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1-[2,4-Dichloro-beta-(p-chlorobenzyloxy)phenethyl]-3-(p-fluorophenacyl)imidazolium chloride, m.p. 163 C., in a yield of 9 parts by the reaction of 7.6 parts of 1-[2,4-dichlorobeta-(p-chlorobenzyloxy)phenethyl]imidazole and 3.8 parts of <strong>[700-35-6]2-chloro-p-fluoroacetophenone</strong>.
With diethylamine; In hexane; isopropyl alcohol;Resolution of racemate;
General procedure: The racemic mixtures of ecanazole and sulconazole (MilliporeSigma)were separated by an Agilent 1100 HPLC system(Agilent Technologies, Santa Clara, CA, USA) at a flow rate of 1ml/min. Separation was achieved with a cellulose tris 3,5-dimethylphenylcarbamate Chiralicar column (Chiral Technologies,West Chester, PA, USA). The mobile phase used in thisstudywas hexane-2 propanol-diethylamin (485:14:1 v/v/v) andthe detection was carried out at 280 nm. (Retention times: R<strong>[27220-47-9]econazole</strong>40 min and S-<strong>[27220-47-9]econazole</strong> 48 min/R-sulconazole 100min and S-sulconazole 140 min). Enantiomer characterizationwas determined as previously described in Aboul-Enein and Ali(40).
General procedure: To a suspension of sodium hydride (1.1mmol) in DMF (5ml), a solution of alcohol 4 (1mmol) in DMF (10ml) was treated at -5C, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 1.5h. Then the mixture was cooled at 0C and a solution of the substituted benzyl chloride or benzyl bromide in DMF (5ml) was added. The resulting mixture was stirred again for another 1h at room temperature. After adding water (20ml) to quenching the action, the aqueous phase was extracted with ethyl acetate (3×25ml), the organic phase was washed with water (150ml), dried over Na2SO4. 5a-5l were afford by column chromatography.
ethyl 2-(3-(2-((4-chlorobenzyl)oxy)-2-(2,4-dichlorophenyl) ethyl)-2-thioxo-2,3-dihydro-1H-imidazol-1-yl)-2-fluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With sulfur; sodium dithionite; In 1,2-dichloro-ethane; at 80℃; for 24h;Sealed tube;
<strong>[27220-47-9]Econazole</strong> (0.4 mmol) was added to an oven-dried 15 mL sealed tube equipped with a magnetic stirrer with a magnetic stir bar,Sulfur powder (S8) (0.8mmol),Ethyl bromofluoroacetate (1.0 mmol),Under Na2S2O4 (0.8 mmol) as a catalyst,The solvent was stirred in a solution of 1,2-dichloroethane (DCE) (2.0 mL) at 80 C for 24 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and the mixture was extracted with dichloromethane.The combined organic layers were dried over anhydrous Na 2 SO 4 and then evaporated.The solvent was evaporated in vacuo on the instrument.Fast column chromatography using 300-400 mesh silica gel,The crude mixture was purified by (preparative TLC monitoring plate) (petroleum (PE): ethyl acetate (EA) = 3:1).The white solid product (II-46) was obtained, m.p.: 98.5 to 100.1 C, yield 65%.
ethyl 2-(3-(2-((4-chlorobenzyl)oxy)-2-(2,4-dichlorophenyl) ethyl)-2-selenoxo-2,3-dihydro-1H-imidazol-1-yl)-2-fluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
With selenium; sodium dithionite; In 1,2-dichloro-ethane; at 100℃; for 24h;Sealed tube;
<strong>[27220-47-9]Econazole</strong> (0.4 mmol) was added to an oven-dried 15 mL sealed tube equipped with a magnetic stir bar with a magnetic stirrer.Selenium powder (Se) (0.8 mmol),Ethyl bromofluoroacetate (1.0 mmol)In Na2S2O4 (0.8mmol)The solvent under the catalyst was 1,2-dichloroethane (DCE) (2.0 mL).The reaction in the solution was stirred at 100 C for 24 hours. After the reaction,The reaction mixture was cooled to room temperature and the mixture was extracted with dichloromethane.The combined organic layers were dried over anhydrous Na2SO4. Fast column chromatography using 300-400 mesh silica gel,Purification of the crude mixture by (preparative TLC monitoring of the spot plate (petroleum (PE): ethyl acetate (EA) = 5:1),Obtaining a yellow oily product (II-50),The yield was 43%.
1-(2-((4-chlorobenzyl)oxy)-2-(2,4-dichlorophenyl)ethyl)-3-(difluoromethyl)-1,3-dihydro-2H-imidazole-2-thione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With sulfur; rongalite; In N,N-dimethyl acetamide; at 100℃; for 24h;Sealed tube;
<strong>[27220-47-9]Econazole</strong> (0.4 mmol) and sulfur powder (S8) (0.8 mmol) were added to an oven-dried 15 mL sealed tube equipped with a magnetic stir bar with a magnetic stir bar.Ethyl bromodifluoroacetate (1.0 mmol) in sodium hydroxymethanesulfinate (HOCH2SO2Na) (0.8 mmol) as a solventThe reaction was stirred at 100 C for 24 hours in a solution of N,N-dimethylacetamide (DMA) (2.0 mL).After the reaction is completed, the reaction mixture is cooled to room temperature. The mixture is saturated with brine and ethyl acetate.Ester solvent extraction,The combined organic layers were dried over anhydrous Na 2SO Flash column chromatography was performed using 300-400 mesh silica gel, and the crude mixture was purified by preparative TLC monitoring spotting.The yellow solid product (I-31) was obtained, m.p.: 89.0 - 89.9 C, yield 48%.
1-benzyl-3-(difluoromethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-thione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With selenium; potassium carbonate; In N,N-dimethyl acetamide; at 100℃; for 24h;Sealed tube;
<strong>[27220-47-9]Econazole</strong> (0.4 mmol) and selenium powder (Se) (0.8 mmol) were placed in an oven-dried 15 mL sealed tube equipped with a magnetic stir bar with a magnetic stir bar.Ethyl bromodifluoroacetate (1.0 mmol) in anhydrous potassium carbonate (K2CO3) (0.8 mmol) as a solvent solvent N,N-dimethylacetamide (DMA) (2.0 mL)The reaction in the solution was stirred at 100 C for 24 hours.After the reaction was completed, the reaction mixture was cooled to room temperature and the mixture was extracted with saturated brine and ethyl acetate.The combined organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo on a rotary evaporator the solvent.Flash column chromatography was performed using 300-400 mesh silica gel, and the crude mixture was purified by preparative TLC monitoring spotting.The product (I-36) was obtained as a yellow oil, yield 55%.
Stage #1: (2E)-but-2-enedioic acid; 1-[2,4-dichloro-β-(p-chlorobenzyloxy)phenethyl]imidazole In propan-2-one for 1h; Milling;
Stage #2: In ethyl acetate; propan-2-one at 55℃; for 3h;
Stage #3: for 96h;
Preparation of cocrystal 1 .
The current cocrystal 1 was gained by the combination of acetone-assisted grinding and solution volatilization approach. In short, raw drug ENZ (76.40 mg, 0.2 mmol) was mixed with FA (11.60 mg, 0.1 mmol) in 2:1 mo- lar ratio, and the mixture solids were then ground with 20 μL of acetone in four batches added in the process, till the mixture be- comes dried ( ca. 60 min). After preliminarily determining the for- mation of the novice crystalline phase by X-ray powder diffraction test, the received solid sample was spanided into two parts. One was dissolved in a minimal volume of mixture solvent of acetone and ethyl acetate (3:4, v/v) under stirring violently for about 3 h at 55 °C, and the other was retained as the seed crystal. The ob- tained solution was filtered and then the seed crystals said above were scattered into the solution with evaporating slowly and re- maining undisturbed thereafter. The transparent columnar single crystals of cocrystal 1 fit for SCXRD analysis were collected after approximately four-day evaporation.
Stage #1: maleic acid; 1-[2,4-dichloro-β-(p-chlorobenzyloxy)phenethyl]imidazole In acetonitrile Milling;
Stage #2: In ethyl acetate; acetonitrile at 55℃; for 3h;
Preparation of molecular salt 2 .
An analogous solvent-assisted grinding together with solvent evaporation method was adopted in the course preparation of molecular salt 2 . Herewith, an equimolar amount of ENZ (38.20 mg, 0.1 mmol) and MA (11.60 mg, 0.1 mmol) was mixed and ground with acetonitrile assisted. After preliminary detection with the help of X-ray powder diffraction technique, the acquired new crystalline powder dissolved in a mixed solvent of acetonitrile and ethyl acetate (1:3, v/v) was then heated at 55 °C for 3 h with strong magnetic stirring, the reaction system was cooled and filtered, and the selected transparent columnar single crystals of molecular salt 2 suitable for SCXRD test were obtained subsequent to the volatilization for 3 ∼5 days.