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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
Imidazole is a widely used organic compound with various biological activities, including serving as an enzyme inhibitor and drug precursor. Imidazole is mainly used in biocatalysis, drug synthesis, and as an inhibitor of various enzymes (e.g., heparinase and some bacterial enzymes). It is also utilized in research to study enzyme mechanisms and drug actions.
Synonyms: 1,3-Diaza-2,4-cyclopentadiene; Glyoxaline
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Synthesis of (2 S, 3 R, 4 R)-Dihydroxyisoleucine for Use in Amatoxin Synthesis
Chandra, Shambhu Deo ; Gunasekera, Shanal ; Noichl, Benjamin Philipp ; Patrick, Brian O ; Perrin, David M ;
Abstract: We report a streamlined synthesis of (2S,3R,4R)-4,5-dihydroxy isoleucine (DHIle), an amino acid found in α-amanitin, which appears to be critical for toxicity. This synthetic route is transition metal-free and enables the production of significant quantities of DHIle with suitable protection for use in peptide synthesis. Its incorporation into a cytotoxic amatoxin analog is reported.
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Surveying the scope of aromatic decarboxylations catalyzed by prenylated-flavin dependent enzymes
Anushree Mondal ; Pronay Roy ; Jaclyn Carrannatto ; Prathamesh M. Datar ; Daniel J. DiRocco ; Katherine Huntera and E. Neil G. Marsh
Abstract: The prenylated-flavin mononucleotide-dependent decarboxylases (also known as UbiD-like enzymes) are the most recently discovered family of decarboxylases. The modified flavin facilitates the decarboxylation of unsaturated carboxylic acids through a novel mechanism involving 1,3-dipolar cyclo-addition chemistry. UbiD-like enzymes have attracted considerable interest for biocatalysis applications due to their ability to catalyse (de)carboxylation reactions on a broad range of aromatic substrates at otherwise unreactive carbon centres. There are now ∼35[thin space (1/6-em)]000 protein sequences annotated as hypothetical UbiD-like enzymes. Sequence similarity network analyses of the UbiD protein family suggests that there are likely dozens of distinct decarboxylase enzymes represented within this family. Furthermore, many of the enzymes so far characterized can decarboxylate a broad range of substrates. Here we describe a strategy to identify potential substrates of UbiD-like enzymes based on detecting enzyme-catalysed solvent deuterium exchange into potential substrates. Using ferulic acid decarboxylase (FDC) as a model system, we tested a diverse range of aromatic and heterocyclic molecules for their ability to undergo enzyme-catalysed H/D exchange in deuterated buffer. We found that FDC catalyses H/D exchange, albeit at generally very low levels, into a wide range of small, aromatic molecules that have little resemblance to its physiological substrate. In contrast, the sub-set of aromatic carboxylic acids that are substrates for FDC-catalysed decarboxylation is much smaller. We discuss the implications of these findings for screening uncharacterized UbiD-like enzymes for novel (de)carboxylase activity.
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Purchased from AmBeed: 27916-43-4 ; 2438-05-3 ; 501-89-3 ; 42287-94-5 ; 776-79-4 ; 53473-36-2 ; 7251-61-8 ; 42287-97-8 ; 1621-91-6 ; 37718-11-9 ; 288-13-1 ; 86-73-7 ; 104-53-0 ; 2018-90-8 ; 87-66-1 ; 135-19-3 ; 1664-57-9 ; 289-80-5 ; 693-95-8 ; 55-22-1 ; 102-93-2 ; 1477-50-5 ; 1632-76-4 ; 4780-79-4 ; 16642-79-8 ; 3581-89-3 ; 501-97-3 ; 771-50-6 ; 98-98-6 ; 619-64-7 ; 100-51-6 ; 402-45-9 ; 59-67-6 ; 93-60-7 ; 273-53-0 ; 2084-13-1 ; 51-17-2 ; 2459-09-8 ; 2459-07-6 ; 95-16-9 ; 459-31-4 ; 90-05-1 ; 150-76-5 ; 103-25-3 ; 271-44-3 ; 6293-56-7 ; 2550-26-7 ; 288-32-4 ; 501-52-0 ; 2001-32-3 ; 1592-38-7 ; 95-15-8 ; 91-19-0 ; 1122-61-8 ; 3724-19-4 ; 20173-24-4 ; 118-31-0 ; 6125-24-2 ; 60-12-8 ; 90-15-3 ; 120-72-9 ; 822-36-6 ; 288-47-1 ; 288-42-6 ; 2038-57-5 ; 38628-51-2 ; 1929-29-9 ; 15009-91-3 ; 1505-50-6 ; 581-40-8 ; 616-47-7 ; 1571-33-1
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Nguyen, Long T. ; Rananaware, Santosh R. ; Yang, Lilia G. ; Macaluso, Nicolas C. ; Ocana-Ortiz, Julio E. ; Meister, Katelyn S. , et al.
Abstract: CRISPR-Cas-based diagnostics have the potential to elevate nucleic acid detection. CRISPR-Cas systems can be combined with a pre-amplification step in a one-pot reaction to simplify the workflow and reduce carryover contamination. Here, we report an engineered Cas12b with improved thermostability that falls within the optimal temperature range (60°C-65°C) of reverse transcription-loop-mediated isothermal amplification (RT-LAMP). Using de novo structural analyses, we introduce mutations to wild-type BrCas12b to tighten its hydrophobic cores, thereby enhancing thermostability. The one-pot detection assay utilizing the engineered BrCas12b, called SPLENDID (single-pot LAMP-mediated engineered BrCas12b for nucleic acid detection of infectious diseases), exhibits robust trans-cleavage activity up to 67°C in a one-pot setting. We validate SPLENDID clin. in 80 serum samples for hepatitis C virus (HCV) and 66 saliva samples for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with high specificity and accuracy. We obtain results in as little as 20 min, and with the extraction process, the entire assay can be performed within an hour.
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Exploring Eutectic Mixing of Quinones for Engineering High Energy-Density Electrolytes
Emily Penn ; Antonio Baclig ; Devi Ganapathi ; William C. Chueh ;
Abstract: Eutectic electrolytes can attain high concentrations of redox-active species, offering a path toward high energy density redox flow batteries. Here we introduce a new entropically-driven eutectic mixing approach using organic small molecules. By mixing chemically similar redox-active species, we engineer highly concentrated, low viscosity liquids composed almost entirely of redox-active molecules. Using quinones as a model system, we discover a ternary benzoquinone eutectic mixture and a binary naphthoquinone eutectic mixture which have theoretical redox-active electron concentrations of 16.8 and 8.8 M e–, respectively. We investigate compatibility with protic supporting electrolytes and quantify ionic conductivity and viscosity of quinone eutectic electrolytes across multiple states of charge. A binary naphthoquinone eutectic electrolyte with a protic ionic liquid supporting electrolyte (7.1 M e–, theoretical volumetric capacity 188 Ah L–1) achieves a volumetric capacity of 49 Ah L–1 in symmetric static cell cycling. These preliminary results suggest that entropy-driven eutectic mixing is a promising strategy for developing high-energy density flow battery electrolytes.
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Berg, Kaja ; Hegde, Pooja ; Pujari, Venugopal ; Brinkmann, Marzena ; Wilkins, David Z. ; Parish, Tanya , et al.
Abstract: The electron transport chain (ETC) in the cell membrane consists of a series of redox complexes that transfer electrons from electron donors to acceptors and couples this electron transfer with the transfer of protons (H+) across a membrane. This process generates proton motive force which is used to produce ATP and a myriad of other functions and is essential for the long-term survival of Mycobacterium tuberculosis (Mtb), the causative organism of tuberculosis (TB), under the hypoxic conditions present within infected granulomas. Menaquinone (MK), an important carrier molecule within the mycobacterial ETC, is synthesized de novo by a cluster of enzymes known as the classic/canonical MK biosynthetic pathway. MenA (1,4-dihydroxy-2-naphthoate prenyltransferase), the antepenultimate enzyme in this pathway, is a verified target for TB therapy. In this study, we explored structure-activity relationships of a previously discovered MenA inhibitor scaffold, seeking to improve potency and drug disposition properties. Focusing our campaign upon three molecular regions, we identified two novel inhibitors with potent activity against MenA and Mtb (IC50 = 13-22 μM, GIC50 = 8-10 μM). These analogs also displayed substantially improved pharmacokinetic parameters and potent synergy with other ETC-targeting agents, achieving nearly complete sterilization of Mtb in combination therapy within two weeks in vivo. These new inhibitors of MK biosynthesis present a promising new strategy to curb the continued spread of TB.
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Keywords: 1,4-dihydroxy-2-naphthoate prenyltransferase ; MenA ; MenA inhibitors ; Menaquinone ; Mtb ; Mycobacterium tuberculosis ; Piperidine derivatives ; SAR
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Purchased from AmBeed: 25952-53-8 ; 90719-32-7 ; 872-85-5 ; 6457-49-4 ; 3769-41-3 ; 10338-57-5 ; 135-19-3 ; 135-19-3 ; 28177-48-2 ; 22246-18-0 ; 122334-37-6 ; 91914-06-6 ; 10040-98-9 ; 161975-39-9 ; 150-76-5 ; 371-41-5 ; 63754-96-1 ; 288-32-4 ; 3380-34-5 ; 1677-46-9 ; 166815-96-9 ; 700-57-2 ; 1204-86-0 ; 21725-69-9 ; 367-12-4 ; 1003-29-8 ; 627-35-0 ; 27292-49-5 ; 104324-16-5 ; 123855-51-6 ; 180847-23-8 ; 4328-13-6 ; 875401-70-0 ; 405272-71-1 ; 63614-86-8 ; 1420942-13-7 ; 25952-53-8 ; 1420895-21-1 ; 1078-18-8 ; 32363-45-4 ; 69564-68-7 ; 31519-22-9 ; 22246-18-0 ; 189618-33-5 ; 180847-24-9 ; 6264-98-8 ; 946680-75-7 ; 63608-38-8 ; 713-68-8 ; 62810-39-3 ; 189618-32-4 ; 63608-31-1 ; 15789-05-6 ; 63712-27-6 ; 63608-33-3 ; 63608-35-5
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CAS No. : | 288-32-4 |
Formula : | C3H4N2 |
M.W : | 68.08 |
SMILES Code : | C1=NC=CN1 |
Synonyms : |
1,3-Diaza-2,4-cyclopentadiene; Glyoxaline
|
MDL No. : | MFCD00005183 |
InChI Key : | RAXXELZNTBOGNW-UHFFFAOYSA-N |
Pubchem ID : | 795 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H302-H314-H360 |
Precautionary Statements: | P280-P301+P330+P331-P305+P351+P338-P310-P303+P361+P353 |
Class: | 8 |
UN#: | 3263 |
Packing Group: | Ⅲ |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.31% | With sodium hydride In N,N-dimethyl-formamide at 58 - 62℃; for 3 h; Cooling with ice | (2)Take a concentration of 20percent sodium hydride in DMF, under icecooling,to 2ml / s Was added dropwise with stirring speedof 20percent of the concentration of imidazole in DMF, the reaction was stirred at 60 ° C 60min, after cooling in an ice salt bathmethod, was slowly added to the intermediate product 1, the sodium hydride Of DMF, imidazole in DMF and the weight ratioof the intermediate product as a 7: 7: 5 stirred at 60 ° C in 120min reaction mix, after cooling in an ice salt bath method, areaction solution adding to said reaction mixture 25percent by weight of nhexanewas accounted for the reaction, at a speed of 3rev / sec After stirring for 15min, plus The reaction solution into account the 350percent by weight of the ice, with 3 rev / sec stirreduntil evolution ceased Shen After the precipitate was filtered, the filter cake with accounting for 1/3 times the weight of thefilter cake was washed with water once, in order to speed 2830r / min Conditions centrifugal drying 60min, with the centrifugalaccounted for 2.5 times the weight of the resulting product was dried and 0.05 Times with ethyl acetate and activated carbon,was allowed to stand at 5° C was recrystallized from 13 hours, 50 ° C and By recrystallization of the obtained product wasdried to obtain intermediate 2 detected by HPLC. Intermediate 2 71.5percent yield, wherein the desired product 1(2hydroxy4(4chlorophenyl)butanoic Yl) 1Hydrogen imidazolecontent was 99.31 percent |
99.31% | Stage #1: With sodium hydride In N,N-dimethyl-formamide at 30℃; for 1 h; Cooling with ice Stage #2: at 60℃; for 2 h; Cooling with ice |
(1) take 7kg concentration of 20percent sodium hydride DMF solution,Under an ice bath condition, 7kg of imidazole DMF solution with a concentration of 20percent was added dropwise with stirring at a speed of 2ml / s and the reaction was stirred at 60 ° C for 60min; after cooling with an ice-salt bath method, 5kg of 1-chloro-4 - (4-chlorophenyl) -2-butanol stirred at 60 ° C for 120min, cooled with ice salt bath to obtain the reaction solution;(2) Take the reaction solution obtained in the step (1), add n-hexane accounting for 25percent of the weight of the reaction solution, stir for 15 min at a speed of 3 rev / sec, add ice water of 350percent Stirring at a speed of 3 revolutions / second to stop the precipitation precipitation, filtering, washing the filter cake with 1/3 times of the weight of the filter cake for 1 time, centrifuging at the speed of 2825r / min for 60 minutes, The obtained product was 2.5 times in weight and 0.05 times in ethyl acetate and activated carbon, and was allowed to stand at -5 ° C for 13 hours for recrystallization. The product obtained after recrystallization was dried at 50 ° C. After testing, the yield of the product of this example was 71.4percent.Using HPLC and standards on the target product and impuritiesThe amount of testing. After testing,The target product1- (2-hydroxy-4- (4-chlorophenyl) butyl) -1-hydro-imidazoleContent of 99.31percent1- (1-Chloro-4- (4-chlorophenyl) butan-2-yl) -1H-imidazoleContent of 0.57percent4- (4- (1-Hydroxyimidazol-1-yl) phenyl) -1-chloro-2-butanolThe content is 0.08percent. |
99.31% | Stage #1: With sodium hydride In N,N-dimethyl-formamide at 60℃; for 1 h; Stage #2: at 60℃; for 2 h; |
Take 7kg of 20percent sodium hydride in DMF and add dropwise at 2ml/s in ice bath.7kg concentration of 20percent imidazole in DMF, stirred at 60 ° C reaction 60min;After cooling with an ice salt bath, 5 kg of 1-chloro-4-(4-chlorophenyl)-2-butanol was slowly added, and the reaction was stirred at 60° C. for 120 min. After cooling with an ice salt bath, the reaction liquid was obtained; The reaction solution was added with 25percent by weight of n-hexane, stirred at a rate of 3 revolutions per second for 15 minutes, and then added with ice water of 350percent by weight of the reaction solution and stirred at a rate of 3 revolutions per second to stop. Precipitation precipitation, filtration, filter cake weight 1/3 of the water filter cake washed once, at a speed of 2825r/min centrifugal drying 60min, with the weight of the product obtained by the centrifugal drying 2.5 times and 0.05 times the weight of acetic acid The ethyl ester and the activated carbon were recrystallized at -5°C for 13 hours, and the recrystallized product was dried at 50°C to give 1-(2-hydroxy-4-(4-chlorophenyl)butyl). -1 hydrogen-imidazole, purity 99.31percent. |
88.2% | With sodium hydride In N,N-dimethyl-formamide at 20 - 60℃; for 4.5 h; | (2) Synthesis of 1- (4- (4-chlorophenyl) -2-hydroxybutyl) imidazole. The reaction flask was charged with imidazole and dry DMF. The mass ratio of imidazole to DMF was 24: Adding 3-4 portions of sodium hydride in the next portion, stirring at room temperature till no gas was generated, raising the temperature to 60 ° C, mixing 1-chloro-4- (4-chlorophenyl) -2-butanol with DMF to obtain a mixed solution 3, The mass ratio of 1-chloro-4- (4-chlorophenyl) -2-butanol and DMF in the mixed solution 3 of imidazole and sodium hydride was 24: 7.9: 80: 94.8. The mixed solution was added dropwise to the reaction flask , The dropwise addition was completed for 3.5 hours, the reaction temperature was maintained at 60 ° C, the reaction was continued for 1 hour after the dropwise addition was completed, and then cold water was slowly added until all the solids were precipitated and filtered to obtain 1- (4- (4-chlorobenzene Yl) -2-hydroxy-butyl) imidazole; |
85% | With sodium hydroxide; N-benzyl-N,N,N-triethylammonium chloride In water; toluene at 0 - 95℃; for 3 h; | Example 1. Preparation of (1-f4- (4-chlorophenvl)-2-hydroxy-n-butvll-imidazole) (IV); To a solution of 56.7 g (0.26 mol) of 1-chloro-4-chlorophenyl-2-butanol (J. of Medicinal Chemistry, 1978. Vol. 21. No. 8. p. 842) in 200 ml of toluene 36.2 g (0.9 mol) of sodium hydroxide dissolved in 100 ml of water, 6.4 g (0.028 mol) of benzyltriethyammonium chloride and 35.2 g (0.51 mol) of imidazole (III) are added. The reaction mixture is heated at 93-95 °C for one hour then the temperature is returned to about 60 °C, the phases are separated and to the organic layer water (100 ml) is added. The mixture is first stirred at 22-25 °C for 1 hour then at 0-5 °C for two hours. The crystals are separated by filtration, washed with water (2 x 35 ml) of 0-5 °C to yield 74 g of wet (1- [4- (4-chlorophenyl)-2-hydroxy-n-butyl]-imidazole) which is dried at maximum 50 °C in vacuo to give 61.6 g (95 percent) of the product. Recrystallization from ethyl acetate gives 52.4 g (85 percent) of dry product melting at 104-106 °C. |
71.4% | Stage #1: With sodium hydride In N,N-dimethyl-formamide at 60℃; for 1 h; Cooling with ice Stage #2: at 60℃; for 2 h; Cooling with ice |
(1) Take 7kg of 20percent sodium hydride in DMF. Under ice bath conditions, At a rate of 2 ml/s, 7 kg of a 20percent imidazole DMF solution was added dropwise while stirring. Stir the reaction at 60 ° C 60min; After cooling with ice salt bath, 5 kg of 1-chloro-4-(4-chlorophenyl)-2-butanol is added slowly, Stirring reaction at 60 ° C 120min, after cooling with ice salt bath, the reaction solution; (2) Take the reaction solution obtained in step (1), Add 25percent by weight of the reaction solution of n-hexane, After 15 min stirring at 3 rpm, Then add ice water, which accounts for 350percent of the weight of the reaction solution, Stir at a speed of 3 revs/second to stop precipitation after filtration. Wash the cake once with 1/3 of the weight of the cake, Drying at a speed of 2825r/min for 60min. With ethyl acetate and activated carbon that weighed 2.5 times and 0.05 times the weight of the centrifugally dried product, respectively. After recrystallization at -5°C for 13 hours, the recrystallized product was dried at 50°C to obtain it. Upon detection, the yield of the product of this example was 71.4percent. The target product and impurity levels were determined using HPLC and standards. After testing, The target product, 1-(2-hydroxy-4-(4-chlorophenyl)butyl)-1H-imidazole, has a content of 99.31percent. The content of 1-(1-chloro-4-(4-chlorophenyl)butan-2-yl)-1-hydro-imidazole is 0.57percent. The content of 4-(4-(1H-hydrogen-imidazol-1-yl)phenyl)-1-chloro-2-butanol was 0.08percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | A mixture of imidazole (1 .36 g, 20.0 mmol) and sodium hydroxide (0.80 g, 20.0 mmol) in DMSO was heated to 90 C for 2 h, and then cooled to room temperature. A solution of 1 -bromooctane (3.46 g, 19.0 mmol) in DMSO was added dropwise to the mixture. After stirring at room temperature for 3 h, the mixture was heated up slowly to 65 C for 16 h with constant stirring. The solution obtained was mixed with water and the product was extracted 4 times with diethyl ether. The diethyl ether phases were combined and dried with sodium sulfate. Diethyl ether was removed under vacuum and the intermediate (9) was obtained as yellow liquid (2.89 g, 89 %). 1 H NMR (DMSO-d6): delta 7.61 (s, 2H), 7.15 (s, 1 H), 6.87 (s, 1 H), 3.93 (t, 2H), 1 .68 (m, 2H), 1 .25 (m, 10H), 0.85 (t, 3H). | |
87.7% | With sodium hydroxide; In dimethyl sulfoxide; at 20 - 25℃;Inert atmosphere; | To a flask equipped with a stirrer, Add the thermometer to the three necked flask 0 · 440 g (11.0 mmol) of NaOH, 0.714 g (10.5 mmol) of imidazole and 10 mL of dimethylsulfoxide (DMSO) were stirred under nitrogen at 20 C to 25 C to give a clear solution. To this was added dropwise 1.93 g (10.0 mmol)Bromo octane, reaction 4 ~ 6 h, the reaction into 10 mL of water extracted with chloroform 3 X 10 mL, and then washed with water chloroform layer 4 ~ 5 times, and then dried with anhydrous MgS04, filtered to get the filtrate, Removal of chloroform yielded a pale yellow liquid, 1.58 g of N-octylimidazole, in 87.7% yield. |
85% | With sodium hydroxide; In tetrahydrofuran; water;Reflux; | General procedure: A solution of imidazole 3 (30 mmol) in THF (60 mL) was treated with NaOH (25 mL, 40% aq) and the alkyl bromide (30 mmol), and the reaction was refluxed overnight. The solvent was evaporated and the crude reaction mixture was extracted with CH2Cl2 against water. The organic layer was washed with water, dried over MgSO4 and concentrated. The final product was distilled under vacuum (~5 mbar) to provide 4 as yellow oily liquid in 80-85% yield. |
82.3% | General procedure: A mixture of imidazole (30 mmol, 2.04 g), potassiumhydroxide (30 mmol, 1.68 g) and dimethyl sulfoxide(10 mL) was stirred for 2 h at room temperature. Afterthat, alkyl bromide (25.0 mmol of 1-bromohexane, 1-bromooctane,1-bromodecane, 1-bromododecane, 1-bromotetradecane,1-bromohexadecane, or 1-bromooctadecane)was dropped in slowly and the mixture was stirred for anadditional 4 h. Upon completion, water (30 mL) was addedto the resulting mixture followed by extraction with chloroform(5 x 30 mL). The combined organic layer wasdried over anhydrous magnesium sulfate and the filtratewas concentrated under reduced pressure. The residue wassubjected to flash chromatography with ethyl acetate aseluent to give N-alkyl imidazole. The respective yields ofN-hexyl imidazole, N-octyl imidazole, N-decyl imidazole,N-dodecyl imidazole, N-tetradecyl imidazole, N-hexadecylimidazole and N-octadecyl imidazole are 84.6, 82.3, 81.2,80.5, 80.4, 79.8 and 79.6 %. | |
60% | Imidazole (3.41 g, 50 mmol) and NaH (1.34 g, 54 mmol) were dissolved in THF (10 mL) under N2 in an ice bath for 45 min, followed by addition of 1-bromooctane (9.65 g, 50 mmol). The solution was stirred for 24 h at room temperature and then concentrated under reduced pressure after filtration.The residue was purified by flash chromatography (SiO2; petroleum ether/ethyl acetate5 : 1 as eluent) to give 1 as alight yellow oil (5.97 g, 60 %). deltaH (CDCl3, 400 MHz) 7.42 (1H, s), 7.01 (1H, s), 6.87 (1H, s), 3.89 (2H, t, J 8.0), 1.76-1.73 (2H, m), 1.31-1.25 (10H, m), 0.87 (3H, t, J 7.2). deltaC (CDCl3, 100 MHz) 136.2, 128.4, 118.1, 46.4, 31.2, 30.6, 28.6, 28.5,26.0, 22.1, 13.6. m/z (ESI) 181 ([M + H]+). m/z 181.1708. HRMS (ESI) Anal. Calc. for C11H21N2 ([M + H]+) 181.1705. | |
General procedure: These compoundswere obtained fromthe reaction of the sodium salt of imidazole and 1-bromoalkanes, as follows: to a 3-necked round-bottom flask, provided with a reflux condenser, dropping funnel, and inlet for dry nitrogen was added a solution of imidazole (7.49 g; 0.11 mol) in dry ethanol (25 mL). Small pieces of sodium (2.53 g, 0.11 mol), were slowly introduced, the mixture was vigorously stirred until the metal has dissolved and then heated under reflux for 2 h. The mixture was cooled to room temperature; the appropriate 1-bromoalkane (0.10 mol; 16.50 g, 17.91 g, 19.31 g, 22.12 g for R ¼ C6; C7; C8 and C10, respectively)was added slowly (ca. 30 min); then the mixture was refluxed for 2 h. The mixture was cooled to room temperature, the precipitated NaBr was filtered off; the ethanol evaporated, the residual oilwas washed with water, and then dried with anhydrous MgSO4. The N-(1-alkyl)imidazoles were purified by fractional distillation (yields before distillation ca. 98%); their purity was confirmed with 1H NMR spectroscopy (results not shown). | ||
General procedure: N-Hexadecylbromide (11.35 g, 37.2 mmol) was dissolved in dimethylformamide (DMF, 50 mL) and then added to a solution of the sodium salt of imidazole, which was formed by the reaction of imidazole (5.0 g, 74 mmol) with sodium hydride (2.66 g, 111 mmol) in DMF (50 mL). The mixture was heated at 60 C for 6 h, cooled, and diluted with water. After extraction with ethyl acetate (EtOAc), the extract was washed with brine and water, and then dried with sodium sulfate. The solvent was separated by reduced pressure distillation and N-alkylimidazole was obtained as a pale yellow oily product. | ||
With potassium hydroxide; In acetonitrile; for 4h;Reflux; | General procedure: N-Butylimidazole and N-octylimidazole were synthesized fol-lowing the procedure of literature [44]: To a round-bottomedflask, imidazole (6.0 g, 88 mmol), 1-bromobutane/1-bromooctane(90 mmol), acetonitrile (50 mL) and potassium hydroxide (9.9 g,177 mmol), were added in sequence. The reaction mixture wasrefluxed for 4 h and then cooled down to room temperature. Afterevaporating the solvent, the residue was purified by a flash col-umn chromatography utilizing ethyl acetate/methanol (v/v = 25:1)as eluent. The pure product of 1-butylimidazole/1-octylimidazolewas isolated as a pale yellow oil (?83%). N-Octylimidazole:1H NMR: (CDCl3): (ppm) = 0.87 (t, J = 6.5 Hz,3H, CH3), 1.28 (br, 10H, CH2), 1.77 (br, 2H, CH2), 3.92 (t, J = 7.2 Hz,2H, CH2), 6.90 (s, 1H, ImH), 7.04 (s, 1H, ImH), 7.45 (s, 1H, ImH).13CNMR (CDCl3): (ppm) = 13.9, 22.5, 26.4, 28.9, 29.0, 31.0, 31.6, 46.9,118.7, 129.2, 136.9. | |
With sodium hydroxide; In acetone; at 20℃; for 12h; | N-alkylimidazoles were synthesized using a previously reported method with minor modification. Typically, to a solution of imidazole (1 mol equiv.) and sodium hydroxide (1 mol equiv.) in acetone (50 mE) was added 1 -bromoalkane (0.8 mol equiv.). After stirring at room temperature for 12 h, a Nal3r precipitate was filtered and acetone removed under reduced pressure. A residual oily mass was re-dissolved in dichloromethane and extracted three times with water. Finally, an organic phase was dried on anhydrous sodium sulfate and dicholoromethane was removed under reduced pressure to produce brown oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.6% | Compound XIII (880g, 12.9mol, 1.0eq.) In the autoclave 50L, 12L DMF were dissolved, cooled To below 0 °C, triethylamine (1308g, 12.9mol, 1.0eq. ) The reaction was kept 30min, 0 ° C solution of the following threePhenyl chloride (3605.0g, 12.9mol, 1.0eq. ) In DMF (16L), drops Bi, 15 ° C overnight with stirring 16 h. Thereaction mixture was poured into water, large amount of solid precipitated, suction filtered, the filter cake washedwith water, drained, dried to obtain compound XIV-1 White The solid 3835.1g, Yield: 95.6percent. | |
91% | 1-trityl-midazol (Compound 28, Scheme 19) was prepared by adding Et3N (5.1 ml, 36.7 mmol) at 0° C. to a stirred solution of the imidazole Compound 27 (2.5 grams, 36.7 mmol) dissolved in 75 ml DMF. After 30 minutes of stirring, trityl-chloride (10.3 grams, 36.7 mmol) dissolved in DMF (45 ml) was added slowly to the reaction mixture, and the reaction mixture was allowed to reach room temperature while stirred continuously for over night. Thereafter the reaction mixture was quenched with cold water (1 L) to precipitate a solid, which was collected by filtration and recrystallized from hexane/DCM to afford Compound 28 as a white solid (91percent yield).1H NMR (500 MHz, CDCl3)-delta: 7.47 (s, 1H), 7.33-7.30 (m, 9H), 7.16-7.12 (m, 6H), 7.07 (s, 1H), 6.83 (s, 1H). | |
90% | With ammonium chloride; triethylamine; In dichloromethane; | Example 22 Synthesis of 1-tritylimidazole (5) To a solution of trityl chloride (5.58 g, 20.0 mmol.) in dry methylene chloride (100 ml) cooled down to 0° C. and stirred under Ar, was added dropwise over 1.5 hours a solution of imidazole (1.36 g, 20.0 mmol.) and triethylamine (2.7 mml, 20 mmol.) in 50 ml dry methylene chloride. At the end of the addition, the reaction mixture was allowed to warm up to room temperature and stirred under Ar at that temperature overnight. The reaction mixture was then washed with 20 ml of a 10percent solution of ammonium chloride, then with 20 ml of distilled water. The organic phase was dried over magnesium sulfate and evaporated in vacuo to yield quantitatively a white solid. Recrystallization from methylene chloride/hexanes yielded 5.60 g of (5) (yield=90percent after recrystallization). m.p. 214° C.; 1H NMR (200 MHz, CDCl3) delta7.43 (m, 1H, NCHN), 7.3-7.4 (m, 9H, 3*C6H5), 7.1-7.2 (m, GH, 3*C6H5), 7.0 (m, 1H, Ph3CNCH=CH), 6.81 (m, 1H, Ph3CNCH=CH); 13C NMR (50 MHz, CDCl3) delta142.3, 139.0, 129.6, 128.2, 128.3, 121.6. |
90% | With ammonium chloride; triethylamine; In dichloromethane; | Example 22 Synthesis of 1-tritylimidazole (5) STR73 To a solution of trityl chloride (5.58 g, 20.0 mmol.) in dry methylene chloride (100 ml) cooled down to 0° C. and stirred under Ar, was added dropwise over 1.5 hours a solution of imidazole (1.36 g, 20.0 mmol.) and triethylamine (2.7 mml, 20 mmol.) in 50 ml dry methylene chloride. At the end of the addition, the reaction mixture was allowed to warm up to room temperature and stirred under Ar at that temperature overnight. The reaction mixture was then washed with 20 ml of a 10percent solution of ammonium chloride, then with 20 ml of distilled water. The organic phase was dried over magnesium sulfate and evaporated in vacuo to yield quantitatively a white solid. Recrystallization from methylene chloride/hexanes yielded 5.60 g of (5) (yield=90percent after recrystallization). m.p. 214° C.; 1 H NMR (200 MHz, CDCl3) delta 7.43 (m, 1H, NCHN), 7.3-7.4 (m, 9H, 3xC6 H5), 7.1-7.2 (m, 6H, 3xC6 H5), 7.0 (m, 1H, Ph3 CNCH=CH), 6.81 (m, 1H, Ph3 CNCH=CH); 13 C NMR (50 MHz, CDCl3) delta 142.3, 139.0, 129.6, 128.2, 128.3, 121.6. |
90% | With ammonium chloride; triethylamine; In dichloromethane; | Example 22 Synthesis of 1-tritylimidazole (5) STR70 To a solution of trityl chloride (5.58 g, 20.0 mmol.) in dry methylene chloride (100 ml) cooled down to 0° C. and stirred under Ar, was added dropwise over 1.5 hours a solution of imidazole (1.36 g, 20.0 mmol.) and triethylamine (2.7 mml, 20 mmol) in 50 ml dry methylene chloride. At the end of the addition, the reaction mixture was allowed to warm up to room temperature and stirred under Ar at that temperature overnight. The reaction mixture was then washed with 20 ml of a 10percent solution of ammonium chloride, then with 20 ml of distilled water. The organic phase was dried over magnesium sulfate and evaporated in vacuo to yield quantitatively a white solid. Recrystallization from methylene chloride/hexanes yielded 5.60 g of (5) (yield=90percent after recrystallization). m.p. 214° C.; 1 H NMR (200 MHz, CDCl3) delta7.43 (m, 1H, NCHN), 7.3-7.4 (m, 9H, 3*C6 H5), 7.1-7.2 (m, 6H, 3*C6 H5), 7.0 (m, 1H, Ph3 CNCH=CH), 6.81 (m, 1H, Ph3 CNCH=CH); 13 C NMR (50 MHz, CDCl3) delta142.3, 139.0, 129.6, 128.2, 128.3, 121.6. |
In 5,5-dimethyl-1,3-cyclohexadiene; water; ethyl acetate; | EXAMPLE VII 1-TRITYLIMIDAZOLE To a stirred solution of 23.5 g (0.35 mole) of imidazole in 425 mL of ethyl acetate was added 48.0 g (0.32 mole) of triphenylmethyl chloride. The mixture was stirred for 20 hours and then 500 mL of water was added. After being stirred for an additional 2 hours, the mixture was filtered. The ethyl acetate layer was separated, dried (MgSO4) and concentrated. Recrystallization of the residue from xylene gave 41 g of white crystals, mp 222°-225° C.. |
Yield | Reaction Conditions | Operation in experiment |
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37% | In tetrahydrofuran; methanol; chloroform; | 1. 2-Imidazol-1-yl-N-methoxy-N-methyl-acetamide 60percent sodium hydride in oil (0.296 g, 7.4 mol) was washed with tetrahydrofuran and suspended in additional tetrahydrofuran (10 ml). To this was added imidazole (0.506 g, 7.43 mol) followed by stirring at 25° C. for 1 hour. To the mixture was added a solution of <strong>[67442-07-3]2-chloro-N-methoxy-N-methyl-acetamide</strong> (1.02 g, 7.4 mmol, prepared per Tetrahedron Letters Vol. 30, No. 29, pp3779-80, 1989.) followed by stirring at 25° C. for 15. The mixture was filtered, and the filtrate was evaporated to an oil in vacuo and purifide by chromatography on silica gel eluted with a gradient of chloroform to 10percent methanol:chloroform giving a solid 0.46 g, 37percent yield. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 4h; | A solution of tert-butyl 3-bromo-4-oxopiperidine-l-carboxylate (Intermediate 55, 0.50 g, 1.8 mmol), imidazole (0.14 g, 2 mmol), potassium carbonate (0.25 g, 1.8 mmol) and DMF (3 ml) was warmed to 50 °C and stirred for 4h. The reaction mixture was cooled to room temperature and diluted with EtOAc (50 ml). The resultant mixture was filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography <n="112"/>- Ill -(methanol/DCM gradient, 0-10percent) to provide the title compound as a white solid (0.27 g). MS (ESP) (M-H)': 264.2 for C3HI9N3O3; NMR (CDCl3): 1.41 (s, 9 H), 2.50 (m, 2 H), 2.55 (m, 1 H), 3.14-3.33 (m, 2 H), 4.50 (m, 1 H), 4.79 (dd, 1 H), 6.80 (s, 1 H), 6.98 (s, 1 H), 7.39 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
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In ethyl acetate; N,N-dimethyl-formamide; | Example 4 Synthesis of Compounds 4 and 13 2-Cyano-6-t-butyldiphenylsiloxy-benzothiazole. A solution of <strong>[939-69-5]2-cyano-6-hydroxybenzothiazole</strong> (5.0 g, 28 mmol) in 100 ml of anhydrous DMF under inert atmosphere was treated with 2.9 g of imidazole (4.2 mmol) followed by t-butyldiphenylchlorosilane (9.34 g, 34 mmol). The reaction was stirred at room temperature for 3 h and then diluted with 200 ml of ethyl acetate and washed with water (4*400 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography, eluding with 5-10percent ethyl acetate/hexanes to afford 13.0 g of the desired product containing ~10percent silyl impurity in quantitative yield. The product was taken on without further purification. 1 H NMR (CDCl3): delta1.12 (s, 9H); 7.13-7.46 (m, 8H); 7.70-7.72 (m, 4H); 7.92-7.95 (d, 1H). | |
In ethyl acetate; N,N-dimethyl-formamide; | Example 4 Synthesis of Compounds 4 and 13 2-Cyano-6-t-butyldiphenylsiloxy-benzothiazole. A solution of <strong>[939-69-5]2-cyano-6-hydroxybenzothiazole</strong> (5.0 g, 28 mmol) in 100 ml of anhydrous DMF under inert atmosphere was treated with 2.9 g of imidazole (4.2 mmol) followed by t-butyldiphenylchlorosilane (9.34 g, 34 mmol). The reaction was stirred at room temperature for 3 h and then diluted with 200 ml of ethyl acetate and washed with water (4*400 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography, eluding with 5-10percent ethyl acetate/hexanes to afford 13.0 g of the desired product containing ~10percent silyl impurity in quantitative yield. The product was taken on without further purification. 1 H NMR (CDCl3): delta 1.12 (s, 9H); 7.13-7.46 (m, 8H); 7.70-7.72 (m, 4H); 7.92-7.95 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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In EtCO2 H; | EXAMPLE 3 N-([2-Pyridyl]diphenylmethyl)imidazole (4) A solution of diphenyl-2-pyridylmethanol (0.50 g, 1.9 mmol) and imidazole (0.50 g, 7.4 mmol) in 2 mL of EtCO2 H was heated to reflux under N2 for 7 h. The crude product was isolated as described for (2) and purified by flash chromatography (60 g SiO2, EtOAc) to give 0.08 g (13.5percent) of a yellow solid. This material was further purified by trituration (4:1 hexanes-Et2 O) followed by recrystallization from EtOAc to give 0.03 g of (4), m.p. 214.5°-216.5° C. IR (KBr) 1584, 1487, 1462, 1444, 1430, 1212, 1066, 760, 710, 702, 666 cm-1. NMR (CDCl3): d 7.05 (m, 7H); 7.3 (m, 7H); 7.65 (m, 2H); 8.70 (d, J=4, further split, 1H). Anal. Calc'd (C21 H17 N3): C, 81.00; H, 5.50; N, 13.50. Found: 81.17; 5.50; 13.69. |
Yield | Reaction Conditions | Operation in experiment |
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With trimethylsilyl trifluoromethanesulfonate; In dichloromethane; | EXAMPLE 4 N-([4,4',4"]-Trichlorotrityl)imidazole (7) To a stirred solution of tris(4-chlorophenyl)methanol (0.36 g, 1.0 mmol) and imidazole (0.20 g, 2.9 mmol) in 2 mL of CH2 Cl2 under N2 at RT was added 0.40 mL (2.0 mmol) of trimethylsilyl triflate. After 1 h, the crude product was isolated as described for (2) and purified by flash chromatography (10percent EtOAc-hexanes.(R).EtOAc) to give 0.25 g of a semisolid. This material was triturated with 5percent Et2 O-hexanes to give 0.20 g of (7) as a white solid, m.p. 153°-155° C. IR (KBr) 1490, 1399, 1217, 1097, 1080, 1013, 815 cm-1. NMR (CDCl3): d 6.77, 7.10, 7.41 (each s, 1H, imidazole CH); 7.04 (dt, 6H); 7.33 (dt, 6H). Anal. Calc'd (C22 H15 N2 Cl3): C, 63.86; H, 3.65; N, 6.77. Found: 63.96; 3.95; 6.70. |
Yield | Reaction Conditions | Operation in experiment |
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In acetic acid; | EXAMPLE 1 N-(Triphenylmethyl)imidazole (2) A stirred suspension of triphenylmethanol (2.6 g, 10 mmol) and 1.36 g (20 mmol) of imidazole in 10 mL of HOAc was heated to 100° C. under N2 for 1 h. The cooled mixture was diluted with Et2 O and washed with water, saturated Na2 CO3, water (until neutral), brine, dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography (110 g SiO2, 25percent-50percent EtOAc-hexanes) to give 0.78 g (25percent) of a solid. This was recrystallized from EtOAc to give 0.20 g of (2), m.p. 221°-223° C. IR (KBr) 1489, 1443, 1210, 1072, 750, 701, 662 cm-1. NMR (CDCl3): d 6.82, 7.07, 7.47 (all t, J=1, imidazole CH); 7.14 (m, 6H); 7.32 (m, 9H). Anal. Calc'd (C22 H18 N2): C, 85.13; H, 5.84; N, 9.03. Found: 85.16; 5.87; 9.02. |
Yield | Reaction Conditions | Operation in experiment |
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With 1,1'-carbonyldiimidazole; In N-methyl-acetamide; dichloromethane; ethyl acetate; | EXAMPLE II N-(2-Hydroxyethyl)-N'-(isoquinolin-6-yl)-N-[4-[2-(methoxycarbonyl)ethyl]phenyl]-urea To 7.2 g of imidazole and 10.1 g of N,N'-carbonyldiimidazole in 100 ml of dimethylformamide are added dropwise, at a temperature of 0° to 10° C., 9.0 g of <strong>[23687-26-5]6-aminoisoquinoline</strong> in 70 ml of dimethylformamide. After 2 hours stirring at ambient temperature, 15.3 g of N-(2-hydroxyethyl)-4-[2-(methoxycarbonyl)ethyl]aniline in 20 ml of dimethylformamide are added dropwise and the mixture is stirred for 21/2 days at ambient temperature. The mixture is diluted with 750 ml of ethyl acetate and extracted twice with water and saturated saline solution. The organic phase is separated off, dried and evaporated down. The residue is purified by chromatography over a silica gel column using ethyl acetate/methylene chloride/methanol=70:30:10. Yield: 4.8 g (19percent of theory), Rf value: 0.48 (silica gel; methylene chloride/methanol/ethyl acetate=20:1:1) |
Yield | Reaction Conditions | Operation in experiment |
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72% | In n-heptane; water; ethyl acetate; toluene; | EXAMPLE 1 A room temperature solution of 1-chloro-2,4-diaminobenzene (1.43 g, 10 mmol), 1-hexadecanesulfonyl chloride (3.24 g, 10 mmol), imidazole (0.68 g, 10 mmol) and toluene (20 mL) was stirred for 1 hr. Isopropyl alcohol (20 mL) was added and the reaction mixture was heated at 60° C. for 2 hours. Analysis by thin layer chromatography (tlc) (40percent ethyl acetate and 60percent heptane) indicated incomplete acylation and additional 1-hexadecanesulfonyl chloride (0.7 g, 2 mmol) was added and the reaction mixture was stirred at 60°-62° C. for an additional hour, at which time the reaction appeared to be complete by tlc analysis. The reaction solution was treated with hot water (50 mL) and the layers separated. The toluene layer was further washed twice with 50 mL of hot water. Heptane (20 mL) was added to the recovered toluene layer to precipitate the product, N-(3-amino-4-chlorophenyl)-1-hexadecanesulfonamide, which was isolated by cooling the mixture to about 0° C. and collecting the product by vacuum filtration. After being washed with cold heptane, the product was dried (yield=3.12 g, 72percent of the theoretical yield) and it melted at 103°-104° C. No impurities were observed by H1 NMR analysis. |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 1.0h;Heating / reflux; | C. To a solution of compound 26c (1.136 g, 5.01 mmol) in 50 mL CH3CN was added imidazole (0.514 g, 7.55 mmol) and iPr2NEt (1.75 mL, 10.0 mmol). The reaction was heated at reflux for 1 hour then concentrated in vacuo to a residue. The residue was purified via silica gel chromatography (40-80percent EtOAc/heptane) to give compound 26d as a waxy yellow solid. MS: M+H+=258, 1H NMR (d6-DMSO): delta 9.66 (s, 1H), 9.13 (s, 1H), 8.13 (s, 1H), 7.65 (s, 1H), 7.21 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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With CO2; potassium carbonate; | EXAMPLE 9 544 g (8 moles) of imidazole, 1,380 g (10 moles) of potassium carbonate and 1,000 ml of liquid CO2 were reacted for 2.5 hours under 120 bar and at 219° C. in an autoclave. The end product was precipitated by acidifying the mixture to pH 3 and slowly heating it to 100° C. in the course of 1 hour. The product was dried to give 606 g (67.6percent of theory) of imidazole-4-carboxylic acid, which melted at 220° C. with decomposition (evolution of CO2). |
Yield | Reaction Conditions | Operation in experiment |
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With sulfuric acid; In N-methyl-acetamide; | 1A(a); (1S,5R,6S,7R)-7-Benzoyloxy-6-(dimethyl-tert.-butylsilyloxymethyl)-2-oxabicyclo[3,3,0]octan-3-one At 0° C., 65 g of tert.-butyldimethylsilyl chloride is added to a solution of 100 g of (1S,5R,6S,7R)-7-benzoyloxy-6-hydroxymethyl-2-oxabicyclo[3,3,0]octan-3-one and 62 g of imidazole in 110 ml of dimethylformamide, and the mixture is stirred under argon for 24 hours at 24° C. Subsequently, the mixture is diluted with 6 l of ether, shaken twice with 5percent sulfuric acid, four times with water, dried over magnesium sulfate, and evaporated under vacuum. The residue is recrystallized from hexane/methylene chloride, thus obtaining 137 g of the silyl ether as colorless crystals (mp 75° C.). |
Yield | Reaction Conditions | Operation in experiment |
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In N-methyl-acetamide; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; | EXAMPLE 1 (1S,5R,6S,7R)-6-tert-Butyldimethylsilyloxymethyl-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one A solution of 11.052 g of (1S,5R,6S,7R)-6-hydroxymethyl-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one (DOS No. 2,610,718) in 54.0 ml of absolute dimethylformamide is combined with 3.03 g of imidazole and 6.63 g of tert-butyldimethylsilyl chloride, and the mixture is stirred for 3 hours at room temperature. The solution is subsequently precipitated into 500 ml of ice water, the precipitate is suctioned off, and the residue is dissolved in methylene chloride. The organic solution is dried over magnesium sulfate and concentrated. The crude product is recrystallized from hexane, thus obtaining 15.30 g of the title compound, mp 75.8° C. |
Yield | Reaction Conditions | Operation in experiment |
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82.7% | With pyridine; In acetonitrile; | EXAMPLE 11 Preparation of 1-triphenylmethylimidazole A mixture of pyridine (15 ml), diphenyl phosphite (2.34 g, 10 mmole), imidazole (0.68 g, 10 mmole) and triphenylmethanol (2.08 g, 8 mmole) was refluxed for 3 hours. Pyridine was removed under reduced pressure, and the residue was extracted with dichloromethane. The extract was washed with a 5percent aqueous hydroxide solution and water in order, dried and evaporated. Recrystallization of the residue (2.23 g) from acetonitrile gave 2.05 g of 1-triphenylmethylimidazole as colorless needles. Yield, 82.7percent. M.P., 221°-223° C. Elementary analysis: Calcd. for C22 H18 N2: C, 85.13percent; H, 5.85percent; N, 9.03percent. Found: C, 85.20percent; H, 6.03percent; N, 9.21percent. |
Yield | Reaction Conditions | Operation in experiment |
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100% | In dichloromethane; | (a) tert-Butyl-dimethyl-[2-(2-nitro-phenyl)-ethoxy]-silane. A solution of 2-(2-nitro-phenyl)ethanol (10 g, 59 mmol) in CH2Cl2 (100 mL), was treated with imidazole (11.72 g, 77.7 mmol) followed by tert-butyl-dimethylsilylchloride (5.62 g, 82.6 mmol). A white precipitate formed upon the addition and the reaction was stirred 2.5 hours. The mixture was filtered and diluted with CH2Cl2 (100 mL) and was washed with 0.1 N HCl, H2O, saturated aq NaHCO3, and brine. The organic layer was dried over MgSO4, filtered and concentrated to give a transparent oil which was placed under high vacuum overnight to give the title compound (16.8 g, 100percent) as a transparent oil. 1H NMR (400 MHz, DMSO-d6) -0.11 (s, 6H), 0.77 (s, 9H), 3.03 (t, J=6 Hz, 2H), 3.79 (t, J=6 Hz), 7.42-7.54 (m, 2H), 7.62 (ddd, J=<1, 6, 7 Hz, 1H), 7.88 (dd, J=<1, 7 Hz, 1H). MS (electrospray, m/z) 282 (M++1). |
96% | In dichloromethane; | (a) tert-Butyl-dimethyl-[2-(2-nitro-phenyl)-ethoxy]-silane. A solution of 2-(2-nitro-phenyl)ethanol (100 g, 590 mmol) in CH2Cl2 (800 mL), was treated with imidazole (117 g, 777 mmol) followed by tert-butyl-dimethylsilylchloride (562 g, 826 mmol). A white precipitate formed upon the addition and the reaction was stirred 2.5 hours. The mixture was filtered and diluted with CH2Cl2 (300 mL) and was washed with 0.1 N HCl (300 mL), H2O (400 mL), saturated aq NaHCO3 (400 mL), and brine (400 mL). The organic layer was dried over MgSO4, filtered and concentrated to give the title compound (160 g, 96percent) as a transparent oil. 1H NMR (400 MHz, DMSO-d6) -0.11 (s, 6H), 0.77 (s, 9H), 3.03 (t, J=6 Hz, 2H), 3.79 (t, J=6 Hz), 7.42-7.54 (m, 2H), 7.62 (ddd, J=<1, 6, 7 Hz, 1H), 7.88 (dd, J=<1, 7 Hz, 1H). MS (electrospray, m/z) 282 (H++1). |
Yield | Reaction Conditions | Operation in experiment |
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In acetonitrile; for 1.5h;Reflux; Inert atmosphere; | Alternatively both steps of the process can be performed in a single reaction vessel without isolation of the imidazolium intermediate. A 5 L round bottom flask equipped with mechanical stirring was flame-dried and cooled under Ar. Acetonitrile (800 mL), imidazole (79 g, 115 mmol), N,N'-diphenyl-N,N'-bis(3-methylphenyl)benzidine (mTBD) (100 g, 192 mmol), and trifluoroacetic anhydride (323 mL, 233 mmol) were combined and the mixture was heated to reflux and monitored by HPLC. The reaction was complete in less than 1.5 h to form the tetrasubstituted imidazoline product. The reaction mixture was removed from the oil bath and THF (1.6 L) and HCl (2 M aq, 800 mL) was added. The mixture was returned to the heating bath and stirred at 90 C for 16 h. No starting material remained with the tetrasubstituted imidazoline compound fully hydrolyzed to the tetraformyl product. The mixture was cooled to room temperature, diluted with MeOH (500 mL, drop-wise) and slowly poured into 4 L of water. This mixture was filtered to obtained a rust-coloured solid which contained byproducts. The mixture was dissolved in THF (1.2 L) and added drop-wise to a mixture of MeOH/water (5 L, 1:1). The resulting yellow solid was collected by filtration (144 g as wet solid). The sample was further purified by dissolving in toluene and filtering through a celite plug. All pure material was eluted from the plug by subsequent elution with THF. The product was obtained as adducts of toluene and THF. Taking into account the mass of included solvent in the purified product the total mass obtained was 85 g. |
Yield | Reaction Conditions | Operation in experiment |
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Methyl 6-chloro-5-nitronicotinate (2.17 g, 10.0 mmol) was dissolved in ethyl acetate (55 mL) and imidazole (4.09 g, 60 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and treated with 5 nCl2-2H2O (13.5 g, 60.0 mmol). It was heated to 70° C. for 2 h, diluted with potassium carbonate (sat. aq.) and extracted with ethyl acetate (5.x.20 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a crude yellow solid, which was used in the next step without further purification. [M+H] calc'd for C10H10N4O2, 219; found, 219. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In dichloromethane; | (i) Preparation of (2-iodoethoxy)-tert-butyldimethylsilane To a stirred solution of 2-iodoethanol (17.2 g; 100 mmol) and imidazole (8.17 g; 120 mmol) in dichloromethane (100 mL) was added tert-butyldimethylsilyl chloride (15.83 g; 105 mmol) at such a rate that the reaction temperature did not rise above 30° C. Upon complete addition the solution was left stirring for 17 h, then washed with water (2*50 mL) and brine (50 mL) and dried over MgSO4. Evaporation of the solvent afforded the target compound (28.0 g; 97.8 mmol; 98percent) as a colourless liquid. 1H-NMR (400 MHz) (CDCl3): delta=3.83 (t, 2H, J=7.0 Hz), 3.83 (t, 2H, J=7.0 Hz), 3.20 (t, 2H, J=7 Hz), 0.90 (s, 9H), 0.08 (s, 6H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; | [4-(Benzyloxy)phenethoxy](tert-butyl)dimethylsilane 2-[4-(Benzyloxy)phenyl]ethanol (11.4 g, 50.7 mmol) was dissolved in 100 mL of DCM and cooled to 0 °C. Imidazole (4.2 g, 61.2 mmol) and TBSCI (8.5 g, 56.0 mmol) were successively added portionwise and the resulting white suspension was warmed to room temperature and stirred for 21 h. Then, the reaction was quenched with MeOH (15 mL), vigorously stirred for 5 min and evaporated to dryness under vacuum. The resulting white solid was dissolved with EtOAc (5x) and the resulting organic phase was successively washed with sat. aq. solution of NH4Cl (3x), 10percent aq. NaHCO3 (3x) and brine (2x). The organic layer was dried over anhydrous MgSO4 and evaporated to dryness under vacuum to afford 17.1 g of a white solid which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate; In acetone;Reflux; | General procedure: Briefly, a mixture of imidazole (100 mmol), alkyl bromide (100 mmol) and K2CO3 (200 mmol) inacetone (200 mL) was refluxed overnight. Upon filtration and solvent removal, the remaining residuewas subjected to flash chromatography with ethyl acetate to produce >90percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 3h; | To a suspension of methyl 6- chloropyridazine-3-carboxylate (1 g, 5.8 mmol) and imidazole (400 mg, 5.8 mmol) in dry DMF (10 mL), was added K2CO3 (950 mg, 6.8 mmol) and the reaction mixture was stirred at 120 C for 3h. The reaction was monitored by LCMS. After complete conversion to methyl 6- (1 H-imidazol-1-yl)pyridazine-3-carboxylate, 2.5 M aq. LiOH (2.8 mL, 6.96 mmol) was added to the reaction mixture and stirred at 60 C for 1 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was acidified with aq.1 M HCI and the resulting precipitate was filtered and washed with water, to obtain the acid A (720 mg) as an off-white solid which was used in the next step without further purification. LC-MS (ESI+): m/z 191.0 [M+H]+. |
Tags: Imidazole | 1,3-Diaza-2,4-cyclopentadiene | Buffer | Other Buffers | Imidazole | Antibacterial | Structure | Anti-Infection | Biological Buffers | Gene Cloning | 288-32-4
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