- Synthesis and crystal structure of [α-(2,4-difluorophenyl)-α-(1H-1,2,4-triazole-1-ylmethyl)-1H-1,2,4-triazole-1-ethanol]Cu(II) complex
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A novel complex of copper(II) was prepared by reaction of CuCl2 and fluconazole at reflux in water and tetrahydrofuran. Its structure was determined by single crystal X-ray diffraction analysis. The crystals are monoclinic space group C2/c with a = 23.490(2), b = 9.4719(9), c = 19.8459(18) ?, α = 90.00, β = 123.639(2), γ = 90.00°, V = 3676.2(6) ?3, Z = 4, F(000) = 1676, Dc = 1.480 g/cm3, μ = 0.815 mm-1, the final R = 0.0526 and wR = 0.1688. A total of 8828 reflections were collected, of which 3244 were independent (Rint = 0.0344).
- Wang, Yongfen,Bian, Chuanzhou
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- The Application of a Continuous Grignard Reaction in the Preparation of Fluconazole
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The application of continuous methods in the synthesis of active pharmaceutical ingredients continues to receive significant attention in the academic as well as the industrial research communities. One of the major advantages of continuous methods is the ability to safely access kinetic synthons as well as highly reactive reagents that are typically unavailable through traditional batch methods. In this work, we report the high-yielding, clean formation of an aryl-turbo Grignard and its selective addition to a highly-enolizable 1,3-dichloroacetone, for the continuous synthesis of a key intermediate for fluconazole, a widely-prescribed anti-fungal agent. In addition, process optimization of the final API was also carried out to arrive at a semi-continuous method to this essential medicine.
- Korwar, Sudha,Amir, Somi,Tosso, Perrer N.,Desai, Bimbisar K.,Kong, Caleb J.,Fadnis, Swara,Telang, Nakul S.,Ahmad, Saeed,Roper, Thomas D.,Gupton, B. Frank
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- Rapid synthesis of some new propanol derivatives analogous to fluconazole under microwave irradiation in solventless system
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Fluconazole and a series of 2-(2,4-difluorophenyl)-1-(1H-1,2,4 triazol-1-yl- methyl)-3-(substituted heterocycl)-propan-2-ol which are analogous to fluconazole,were synthesized via the reaction of 2-(2,4-difluorophenyl)-2- [1-(1,2,4-triazolmethide)]oxiran with various heterocyclic system under microwave irradiation in solventless system.
- Heravi, Majid M.,Motamedi, Radineh
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- Hydrogen Bond Directed Photocatalytic Hydrodefluorination and Methods of Use Thereof
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Methods of synthesizing compounds comprising fluorinated aryl groups are disclosed, wherein said methods utilize hydrogen bond directed photocatalytic hydrodefluorination.
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- Continuous Flow Synthesis of Terminal Epoxides from Ketones Using in Situ Generated Bromomethyl Lithium
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A scalable procedure for the direct preparation of epoxides from ketones has been developed. The method is based on the carefully controlled generation of (bromomethyl)lithium (LiCH2Br) from inexpensive CH2Br2 and MeLi in a continuous flow reactor. The reaction has shown excellent selectivity for a variety of substrates, including α-chloroketones, which typically fail under classic Corey-Chaykovsky conditions. This advantage has been used to develop a novel route toward the drug fluconazole.
- Von Keutz, Timo,Cantillo, David,Kappe, C. Oliver
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supporting information
p. 10094 - 10098
(2019/12/24)
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- Method for preparing fluconazole
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The invention provides a method for preparing fluconazole. The method comprises the following steps: reacting a structure compound in a formula I, trimethylsulfoxonium bromide and 1,2,4-triazole in the effect of an alkaline catalyst to obtain the fluconazole. Compared with the prior art, the method has the advantages that trimethylsulfoxonium bromide is adopted to prepare the fluconazole, and bromide ions in the trimethylsulfoxonium bromide have relatively weak nucleophilicity to effectively avoid occurrence of side reaction, so that the yield and purity of fluconazole can be improved. Furthermore, the trimethylsulfoxonium bromide adopted for reacting has high molar mass utilization, low price and remarkable cost advantages.
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Paragraph 0031; 0066; 0067; 0068; 0075; 0076
(2017/07/21)
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- A preparation method of fluconazole
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The invention discloses a preparation method of fluconazol and belongs to the field of pharmaceutical chemistry and chemical synthesis. The preparation method comprises the following reaction processes: adopting low-price and easily-available epoxy chloropropane as a raw material to react with 1,2,4-triazole; then performing oxidation by using sodium hypochlorite; and finally, reacting with a prepared 2,4-difluorophenyl magnesium lithium reagent to prepare fluconazol. The invention provides a brand-new synthetic route and a process, the reaction of each step is easy to operate, the process is simple, the use of a reagent with high toxicity, high environmental protection pressure and high price is effectively avoided, the reaction total yield is improved, the product cost is effectively reduced, and large-scale production can be realized more easily.
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Paragraph 0049-0051; 0065-0068
(2017/08/25)
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- Synthesis of novel fluconazoliums and their evaluation for antibacterial and antifungal activities
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A series of novel fluconazoliums were synthesized and their bioactive evaluation as potential antibacterial and antifungal agents were described. Some target compounds displayed good and broad-spectrum antimicrobial activities with low MIC values ranging from 0.25 to 64 μg/mL against all the tested strains, including three Gram-positive bacteria (Staphylococcus aureus, MRSA and Bacillus subtilis), three Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa and Bacillus proteus) as well as two fungi (Candida albicans and Aspergillus fumigatus). Among all tested title compounds, the octyl, dichlorobenzyl, naphthyl and naphthalimino derivatives gave comparable or even better antibacterial and antifungal efficiency in comparison with the reference drugs Fluconazole, Chloromycin and Norfloxacin.
- Zhang, Yi-Yi,Mi, Jia-Li,Zhou, Cheng-He,Zhou, Xiang-Dong
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p. 4391 - 4402
(2011/11/06)
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- Methods for predicting the response to statins
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The invention provides methods for optimizing therapeutic efficacy for treating hypercholesterolemia in a subject having a cardiovascular disease (CVD), comprising (a) determining subject characteristics that affect the likelihood of reaching a goal level of low density lipoprotein (LDL); and (b) obtaining success probabilities of a variety of statin treatments for reaching said goal level of LDL using said subject characteristics and a multivariate model; and (c) administrating the optimal statin treatment with the highest success probability of step (b) to said subject thereby optimizing therapeutic efficacy for treating hypercholesterolemia in said subject.
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- CRYSTALLINE 1-[2-(2,4-DIFLUOROPHENYL)-OXIRANYL METHYL]-1H-1,2,4-TRIAZOLE
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A crystalline form of the compound 1-[2-(2,4-difluorophenyl)-oxiranyl methyl]-1H-1,2,4-triazole and a process for preparing the form. The crystalline form can be used for preparing fluconazole.
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Page/Page column 3; 4
(2008/06/13)
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- Process for the purification of fluconazole
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The present invention relates to processes for the purification of crude fluconazole including at least a first leaching, a second leaching, and an acid/base treatment and to highly purified fluconazole produced from the processes.
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Page/Page column 5-6
(2008/06/13)
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- An improved method for the addition reactions of 1,3-dichloroacetone with combined organolithium-cerium trichloride reagents
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Alkyl-, phenyl- and alkynyllithium reagents in combination with anhydrous cerium(III) chloride underwent addition reactions with 1,3-dichloroacetone in a very efficient manner. The addition products are versatile precursors for 2-substituted epichlorohydrins and glycidols. Fluconazole, a potent antifungal agent, was thus synthesized in 67% yield by addition of 1,3-dichloroacetone to 2,4-difluorophenyllithium in the presence of cerium(III) chloride, followed by substitution of the chlorine atoms with 1,2,4-triazole.
- Chen, Same-Ting,Fang, Jim-Min
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p. 927 - 930
(2007/10/03)
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- Chemical compounds having ion channel blocking activity for the treatment of immune dysfunction
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The present invention relates to chemical compounds having inhibitory activity on an intermediate conductance Ca 2+ activated potassium channel (IK Ca), and the use of such compounds for the treatment or alleviation of diseases or conditions relating to immune dysfunction. Moreover, the invention relates to a method of screening a chemical compound for inhibitory activity on an intermediate conductance Ca 2+ activated potassium channel (IK Ca).
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- Process for the manufacture of bis-triazole compounds and intermediates useful in the manufacture thereof having antifungal activity
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PCT No. PCT/CA96/00483 Sec. 371 Date Feb. 24, 1998 Sec. 102(e) Date Feb. 24, 1998 PCT Filed Jul. 17, 1996 PCT Pub. No. WO97/03971 PCT Pub. Date Feb. 6, 1997The present invention relates to a process to prepare a compound of formula (I) wherein Y and Z can be identical or different and represent a halogene. The bis-triazole compounds of formula (I) and intermediates have antifungal activity.
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- PROCESS FOR PREPARING BIOLOGICALLY ACTIVE DERIVATIVES OF 1,2,4-TRIAZOL AND INTERMEDIARIES USEFUL IN THIS PROCESS
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A process for the preparation of fluconazole, which is a well blown antifungal agent, and of pharmaceutically acceptable salts thereof is disclosed, wherein a novel compound of the formula (IV) wherein R represents H, benzyl, triphenylmethyl and COOR1with R1being alkyl or aryl, preferably tert-butyl or ethyl, and Z represents a triazole radical or hydrazine radical optionally substituted by R being defined as above, optionally in the salt form, is reacted with s-triazine. The novel compound (IV) is an object of the invention as well.
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- Preparation of fluconazole and pharmaceutically acceptable salts thereof
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A process for preparing fluconazole, including the steps of (1) acylating 1,3-difluorobenzene (DFB) to obtain 2-chloro-2',4'-difluoroacetophenone (CAP); (2) alkylating 4-amino-4H-1,2,4-triazole (4-AT) with CAP to obtain 2-(1H-1,2,4-triazol-1-yl)-2',4'-difluoroacetophenone (TAAP) salt; (3) deaminating TAAP salt to obtain TAAP; and (4) reacting TAAP with 1,2,4-triazole to obtain fluconazole.
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- Commercial process for the manufacture of fluconazole and intermediates useful in the manufacture thereof
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A process for making Fluconazole is provided comprising carrying out the following scheme of reaction: STR1
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- Processes for the preparation of 1,3-bis(1,2,4-triazol-1-yl)-propan-2-ol derivatives
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The invention provides a regiospecific process for the preparation of 1,3-bis(1,2,4-triazol-1-yl)-propan-2-ol derivatives comprising reacting an oxirane acid salt or an oxirane, under acidic conditions, with 4H-4-amino-1,2,4-triazole. The process is particularly useful for preparing fluconazole which is useful in the treatment of fungal infections in animals and humans.
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- Process for the preparation of 1,3-bis (1,2,4-triazol-1-yl)-propan-2-ol derivatives
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The invention provides a regiospecific process for the preparation of 1,3-bis(1,2,4-triazol-1-yl)-propan-2-ol derivatives of the general formulas I and Ia: wherein: Ris alkyl, cycloalkyl, aryl or aralkyl optionally substituted by one or more same or different halogen groups; and Xis the anion of a strong acid; comprising reacting an oxirane acid salt of the general formula II: wherein R and X are as defined above; or reacting an oxirane of the general formula II': wherein R and X are as defined above, under acidic conditions, with 4H-4-amino-1,2,4-triazole of the formula III: and optionally deaminating a compound of the formula Ia to form a compound of formula I.
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- Conversion of 4-amino-4H-1,2,4-triazole to 1,3-bis(1H-azol-1-yl)-2-aryl- 2-propanols and 1-phenacyl-4-[(benzoyl or 4-toluenesulfonyl)-imino]-(1H- 1,2,4-triazolium) ylides [1]
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A series of 1,3-bis(1H-azol-1-yl)-2-aryl-2-propanols 17 were synthesized in an one-pot procedure by reacting 1-aryl-2-(1H-1,2,4-triazol-1-yl)- or 1- aryl-2-(1H-imidazol-1-yl)ethanones with dimethylsulfoxonium methide in the presence of either 1,2,4-triazole or imidazole. The aromatic groups in 17 were either 4-bromo-, 4-chloro-, 2,4-dichloro- or 2,4-difluorophenyl. 4- Amino-4H-1,2,4-triazole was acylated with either benzoyl or 4-toluene- sulfonyl chloride to afford [4-(benzoyl or 4-toluenesulfonyl)amino]-4H- 1,2,4-triazole. Subsequent alkylations with 4-bromo- or 4-chlorophenacyl bromide produced 1-(4-bromo- or 4-chlorophenacyl)-4-[(benzoyl- or 4- toluenesulfonyl)amino]-1H-1,2,4-triazolium bromides. Neutralizations of these salts provided the corresponding ylides.
- Narayanan,Chapman,Upadhyaya,Bauer
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p. 1405 - 1412
(2007/10/02)
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- Pharmaceutical preparations
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A pharmaceutical preparation for parenteral administration of a drug consisting of a solvent system containing: (a) 0 to 65% by weight of α-tetrahydrofurfuryl-ω-hydroxy-polyloxyethylene; (b) 10 to 100% by weight polyethylene glycol with a mean molecular weight of 200 to 600; and (c) 0 to 35% by weight of water The sum of components (a) and (b) amounting to at least 65% by weight, and one or more therapeutically active compounds of the formula STR1 wherein R1 denotes a phenyl radical optionally substituted with 1 to 3 substituents independently selected from the group consisting of F, Cl, Br, I, CF3, C1 to C4 alkyl, and C1 to C4 alkoxy, or 5-chloro-pyrid-2-yl; X denotes OH, F, Cl or Br; R2 is H, CH3 or F; and R3 is H or F.
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- Antifungal 1,3-bis-triazolyl-2-propanol derivative
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2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol and its pharmaceutically acceptable acid addition salts are disclosed. This particular bis-triazole derivative and its aforesaid salts are useful for treating fungal infections in animals, including humans. Methods for preparing these compounds from known starting materials are provided.
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