- Heteroaryl hydroxycarbonylation: An efficient, robust, practically scalable approach using formyl acetate as the co source
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A simple, efficient, regioselective, and scalable palladium-catalyzed hydroxycarbonylation of heteroaryl halides to corresponding carboxylic acids using acetic-formic anhydride in presence of Pd(OAc)2, dppf, and diisopropylethyl amine in dimethyl formamide at 80-90 °C in excellent yields. Taylor & Francis Group, LLC.
- Gadakh, Amol V.,Chikanna, Dinesh,Rindhe, Sahebrao S.,Karale, Bhausaheb K.
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- Oxidation of imidazole- and pyrazole-derived aldehydes by plant aldehyde dehydrogenases from the family 2 and 10
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Plant cytosolic aldehyde dehydrogenases from family 2 (ALDH2s, EC 1.2.1.3) are non-specific enzymes and participate for example in the metabolism of acetaldehyde or biosynthesis of phenylpropanoids. Plant aminoaldehyde dehydrogenases (AMADHs, ALDH10 family, EC 1.2.1.19) are broadly specific and play an important role in polyamine degradation or production of osmoprotectants. We have tested imidazole and pyrazole carbaldehydes and their alkyl-, allyl-, benzyl-, phenyl-, pyrimidinyl- or thienyl-derivatives as possible substrates of plant ALDH2 and ALDH10 enzymes. Imidazole represents a building block of histidine, histamine as well as certain alkaloids. It also appears in synthetic pharmaceuticals such as imidazole antifungals. Biological compounds containing pyrazole are rare (e.g. pyrazole-1-alanine and pyrazofurin antibiotics) but the ring is often found as a constituent of many synthetic drugs and pesticides. The aim was to evaluate whether aldehyde compounds based on azole heterocycles are oxidized by the enzymes, which would further support their expected role as detoxifying aldehyde scavengers. The analyzed imidazole and pyrazole carbaldehydes were only slowly converted by ALDH10s but well oxidized by cytosolic maize ALDH2 isoforms (particularly by ALDH2C1). In the latter case, the respective Km values were in the range of 10–2000 μmol l?1; the kcat values appeared mostly between 0.1 and 1.0 s?1. The carbaldehyde group at the position 4 of imidazole was oxidized faster than that at the position 2. Such a difference was not observed for pyrazole carbaldehydes. Aldehydes with an aromatic substituent on their heterocyclic ring were oxidized faster than those with an aliphatic substituent. The most efficient of the tested substrates were comparable to benzaldehyde and p-anisaldehyde known as the best aromatic aldehyde substrates of plant cytosolic ALDH2s in vitro.
- Fr?mmel, Jan,Kon?itíková, Radka,Kope?ny, David,Soural, Miroslav,?ebela, Marek
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- Organic-inorganic hybrid materials constructed from inorganic lanthanide sulfate skeletons and organic 4,5-imidazoledicarboxylic acid
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Five different types of the lanthanide sulfate-carboxylates family, [La2(SO4)(Himdc)2(H2O)2] 1, [Gd2(SO4)2(Himdc)(H2O) 3]·H2O 2, [Ln2(SO4) 2(Himdc)(H2O)3]·H2O (Ln = Gd 3a, Eu 3b), [Eu6Cu(SO4)6(Himdc) 4(H2O)14] 4, and [Ln(Himc)(SO 4)(H2O)] (Ln = Eu 5a, Gd 5b, Tb 5c, Dy 5d, Er 5e); H 2imc = 4-imidazolecarboxylic acid, H3imdc = 4,5-imidazoledicarboxylic acid) have been obtained by hydrothermal reactions of Ln2O3, transition metal sulfates and H3imdc at 170 °C and characterized by means of elemental analyses, IR, TG analysis, luminescence spectroscopy and single crystal X-ray diffraction. The 3D structure of 1 is constructed from alternately linkages of organic {La(Himdc)} layers and inorganic {La2O2(SO4)} layers, with the La atoms as hinges. 2 and 3a/3b both contain alternately arranged 1D left- and right-handed helical {Ln(imdc)} chains bridged by SO42- anions to form a 3D framework with 1D rectangle-like channels along the b axis. The structural differences of 2 and 3a/3b lie in the linkages of the SO 42- anions. Complex 4 consists of 2D tubular Eu-sulfate layers pillared by {Cu(Himdc)2} units to generate a 3D network. Complexes 5a-5e possess 2D bamboo-raft-like layer structures based on helical tubes. Interestingly, H2imc comes from the in-situ decarboxylation of H3imdc in the hydrothermal reactions. The luminescence properties of the complexes 3a, 4, 5a 5c, 5d were investigated in solid state at room temperature. The Royal Society of Chemistry.
- Sun, Yan-Qiong,Yang, Guo-Yu
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- Synthesis method of 1H-imidazole-4-carboxylic acid
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The invention discloses a synthesis method of 1H-imidazole-4-carboxylic acid. The method comprises steps as follows: (1) a hydrochloric acid solution is added to a reaction kettle, chromium trioxide is added under the stirring condition, the mixture is stirred uniformly and heated to 40-50 DEG C, pyridine is dropwise added, the mixture is stirred to react for 2-3 h after pyridine is dropwise added, PCC (pyridinium chlorochromate) is prepared, TiO2 is added, a dichloromethane solution of 4-methylimidazole is dropwise added under the stirring condition, the mixture is subjected to a reaction at40-50 DEG C for 3-4 h, then, filtration and centrifugation are performed, an organic layer is collected, reduced pressure distillation is performed, and 1H-imidazole-4-formaldehyde is prepared; (2) prepared 1H-imidazole-4-formaldehyde and dichloromethane are mixed, the obtained mixture is heated to 40-50 DEG C, KMnO4 is added, the mixture is mixed uniformly and stirred for a reaction for 3-4 h, filtration, reduced pressure distillation and recrystallization are performed, and 1H-imidazole-4-carboxylic acid is prepared. The synthesis method is simple to operate and mild in condition, fewer by-products are produced, the product purity is high and the product yield is higher.
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Paragraph 0022; 0029; 0036; 0043; 0050
(2018/05/16)
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- Efficient synthesis method of pharmaceutical intermediate 1H-imidazole-4-formic acid
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The invention discloses an efficient synthesis method of a pharmaceutical intermediate 1H-imidazole-4-formic acid. The efficient synthesis method specifically comprises the following steps: firstly, preparing a titanium dioxide/titanium niobate compound catalyst; then taking 2-thiol-4-imidazole ethyl formate as a raw material; preparing 1H-imidazole-4-ethyl formate under the action of a hydrogen peroxide solution and a compound catalyst; then enabling the 1H-imidazole-4-ethyl formate to react with alkali liquid to prepare a target product. The efficient synthesis method disclosed by the invention has a simple reaction process and raw materials are cheap and easy to obtain; the prepared target product is simple to separate and the yield reaches 90 percent or more.
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Paragraph 0022; 0027; 0028; 0033; 0034; 0039; 0040; 0045
(2018/12/14)
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- Preparation method of 1H-imidazole-4-carboxylic acid
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The invention discloses a preparation method of 1H-imidazole-4-carboxylic acid. The preparation method includes dissolving 4-methylimidazole into an organic solvent, adding an oxidizing agent and a catalyst with stirring evenly, heating to 70-90 DEG C at a normal pressure, feeding oxygen, conducting refluxing reaction for 90-120 minutes and purifying to obtain the 1H-imidazole-4-carboxylic acid. The preparation method has the advantages that the preparation method is capable of preparing the 1H-imidazole-4-carboxylic acid through a one-step method, and is mild in reaction condition, high in conversion rate and simple in aftertreatment operation by the aid of a novel catalyst system, thereby having a promising industrial prospect.
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Paragraph 0018-0029
(2017/06/02)
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- Method for catalytically synthesizing 1H-imidazole-4-carboxylic acid through inorganic-salt composite catalyst
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The invention discloses a method for catalytically synthesizing 1H-imidazole-4-carboxylic acid through an inorganic-salt composite catalyst. Ethyl acetamidoacetate serves as a raw material and is enolized, cyclized, subjected to catalytic oxidation desulfurization and hydrolyzed to prepare the target compound; the method includes the three steps of preparing 2-sulfydryl-4-ethyl imidazolecarboxylate, preparing ethyl imidazole-4-carboxylate and preparing the 1H-imidazole-4-carboxylic acid; the inorganic-salt composite catalyst is prepared in the mode that barium sulfate, ferric nitrate and iron sulfate are compounded. The development method is a synthetic technology which is economical, environmentally friendly and easy to operate; the inorganic-salt composite catalyst is provided and added in an inorganic-salt solid mode, the cost of a raw material of the catalyst is low, a preparing method is environmentally friendly and simple, the selectivity of the catalytic effect of the catalyst is high, the yield is remarkably increased, by products are avoided, the catalyst can be recycled, and the quite high market promotion value is achieved.
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Paragraph 0010; 0088; 0089
(2016/10/17)
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- Preparation method of 1H-imidazole-4-carboxylic acid
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The invention discloses a synthesis method of 1H-imidazole-4-carboxylic acid, and belongs to the field of chemical synthesis. A target compound is prepared through optimized enolization, cyclization, catalytic oxidation desulfurization and hydrolysis reaction with ethyl acetamidoacetate as the raw material, the yield of 1H-imidazole-4-carboxylic acid is increased, antimony butter is added as the catalyst for catalytic oxidation desulfurization reaction, the yield of 1H-imidazole-4-carboxylic acid is increased, energy consumption is lowered, and economic benefits are improved.
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Paragraph 0083; 0094; 0095; 0096; 0097
(2016/10/10)
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- Synthesis method of 4(5)-hydroxymethylimidazole
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The invention discloses a synthesis method of 4(5)-hydroxymethylimidazole. With 4,5-imidazoledicarboxylic acid as the raw material, decarboxylic reaction, esterification reaction and reduction reaction are conducted, manganese dioxide solid, ferric sulfate powder and a loaded Ni-Cu/SiO2 catalyst are added for catalytic reaction, reaction efficiency is improved, and reaction operation is simplified; meanwhile, the reaction process is improved, that is, the precipitation of 4(5)-imidazole carboxylic acid imidazole is promoted by adding sodium nitrate solid 5, the addition of concentrated sulfuric acid and a sodium hydroxide solution for neutralizing concentrated sulfuric acid is reduced by adding a catalyst, reaction consumption is reduced, reaction efficiency is improved, reaction operation is simplified, and high industrial popularization value is achieved.
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Paragraph 0074; 0075
(2016/12/01)
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- Aggrecanase-2 inhibitors based on the acylthiosemicarbazide zinc-binding group
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Osteoarthritis is a disabling disease characterized by the articular cartilage breakdown. Aggrecanases are potential therapeutic targets for the treatment of this pathology. At the starting point of this project, an acylthiosemicarbazide was discovered to inhibit aggrecanase-2. The acylthiosemicarbazide Zn binding group is also a convenient linker for library synthesis. A focused library of 920 analogs was thus prepared and screened to establish structure-activity relationships. The modification of the acylthiosemicarbazide was also explored. This strategy combining library design and discrete compounds synthesis yielded inhibitor 35, that is highly selective for aggrecanases over a panel of metalloproteases and inhibits the degradation of native fully glycosylated aggrecan. A docking study generated binding conformations explaining the structure-activity relationships.
- Maingot, Lucie,Elbakali, Jamal,Dumont, Julie,Bosc, Damien,Cousaert, Nicolas,Urban, Agathe,Deglane, Gaelle,Villoutreix, Bruno,Nagase, Hideaki,Sperandio, Olivier,Leroux, Florence,Deprez, Benoit,Deprez-Poulain, Rebecca
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p. 244 - 261
(2013/10/01)
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- 6,7- DIHYDROIMIDAZO [1,5-A] PYRAZIN-8 (5H) - ONE DERIVATIVES AS PROTEIN KINASE MODULATORS
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There are provided 3,5-disubstituted derivatives of 6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one compounds of formula (I) or a pharmaceutically acceptable salt thereof as defined in the present specification, which modulate the activity of protein kinases. The compounds are therefore useful in treating diseases caused by dysregulated protein kinase activity. In particular, such diseases to be treated with a compound of formula (I) of the present invention is one caused by and/or associated with disregulated protein kinase activity selected from the group consisting of cancer, viral infection, prevention of AIDS development in HIV-infected individuals, cell proliferative disorders, autoimmune and neurodegenerative disorders. The present invention also relates to processes for preparing the compounds of formula (I), combinatorial libraries thereof, pharmaceutical compositions comprising them, and methods of treating diseases utilizing pharmaceutical compositions comprising a compound of formula (I).
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Page/Page column 26
(2011/08/21)
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- Synthesis and SAR of novel imidazoles as potent and selective cannabinoid CB2 receptor antagonists with high binding efficiencies
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The synthesis and structure-activity relationship studies of imidazoles are described. The target compounds 6-20 represent a novel chemotype of potent and CB2/CB1 selective cannabinoid CB2 receptor antagonists/inverse agonists with very high binding efficiencies in combination with favourable log P and calculated polar surface area values. Compound 12 exhibited the highest CB2 receptor affinity (Ki = 1.03 nM) in this series, as well as the highest CB2/CB1 subtype selectivity (>9708-fold).
- Lange, Jos H.M.,van der Neut, Martina A.W.,Wals, Henri C.,Kuil, Gijs D.,Borst, Alice J.M.,Mulder, Arie,den Hartog, Arnold P.,Zilaout, Hicham,Goutier, Wouter,van Stuivenberg, Herman H.,van Vliet, Bernard J.
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scheme or table
p. 1084 - 1089
(2010/06/11)
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- PHARMACEUTICAL AND COSMETIC COMPOSITIONS COMPRISING UROCANIC ACID DERIVATIVES AS RADICAL SCAVENGERS OR ANTIOXIDANTS
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Upon exposure to UVB, the epidermal component trans-urocanic acid is not only photoisomerized into cis-urocanic acid, but will also, at least in part, be photooxidized into urocanic acid oxidation products. We hypothesized that urocanic acid oxidation products can mimic UV-induced systemic immunosuppression comparable to the suppressive properties already established for cis-urocanic acid. A crude mixture of urocanic acid oxidation products showed a significant suppression of the sensitization phase of the systemic contact hypersensitivity response to picryl chloride. Three of the urocanic acid oxidation products were selected for this study: imidazole-4-carboxylic acid, imidazole-4-carboxaldehyde and imidazole-4-acetic acid. Effects on the sensitization-, elicitation- and post-elicitation phase of contact hypersensitivity to picryl chloride in BALB/c mice were studied and compared to the effects of cis-urocanic acid. Imidazole-4-carboxaldehyde was equally effective at suppressing the sensitization phase as cis-urocanic acid. The triplet combination of the imidazoles showed more pronounced suppression than that induced by cis-urocanic acid. The most effective compounds for the suppression of the elicitation phase appeared to be imidazole-4-acetic acid and cis-urocanic acid. Significant suppression of the post-elicitation phase was only obtained with the triplet combination of imidazole-4-carboxaldehyde, imidazole-4-carboxylic acid and imidazole-4-acetic acid, which combination appeared to be effective at all three tested phases, Because these three urocanic acid oxidation products are present in UVB-exposed human stratum corneum, these compounds may play a role in UVB-induced immunosuppression.
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Page/Page column 5; 14; 15; 22
(2008/06/13)
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- Aqueous biphasic oxidation: A water-soluble polyoxometalate catalyst for selective oxidation of various functional groups with hydrogen peroxide
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A "sandwich" type polyoxometalate, Na12[(WZn 3(H2O)2][(ZnW9O34) 2], was used as an oxidation catalyst in aqueous biphasic reaction media to effect oxidation of alcohols, diols, pyridine derivatives, amines and aniline derivatives with hydrogen peroxide. The catalyst was shown by 183W NMR to be stable in aqueous solutions in the presence of H 2O2 and showed only minimal non-productive decomposition of the oxidant. Secondary alcohols were selectively oxidized to ketones, while primary alcohols tended to be oxidized to the corresponding carboxylic acids, although secondary alcohols were selectively oxidized in the presence of primary alcohols. Vicinal diols yielded carbon-carbon bond cleavage products in very high yields. Pyridine derivatives were oxidized to the respective TV-oxides, but strongly electron-withdrawing moieties inhibited the oxidation reaction. Primary amines were oxidized to the oximes, but significantly hydrolyzed in situ. Aniline derivatives were oxidized to the corresponding azoxy or nitro products depending on the substitution pattern in the aromatic ring. Catalyst recovery and recycle was demonstrated.
- Sloboda-Rozner, Dorit,Witte, Peter,Alsters, Paul L.,Neumann, Ronny
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p. 339 - 345
(2007/10/03)
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- INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
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The present invention comprises analogs of the CAAX motif of the protein Ras that is modified by farnesylation in vivo. These CAAX analogs inhibit the farnesylation of Ras. Furthermore, these CAAX analogues differ from those previously described as inhibitors of Ras farnesyl transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production
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- 7-oxabicycloheptane imidazole prostaglandin analogs useful in the treatment of thrombotic and vasospastic disease
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7-Oxabicycloheptane imidazole prostaglandin analogs are provided which are useful in treating thrombotic and vasospastic disease and have the structural formula STR1 wherein m is 0, 1, 2, 3 or 4; n is 1, 2 or 3; and p is 1, 2 or 3; Z is --CH=CH--, --CH2 CH2 -- or STR2 wherein Y is 1 or a single bond; R is CO2 H, CO2 lower alkyl, CO2 alkali metal, CONHSO2 R2 (wherein R2 is lower alkyl or aryl) or --CH2 -5-tetrazolyl; A is CHOH, C=O, STR3 (wherein R3 is H or lower alkyl), or a single bond; R1 is lower alkyl, aryl, cycloalkyl or H, R1 can be H only when A is a single bond.
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- Preparation of imidazole-4(5)-monocarboxylic acids and their salts or betaines
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Imidazole-4(5)-monocarboxylic acids and their salts or betaines are prepared by reacting an imidazole with carbon dioxide and an alkali metal carbonate, an alkali metal bicarbonate and/or an alkali metal hydroxide at from 140° to 230° C. and under from 2 to 350 bar and, if desired, then reacting the product with an acid. The imidazole-4(5)-monocarboxylic acids which can be prepared by the process of the invention are useful starting materials for the preparation of dyes, crop protection agents and drugs.
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- New Synthesis of 2-Nitroimidazoles
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1-Triphenylmethylimidazoles are treated with n-butyllithium in tetrahydrofuran at 0 deg C to form the 2-lithio derivatives.The latter species react with n-propyl nitrate to give 1-trityl-2-nitroimidazoles which, after acid hydrolysis, provide the correspondine 2-nitroimidazoles. 2-Nitroimidazole was obtained from imidazole from overall yields of 27-35percent; 4-methyl-2-nitroimidazole was obtained in 40percent overall yield from 4-methylimidazole.Imidazole-4,5-dicarboxylic acid was converted, in several steps, to 1-tritylimidazole-4-methanil, and the latter compound was transformed into 2-nitroimidazole-4-methanol in an overall yield of 18percent.Protection of the hydroxymethyl function was found to be unnecessary during carbanion formation and nitration.Attempts to nitrate 1-methylimidazole or 1-methoxymethylimidazole by the same procedure failed.
- Davis, Dwight P.,Kirk, Kenneth L.,Cohen, Louis A.
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p. 253 - 256
(2007/10/02)
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