Method of producing fluorine-containing derivatives of 1,2,4-triazole or methanesulfonate salts ther

专利摘要:
Triazole antifungal agents of the formula:- …<CHEM>… and their O-esters and O-ethers,… where R is a phenyl group optionally substituted by 1 to 3 substituents each independently selected from F, Cl, Br, I, trifluoromethyl, C1-C4 alkyl and C1-C4 alkoxy, or R is a 5-chloro-pyrid-2-yl group;… and n is zero or an integer of from 1 to 5;… and their pharmaceutically and agriculturally acceptable salts. …<??>The compounds are useful as human and agricultural fungicides.
公开号:SU1468416A3
申请号:SU833640802
申请日:1983-08-12
公开日:1989-03-23
发明作者:Ричардсон Кеннет；Джон Виттл Питер
申请人:Пфайзер Корпорейшн (Фирма)；
IPC主号:

专利说明:

The invention relates to methods for producing fluorine-containing 1,254-triazole derivatives of the formula
HE
., y-sn, -s- (sg.llsgz
N
X
where p O, 1 or 2;
X is 2,4-di (rtorphenyl, 2,4-dichlorophenyl, 4-bromo-2,5-difluorophenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 2-fluorophenyl, 2,4,6-trifluorophenyl, 2,5-difluorophenyl or 2-fluoro-4-chlorophenyl.
or their methanesulfonate salts with antifungal activity.
The purpose of the invention is to develop a method for obtaining new fluorine-containing 1,2,4-triazole derivatives, which have a higher antifungal activity compared with the known preparations.
Example 1. Crawling of 2-G2,4- -difluorophenyl- - (1H-1,2,4-triazolyl-1) -3,3, 3-trifluoropropanol-2.
A hexane solution of n-butyl lithium (1.55 M, 8.6 ml, 14.9 mmol) was added to 6 ml of sulfuric ether and the solution was cooled to -78 ° C. A solution of 3.03 g is added dropwise over 15 minutes.
oa
(15.7 mmol) 2,4-difluorobromobenzene in 100 ml of sulfuric ether. The mixture is stirred at -78 ° C for a further 15 minutes. A solution of 2.4 g (12 e6 mmol) of 1 bromine-3, 3 of 3-trifluoropropanol 2 in 100 ml of sulfuric ether is added dropwise over 15 minutes, and the mixture is stirred at -78 ° C for a further 30 minutes. A solution of 2 ml of glacial acetic acid in 5 ml of sulfuric ether, then 15 ml of water is added, and the mixture is allowed to warm to separate the aqueous layer and washed with sulfuric ether (2 x 30 ml). The combined extracts in sulfuric ether are dried over magnesium sulphate, evaporated to a residual oil, dissolved in 40 ml of dimethylformamide. 2.5 g (36.2 mmol) of 5254 triazole and 10 g (mmol) of anhydrous potassium carbonate are added to the solution. The mixture is stirred at 70 ° C for 18 h. The mixture is cooled, poured into 150 ml of water and extracted with ethyl acetate ( 3x100 ml). The combined ethyl acetate extracts are washed with 100 ml of water, dried over magnesium sulphate and evaporated. The residue was chromatographed over magnesium sulphate and evaporated. The residue is chromatographed on silica gel (230--400 ml) and eluted with a mixture of ethyl acetate and hexane (60t40 vol.), And after a single recrystallization from ethyl acetate-hexane, the target compound w / r is 1.7 g (47% ) with t, pl. 110-1.11 ° C.
Found,%: carbon 45,16; hydrogen 2.73; nitrogen 14.56.
C ,, KgF, N, 0.
Calculated,%: carbon 45.05; hydrogen 2.75; nitrogen 14.33.
Examples 2-7. The compounds in examples 2-7 are prepared analogously to example 1, using the appropriate aryllithium (examples 2, 3, 5, and 6) or Grignard reagent (examples 4 and 7). In examples 4 and 6, in the final reaction stage, instead of dimethylformamide is used tetrahydrofuran,
The data in examples 1-7 are summarized in table 1.
Example 8.A, Preparation of 1-bromo-3,3,4,4-pentanfluorobutanone
3.9 g (0.02407 mol) of methylpentafluoroethyl ketone (TAGS., 78, 2268-2270 (1956)) is stirred at room temperature using concentrated fridge with dry ice and cooled with dry ice (2) with vigorous stirring slowly for 2 1.92 g (OO012035 mol) of bromine is added. The mixture is stirred for 1 hour at room temperature and then at 50 ° C for 1 hour. The resulting amber solution is distilled at atmospheric pressure to obtain one main fraction 4.41 g ( 76%), bp 9A-97 ° C. Mass spectral analysis confirmed the structure, showing paired e ions at 240 and 242, sootvetstvuyushaya G.H, BrF50 (2 Bg isotope)
I
B, Preparation of 2- (2,4-difluorophenyl) -3,3,4,4-n-pentafluoro-1 - (1H-1,2,4-three azolyl-) butanol-2.
n-Butyl lithium (3.32 ml of a 1.5 molar solution in hexane. 0.00498 mol in sulfuric ether (5 ml) is cooled and stirred at -78 s. IsOr solution (0 , 00519 mol) 2,4-difluorobromobenzene in 8 ml of sulfuric ether. The reaction mixture is kept at -78 C for 15 min. Then 1.0 g (0.00415 mol) of 1-bromo is added over 15 min. 3,3,4,4-4-Pentafluorobutanol in 6 ml of ether. The mixture is stirred for 30 minutes at -78 C. 0.7 g of acetic acid with 5 ml of ether and then 8 ml of water are added. The mixture allows the room to be taken temperature. The ether layer is separated, and the aqueous layer is removed to 15 mL of ether each time. The combined ether layers are dried over magnesium sulfate and evaporated to give an oil. 0.86 g (0.01245 mol) of 1,2,4-triazole, 5.73 g (0 , 0415 mol) anhydrous potassium carbonate and 15 ml of anhydrous dimethylformamide. The mixture is heated and stirred at 80 ° C for 3.5 hours, cooled to room temperature and poured into 15 ml of water. Then the mixture is extracted with 3x60 ml of methylene chloride, and the combined organic the extracts are dried over magnesium sulphate, evaporated and the residual brown oil is chromatographed, pre-evaporated with or gel gel (230-400 mesh), the elution was carried out with a mixture of ethyl acetate and hexane (60:40;), to give the title compound as a white solid (400 mg, 28%). Mp 95-96 ° C after recrystallization from cyclohexane.
Found,%: carbon 41.1 2.3; nitrogen 12.0.
hydrogen
CnH6P7NsO
Calculated,%: C 42.0; H 2.3; N 12.2.
Examples 9-13. Using the appropriate starting materials, the compounds were prepared (examples 9-13) in analogy to example 8.
The data in examples 9-13 are summarized in table 2..i
Example 14. Obtaining 2- (2,4 difluorophenyl) -3,3,4,5,5,5-heptafluoro-1- (1H 1,2,4-triazolyl) -pentanol-2.
To a solution of 0.5 g (0.017 mol) of heptafluoropropyl iodide in 20 ml of ether, cooled to -78 ° C, phenyl magnesium bromide (5.6 ml of 3-molar solution in ether, 0.017 mol) is added dropwise at a rate of that the temperature of the reaction mixture does not exceed -50 ° C. After adding fentigmagnesium bromide, the mixture is stirred at -50 ° C for 30 minutes and cooled again to -78 ° C. A solution of 3.6 g (0.019 mol) of 2-chloro- is added dropwise. 2,4-difluoroethophenone in 20 ml of sulfuric ether at a rate such that the temperature does not rise above -50 ° C. After the addition is complete, the reaction mixture is allowed to warm to -20 ° C and stirred at this temperature for 2 hours. A solution of 3 ml of glacial acetic acid in 5 ml of sulfuric ether and then 15 ml is added. water. The mixtures are allowed to warm to about 5 ° C. The bauded phase is separated and extracted with ether (2 x 50 ml). The combined ether extracts are dried over magnesium sulphate and evaporated to give 7 g of a pale yellow oil. The resulting oil is added to a mixture of 5.87 g (0.085 mol) of 1,2,4-triazole and 17.5 g (0.127 mol) of anhydrous carbonate. potassium in 60 ml of dimethylformamide, and the mixture is stirred at 80 ° C for 3 hours. Then the reaction mixture is cooled, the dimethylformamide is evaporated and the residue is extracted with a mixture of water (200 ml) and 150 ml of ethyl acetate. The aqueous layer was separated and extracted three times with ethyl acetate (3 x 150 ml). The combined ethyl acetate extracts are sequentially washed with aqueous sodium bisulfite and water, dried over magnesium sulfate, evaporated, and the residue is chromatographed on flash evaporation on a silica gel.
kagel (230-400 mesh) eluted with a mixture of hexane and isopropyl alcohol and 0.88 ammonia-CHyroxide (F0: 20:; 1.5 vol.). The yield of the target compound is after a single recrystalline; —zation from hexane, dichloromethane 1:51 g (23%). M.p. 128 ° C.
Found,%: carbon 39.8; hydrogen 2.0; nitrogen 10, 6.
C, h1 Calculated
F.l-uO.
%: carbon 39.7; hydrogen 2.1; nitrogen 10.7,
Example 15. Analogously to Example 14 of 14, 2 (4-fluorophenyl) -3.3, 4,4,5,5.5-heptafluoro-1- (1K-1,2-4-triazolyl-1) -pentanol-2 is obtained , istizlu corresponding source materials Exit 7%. M.p. product 126-127 ° C.
0 Found%: carbon 41.9; hydrogen 2.4; nitrogen 11.3. C ,, U, FgN30
Calculated,%: C 41.6; H 2.4: N 11.2,
5 Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from strong acids that produce non-toxic salts of acids, for example hydrochloric, hydrobromic, sulfuric, oxalic and. methanesulfonic acid.
Salts are prepared by standard l method, for example, by mixing the solutions of equimolar amounts of free salt
5 nova and required acid; the target product is separated by filtration if the salt is non-soluble. or by discharging the solvent.
It is also possible to use the salts of shelloch0 Hbix metals produced in the standard way.
The compounds of formula (I) and their pharmaceutically acceptable salts are
5 antifungals with 1 preparations, which can be used to suppress fungal infection in animals, including humans. For example, they can be used to treat places of fungal disease in humans caused by Candida, Trichophyton, Microsporum or Epidermophyton, among other species, or fungal diseases caused by Candida albi5 cans (for example, thrush and vaginal candidiasis). It is also possible to use the proposed compounds for the treatment of systemic fungal diseases.
7146
To assess the in vitro antifungicide activity of the compounds, the minimum inhibitory concentration (MoKo) is determined, equal to the concentration of the test compound in a suitable medium, in which the growth of certain microorganisms is suppressed. In practice, a series of agar plates containing the test compound at a certain concentration are contaminated with a standard culture, for example, Candida albicans, and each plate is kept at 37 ° C for 48 hours. The plates are then checked for the presence or absence of fungal growth and the appropriate value of the minimum inhibitory concentration (mc) is determined.
The in vivo evaluation of the compounds of the invention was carried out with different doses of intraperitoneal or intravenous injections or oral administration in mice that were infected with a strain of Candida albicans. Activity is assessed by the survival rate of the treated group of mice after the death of the group of mice that were not treated5 and followed up for 48 hours. The dose at which the compound provides 50% non-survival is determined: during infection ().
In medical practice in dermatologists, antifungal compounds of formula (I) can be used alone, but usually they are given in a mixture with a pharmaceutical carrier, depending on the treatment regimen adopted and the current pharmaceutical practice.
When administered orally or parenterally to a human, the daily dose of the antifungal compounds of formula (I) is from 0.1 to 10 mg / kg (in separate dosages) when administered orally or parenterally. Thus, tablets or capsules will contain from 5 mg to 0.5 of the active compound for administration or two or more at once, as required. In any case, the actual dosage determines the condition of the patient and it depends on the age, weight, and response of the particular patient. The above results correspond to the mean value; Of course, there are individual cases where it is more advantageous to use higher or lower dosages.
6.8
The compounds of formula (I) and their salts are also active against various plant pathogenic fungi, for example, rust, mildew and mold. Thus, the present compounds can be used to treat plants or seeds in order to prevent or suppress such diseases.
Assessment of the activity of compounds against fungi parasitizing plants j in vitro is carried out according to the minimum inhibitory concentrations of the compounds by the considered method, except that the plants are kept at 30 ° C for 48 hours or longer before testing them for the presence or absence of growth.
The test results in the form of values obtained by oral administration to the fungi against the fungus Candida albicans, .a also characterizing the toxicity of the values are given in Table 3.
As can be seen from Table 3, the compounds obtained in accordance with the invention have a significantly higher antifungal activity than the most effective drug currently used, ketoconazole.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining the fluorine-containing derivatives of 1,2, A-triazole of the formula
HE
N-CHo-C- (CF) CF3
N
I
X
where n is O, 1 or 2;
X - difluorophenyl, 2,4-dichlorophenyl, 4-bromo-2,5-difluorophenyl 5 4-trifluoromethylphenyl, 4-fluorophenyl, 2-fluorophenyl, 2,4,6-trifluorophenyl, 2,5-difluorophenyl or 2 -fluoro-4-chlorophenyl, or their methanesulfonate salts, meaning that 1,2,4-triazole in the presence of an alkaline agent is reacted with a compound of the formula
HE
Na1-CH2-C - () PSGs
X
where D and p have the indicated meanings;
Hal chlorine or bromine, in an organic solvent when heated in case of need. Priority n
08/14/82 when
11.11.82 with or
bridges up to 30 ° C with a subsequent release of the desired product as a free base or methanesulfonate salt
featured:
Table 1
T a b l and c a 3

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB8223459|1982-08-14|

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GB8231309|1982-11-02|

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