- Synthetic method of non-steroidal antiinflammatory drug pain killing
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The invention discloses a synthesis method of non-steroidal anti-inflammatory drug tolmetin. The methodcomprises the following steps: sequentially preparing a sulfuric acid-containing acetonedicarboxylic acid crude product, 2-(2-acetoxy)-1-methyl-1H-pyrrole-3-formic acid and 2-(2-alkyl acetate)-1-methyl-1H-pyrrole-3-formic acid by taking citric acid or citric acid monohydrate as a raw material; and carrying out decarboxylation, acylation, hydrolysis and acidification to obtain tolmetin. The synthetic method provided by the invention overcomes the defect that the existing tolmetin preparation process depends on N-methylpyrrole, and is a low-cost, low-pollution and high-yield synthetic method of non-steroidal anti-inflammatory drug tolmetin.
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- Copper-Catalyzed Selective Pyrrole Functionalization by Carbene Transfer Reaction
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1H-Pyrroles can be directly functionalized by means of the incorporation of carbene groups from diazo compounds, in a process catalyzed by TpxCu complexes (Tpx=hydrotrispyrazolylborate ligand). The reactions take place with a complete selectivity toward the formal insertion of the carbene into the Cα?H bond, leading to alkylated pyrroles, with no modification of the Cβ?H, N?H or C=C bonds of the pyrrole unit. Alkyl substituents at C-ring as well as alkyl, aryl, allyl or alkyne substitution at N atom are tolerated, the strategy affording 20 new pyrrole derivatives. The observance of partial deuteration at the methylene group when the reaction is carried out with added D2O serves to discard the direct insertion of the carbene group into the Csp2?H bond, the alternative electrophilic attack to the pyrrole ring being feasible. (Figure presented.).
- Rodríguez, Anabel M.,Molina, Francisco,Díaz-Requejo, M. Mar,Pérez, Pedro J.
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supporting information
p. 1998 - 2004
(2020/03/04)
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- Tridentate Nickel(II)-Catalyzed Chemodivergent C-H Functionalization and Cyclopropanation: Regioselective and Diastereoselective Access to Substituted Aromatic Heterocycles
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A Schiff-base nickel(II)-phosphene-catalyzed chemodivergent C-H functionalization and cyclopropanation of aromatic heterocycles is reported in moderate to excellent yields and very good regioselectivity and diastereoselectivity. The weak, noncovalent interaction between the phosphene ligand and Ni center facilitates the ligand dissociation, generating the electronically and coordinatively unsaturated active catalyst. The proposed mechanisms for the reported reactions are in good accord with the experimental results and theoretical calculations, providing a suitable model of stereocontrol for the cyclopropanation reaction.
- Nag, Ekta,Gorantla, Sai Manoj N. V. T.,Arumugam, Selvakumar,Kulkarni, Aditya,Mondal, Kartik Chandra,Roy, Sudipta
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supporting information
p. 6313 - 6318
(2020/09/02)
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- Directed Evolution of a Cytochrome P450 Carbene Transferase for Selective Functionalization of Cyclic Compounds
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Transfers of carbene moieties to heterocycles or cyclic alkenes to obtain C(sp2)-H alkylation or cyclopropane products are valuable transformations for synthesis of pharmacophores and chemical building blocks. Through their readily tunable active-site geometries, hemoprotein "carbene transferases" could provide an alternative to traditional transition metal catalysts by enabling heterocycle functionalizations with high chemo-, regio-, and stereocontrol. However, carbene transferases accepting heterocyclic substrates are scarce; the few enzymes capable of heterocycle or cyclic internal alkene functionalization described to date are characterized by low turnovers or depend on artificially introduced, costly iridium-porphyrin cofactors. We addressed this challenge by evolving a cytochrome P450 for highly efficient carbene transfer to indoles, pyrroles, and cyclic alkenes. We first developed a spectrophotometric high-throughput screening assay based on 1-methylindole C3-alkylation that enabled rapid analysis of thousands of P450 variants and comprehensive directed evolution via random and targeted mutagenesis. This effort yielded a P450 variant with 11 amino acid substitutions and a large deletion of the non-catalytic P450 reductase domain, which chemoselectively C3-alkylates indoles with up to 470 turnovers per minute and 18000 total turnovers. We subsequently used this optimized alkylation variant for parallel evolution toward more challenging heterocycle carbene functionalizations, including C2/C3 regioselective pyrrole alkylation, enantioselective indole alkylation with ethyl 2-diazopropanoate, and cyclic internal alkene cyclopropanation. The resulting set of efficient biocatalysts showcases the tunability of hemoproteins for highly selective functionalization of cyclic targets and the power of directed evolution to enhance the scope of new-to-nature enzyme catalysts.
- Brandenberg, Oliver F.,Chen, Kai,Arnold, Frances H.
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supporting information
p. 8989 - 8995
(2019/06/13)
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- Continuous Flow Homolytic Aromatic Substitution with Electrophilic Radicals: A Fast and Scalable Protocol for Trifluoromethylation
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We report an operationally simple and rapid continuous flow radical C?C bond formation under Minisci-type reaction conditions. The transformations are performed at or below room temperature employing hydrogen peroxide (H2O2) and dimethylsulfoxide (DMSO) as reagents in the presence of an FeIIcatalyst. For electron-rich aromatic and heteroaromatic substrates, C?C bond formation proceeds satisfactorily with electrophilic radicals including.CF3,.C4F9,.CH2CN, and.CH2CO2Et. In contrast, electron-poor substrates exhibit minimal reactivity. Importantly, trifluoromethylations and nonafluororobutylations using CF3I and C4F9I as reagents proceed exceedingly fast with high conversion for selected substrates in residence times of a few seconds. The attractive features of the present process are the low cost of the reagents and the extraordinarily high reaction rates. The direct application of the protocol to dihydroergotamine, a complex ergot alkaloid, yielded the corresponding trifluoromethyl ergoline derivative within 12 seconds in a continuous flow microreactor on a 0.6 kg scale. The trifluoromethyl derivative of dihydroergotamine is a promising therapeutic agent for the treatment of migraines.
- Monteiro, Júlia L.,Carneiro, Paula F.,Elsner, Petteri,Roberge, Dominique M.,Wuts, Peter G. M.,Kurjan, Katherine C.,Gutmann, Bernhard,Kappe, C. Oliver
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supporting information
p. 176 - 186
(2017/01/09)
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- Synthesis and reaction of chiral 4,5-disubstituted 2-oxazolidinones from 3-ethoxy-6-(N-alkyl-N-tert-butoxy- carbonyl)aminohexa-2,4-dienoates in the presence of concentrated sulfuric acid supported on silica gel
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Reaction of chiral 3-ethoxy-6-(N-alkyl-N-tert-butoxycarbonyl)amino-hexa- 2,4-dienoates (3) and related compounds with 97% concentrated sulfuric acid supported on silica gel proceeded stereo- and regio-selectively to yield chiral 4,5-disubstituted N-alkyl-2-oxazolidinones (7). Under the limited conditions, 7 were converted into N-alkyl-2-pyrrolylacetates (8) and 2- oxazolidinone derivatives (12) which may serve as a chiral auxiliary.
- Kawano, Tomikazu,Negoro, Kenji,Nitta, Hajime,Ueda, Ikuo
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p. 1261 - 1278
(2007/10/03)
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- Synthesis of Ethyl Arylacetates by Means of Friedel-Crafts Reaction of Aromatic Compounds with Ethyl α-Chloro-α-(methylthio)acetate
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Friedel-Crafts reaction of aromatic compounds with ethyl α-chloro-α-(methylthio)acetate (1) gave ethyl α-(methylthio)arylacetates (2), which were readily converted into ethyl arylacetates (3) by reductive desulfurization with Raney nickel or zinc dust-acetic acid.The reactions were applied to the syntheses of ibufenac (5) and alclofenac (6), which are anti-inflammatory agents.
- Tamura, Yasumitsu,Choi, Hong Dae,Shindo, Hirohisa,Ishibashi, Hiroyuki
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p. 915 - 921
(2007/10/02)
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- Preparation of pyrrole-2-acetates
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Loweralkyl 1-methylpyrrole-2-acetates are prepared by the reduction of loweralkyl α-imino-1-methylpyrrole-2-acetates using sodium dithionite as the reducing agent.
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- Preparation of pyrrole-2-acetates
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Loweralkyl 1-methylpyrrole-2-acetates are prepared by the recuction of loweralkyl α-imino-1-methylpyrrole-2-acetates using a divalent sulfur reducing agent.
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- Preparation of pyrrole-2-acetates
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Loweralkyl 1-loweralkyl-pyrrole-2-glyoxylates are reduced by the base-catalyzed action of hydrogen sulfide under pressure of at least 30 p.s.i. to loweralkyl 1-loweralkyl-pyrrole-2-acetates.
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- Preparation of pyrrole-2-acetic acid derivatives
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Catalytic dehydrogenation of Δ-2,α-pyrrolidenemalonates and Δ-2,α-pyrrolidenemalononitriles yields pyrrole-2-acetates and pyrrole-2-acetonitriles, respectively. Subsequent hydrolysis of the latter affords pyrrole-2-acetic acids.
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