- Synthesis and evaluation of stable, efficient, and recyclable carbonylation catalysts: Polyether-substituted lmidazolium carbonyl cobalt lonic liquids
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The synthesis and catalytic performance of stable, efficient, and recyclable multi-functionalized ionic liquid catalysts are reported for the first time. Through an optimized synthetic strategy, a series of polyether-substituted imidazolium cobalt tetracarbonyl salts, [H(OCH2CH2)nbim] [Co(CO)4)] (n = 8, 15, and 22, bim = butylimidazolium), and their intermediates, were successfully synthesized and characterized by IR, UV-vis, 1H NMR, 13C NMR, and TGA. The stability, solubility, and critical solution temperature of the ionic liquids were also determined. A thermoregulated phase-separation catalysis system for the hydroesterification of olefins has been established based on the above multi-functionalized ionic liquid catalyst. The results show that this catalysis system has a high recycling efficiency, and provides a potential method for an environmentally benign carbonylation process.
- Lv, Zhiguo,Jiang, Yongfei,Zhou, Chao,Guo, Zhenmei,Ma, Xiuling,Chen, Qiang,Nie, Tao,Song, Hongbing
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Read Online
- On-Line Determination of Lipase Activity and Enantioselectivity Using An Immobilized Enzyme Reactor Coupled To A Chiral Stationary Phase
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Lipase has been immobilized on an artificial immobilized membrane HPLC phase and the enzyme reactor coupled to a HPLC chiral stationary phase.The resulting system was used for on-line determination of enantioselectivity of the immobilized enzyme.
- Zhang, Xiao-Ming,Wainer, Irving W.
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Read Online
- Room-temperature Pd-catalyzed methoxycarbonylation of terminal alkynes with high branched selectivity enabled by bisphosphine-picolinamide ligand
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We report the room-temperature Pd-catalyzed methoxy-carbonylation with high branched selectivity using a new class of bisphosphine-picolinamide ligands. Systematic optimization of ligand structures and reaction conditions revealed the significance of both
- Chen, Fen-Er,Ke, Miaolin,Liu, Ding,Ning, Yingtang,Ru, Tong
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supporting information
p. 1041 - 1044
(2022/01/28)
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- Membrane transport inspired hydrolysis of non-activated esters at near physiological pH
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A positively charged micelle loaded with substrates was transported selectively to the reaction site (cathode) to promote the proximity and localization of the reactants (ester and hydroxide). The guided vehicular delivery coupled with electrolysis allows the hydrolysis of non-activated esters at near physiological pH with significant yields along with recyclability.
- De Sarkar, Suman,Mahanty, Kingshuk,Mandal, Raki,Mandal, Subhendu,Tarafdar, Pradip K.
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supporting information
p. 11088 - 11091
(2021/10/30)
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- Green Esterification of Carboxylic Acids Promoted by tert-Butyl Nitrite
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In this work, the green esterification of carboxylic acids promoted by tert-butyl nitrite has been well developed. This transformation is compatible with a broad range of substrates and exhibits excellent functional group tolerance. Various drugs and substituted amino acids are applicable to this reaction under near neutral conditions, with good to excellent yields.
- Cheng, Xionglve,Jiang, Gangzhong,Li, Xingxing,Tao, Suyan,Wan, Xiaobing,Zhao, Yanwei,Zheng, Yonggao
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supporting information
p. 2713 - 2718
(2021/06/25)
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- Preparation method of carboxylic ester compound
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The invention relates to a preparation method of a carboxylic ester compound, which comprises the following steps: reacting carboxylic acid with methanol in air under the catalysis of nitrite to obtain an ester compound, the preparation method disclosed by the invention has the advantages of rich raw material sources, cheap and easily available catalyst, mild reaction conditions, simplicity and convenience in operation and the like, a series of fatty carboxylic acids can be modified with high yield, and particularly, the traditional esterification method is generally not suitable for esterification of drug molecules. By utilizing the method, a series of known drug molecules can be modified, so that a shortcut is provided for discovering new drug molecules.
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Paragraph 0026-0027
(2021/03/30)
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- Cu(II) complexes of hydrazones–NSAID conjugates: synthesis, characterization and anticancer activity
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The hydrazones of nonsteroidal anti-inflammatory drugs (NSAIDs) diclofenac and ibuprofen are synthesized with aldehydes of pyridine and imidazole and are characterized by 1H, 13C and mass spectroscopy. Cu(II) complexes of hydrazones constructed from these ligands possess square planar geometry for bidentate diclofenac-hydrazone and tridentate ibuprofen-hydrazone conjugates with [Cu(L)2] and [Cu(L)Cl] compositions, respectively. The observed irreversible Cu(II)/Cu(I) redox couple in the range of +0.20 to +0.61 V is due to the substantial distortion in the square-planar geometry. ESR studies indicate the appreciably covalent character within M–L bonding due to extensive delocalization of electron from d x2–-y2 orbital. The hydrazone–NSAID conjugates exhibit substantial cytotoxicity against A-549, HCT-116 and MDA-MB-231 cancer cell lines with ibuprofen-imidazole-hydrazone ligand possessing the lowest IC50 (2.26 μM) amongst the synthesized NSAID-conjugates. Interestingly, its Cu(II) complex also displays excellent anticancer activity against MDA-MB- 231 with IC50 value of 3.58 μM. Such a feature may be ascribed to the synergistic association of Cu(II)–NSAID–hydrazone linkage. Thus, conjugation of NSAID with hydrazone and its complexation with a bioactive metal ion may be regarded as a potential strategy for designing of non-platinum anticancer agents.
- Bandyopadhyay, Parbati,Basu, Soumya,Chikate, Rajeev,Chikate, Tanmayee,Kaur, Jatinder
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p. 3186 - 3202
(2020/12/22)
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- A Single Enzyme Mediates the "quasi-Living" Formation of Multiblock Copolymers with a Broad Biomedical Potential
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This study describes a unique "quasi-living"block copolymerization method based on an initiation by a single enzyme. We use this term to describe a process where a preformed polymer chain can be reactivated to continue propagating with a second or third comonomer without addition of new catalyst. The presented strategy involves a laccase (oxidoreductase) mediated initial polymerization of 4-hydroxyphenylacetic acid to a homopolymer containing phenolic terminal units, which in turn can be easily reactivated by the same enzyme in the same reaction vessel to continue propagation with a second monomer (tyramine). Increased copolymer yield (up to 26.0percent) and polymer molecular mass (up to Mw = 116 ?000 Da) are achieved through the addition of previously developed micellar and hydrogel enzyme complexing agents. The produced poly(tyramine)-b-poly(4-hydroxyphenylacetic acid)-b-poly(tyramine) is water-soluble and able to self-assemble in aqueous solution. Both tyramine blocks were successfully modified with ibuprofen moieties (up to 24.6percent w/w load) as an example for potential polymer drug conjugation. The copolymerization could be further extended with addition of a third (fluorescent) comonomer in the same reaction vessel to yield a fluorescent pentablock copolymer. The successful modifications and advantageous solution behavior of the produced copolymers demonstrate their viability as versatile drug delivery and/or bioimaging agents, as confirmed by cytotoxicity and cellular uptake studies.
- Gitsov, Ivan,Guo, Dandan,Luo, Juntao,Scheibel, Dieter Michael
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p. 2132 - 2146
(2020/07/15)
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- Synthesis, anti-inflammatory activity, and molecular docking studies of some novel Mannich bases of the 1,3,4-oxadiazole-2(3H)-thione scaffold
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A series of novel ibuprofen and salicylic acid-based 3,5-disubstituted-1,3,4-oxadiazole-2(3H)-thione derivatives was synthesized, and they were evaluated as potential anti-inflammatory agents. Following the structure identification studies employing IR, 1H nuclear magnetic resonance (NMR), 13C NMR, and elemental analysis, the title compounds were tested by cyclooxygenase (COX)-1 and COX-2 inhibition assays concomitant to lipopolysaccharide (LPS)-induced nitric oxide and prostaglandin production prevention experiments. The results indicated that the majority of the compounds displayed either a superior or comparable activity in preventing both LPS-induced NO production and COX-1 activity in comparison to the activities of the reference molecules. Furthermore, docking studies were also performed to reveal possible interactions with the COX enzymes.
- Ozyazici, Tugce,Gurdal, Enise E.,Orak, Duygu,Sipahi, Hande,Ercetin, Tuba,Gulcan, Hayrettin O.,Koksal, Meric
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- Design and Scalable Synthesis of N-Alkylhydroxylamine Reagents for the Direct Iron-Catalyzed Installation of Medicinally Relevant Amines**
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Secondary and tertiary alkylamines are privileged substance classes that are often found in pharmaceuticals and other biologically active small molecules. Herein, we report their direct synthesis from alkenes through an aminative difunctionalization reaction enabled by iron catalysis. A family of ten novel hydroxylamine-derived aminating reagents were designed for the installation of several medicinally relevant amine groups, such as methylamine, morpholine and piperazine, through the aminochlorination of alkenes. The method has excellent functional group tolerance and a broad scope of alkenes was converted to the corresponding products, including several drug-like molecules. Besides aminochlorination, the installation of other functionalities through aminoazidation, aminohydroxylation and even intramolecular carboamination reactions, was demonstrated, further highlighting the broad potential of these new reagents for the discovery of novel amination reactions.
- Delcaillau, Tristan,Falk, Eric,Gürtler, Laura,Makai, Szabolcs,Morandi, Bill
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supporting information
p. 21064 - 21071
(2020/09/21)
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- Palladium-Catalyzed Alkoxycarbonylation of sec-Benzylic Ethers
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Herein, we report the palladium-catalyzed synthesis of 3-arylpropionate esters starting from secondary benzylic ethers. With this investigation it could be shown that ethers are suitable starting materials in addition to the established carbonylation reactions of olefins, alcohols, or aryl halides.
- Beller, Matthias,Jackstell, Ralf,Maes, Bert U. W.,Schneider, Carolin
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- Selective benzylic C–H monooxygenation mediated by iodine oxides
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A method for the selective monooxdiation of secondary benzylic C–H bonds is described using an N-oxyl catalyst and a hypervalent iodine species as a terminal oxidant. Combinations of ammonium iodate and catalytic N-hydroxyphthalimide (NHPI) were shown to be effective in the selective oxidation of n-butylbenzene directly to 1-phenylbutyl acetate in high yield (86%). This method shows moderate substrate tolerance in the oxygenation of substrates containing secondary benzylic C–H bonds, yielding the corresponding benzylic acetates in good to moderate yield. Tertiary benzylic C–H bonds were shown to be unreactive under similar conditions, despite the weaker C–H bond. A preliminary mechanistic analysis suggests that this NHPI-iodate system is functioning by a radical-based mechanism where iodine generated in situ captures formed benzylic radicals. The benzylic iodide intermediate then solvolyzes to yield the product ester.
- LaMartina, Kelsey B.,Kuck, Haley K.,Oglesbee, Linda S.,Al-Odaini, Asma,Boaz, Nicholas C.
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supporting information
p. 602 - 609
(2019/04/17)
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- Preparation method for ibuprofen methyl ester
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The invention provides a preparation method for ibuprofen methyl ester. The preparation method comprises the following steps: 1) adding ibuprofen into methanol, dropwise adding sulfoxide chloride, andcarrying out a reaction; and 2) washing a reaction solution with water, and subjecting an organic layer to reduced-pressure distillation so as to obtain the ibuprofen methyl ester. The objective of the invention is to provide an ibuprofen methyl ester preparation method with the advantages of stable process, simple operation, strong operability and applicability to industrialization. The preparation method provided by the invention has a yield of 97% or more; a product has high quality; and the content of HPLC is up to 99% or more.
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Paragraph 0115-0022
(2019/04/18)
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- Synthesis and Biological Evaluation of New Ibuprofen-1,3,4-oxadiazole-1,2,3-triazole Hybrids
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A new hybrid polydentate template comprising distinctive pharmacophoric groups, namely, ibuprofen, 1,3,4-oxadiazole, and 1,2,3-triazole linked through a thioether bridge was achieved by one-pot synthesis by exploring multicomponent Cu-catalyzed “click chemistry” approach. The target structures were characterized by NMR, IR, and LC-Mass. The X-ray analysis of 2-(1-(4-isobutylphenyl)ethyl)-5-(((1-(3-nitrophenyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-1,3,4-oxadiazole (8a) confirmed the assigned structure. The in vitro antibacterial and anticancer activity of these compounds revealed that 2-(1-(4-isobutylphenyl)ethyl)-5-(((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)thio)-1,3,4-oxadiazole (8b) demonstrated more potent antibacterial activity against Gram-negative strains (Escherichia coli and Pseudomonas aeruginosa) and 2-(((1-(2,4-dimethylphenyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-5-(1-(4 isobutylphenyl)ethyl)-1,3,4-oxadiazole (8e) exhibited anticancer activity with IC50 of 27.50 and 31.03?μg/mL against HeLa and MCF-7 cell lines, respectively.
- Rayam, Parsharamulu,Polkam, Naveen,Kummari, Bhaskar,Banothu, Venkanna,Gandamalla, Durgaiah,Yellu, Narsimha Reddy,Anireddy, Jaya Shree
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p. 296 - 305
(2018/12/13)
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- Continuous Heterogeneous Photocatalysis in Serial Micro-Batch Reactors
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Solid reagents, leaching catalysts, and heterogeneous photocatalysts are commonly employed in batch processes but are ill-suited for continuous-flow chemistry. Heterogeneous catalysts for thermal reactions are typically used in packed-bed reactors, which cannot be penetrated by light and thus are not suitable for photocatalytic reactions involving solids. We demonstrate that serial micro-batch reactors (SMBRs) allow for the continuous utilization of solid materials together with liquids and gases in flow. This technology was utilized to develop selective and efficient fluorination reactions using a modified graphitic carbon nitride heterogeneous catalyst instead of costly homogeneous metal polypyridyl complexes. The merger of this inexpensive, recyclable catalyst and the SMBR approach enables sustainable and scalable photocatalysis.
- Pieber, Bartholom?us,Shalom, Menny,Antonietti, Markus,Seeberger, Peter H.,Gilmore, Kerry
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supporting information
p. 9976 - 9979
(2018/03/21)
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- Synergistic Catalysis for the Umpolung Trifluoromethylthiolation of Tertiary Ethers
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The first transition-metal-free, site-specific umpolung trifluoromethylthiolation of tertiary alkyl ethers has been developed, achieving the challenging tertiary C(sp3)–SCF3 coupling under redox-neutral conditions. The synergism of organophotocatalyst 4CzIPN and BINOL-based phosphorothiols can site-selectively cleave tertiary sp3 C(sp3)–O ether bonds in complex molecules initiated by a polarity-matching hydrogen-atom-transfer (HAT) event. The incorporation of several competing benzylic and methine C(sp3)?H bonds in alkyl ethers has little influence on the regioselectivity. Selective difluoromethylthiolation of C?O bonds has also been achieved. This represents not only an important step forward in trifluoromethylthiolation but also a promising means for site-selective C?O bond functionalization of unsymmetrical tertiary alkyl ethers.
- Xu, Wentao,Ma, Junyang,Yuan, Xiang-Ai,Dai, Jie,Xie, Jin,Zhu, Chengjian
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supporting information
p. 10357 - 10361
(2018/08/06)
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- Synthesis and antinociceptive evaluation of bioisosteres and hybrids of naproxen, ibuprofen and paracetamol
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The aim of this work was to design, synthesize and characterize the potential anti-nociceptive and anti-inflammatory activities of a new series of bioisosteres and hybrids from known non-steroidal anti-inflammatory drugs (NSAIDs). The compounds 4-(acetylamino)phenyl (2S)-2-(6-methoxy-2-naphthyl)propanoate (GUF-1) and 4-(acetylamino)phenyl 2-(R,S)-(4-isobutylphenyl)propanoate (GUF-2) were synthesized as hybrids (also known as heterodimers); whereas those named 2-(R,S)-(4-isobutylphenyl)-N-1H-tetrazol-5-ylpropanamide (GUF-3), (2S)-2-(6-methoxy-2-naphthyl)-N-1H-tetrazol-5-ylpropanamide (GUF-4), [2-(R,S)-N-hydroxy-2-[4-(2-methylpropyl)phenyl]propanamide] (GUF-5), and (2S)-N-hydroxy-2-(6-methoxy-2-naphthyl)propanamide (GUF-6) were synthesized as bioisosteres of the NSAIDs paracetamol, ibuprofen, and naproxen, respectively. All these compounds were characterized by spectroscopic and spectrometric analysis. Antinociceptive activity of GUF-1 to GUF-6 was evaluated using the formalin test in rats. Pharmacological responses of GUF-1, GUF-2 (hybrids), and GUF-5 (bioisostere) demonstrated significant antinociceptive effects; thus these compounds were assayed in an inflammation test like carrageenan-induced paw oedema in rats. Complete molecular docking of cyclooxygenase and the GUF-1 and GUF-2 hybrids showed high docking scores, compared to the reference drugs. Our data demonstrate that compounds GUF-1, GUF-2, and GUF-5 possesses antinociceptive and antiinflammatory activities resembling and improving those known for the traditional NSAIDs, paracetamol, naproxen and ibuprofen.
- González-Trujano, María Eva,Uribe-Figueroa, Gerardo,Hidalgo-Figueroa, Sergio,Martínez, Ana Laura,Déciga-Campos, Myrna,Navarrete-Vazquez, Gabriel
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p. 553 - 562
(2018/03/08)
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- Stereoselective Ketone Rearrangements with Hypervalent Iodine Reagents
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The first stereoselective version of an iodine(III)-mediated rearrangement of arylketones in the presence of orthoesters is described. The reaction products, α-arylated esters, are very useful intermediates in the synthesis of bioactive compounds such as ibuprofen. With chiral lactic acid-based iodine(III) reagents product selectivities of up to 73 % ee have been achieved.
- Malmedy, Florence,Wirth, Thomas
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supporting information
p. 16072 - 16077
(2016/10/30)
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- Novel 1,3,4-oxadiazole/oxime hybrids: Synthesis, docking studies and investigation of anti-inflammatory, ulcerogenic liability and analgesic activities
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A novel group of 1,3,4-oxadaiazoles, a group known for their anti-inflammatory activity, is hybridized with nitric oxide (NO) releasing group, oxime, for its gastro-protective action and potential synergistic effect. The synthesized hybrids were evaluated for their anti-inflammatory, analgesic, antioxidant and ulcerogenic activities. Most of the tested compounds showed excellent anti-inflammatory activity with compound 8e being more active than indomethacin. They also showed moderate analgesic activity but no antioxidant one. The ability of the synthesized compounds to inhibit COX-1 and COX-2 is studied and the prepared compounds were able to inhibit both COXs non-selectively with IC50s of 0.75–70.50?μM. Docking studies revealed the mode of interaction of the tested compounds into the empty pocket of the isozymes. All of the synthesized compounds interact with COXs active site with energy scores comparable to that of ibuprofen. All compounds showed a safer profile on the stomach tissue integrity compared to conventional NSAIDs. The designed strategy was applied to ibuprofen to introduce ibuprofen/oxadiazole/NO hybrid. The synthesized ibuprofen hybrid is a promising alternative to ibuprofen having similar anti-inflammatory activity but with safer GIT profile.
- Abd-Ellah, Heba S.,Abdel-Aziz, Mohamed,Shoman, Mai E.,Beshr, Eman A.M.,Kaoud, Tamer S.,Ahmed, Al-Shaimaa F.F.
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supporting information
p. 48 - 63
(2016/09/28)
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- The digital code driven autonomous synthesis of ibuprofen automated in a 3D-printer-based robot
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An automated synthesis robot was constructed by modifying an open source 3D printing platform. The resulting automated system was used to 3D print reaction vessels (reactionware) of differing internal volumes using polypropylene feedstock via a fused deposition modeling 3D printing approach and subsequently make use of these fabricated vessels to synthesize the nonsteroidal antiinflammatory drug ibuprofen via a consecutive one-pot three-step approach. The synthesis of ibuprofen could be achieved on different scales simply by adjusting the parameters in the robot control software. The software for controlling the synthesis robot was written in the python programming language and hard-coded for the synthesis of ibuprofen by the method described, opening possibilities for the sharing of validated synthetic 'programs' which can run on similar low cost, user-constructed robotic platforms towards an 'open-source' regime in the area of chemical synthesis.
- Kitson, Philip J.,Glatzel, Stefan,Cronin, Leroy
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supporting information
p. 2776 - 2783
(2017/01/09)
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- A three-minute synthesis and purification of ibuprofen: Pushing the limits of continuous-flow processing
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In a total residence time of three minutes, ibuprofen was assembled from its elementary building blocks with an average yield of above 90% for each step. A scale-up of this five-stage process (3 bond-forming steps, one work-up, and one in-line liquid-liquid separation) provided ibuprofen at a rate of 8.09 gh-1 (equivalent to 70.8 kg y-1) using a system with an overall footprint of half the size of a standard laboratory fume hood. Aside from the high throughput, several other aspects of this synthesis expand the capabilities of continuous-flow processing, including a Friedel-Crafts acylation run under neat conditions and promoted by AlCl3, an exothermic in-line quench of high concentrations of precipitation-prone AlCl3, liquid-liquid separations run at or above 200 psi to provide solvent-free product, and the use of highly aggressive oxidants, such as iodine monochloride. The use of simple, inexpensive, and readily available reagents thus affords a practical synthesis of this important generic pharmaceutical.
- Snead, David R.,Jamison, Timothy F.
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supporting information
p. 983 - 987
(2015/03/05)
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- Synthesis of amide derivatives of some nonsteroidal antiinflammatory drugs as potential pro-drugs
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The present invention presents a method for masking acidic groups existing in NSAI drugs to prevent or to reduce the hazards of NSAI drugs to GI (gastrointestinal) system. The developed method comprises production of new amide derivatives by methyl esterification of carboxylic acid groups which belong to NSAI drugs and then amidification of the same. The invention is also related to the amide derivatives of new NSAI drugs which are suitable for use as pro-drugs.
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Paragraph 0016; 0041; 0043
(2015/06/16)
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- Weak Coordination Promoted Regioselective Oxidative Coupling Reaction for 2,2′-Difunctional Biaryl Synthesis in Hexafluoro-2-propanol
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An unprecedented weak coordination promoted dehydrogenative cross-coupling reaction has been developed by palladium catalysis, which provides a convenient access to a wide range of 2,2′-difunctional biaryls from easily accessible substrates. Both HFIP solvent and oxidants serve as the critical factors in this new reaction. A plausible mechanism involving Pd(II)/Pd(IV) is proposed. The reaction demonstrates excellent reactivity, broad functional-group tolerance and high yields.
- Zhang, Chao,Rao, Yu
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supporting information
p. 4456 - 4459
(2015/09/28)
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- Copper-catalysed ring-opening trifluoromethylation of cyclopropanols
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A copper-catalysed ring-opening trifluoromethylation reaction of cyclopropanols has been developed. Various β-trifluoromethyl ketones are obtained in good to excellent yields under mild reaction conditions. The present method also exhibits good functional-group compatibility. The mechanism of this new ring-opening trifluoromethylation reaction was investigated by radical trapping reactions.
- He, Xia-Ping,Shu, Yong-Jin,Dai, Jian-Jun,Zhang, Wen-Man,Feng, Yi-Si,Xu, Hua-Jian
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supporting information
p. 7159 - 7163
(2015/07/01)
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- Highly efficient C-H hydroxylation of carbonyl compounds with oxygen under mild conditions
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A transition-metal-free Cs2CO3-catalyzed α-hydroxylation of carbonyl compounds with O2 as the oxygen source is described. This reaction provides an efficient approach to tertiary α-hydroxycarbonyl compounds, which are highly valued chemicals and widely used in the chemical and pharmaceutical industry. The simple conditions and the use of molecular oxygen as both the oxidant and the oxygen source make this protocol very environmentally friendly and practical. This transformation is highly efficient and highly selective for tertiary C(sp3)-H bond cleavage. OH, so simple! A transition-metal-free Cs2CO 3-catalyzed α-hydroxylation of carbonyl compounds with O 2 provided a variety of tertiary α-hydroxycarbonyl compounds (see scheme; DMSO=dimethyl sulfoxide), which are widely used in the chemical and pharmaceutical industry. The simple conditions and the use of molecular oxygen as both the oxidant and the oxygen source make this protocol very efficient and practical.
- Liang, Yu-Feng,Jiao, Ning
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supporting information
p. 548 - 552
(2014/01/23)
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- N-2-Hydroxybenzaldehyde acylhydrazone-Fe(iii) complex: Synthesis, crystal structure and its efficient and selective N-methylation
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N-Methyl-N′-2-hydroxybenzaldehyde acylhydrazones have been chemospecifically synthesized in good yield by N-methylation of the Fe(iii) complexes of N-2-hydroxybenzaldehyde acylhydrazones with methyl iodide in tetrahydrofuran. The reaction proceeds with the exclusive formation of the N-methyl derivative without any concurrent O-methylation side reactions. In addition, the N-methylation reaction occurred simultaneously with a complete deprotection step (elimination of the metal ion). As a result, the N-methyl product was obtained in excellent purity without time-consuming chromatographic workup. A free N-2-hydroxybenzaldehyde acylhydrazone ligand could not be methylated under the same conditions. This journal is the Partner Organisations 2014.
- Li, Zhiyou,Wu, Lamei,Zhang, Tao,Huang, Zhengxi,Qiu, Guofu,Zhou, Zhongqiang,Jin, Longfei
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p. 7554 - 7560
(2014/05/20)
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- Enantioselective resolution of racemic ibuprofen esters using different lipases immobilized on octyl sepharose
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Here we report the stereoselective hydrolysis of racemic esters catalyzed by Candida rugosa lipase (CRL) and Rhizopus oryzae lipase (ROL) immobilized on octyl-sepharose via physical adsorption. Hydrophobic immobilization caused to almost six fold hyperactivation with 229.2 and 81.3 U/mg enzyme for immobilized CRL and ROL, respectively (13.2 and 48.75 U/mg for corresponding free enzyme). Based on the preliminary results, CRL was chosen for further investigation. The performance and yield of the reaction were evaluated as a function of the critical reaction parameters such as temperature, enzyme to substrate ratio and organic co-solvent. An increase in the temperature resulted to decrease in enantioselectivity of hydrolysis reaction. The hydrolysis reactions were carried out in presence of two organic solvents; n-hexane and isooctane. Generally n-hexane was a better co-solvent compared to isooctane. High enantioselective hydrolysis of the racemic esters (yielding S(+) ibuprofen; ee ≤ 95%) can be achieved using the immobilized CRL. Among various esters the kinetic resolution of ibuprofen butyl ester yielded the best results (E value 70 and 74; conversion 14.6 and 8.9 in n-hexane and isooctane, respectively). The immobilized derivatives were re-used in four cycles and showed little decrease in enantiomeric excess of (S)-ibuprofen. 96.7 eep and conversion 14.6 in first cycle reached to 90.5 eep and conversion 11.3 in the forth cycle.
- Yousefi, Maryam,Mohammadi, Mehdi,Habibi, Zohreh
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- Simultaneous identification of Fenton degradation by-products of diclofenac, ibuprofen and ketoprofen in aquatic media by comprehensive two-dimensional gas chromatography coupled with mass spectrometry
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Diclofenac, ibuprofen and ketoprofen are anti-inflammatory drugs intensively used both in human and animal treatment. Due to their high stability these compounds are partially removed by wastewater treatment plants and from this reason the development of some alternative treatments such as advanced oxidative processes are necessary. The main problems in the optimization of an advanced oxidative process rise from the difficulties which appear in the identification of degradation by-products necessary for the establishment of degradation pathway. In this paper a developed method for the simultaneous identification of Fenton degradation by-products of the three above mentioned pharmaceuticals is presented. The obtained results show the comprehensive two-dimensional gas chromatography coupled with mass spectrometry as a proper method for the analysis of the complex mixture of compounds resulted from the Fenton degradation process. Moreover, some compounds never mentioned in the scientific literature were identified. (Chemical Equation Presented).
- Beldean-Galea, Mihail Simion,Coman, Virginia,Copaciu, Florina,Thiébaut, Didier,Vial, Jér?me
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p. 1021 - 1027
(2015/07/15)
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- Inhibition of human α-methylacyl CoA racemase (AMACR): A target for prostate cancer
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The enzyme α-methylacyl CoA racemase (AMACR) is involved in the metabolism of branched-chain fatty acids and has been identified as a promising therapeutic target for prostate cancer. By using the recently available human AMACR from HEK293 kidney cell cultures, we tested a series of new rationally designed inhibitors to determine the structural requirements in the acyl component. An N-methylthiocarbamate (Ki=98nM), designed to mimic the proposed enzyme-bound enolate, was found to be the most potent AMACR inhibitor reported to date. Enolate mimicry: A range of inhibitors were designed and synthesized to determine the structural requirements for inhibition of the prostate cancer target racemase AMACR using the recently available human enzyme from HEK293 kidney cell cultures. An N-methylthiocarbamate (Ki=98nM), designed to mimic the proposed enzyme-bound enolate, is the most potent AMACR inhibitor reported to date.
- Carnell, Andrew J.,Kirk, Ralph,Smith, Matthew,Mckenna, Shane,Lian, Lu-Yun,Gibson, Robert
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supporting information
p. 1643 - 1647
(2013/10/21)
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- First iodine-catalyzed deallylation of reactive allyl methylene esters
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C-Allyl cleavage has been developed using the inexpensive and mild reagent iodine in dimethylsulfoxide. A variety of compounds with active methylene groups were C-deallylated using this reagent. This method is efficient and operationally simple in comparison to the methods using transition-metal complexes. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.
- Nawghare, Beena R.,Lokhande, Pradeep D.
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p. 1955 - 1963
(2013/06/05)
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- PHTHALIMIDE DERIVATIVES OF NON-STEROIDAL ANTI-INFLAMMATORY COMPOUNDS AND/OR TNF- MODULATORS, METHOD FOR PRODUCING SAME, PHARMACEUTICAL COMPOSITIONS CONTAINING SAME AND USES THEREOF FOR THE TREATMENT OF INFLAMMATORY DISEASES
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The present invention relates to phthalimide derivatives of non-steroidal and/or TNF-α modulating anti-inflammatory compounds as well as the process of obtaining the so-called derivatives, pharmaceutical compositions containing such derivatives and their uses, including use in the treatment of inflammatory diseases, especially those related to chronic inflammatory processes, such as rheumatoid arthritis and intestinal inflammatory diseases (for instance, Chron's disease) and the use of the referred to pharmaceutical compositions as antipyretic, analgesic and platelet antiaggregating medications.
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Page/Page column 29-30
(2012/03/08)
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- PHTHALIMIDE DERIVATIVES OF NON-STEROIDAL ANTI-INFLAMMATORY COMPOUNDS AND/OR TNF-ALPHA MODULATORS, METHOD FOR PRODUCING SAME, PHARMACEUTICAL COMPOSITIONS CONTAINING SAME AND USES THEREOF FOR THE TREATMENT OF INFLAMMATORY DISEASES
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The present invention relates to phthalimide derivatives of non-steroidal and/or TNF-α modulating anti-inflammatory compounds as well as the process of obtaining the so-called derivatives, pharmaceutical compositions containing such derivatives and their uses, including use in the treatment of inflammatory diseases, especially those related to chronic inflammatory processes, such as rheumatoid arthritis and intestinal inflammatory diseases (for instance, Chron's disease) and the use of the referred to pharmaceutical compositions as antipyretic, analgesic and platelet antiaggregating medications.
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Page/Page column 42
(2012/05/20)
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- Facile conversion of racemic ibuprofen to (S)-ibuprofen
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The methyl ester of ibuprofen was quantitatively formed by Fischer esterification and converted into (S)-ibuprofen in 94% yield with an ee of 94% under dynamic kinetic resolution conditions at pH 9.8, using Candida rugosa lipase, and 20% DMSO. The (R)-methyl ibuprofen ester was observed to racemize by chiral HPLC without the Candida rugosa lipase present. The rates of in situ racemization and enzymatic hydrolysis for the dynamic kinetic resolution were determined to be 0.026 ± 0.004 and 0.053 ± 0.004 h-1, respectively. The rate of enzymatic hydrolysis when no DMSO was present was twice as fast but no racemization occurred. A facile purification of enriched (S)-ibuprofen was developed. Overall, 88% of racemic ibuprofen by weight was converted into (S)-ibuprofen with an ee of 99.7%.
- Chavez-Flores, David,Salvador, James M.
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experimental part
p. 237 - 239
(2012/06/15)
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- Identification of novel benzimidazole derivatives as inhibitors of leukotriene biosynthesis by virtual screening targeting 5-lipoxygenase- activating protein (FLAP)
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Pharmacological suppression of leukotriene biosynthesis by 5-lipoxygenase (5-LO)-activating protein (FLAP) inhibitors is a promising strategy to intervene with inflammatory, allergic and cardiovascular diseases. Virtual screening targeting FLAP based on a combined ligand- and structure-based pharmacophore model led to the identification of 1-(2-chlorobenzyl)-2-(1-(4-isobutylphenyl) ethyl)-1H-benzimidazole (7) as developable candidate. Compound 7 potently suppressed leukotriene formation in intact neutrophils (IC50 = 0.31 μM) but essentially failed to directly inhibit 5-LO suggesting that interaction with FLAP causes inhibition of leukotriene synthesis. For structural optimization, a series of 46 benzimidazole-based derivatives of 7 were synthesized leading to more potent analogues (70-72, 82) with IC50 = 0.12-0.19 μM in intact neutrophils. Together, our results disclose the benzimidazole scaffold bearing an ibuprofen fingerprint as a new chemotype for further development of anti-leukotriene agents.
- Banoglu, Erden,Caliskan, Burcu,Luderer, Susann,Eren, Goekcen,Oezkan, Yagmur,Altenhofen, Wolfram,Weinigel, Christina,Barz, Dagmar,Gerstmeier, Jana,Pergola, Carlo,Werz, Oliver
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supporting information; experimental part
p. 3728 - 3741
(2012/08/28)
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- Synthesis and evaluation of anti-inflammatory and analgesic activity of 3-[(5-substituted-1,3,4-oxadiazol-2-yl-thio)acetyl]-2H-chromen-2-ones
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A novel series of 3-[(5-substituted-1,3,4-oxadiazol- 2-yl-thio)acetyl]-2H- chromen-2-one (7a-i) were synthesized by the condensation between the appropriately substituted 5-substituted-1,3,4-oxadiazolyl-2-thione (4a-i) derived from various existing NSAIDs and 3-(2-bromoacetyl)- 2H-chromen-2-one (6) under reflux in the presence of sodium ethoxide. Structure of the synthesized compounds was established on the basis of physicochemical, elemental analysis, and spectral data. The title compounds were screened for in vivo acute anti-inflammatory and analgesic activities at a dose of 200 mg/kg bw. Among the series, four compounds 7c, 7e, 7f, and 7h were found to possess a significant anti-inflammatory and analgesic activity profile. In addition, these compounds were also found to possess a less degree of ulcerogenic potential as compared to standard NSAIDs. Springer Science+Business Media, LLC 2010.
- Ingale, Nista,Maddi, Veeresh,Palkar, Mahesh,Ronad, Pradeepkumar,Mamledesai, Shivalingrao,Vishwanathswamy,Satyanarayana, Darbhamulla
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experimental part
p. 16 - 36
(2012/06/04)
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- Substrate-selective inhibition of cyclooxygenase-2: Development and evaluation of achiral profen probes
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Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid and the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA). We recently reported that (R)-profens selectively inhibit endocannabinoid oxygenation but not arachidonic acid oxygenation. In this work, we synthesized achiral derivatives of five profen scaffolds and evaluated them for substrate-selective inhibition using in vitro and cellular assays. The size of the substituents dictated the inhibitory strength of the analogs, with smaller substituents enabling greater potency but less selectivity. Inhibitors based on the flurbiprofen scaffold possessed the greatest potency and selectivity, with desmethylflurbiprofen (3a) exhibiting an IC50 of 0.11 μM for inhibition of 2-AG oxygenation. The crystal structure of desmethylflurbiprofen complexed to mCOX-2 demonstrated a similar binding mode to other profens. Desmethylflurbiprofen exhibited a half-life in mice comparable to that of ibuprofen. The data presented suggest that achiral profens can act as lead molecules toward in vivo probes of substrate-selective COX-2 inhibition.
- Windsor, Matthew A.,Hermanson, Daniel J.,Kingsley, Philip J.,Xu, Shu,Crews, Brenda C.,Ho, Winnie,Keenan, Catherine M.,Banerjee, Surajit,Sharkey, Keith A.,Marnett, Lawrence J.
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supporting information
p. 759 - 763
(2012/10/29)
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- One-pot esterification and Ritter reaction: Chemo- and regioselectivity from tert-butyl methyl ether
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tert-Butyl methyl ether (TBME) has been effectively used as a reagent for esterification of carboxylic acids. By varying amounts of sulfuric acid, a remarkable regioselectivity in esterification has been demonstrated. Additionally, under the present reaction conditions, one-pot esterification and Ritter reaction are achieved in almost quantitative yield.
- Dawar, Pankaj,Bhagavan Raju,Ramakrishna, Ramesha A.
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supporting information; experimental part
p. 4262 - 4265
(2011/08/21)
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- Oxidative rearrangement of alkyl aryl/heteroaryl ketones by 1,2-aryl/heteroaryl shift using iodic acid
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A method for synthesis of α-aryl/heteroaryl alkanoic acids involving oxidative rearrangement of alkyl aryl/heteroaryl ketones by 1,2-aryl/heteroaryl shift using iodic acid is described. ARKAT-USA, Inc.
- Huddar, Sameerana N.,Deshmukh, Swapnil S.,Akamanchi, Krishnacharya G.
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experimental part
p. 67 - 75
(2011/06/19)
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- The continuous-flow synthesis of ibuprofen
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Let relief flow forth I A three-step, continuous-flow synthesis of ibuprofen was accomplished using a simplified microreactor. By designing a synthesis in which excess reagents and byproducts are compatible with downstream reactions, no intermediate purification or isolation steps are required.
- Bogdan, Andrew R.,Poe, Sarah L.,Kubis, Daniel C.,Broadwater, Steven J.,McQuade, D. Tyler
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supporting information; experimental part
p. 8547 - 8550
(2009/12/31)
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- An improved bouveault-blanc ester reduction with stabilized alkali metals
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Significantly improved Bouveault-Blanc conditions for ester reduction have been developed using sodium in silica gel (Na-SG), a free-flowing powder that can be easily handled in the open atmosphere. Primary alcohols were prepared in excellent yield from a variety of aliphatic esters under mild reaction conditions. The chemistry presented here is far safer than the classic Bouveault-Blanc reduction and is competitive with more modern hydride reduction methods.
- Bodnar, Brian S.,Vogt, Paul F.
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supporting information; experimental part
p. 2598 - 2600
(2009/08/07)
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- Site-specific prodrug release using visible light
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Using a photosensitization-singlet oxygenation-dioxetane cleavage strategy, a photodynamic prodrug system has been developed, whereby drugs bearing carbonyl groups can first be attached to a photosensitizer to give a photosensitizer-drug complex and then released from the complex upon visible light irradiation. Visible light, which has good penetration through tissue, generates singlet oxygen via the photosensitizer, which then releases the prodrug when and where required. With this system, drug mimics and methyl esters of NSAIDs have been successfully incorporated with photosensitizers related to verteporfin and then released by visible light illumination in high to quantitative yields within minutes. Copyright
- Jiang, Michael Y.,Dolphin, David
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p. 4236 - 4237
(2008/10/09)
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- Synthesis and pharmacological evaluation of imidazole derivatives of some non-steroidal anti-inflammatory drugs
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A series of imidazole derivatives of NSAIDs (4a-l) have been prepared by condensation of NSAIDs hydrazides (1,2) with substituted oxazolones and evaluated for anti-inflammatory and gastrointestinal toxicity, which showed good anti-inflammatory activity and reduced gastrointestinal toxicity as compared to parent drug.
- Parcha, Versha,Kaur, Jaswinder,Gupta, Vinay,Anroop
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experimental part
p. 321 - 325
(2009/06/25)
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- Oxidative rearrangements of arylalkanones with 1H-1-hydroxy-5-methyl-1,2,3-benziodoxathiole 3,3-dioxide, a 'green' analog of Koser's reagent
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Previous methods for the conversion of arylalkanones to alkyl 2-arylesters by oxidative rearrangement utilized reagents which either produced toxic metal salts or halogenated organics as by-products. In this report, 1H-1-hydroxy-5-methyl-1,2,3-benziodoxathiole 3,3-dioxide (HMBI) is used to effect this useful transformation, where the reduced iodine reagent is water-soluble and readily recycled.
- Justik, Michael W.
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p. 3003 - 3007
(2008/02/06)
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- The geminal dimethyl analogue of Flurbiprofen as a novel Aβ42 inhibitor and potential Alzheimer's disease modifying agent
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The subtle modification of a selection of Aβ42 inhibiting non-steroidal anti-inflammatory drugs (NSAIDs), through synthesis of the geminal dimethyl analogues, was anticipated to ablate their cyclooxygenase activity whilst maintaining Aβ42 inhibition. Methylflurbiprofen 6 exhibited similar in vitro Aβ42 inhibition to its parent NSAID Flurbiprofen and was further evaluated in the Tg2576 mouse model of Alzheimer's disease and an animal model of gastro-intestinal (GI) impairment, but proved unviable for further clinical development.
- Stock, Nicholas,Munoz, Benito,Wrigley, Jonathan D.J.,Shearman, Mark S.,Beher, Dirk,Peachey, James,Williamson, Toni L.,Bain, Gretchen,Chen, Weichao,Jiang, Xiaohui,St-Jacques, Rene,Prasit, Peppi
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p. 2219 - 2223
(2007/10/03)
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- Trichosporon beigelli esterase (TBE): A versatile esterase for the resolution of economically important racemates
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A hydrolase producing strain Trichosporon beigelli esterase (TBE) isolated from local cottage cheese in its native form has displayed versatility and high efficacy in the kinetic resolution of a wide range of economically important substrates, which include racemic secondary alcohols, such as 1-(6-methoxy-2-naphthyl)ethanol (E ~ 316), 1-(3,4-methylenedioxyphenyl) ethanol and pentanol (E ~ 180 and 156 resp.), and alkyl esters of carboxylic acids such as ibuprofen (E ~ 340), 2-(benzylthio)propanoic acid (E ~ 1000). In other substrates such as in the primary alcohol 2-(6-methoxy-2- naphthyl)propan-1-ol and carboxylic acids such as 2-(5-bromo-6-methoxy-2- naphthyl)propanoic acid, 2-(2-naphthyloxy)propanoic acid, and substituted 2-thiopropanoic acids, it displayed moderate to low selectivity. Commercial lipases such as CCL, PPL, and PSL were also used in the resolution of the substrates for comparative studies.
- Koul, Surrinder,Koul, Jawahir Lal,Singh, Budh,Kapoor, Munish,Parshad, Rajinder,Manhas, Kuldeep S.,Taneja, Subhash C.,Qazi, Ghulam N.
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p. 2575 - 2591
(2007/10/03)
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- Synthesis and optical resolution of 2-aryl-2-fluoropropionic acids, fluorinated analogues of Non-steroidal Anti-inflammatory Drugs (NSAIDs)
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We report the synthesis of optically active 2-aryl-2-fluoropropionic acids 2 as non-epimerizable mimics of 2-arylpropionic acids 1, a class of compounds which have been widely used as non-steroidal anti-inflammatory drugs (NSAIDs). This is a continuation of our research involving the design, synthesis, and evaluation of chiral fluorine-containing organic molecules as effective analogues of pharmacologically important compounds.
- Fujisawa, Hidehito,Fujiwara, Tomoya,Takeuchi, Yoshio,Omata, Kenji
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p. 524 - 528
(2007/10/03)
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- METHOD OF PREPARATION OF DERIVATIVES OF SUBSTITUTED 2-ARYL AIKANOIC ACIDS
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The invention relates to a new preparation method of derivatives of substituted 2--arylaikanoic acids. The compounds are used for the preparation of histaminically active compounds and antiphlogistics. The compounds are prepared by reaction of suitably substituted a-halogen acetophenones with orthoformates with catalysis by mineral and Lewis acids.
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- Prodrugs and mutual prodrugs: Synthesis of some new pyrazolone and oxadiazole analogues of a few non-steroidal anti-inflammatory drugs
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Naproxen, probenecid, diclofenac, ibuprofen and indomethacin were converted to hydrazide derivatives via their methyl ester by reacting with hydrazine hydrate, which were further condensed with β-keto esters to get the pyrazolone derivatives. The hydrazide derivatives of probenecid and diclofenac were also reacted with biphenyl acetic acid while naproxen hydrazide was reacted with p-chloro benzoic acid besides biphenyl acetic acid to synthesize their oxadiazole analogues. Some selected members of the compounds prepared were screened for their anti-inflammatory and analgesic activity.
- Sharma, Vibha,Khan
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- A novel approach to the synthesis of 2-aryl propionates
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A two step conversion of phenyl glyoxylates to 2-aryl-propionates has been accomplished. Esters of phenylglyoxylic acid have been converted to corresponding β,β-dichlorostyrenes. These on further reduction gave esters of 2-arylpropionic acids.
- Patil,Wadia
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p. 2821 - 2827
(2007/10/03)
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- Discovery of γ-lactam hydroxamic acids as selective inhibitors of tumor necrosis factor α converting enzyme: Design, synthesis, and structure-activity relationships
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New γ-lactam TACE inhibitors were designed from known MMP inhibitors. A homology model of TACE was built and examined to identify the S1′ site as the key area for TACE selectivity over MMPs. Rational exploration of the P1′-S1′ interactions resulted in the discovery of the 3,5-disubstituted benzyl ether as a TACE-selective P1′ group. Further optimization led to the discovery of IK682 as a selective and orally bioavailable TACE inhibitor.
- Duan, James J.-W.,Chen, Lihua,Wasserman, Zelda R.,Lu, Zhonghui,Liu, Rui-Qin,Covington, Maryanne B.,Qian, Mingxin,Hardman, Karl D.,Magolda, Ronald L.,Newton, Robert C.,Christ, David D.,Wexler, Ruth R.,Decicco, Carl P.
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p. 4954 - 4957
(2007/10/03)
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- Biomimetic oxidation of ibuprofen with hydrogen peroxide catalysed by Horseradish peroxidase (HRP) and 5,10,15,20- tetrakis-(2',6'-dichloro-3'- sulphonatophenyl)porphyrinatoiron(III) and manganese(III) hydrates in AOT reverse micelles
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The oxidation of ibuprofen with H2O2 catalysed by Horseradish peroxidase (HRP), Cl8TPPS4Fe(III)(OH2)2 and Cl8TPPS4Mn(III)(OH2)2 in AOT reverse micelles gives 2-(4'-isobutyl-phenyl)ethanol (5) and p-isobutyl acetophenone (6) in moderate yields. The reaction of ibuprofen (2) with H2O2 catalysed by HRP form carbon radicals by the oxidative decarboxylation, which on reaction with molecular oxygen to form hydroperoxy intermediate, responsible for the formation of the products 5 and 6. The yields of different oxidation products depend on the pH, the water to surfactant ratio (Wo), concentration of Cl8TPPS4Fe(III)(OH2)2 and Cl8TPPS4Mn(III)(OH2)2 and amount of molecular oxygen present in AOT reverse micelles. The formation of 2-(4'-isobutyl phenyl)ethanol (5) may be explained by the hydrogen abstraction from ibuprofen by high valent oxo- manganese(IV) radical cation, followed by decarboxylation and subsequent recombination of either free hydroxy radical or hydroxy iron(III)/manganese(III) porphyrins. The over-oxidation of 5 with high valent oxo-manganese, Mn(IV)radical cation intermediate form 6 in AOT reverse micelles by abstraction and recombination mechanism. (C) 1999 Elsevier Science Ltd.
- Chauhan,Sahoo
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p. 2629 - 2634
(2007/10/03)
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