- Ketorolac impurity C and preparation method and application thereof
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The invention discloses a ketorolac impurity C and a preparation method and application thereof. According to the method, the ketorolac impurity C is prepared by taking pyrrole as an initial raw material through a series of reactions such as substitution,
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Paragraph 0037-0039
(2021/06/06)
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- Enhancing activity and selectivity in a series of pyrrol-1-yl-1-hydroxypyrazole-based aldose reductase inhibitors: The case of trifluoroacetylation
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Aldose reductase (ALR2) has been the target of therapeutic intervention for over 40 years; first, for its role in long-term diabetic complications and more recently as a key mediator in inflammation and cancer. However, efforts to prepare small-molecule aldose reductase inhibitors (ARIs) have mostly yielded carboxylic acids with rather poor pharmacokinetics. To address this limitation, the 1-hydroxypyrazole moiety has been previously established as a bioisostere of acetic acid in a group of aroyl-substituted pyrrolyl derivatives. In the present work, optimization of this new class of ARIs was achieved by the addition of a trifluoroacetyl group on the pyrrole ring. Eight novel compounds were synthesized and tested for their inhibitory activity towards ALR2 and selectivity against aldehyde reductase (ALR1). All compounds proved potent and selective inhibitors of ALR2 (IC50/ALR2?=?0.043?0.242?μΜ, Selectivity index?=?190?858), whilst retaining a favorable physicochemical profile. The most active (4g) and selective (4d) compounds were further evaluated for their ability to inhibit sorbitol formation in rat lenses ex?vivo and to exhibit substrate-specific inhibition.
- Papastavrou, Nikolaos,Chatzopoulou, Maria,Ballekova, Jana,Cappiello, Mario,Moschini, Roberta,Balestri, Francesco,Patsilinakos, Alexandros,Ragno, Rino,Stefek, Milan,Nicolaou, Ioannis
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p. 328 - 335
(2017/03/09)
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- Hexafluoro-2-propanol-Promoted Intermolecular Friedel-Crafts Acylation Reaction
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The intermolecular Friedel-Crafts acylation was carried out in hexafluoro-2-propanol to yield aryl and heteroaryl ketones at room temperature without any additional reagents.
- Vekariya, Rakesh H.,Aubé, Jeffrey
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supporting information
p. 3534 - 3537
(2016/08/16)
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- An efficient and green method for regio- and chemo-selective Friedel-Crafts acylations using a deep eutectic solvent ([CholineCl][ZnCl2]3)
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[CholineCl][ZnCl2]3, a deep eutectic solvent between choline chloride and ZnCl2, has been used as a dual function catalyst and green solvent for the Friedel-Crafts acylation of aromatic compounds instead of using the moisture-sensitive Lewis acids and volatile organic solvents. The reactions are performed with high yields under microwave irradiation with short reaction times for the synthesis of ketones. Interestingly, indole derivatives are regioselectively acylated in the 3-position under mild conditions with high yields without NH protection. Three new ketone products are synthesized. [CholineCl][ZnCl2]3 is easily synthesized from choline chloride and zinc chloride at a low cost, with easy purification and environmentally benign compounds. [CholineCl][ZnCl2]3 can be reused up to five times without loss of catalytic activity, making it ideal in industrial processes.
- Tran, Phuong Hoang,Nguyen, Hai Truong,Hansen, Poul Erik,Le, Thach Ngoc
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p. 37031 - 37038
(2016/05/24)
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- Antimalarial activity of natural and synthetic prodiginines
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Prodiginines are a family of linear and cyclic oligopyrrole red-pigmented compounds. Herein we describe the in vitro antimalarial activity of four natural (IC50 = 1.7-8.0 nM) and three sets of synthetic prodiginines against Plasmodium falciparum. Set 1 compounds replaced the terminal nonalkylated pyrrole ring of natural prodiginines and had diminished activity (IC 50 > 2920 nM). Set 2 and set 3 prodiginines were monosubstituted or disubstituted at either the 3 or 5 position of the right-hand terminal pyrrole, respectively. Potent in vitro activity (IC50 = 0.9-16.0 nM) was observed using alkyl or aryl substituents. Metacycloprodiginine and more potent synthetic analogues were evaluated in a P. yoelii murine patent infection using oral administration. Each analogue reduced parasitemia by more than 90% after 25 (mg/kg)/day dosing and in some cases provided a cure. The most favorable profile was 92% parasite reduction at 5 (mg/kg)/day, and 100% reduction at 25 (mg/kg)/day without any evident weight loses or clinical overt toxicity.
- Papireddy, Kancharla,Smilkstein, Martin,Kelly, Jane Xu,Shweta,Salem, Shaimaa M.,Alhamadsheh, Mamoun,Haynes, Stuart W.,Challis, Gregory L.,Reynolds, Kevin A.
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experimental part
p. 5296 - 5306
(2011/10/02)
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- A facile, highly efficient synthesis of fully N-confused calix[5]pyrrole
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Fully N-confused calix[5]pyrroles 3 are prepared in high yield by the oligomerization of 3-hydroxyphenylmethylpyrrole 2 under acid-catalysed conditions at room temperature.
- Chen, Qingqi,Wang, Tianyu,Zhang, Yi,Wang, Qiuan,Ma, Jinshi
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p. 1041 - 1049
(2007/10/03)
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- Diethoxymethyl protected pyrroles: Synthesis and regioselective transformations
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Treatment of the acceptor-substituted pyrroles 1a-k with neat triethyl orthoformate gives access to the diethoxymethyl (DEM) protected derivatives 2a-k in high yield. Convenient and mild cleavage was achieved by subsequent treatment of the DEM-pyrroles 2a-k with trifluoroacetic acid in acetonitrile and aqueous NaOH at room temperature. DEM protection proved suitable for a variety of regioselective transformations involving directed orthometalation and iodine-magnesium exchange processes. Furthermore, electrophilic halogenations and Pd-catalyzed coupling reactions were also carried out.
- Bergauer,Gmeiner
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p. 2281 - 2288
(2007/10/03)
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- The regioselective photoinduced aroylation at the 3-position of pyrrole derivatives
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Irradiation of arenecarbothioamide with pyrrole or indole derivatives gave regioselectively 3-aroylpyrrole or -indole derivatives, respectively.
- Oda, Kazuaki,Hiratsuka, Rin,Machida, Minoru
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p. 463 - 470
(2007/10/03)
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- Antifungal agents. VIII. Synthesis and antifungal activities of bipyrryl analogues of bifonazole
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Various bipyrryl analogues of bifonazole were synthesized starting from aryl-3-pyrryl-1-imidazolylmethanes. The introduction of a second pyrryl portion was performed by linking an acrylate moiety at 1-position of the pyrrole ring and then by treatment with TosMIC. The bipyrryl esters were hydrolyzed and decarboxylated to afford the required imidazoles. All new imidazole derivatives were tested against Candida albicans and Candida spp using as standard controls miconazole, bifonazole and ketoconazole.
- Di Santo,Massa,Costi,Simonetti,Retico,Apuzzo,Troccoli
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p. 229 - 236
(2007/10/02)
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- General Methods for Synthesizing 2,4-Diacylpyrroles and their Precursors Containing One or Two Masked Acyl Groups
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A thorough study of the synthesis of 2,4-diacylpyrroles by direct acylation of pyrrole and 2- and 3-acylpyrroles is reported.Among these, Friedel-Crafts acylation of 3-acylpyrroles is the most general and advantageous method because it utilises easily accessible starting materials.In addition it is always regiospecific and readily provides 2,4-diacylpyrroles containing identical or different acyl groups in very high yields (81-100percent) under mild conditions, Alternative procedures concern the synthesis of precursors of 2,4-diacylpyrroles containing one or two acyl groups masked by a 1,3-benzodithiolyl or 1,3-benzoxathiolyl group and subsequent hydrolysis with HgO-35percent aq.HBF4-Me2SO.Overall yields are always good (52-60percent).Indirect acylation constitutes a secure complement to direct acylation when it is necessary to operate in the presence of protected acyl groups.
- Cadamuro, Silvano,Degani, Iacopo,Dughera, Stefano,Fochi, Rita,Gatti, Antonella,Piscopo, Laura
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p. 273 - 284
(2007/10/02)
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- 1-aminoacetamidopyrroles and 1-aminoacetamido-2-(substituted)pyrroles and related compounds
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There are disclosed 1-aminoacetamidopyrroles and 1-amino-2-(substituted)-pyrroles and related compounds of the formula STR1 wherein all substituents are defined herein, which are useful as glycine partial agonists and for the enhancement of learning and memory and for the treatment of memory dysfunctions associated with neurodegenerative disorders and are thus indicated in the treatment of Alzheimer''s disease and other senile dementias.
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- Gas-phase heteroaromatic substitution. 11. Electron transfer mechanism in the gas-phase acylation of simple five-membered heteroarenes
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The results of a study of the gas-phase reactions of unsaturated carbocations, such as the CH3CO+ ion from γ-radiolysis of CH3F/CO mixtures, and the C6H4TCO+ ion from the β-decay of 1,4-ditritiobenzene in the presence of CO, with pyrrole, N-methylpyrrole, furan, and thiophene, are reported.In all systems investigated, acylated heteroarenes represent the predominant reaction products, accompanied by the methylated derivatives in the CH3F/CO radiolytic mixtures, and by the phenylated ones in the 1,4-ditritiobenzene/CO decay samples.All substrates investigated are found to undergo predominat α substitution by both acetyl (88.6-98.4percent (pyrrole); 90.8-98.7percent (N-methylpyrrole); 97.2-98.9percent (furan); 94.9-98.6percent (thiophene)) and benzoyl cations (92.6-96.5percent (pyrrole)) under all conditions.The predominant formation of the α-acylated pyrroles from both reactants (>88percent), whose relative yields appear unaffected within the temperature interval from 303 to 383 K, indicates, in agreement with ancillary FT-ICR mass spectrometric evidence, that gas-phase acylation reactions toward simple five-membered heteroarenes proceed via a two-step substitution mechanism, involving a quasi-resonant single-electron transfer (SET) step followed by recombination of the ensuing radical - radical ion pair.By virtue of this entropy-favored mechanism, gaseous electrophiles with relatively high SCF STO-3G calculated LUMO energies such CH3CO+ and C6H4TCO+ are effectively oriented toward the "soft" Cα sites of the selected heteroarenes, at variance with Klopman's Charge and Frontier Orbital Control predictions.The behavior of gaseous acylating reactants toward simple heteroarenes is discussed and compared with that of other gaseous electrophiles, whose reactivity appears instead in qualitative agreement with Klopman's model.
- Filippi, Antonello,Occhiucci, Giorgio,Sparapani, Cinzia
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p. 740 - 748
(2007/10/02)
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- N-(Triisopropylsilyl)pyrrole. A Progenitor "Par Excellence" of 3-Substituted Pyrroles
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A very effective strategy has been devised for the synthesis of 3-substituted pyrroles based on the use of the triisopropylsilyl (TIPS) moiety as a sterically demanding nitrogen substituent to obstruct the attack of electrophilic reagents at the α positions. 1-(Triisopropylsilyl)pyrrole (1) undergoes highly preferential kinetic electrophilic substitution at the β position with a variety of electrophiles (Br+, I+, NO2+, RCO+, etc.) and fluoride ion induced desilylation of the products provides the corresponding 3-substituted pyrroles in good overall yields.Competitive trifluoroacetylation experiments demonstrate that substitution of TIPS-pyrrole at the α positions is decelerated by a factor of >104, vs pyrrole at the same sites, without affecting reactivity at the β positions. 1-(Triisopropylsilyl)-3-bromopyrrole (2) is readily converted into the 3-lithio compound 44 by bromine-lithium interchange with alkyllithium reagents.This previously unavailable, formal equivalent of 3-lithiopyrrole is itself an excellent source of a wide range of β-substituted pyrroles, many of which would not be directly preparable from 1.TIPS-pyrrole can be 3,4-dihalogenated and these compounds undergo sequential halogen-metal interchange trapping reactions.This process is exemplified by an efficient, three-step synthesis of the antibiotic verrucarin E (63) from the dibromo compound (5).
- Bray, Brian L.,Mathies, Peter H.,Naef, Reto,Solas, Dennis R.,Tidwell, Thomas T.,et al.
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p. 6317 - 6328
(2007/10/02)
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- FRIEDEL-CRAFTS ACYLATION OF 1-TERT-BUTYLDIMETHYLSILYLPYRROLE, A VERY SHORT AND SIMPLE ROUTE TO 3-SUBSTITUTED PYRROLES.
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1-tert-Butyldimethylsilylpyrrole undergoes Friedel-Crafts acylation almost exclusively at β-position giving after sodium fluoride supported hydrolysis the 3-pyrroloketones.
- Simchen, Gerhard,Majchrzak, Michal W.
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p. 5035 - 5036
(2007/10/02)
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- Pyrrole chemistry. XXVIII. Substitution reactions of 1-(phenylsulfonyl)pyrrole and some derivatives
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The preparative value of the 1-(phenylsulfonyl) N-blocking and directing group for the synthesis of 3-acylpyrroles has been further evaluated.Acetylation and benzoylation are strongly regiospecific and give good yields.However, the regiospecificity is not general and other substitution reactions give mixtures of 2- and 3-substitution or even mostly 2-substitution.Friedel and Crafts tert-butylation gives 3-tert-butyl-1-(phenylsulfonyl)pyrrole and provides a useful route to tert-butylpyrrole, but ethylation and isopropylation give mixtures.Acylations of 2- and 3-alkyl-1-(phenylsulfonyl)pyrroles show little evidence of useful regiospecificity.
- Anderson, Hugh J.,Loader, Charles E.,Xu, Ru Xun,Le, Nghia,Gogan, Niall J.,et al.
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p. 896 - 902
(2007/10/02)
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- Regioselective Synthesis of Acylpyrroles
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The regioselective synthesis of several pyrrole derivatives is described.AlCl3-catalyzed acylation reactions of 1-(phenylsulfonyl)pyrrole (1) give 3-acyl derivatives, whereas the corresponding BF3*OEt2-catalyzed reactions give 2-acyl derivatives predominantly.Mild alkaline hydrolysis gives the corresponding acyl-1H-pyrroles in excellent yields.AlCl3-catalyzed reactions of 1 with 1,1-dichloromethyl methyl ether and oxalyl chloride give 1-(phenylsulfonyl)-2-formylpyrrole (6) and 1-(phenylsulfonyl)-2-(chlorocarbonyl)pyrrole (7), respectively. 3-Pyrrolylacetic acid (10) was prepared by thallium(III) nitrate promoted rearrangement of 1-(phenylsulfonyl)-3-acetylpyrrole (2a).Trifluoroacetic anhydride catalyzed cyclization of 4-butyric acid (14) gives 1-(phenylsulfonyl)-7-oxo-4,5,6,7-tetrahydroindole (17).Attempts to cyclize 14 at the 4-position have been unsuccessful.
- Kakushima, Masatoshi,Hamel, Pierre,Frenette, Richard,Rokach, Joshua
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p. 3214 - 3219
(2007/10/02)
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- A SIMPLE AND EFFICIENT ROUTE TO β-SUBSTITUTED PYRROLES
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N-Phenylsulfonylpyrrole undergoes Friedel-Crafts acylation exclusively at the β-position of the pyrrole ring, thus allowing a simple and efficient synthesis of β-acylated pyrroles.
- Rokach, Joshua,Hamel, Pierre,Kakushima, Masatoshi,Smith, Graham M.
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p. 4901 - 4904
(2007/10/02)
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- PYRROLE CHEMISTRY XXV: A SIMPLIFIED SYNTHESIS OF SOME 3-SUBSTITUTED PYRROLES
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A new synthesis is reported which allows the rapid preparation in good yield of 3-aroyl-, 3-acetyl- and 3-nitro- pyrroles from pyrrole utilizing the 1-benzenesulfonyl group as a blocking group.
- Xu, Ru Xun,Anderson, Hugh J.,Gogan, Niall J.,Loader, Charles E.,McDonald, Robert
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p. 4899 - 4900
(2007/10/02)
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- Pyrrole chemistry. XXII. A "one-pot" synthesis of some 4-acylpyrrole-2-carboxaldehydes from pyrrole
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The Vilsmeier-Haack intermediates formed from pyrrole and from 1-methylpyrrole may be acylated under normal Friedel-Crafts conditions.Hydrolytic work-up then gives 4-acylpyrrole-2-carboxaldehydes in good yield.The methoxide/methanol treatment of the 4-trichloroacetylated intermediate leads to methyl 2-formylpyrrole-4-carboxylate.These are all "one-pot" syntheses from pyrrole.The formyl group has been removed from several of the products thus affording some 3-acylpyrroles in two operations.
- Anderson, Hugh J.,Loader, Charles E.,Foster, Aidan
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p. 2527 - 2530
(2007/10/02)
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