100%e.e.) (+) type, be clear crystal, and 17mg (optical purity: 100%e.e.) (-) type is clear crystal.(1) (+)-2-(2,4 difluorobenzene base)-1-(ethylsulfonyl)-1,1-two fluoro-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol [α]
D 21.7+ 21.0 ° of (C=0.1, acetone) fusing point: 120 to 121 ℃ of MS (FAB): 368 (M+H) IR (KBr) ν
MaxCm
-1: 3136,1617,1503,1323
1H-NMR (CDCl
3, δ): 1.48 (3H, t, J=7Hz), 3.41 (2H; q, J=7Hz), 5.14 (1H, d, J=14Hz); 5.37 (1H, d, J=14Hz), 6.11 (1H, s); 6.64-6.96 (2H, m), 7.55-7.82 (1H, m); 7.77 (1H, s), 8.07 (1H, s) (2) (-)-2-(2; the 4-difluorophenyl)-and 1-(ethylsulfonyl)-1,1-two fluoro-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol [α]
D 21.7-21.5 ° of (C=0.1, acetone) fusing points: 120 to 121 ℃ of IR (KBr) ν
MaxCm
-1: 3136,1617,1503,1323MS (FAB): 368 (M+H)
1H-NMR (CDCl
3, δ): 1.48 (J=7Hz), 3.41 (J=7Hz), 5.14 (J=14Hz), 5.37 (J=14Hz), 6.11 (1H, s), (2H, m), (1H, m), 7.77 (1H, s), 8.07 (1H, s) example 22 for 7.55-7.82 for 6.64-6.96 for 1H, d for 1H, d for 2H, q for 3H, t
To 1-(ethylsulfonyl)-1,1-two fluoro-2-(4-fluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol [compound (1c-2)] carries out optical resolution with optically active separating substances post
Except using (±)-2-(4-fluorophenyl)-1-(ethylsulfonyl)-1; 1-two fluoro-3-(1H-1; 2; the 4-triazol-1-yl)-2-propyl alcohol (220mg) replacement (±)-1-(ethylsulfonyl)-1; 1-two fluoro-2-(2; the 4-difluorophenyl)-3-(1H-1; 2; the 4-triazol-1-yl)-the 2-propyl alcohol beyond; according to the method that is similar to example 21, (optical purity: 100%e.e.) (+) type is clear crystal to obtain 100mg by elution order; and 100mg (optical purity: 100%e.e.) (-) type is clear crystal.(1) (+)-1-(ethylsulfonyl)-1,1-two fluoro-2-(4-fluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol [α]
D 20.6+ 23.0 ° of (C=0.1, acetone) fusing points: 131 to 132 ℃ of IR (KBr) ν
MaxCm
-1: 3447,1636,1511,1336MS (FAB): 350 (M+H)
1H-NMR (CDCl
3, δ): 1.46 (3H, t, J=7.5Hz), 3.35 (2H; q, J=7.5Hz), 4.83 (1H, d, J=14.5Hz); 5.27 (1H, d, J=14.5Hz), 5.81 (1H; br.s), and 6.90-7.10 (2H, m), 7.30-7.60 (2H; m), 7.80 (1H, s), 7.90 (1H; s) (2) (-)-1-(ethylsulfonyl)-1,1-two fluoro-2-(4-fluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol [α]
D 20.6+ 20.0 ° of (C=0.1, acetone) fusing points: 131 to 132 ℃ of IR (KBr) ν
MaxCm
-1: 3447,1636,1511,1336MS (FAB): 350 (M+H)
1H-NMR (CDCl
3, δ): 1.46 (3H, t, J=7.5Hz), 3.35 (2H, q, J=7.5Hz), 4.83 (1H, d, J=14.5Hz), 5.27 (1H, d, J=14.5Hz), 5.81 (1H, br.s), 6.90-7.10 (2H, m), (2H, m), 7.80 (1H, s), 7.90 (1H, s) example 23 for 7.30-7.60
With a kind of optical resolution reagent preparation (-)-1-(ethylsulfonyl)-1, the method for 1-two fluoro-2-(2,4 difluorobenzene base)-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol [compound (1c-1)]
Under heating, with (±)-1-(ethylsulfonyl)-1,1-two fluoro-2-(2; the 4-difluorophenyl)-3-(1H-1; 2,4-triazol-1-yl)-2-propyl alcohol (130g) and (+)-3-bromo-camphor-8-sulfonic acid (115.7g) is dissolved in the Virahol (3.0L), carries out the inoculation of crystal seed then.Reaction mixture was at room temperature kept 5 days.Filter to collect sedimentation like this crystal, obtain 135.8g (optical purity: 56.7%e.e.) (-)-1-(ethylsulfonyl)-1,1-two fluoro-2-(2 by this; the 4-difluorophenyl)-3-(1H-1; 2,4-triazol-1-yl)-and (+)-3-bromo-camphor-8-sulfonate of 2-propyl alcohol, be clear crystal.Use Virahol as solvent; the crystalline recrystallization operation that repeats so to obtain; obtain 72.1g (optical purity: 93.1%e.e.) (-)-1-(ethylsulfonyl)-1 by this; 1-two fluoro-2-(2; the 4-difluorophenyl)-3-(1H-1; 2,4-triazol-1-yl)-and (+)-3-bromo-camphor-8-sulfonate of 2-propyl alcohol, be clear crystal.In gained salt, add 5% sodium bicarbonate aqueous solution, be alkalescence, use ethyl acetate extraction then.Extraction liquid washes with water, and dry.Underpressure distillation removes and desolvates then.With resistates recrystallization from ethyl acetate-ether, (optical purity: 99.7%e.e.) (-)-1-(ethylsulfonyl)-1,1-two fluoro-2-(2,4 difluorobenzene base)-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol are clear crystal to obtain 41.4g by this.
Test 1: the effect (external) of anti-candida albicans (Candida albicans)
In each aperture of 96 hole microtiter plates, add 75 μ l with the adjusted rare drug solution of MEM substratum (containing glutamine and carbonate) that has added 10% N of tire serum, add 75 μ l then and be suspended in 4 * 10 in the same medium
4The Candida albicans ATCC44859 of individual cell/ml.The gained mixture is at a kind of CO
2Cultivated 24 hours down at 37 ℃ in the gas incubator.After the cultivation, under a kind of inverted microscope, observe the morphological change of Candida albicans.Compare with the control group of composite medicine not, produce the lowest concentration of drug that obviously suppresses the growth of mycelia build and be appointed as terminal point (ng/ml).Simultaneously, utilize fluconazole and known compound A ((-) in Japanese Patent Application Publication HEI9-227531 number-compound (1c-1)) as being used for correlated medicine.The result is as shown in table 1.
Test 2: the effect (external) of anti-aspergillus fumigatus (Aspergillus fumigatus)
Adding 100 μ l in each aperture of 96 hole microtiter plates (contains glutamine and phenol red, does not conform to carbonate with the RPMI1640 substratum that contains 0.165MMOPS; PH7) adjusted rare drug solution adds 100 μ l6.0 * 10 then
4The gemma suspension of the Aspergillus fumigatus IFM40808 of individual conidium/ml in the above-mentioned substratum that contains 20% ALMA indigo plant (almar Blue).Cultivated 48 hours down at 35 ℃.Carry out naked eyes and judge, do not produce the redden lowest concentration of drug of (it is blue that substratum keeps) of color and be appointed as MIC value (μ g/ml).Simultaneously, utilize fluconazole and known compound A ((-) in Japanese Patent Application Publication HEI9-27531 number-compound (1c-1)) as being used for correlated medicine.The result is as shown in table 1.
Table 1
| Terminal point (ng/ml) | ???MIC(μg/ml) | |
| Test compound | Candida albicans | Aspergillus fumigatus |
| Example 9 | ??????7.8 | ????????2 |
| Example 10 | ??????31.3 | ????????8 |
| Example 11 | ??????7.8 | ????????16 |
| Example 12 | ??????3.9 | ????????1 |
| Example 13 | ??????31.3 | ????????8 |
| Example 15 | ??????31.3 | ????????8 |
| Example 18 | ??????15.6 | ????????8 |
| Example 21 (2) | ??????15.6 | ????????4 |
| Example 22 (2) | ??????15.6 | ????????8 |
| Fluconazole | ??????250 | ????????＞128 |
| Known compound A | ??????62.5 | ????????16 |
Test 3: the effect of anti-candida albicans (in the body)
4 ages in week, male, ICR (CRJ:CD-1) mouse fasting after 6 hours, are seeded in Candida albicans IFM40009 in the mouse tail vein, and the gained amount is 3.0 * 10
6Individual cell/mouse causes infecting by this.Control group is made up of 11 mouse, and the administration group is made up of 5 mouse.Inoculate the back 1 hour oral medicine of giving to be dissolved in 20% polyoxyethylene glycol fungi,, once a day, amount to four times, each 1.25mg/kg then at back 24 hours successive administrations of inoculation.Relatively infect the 14th day the survival condition in back.In addition, measure the survival fate of control group and administration group with Kaplan-Meier method (Cox mantel test).Simultaneously, utilize fluconazole as being used for correlated medicine.The result is as shown in table 2.
Table 2
| Test compound | Average survival fate | The 14th day survival mice: sum in survival mice number of elements/group |
| Example 15 | ??????14.00 *** | ??????????4/5 |
| Fluconazole | ??????11.0 *** | ??????????1/5 |
| Control group | ??????4.5 | ??????????0/11 |
(with respect to control group:
* *P＜0.001)
To the embodiment of preparation be described below.
Example 24: tablet
Example 21 (2) compound 50mg
Crystalline cellulose 50mg
Lactose 50mg
Hydroxypropylcellulose 18mg
Magnesium Stearate 2mg
Amount to 170mg
According to ordinary method, make tablet with above-mentioned composition.Tablet can be made into coated tablet or film garment piece.Example 25: capsule
Example 21 (2) compound 50mg
Light silica anhydride 25mg
Lactose 100mg
Starch 50mg
Sliding 25mg
Amount to 250mg with the mentioned component capsule of packing into No. 1, obtain capsule.Example 26: granule
Example 21 (2) compound 50mg
Lactose 600mg
W-Gum 200mg
Xylo-Mucine 20mg
Hydroxypropylcellulose 130mg
Amount to 1000mg according to ordinary method, make granule with above-mentioned composition.Example 27: powder
Example 21 (2) compound 50mg
Light silica anhydride 20mg
Sedimentary lime carbonate 10mg
Lactose 250mg
Starch 70mg
Amount to 400mg according to ordinary method, make powder with above-mentioned composition.Example 28: injection
Example 21 (2) compound 5mg
Hydrogenated castor oil 85mg
Propylene glycol 60mg
Glucose 50mg
Distilled water for injection is an amount of
Amount to 1ml according to ordinary method, make injection with above-mentioned composition.Example 29: intravenous drip agent
Example 21 (2) compound 50mg
Hydrogenated castor oil 5g
Propylene glycol 10mg
Glucose 14.5mg
Distilled water for injection is an amount of
Amount to 100ml according to ordinary method, make intravenous drip agent with above-mentioned composition.
Claims (7)
1. triazole derivative or its salt by following formula (a 1) representative:
R wherein
1Represent hydrogen atom, low alkyl group or an aralkyl, X
1With X
2Identical or different, each represents a hydrogen atom, a halogen atom or a haloalkyl independently, and n represents one 0 to 2 integer.
2. one kind by 2 of following formula (2) representative, 2-two fluoro-2-ethylmercapto group acetophenone derivatives:
X wherein
1With X
2Identical or different, each represents a hydrogen atom, a halogen atom or a haloalkyl independently.
3. epoxyethane derivative by following formula (3) representative:
X wherein
1With X
2Identical or different, each represents a hydrogen atom, a halogen atom or a haloalkyl independently.
4. preparation method as the desired triazole derivative of claim 1 or its salt, this method comprise make a kind of by 2 of following formula (2) representative, 2-two fluoro-2-ethylmercapto group acetophenone derivatives:
X wherein
1With X
2Identical or different, each represents a hydrogen atom, a halogen atom or a haloalkyl independently, with a kind of epoxy methylene radical introducing agent and 1,2,4-triazole or its reactant salt, carries out the alkylated reaction and the oxidizing reaction of tert-hydroxyl then alternatively.
5. one kind contains just like the desired triazole derivative of claim 1 or its salt medicine as effective constituent.
6. one kind as the desired medicine of claim 5, and this medicine is a kind of antimycotic agent.
7. pharmaceutical composition, said composition contains just like claim 1 triazole derivative required for protection or its salt and a kind of pharmaceutically acceptable carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 98126265 CN1223258A (en) | 1997-12-26 | 1998-12-25 | Triazole derivative or salt thereof, preparation process thereof and pharmaceutical containing said compound as effective ingredient |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP359202/97 | 1997-12-26 | ||
| JP186198/98 | 1998-07-01 | ||
| CN 98126265 CN1223258A (en) | 1997-12-26 | 1998-12-25 | Triazole derivative or salt thereof, preparation process thereof and pharmaceutical containing said compound as effective ingredient |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1223258A true CN1223258A (en) | 1999-07-21 |
Family
ID=5229573
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 98126265 Pending CN1223258A (en) | 1997-12-26 | 1998-12-25 | Triazole derivative or salt thereof, preparation process thereof and pharmaceutical containing said compound as effective ingredient |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1223258A (en) |
-
1998
- 1998-12-25 CN CN 98126265 patent/CN1223258A/en active Pending
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