- Synthesis process of high-purity oxiconazole nitrate
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The invention relates to a synthesis process of high-purity oxiconazole nitrate, and belongs to the technical field of pharmacy, thesynthesis process comprises the following steps: 1, stirring and mixing 2-chloro-1-(2, 4-dichlorophenyl) ethanone, imidazole and absolute methanol, carrying out reflux reaction, adding hydrogen peroxide, ammonia monohydrate and a modified catalyst, continuously reacting, and purifying, and obtaining (Z)-2 '-(1H-imidazole-1-yl)-2, 4-dichloroacetophenone oxime with relatively high purity; 2, (Z)-2 '-(1H-imidazole-1-yl)-2, 4-dichloroacetophenone oxime and 2, 4-dichlorobenzyl chloride are subjected to a substitution reaction, high-purity oxiconazole nitrate is obtained through suction filtration, washing, drying and recrystallization, the traditional synthesis process is analyzed, the synthesis method and the mode of adding a modified catalyst are changed, generation of impurities is reduced, the purity of products in production links is improved, the synthesis steps are reduced, the synthesis route is shortened and the production efficiency is improved.
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Paragraph 0047-0049; 0055-0057; 0059-0060; 0063-0065; ...
(2021/09/15)
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- Discovery of new azoles with potent activity against Candida spp. and Candida albicans biofilms through virtual screening
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Systemic candidiasis is a rampant bloodstream infection of Candida spp. and C. albicans is the major pathogen isolated from infected humans. Azoles, the most common class of antifungals which suffer from increasing resistance, and especially intrinsically resistant non-albicans Candida (NAC) species, act by inhibiting fungal lanosterol 14α-demethylase (CYP51). In this study we identified a number of azole compounds in 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol/ethanone oxime ester structure through virtual screening using consensus scoring approach, synthesized and tested them for their antifungal properties. We reached several hits with potent activity against azole-susceptible and azole-resistant Candida spp. as well as biofilms of C. albicans. 5i's minimum inhibitor concentration (MIC) was 0.125 μg/ml against C. albicans, 0.5 μg/ml against C. krusei and 1 μg/ml against azole-resistant C. tropicalis isolate. Considering the MIC values of fluconazole against these fungi (0.5, 32 and 512 μg/ml, respectively), 5i emerged as a highly potent derivative. The minimum biofilm inhibitor concentration (MBIC) of 5c, 5j, and 5p were 0.5 μg/ml (and 5i was 2 μg/ml) against C. albicans biofilms, lower than that of amphotericin B (4 μg/ml), a first-line antifungal with antibiofilm activity. In addition, the active compounds showed neglectable toxicity to human monocytic cell line. We further analyzed the docking poses of the active compounds in C. albicans CYP51 (CACYP51) homology model catalytic site and identified molecular interactions in agreement with those of known azoles with fungal CYP51s and mutagenesis studies of CACYP51. We observed the stability of CACYP51 in complex with 5i in molecular dynamics simulations.
- Sari, Suat,Kart,?ztürk,Kaynak, F. Betül,Gencel,Ta?kor, Gülce,Karakurt, Arzu,Sara?,E?siz, ?ebnem,Dalkara
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p. 634 - 648
(2019/07/05)
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- Process for the stereospecific preparation of (Z)-1-(2,4-dichlorophenyl)-2-(imidazol-1-yl)-0-(2,4-dichlorobenzyl)-ethanone oxime ether
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For preparing substantially pure (Z)-1-(2,4-dichlorophenyl)-2-(imidazol-1-yl)-0-(2,4-dichlorobenzyl)-ethanone oxime ether having the formula STR1 i.e. the cis-isomer of said oxime ether in a stereospecifically pure form, the pure (Z)-stereoisomer of the corresponding ethanone oxime is first converted into an alkali salt in a polar solvent, such as acetone or dimethylformamide, using an alkali in an amount somewhat less than the equimolar amount with respect to the said ethanone oxime, and is then converted to the desired ether by reacting it at a temperature not higher than 40° C. with a halogen compound capable of forming the desired ether. Isolation of the ether product is obtained as the free base or by precipitating it as an acid addition salt upon addition of a suitable organic or mineral acid, preferably nitric acid.
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- Process for the stereospecific preparation of imidazolyl oximes
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1-Aryl-2-(1H-imidazol-1-yl)-ethanone oxime ethers are known to exist as a mixture of isomers corresponding to the formulae: STR1 To prepare such an isomer in a stereospecifically pure form, the pure stereoisomer of the corresponding ethanone oxime is first converted into an alkali salt in a polar solvent, such as acetone or dimethylformamide, using an alkali in an amount somewhat less than the equimolar amount with respect to the said ethanone oxime, and is then converted to the desired ether by reacting it at a temperature not higher than 40° C. with a halogen compound capable of forming the desired ether. Isolation of the ether product is obtained as the free base or by precipitating it as an acid addition salt upon addition of a suitable organic or mineral acid, preferably nitric acid. A stereospecific ethanone oxime in either its trans- or cis-isomer form corresponding to the formula: STR2 can be stereospecifically synthesized from the corresponding 2-halogen ethanone having the formula A--CO--CH2 --Hal (IV) which, in making the cis oxime (IIc), is first converted with imidazole or a suitably substituted derivative thereof and subsequently oximated by reaction with hydroxylamine in the presence of a molar excess of an alkali at an elevated temperature; or which, in preparing the trans oxime (IIt), is first oximated by reaction with hydroxyl-amine under mild conditions and subsequently converted in the cold with imidazole or a suitably substituted derivative thereof. The products are effective fungicides or bactericides and consequently useful as thermotherapeutic agents in combatting undesirable lower plant organisms in the fields of human as well as veterinary medicine and also as fungicides in agriculture and horticulture.
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