- Racemization and hydrolysis of (S)-naproxen 2,2,2-trifluoroethyl ester in non-polar solvents by strong neutral bases: Implication for ion-pair kinetic basicity and hydrolysis
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By using strong neutral bases as catalyst, a detailed investigation of the racemization of (S)-naproxen 2,2,2-trifluoroethyl ester was conducted in the non-polar solvents isooctane, cyclohexane and n-hexane. The second-order interconversion constant kint* as representing the ion-pair kinetic basicity in isooctane was first estimated and correlated with the equilibrium ion-pair basicity pKip in tetrahydrofuran, giving slopes of 0.768 and 0.689 for non-phosphazene and phosphazene bases, respectively, in the Bronsted correlations. The result was further compared with that for (S)-naproxen 2,2,2-trifluoroethyl thioester, showing about a 1-2 orders of magnitude enhancement of kint* for the corresponding thio-containing analogue. A smaller influence of non-polar solvents (i.e. isooctane, n-hexane and cyclohexane) on kint* was found. Kinetic analysis of the racemization and hydrolysis of (S)-naproxen 2,2,2-trifluoroethyl ester in isooctane and n-hexane containing 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene and water suggests nucleophilic hydrolysis by the base, where the breakdown of tetrahedral intermediates I R1 and IS1 is the rate-limiting step and the hydrolysis constant khy is in proportion to the product of base and ion-pair concentrations. Copyright 2004 John Wiley & Sons, Ltd.
- Lin, Man-Yuan,Lay, Eddy,Wen, Wen-Yen,Dewi, Hamza,Cheng, Yu-Chi,Tsai, Shau-Wei
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- Photochemically Controlled Drug Dosing from a Polymeric Scaffold
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Purpose: To develop the first photoactive biomaterial coating capable of controlled drug dosing via inclusion of synthesised drug-3,5-dimethoxybenzoin (DMB) conjugates in a poly(2-methyoxyethyl acrylate) (pMEA) scaffold. Methods: Flurbiprofen- and naproxen-DMB conjugates were prepared via esterification and characterised via NMR spectroscopy and mass spectrometry following chromatographic purification. Conjugate photolysis was investigated in acetonitrile solution and within the pMEA matrix following exposure to low-power 365?nm irradiation. Photo-liberation of drug from pMEA into phosphate buffered saline was monitored using UV-vis spectroscopy. Results: The synthetic procedures yielded the desired drug conjugates with full supporting characterisation. Drug regeneration through photolysis of the synthesised conjugates was successful in both acetonitrile solution and within the pMEA scaffold upon UV irradiation. Conjugates were retained within the pMEA scaffold with exclusive drug liberation following irradiation and increased drug dose with increasing exposure. Multi-dosing capacity was demonstrated though the ability of successive irradiation periods to generate further bursts of drug. Conclusion: This study demonstrates the first application of photochemically controlled drug release from a biomaterial coating and the feasibility of using pMEA as a scaffold for housing the photoactive drug-DMB conjugates.
- Donnelly, Louise,Hardy, John G.,Gorman, Sean P.,Jones, David S.,Irwin, Nicola J.,McCoy, Colin P.
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- Simple synthetic approach to arylacetic NSAIAs via TosMIC procedure
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Preparation of 1-methylpyrrole-2-acetonitrile, 1-methyl-5-(4-methylbenzoyl) pyrrole-2-acetonitrile and 2-(6-methoxy-2-naphthyl)propionitrile by treatment of 1-methylpyrrole-2-carboxaldehyde, 1-methyl-5-(4-methylbenzoyl)pyrrole-2-carboxaldehyde and, respectively, 6-methoxy-2-acetylnaphthalene with tosylmethylisocyanide (TosMIC) is described. This one-step synthetic procedure is very useful to obtain the nitrile precursors of tolmetin and naproxen, two clinically important non-steroidal antiinflammatory agents (NSAIAs).
- Di Santo,Costi,Massa,Artico
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- Investigation of lipase-catalysed hydrolysis of naproxen methyl ester: use of NMR spectroscopy methods to study substrate-enzyme interaction.
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(+/-)-2-(6-Methoxy-2-naphthyl)propionic acid methyl ester (methyl ester of Naproxen), the precursor of therapeutically important nonsteroidal anti-inflammatory drugs (NSAIDs) was enantioselectively hydrolysed using as biocatalyst Candida rugosa lipase. In research aimed at studying the structure-activity relationship (SAR), NMR spectroscopy methods were employed to identify which Naproxen molecular moiety was essential to the substrate-enzyme interaction. The experimental results, in agreement with previous computer modelling studies and reported kinetic data, gave new information on the enzyme-substrate complex formation in solution.
- Cernia,Delfini,Di Cocco,Palocci,Soro
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- Catalytic α-Deracemization of Ketones Enabled by Photoredox Deprotonation and Enantioselective Protonation
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This study reports the catalytic deracemization of ketones bearing stereocenters in the α-position in a single reaction via deprotonation, followed by enantioselective protonation. The principle of microscopic reversibility, which has previously rendered this strategy elusive, is overcome by a photoredox deprotonation through single electron transfer and subsequent hydrogen atom transfer (HAT). Specifically, the irradiation of racemic pyridylketones in the presence of a single photocatalyst and a tertiary amine provides nonracemic carbonyl compounds with up to 97% enantiomeric excess. The photocatalyst harvests the visible light, induces the redox process, and is responsible for the asymmetric induction, while the amine serves as a single electron donor, HAT reagent, and proton source. This conceptually simple light-driven strategy of coupling a photoredox deprotonation with a stereocontrolled protonation, in conjunction with an enrichment process, serves as a blueprint for other deracemizations of ubiquitous carbonyl compounds.
- Chen, Shuming,Gao, Anthony Z.,Ivlev, Sergei I.,Meggers, Eric,Nie, Xin,Ye, Chen-Xi,Zhang, Chenhao
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supporting information
p. 13393 - 13400
(2021/09/03)
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- Preparation of One-Pot Immobilized Lipase with Fe3O4 Nanoparticles Into Metal-Organic Framework For Enantioselective Hydrolysis of (R,S)-Naproxen Methyl Ester
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Immobilization of enzyme to magnetic metal-organic frameworks (MOF) can preserve biological functionality in harsh environments to increase enzymes activity, stability, and improve reusability. The magnetic Fe3O4 nanoparticles were treated with calix[4]arene tetracarboxylic acid (Calix) and Candida rugosa lipase (CRL), and then encapsulated into the zeolitic imidazole framework-8 (Fe3O4@Calix-ZIF-8@CRL). The lipase activity data of Fe3O4@Calix-ZIF-8@CRL was 2.88 times higher than that of the Fe3O4@ZIF-8@CRL (without Calix). The catalytic properties of immobilized lipases were studied on the enantioselective hydrolysis of R/S-naproxen methyl ester. It was also observed that Fe3O4@Calix-ZIF-8@CRL has excellent enantioselectivity (E=371) compared to Fe3O4@ZIF-8@CRL (E=131). Furthermore, Fe3O4@Calix-ZIF-8@CRL was seen to still retain 30 % of the conversion rate after the fifth reuse. This work may also be useful for the pharmaceutical industry due to the increased reusability and stability of enzymes, the enantiomeric selectivity exhibited by MOF-enzyme biocomposites, and the significant differences in the biological activities of the enantiomers.
- Ozyilmaz, Elif,Ascioglu, Sebahat,Yilmaz, Mustafa
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p. 3687 - 3694
(2021/06/25)
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- Synthesis of rac-ɑ-aryl propionaldehydes via branched-selective hydroformylation of terminal arylalkenes using water-soluble Rh-PNP catalyst
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This work detailed the preparation of a class of water-soluble PNP ligands that differed by the nature of the substitute on phenyl ring of ligands. These ligands were incorporated into water-soluble rhodium-PNP complex catalysts that were used to regioselective hydroformylation of a series of terminal arylalkenes, providing efficient access to rac-α-aryl propionaldehydes in good to excellent yield (up to 97%) and branched-regioselectivity (up to 40:1 b/l ratio). Furthermore, gram-scale and diverse synthetic transformation demonstrated synthetic application of this methodology for non-steroidal antiinflammatory drugs.
- Chen, Fen-Er,Gao, Peng,Ke, Miaolin,Liang, Guanfeng,Ru, Tong
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- New process for synthesizing racemic naproxen based on Heck coupling
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The invention discloses a novel process for synthesizing racemic naproxen based on Heck coupling, which comprises the following steps: (1) carrying out Heck coupling reaction on 2-X substituted-6-methoxynaphthalene and crotonamide in an aprotic organic solvent under the action of a palladium catalyst and alkali to generate 3-(6-methoxynaphthyl-2-)-crotonamide; and (2) carrying out Hofmann degradation reaction on the 3-(6-methoxynaphthyl-2-)-crotonamide in an alkaline solution of hypochlorite to generate 2-(6-methoxynaphthyl-2-)-propionaldehyde, directly adding the 2-(6-methoxynaphthyl-2-)-propionaldehyde into chlorite without separation, and conducting oxidizing at room temperature to obtain racemic naproxen. The process provided by the invention does not need to prepare a highly active Grignard reagent, does not need a harsh anhydrous condition, and is relatively high in conversion rate and easy in product purification.
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Paragraph 0031; 0037; 0038; 0041
(2021/08/06)
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- Visible-Light-Enabled Carboxylation of Benzyl Alcohol Derivatives with CO2 Using a Palladium/Iridium Dual Catalyst
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A highly efficient carboxylation of benzyl alcohol derivatives with CO2 using a palladium/iridium dual catalyst under visible-light irradiation was developed. A wide range of benzyl alcohol derivatives could be employed to provide benzylic carboxylic acids in moderate to high yields. Mechanistic studies indicated that the oxidative addition of benzyl alcohol derivatives was possibly the rate-determining-step. It was also found that a switchable site-selective carboxylation between benzylic C?O and aryl C?Cl moieties could be achieved simply by changing the palladium catalyst.
- Iwasawa, Nobuharu,Jin, Yushu,Toriumi, Naoyuki
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- Naproxen impurity and preparation method thereof
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The invention provides a naproxen impurity R, and the structural formula of the naproxen impurity R is shown in the specification. The invention also provides a preparation method of the naproxen impurity R. The preparation method comprises the following steps of: demethylating naproxen racemate in an acidic medium, and further reacting the demethylated naproxen racemate with 3-bromo-2, 2-dimethyl-1-propanol in the presence of an acid-binding agent to obtain the naproxen impurity R. The naproxen impurity R disclosed by the invention is suitable for being used as an impurity reference substancefor researching the synthesis quality of naproxen and intermediates thereof.
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- Method for synthesizing aryl propionic acid by metal-free catalysis of carbon dioxide carboxylation
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The invention relates to the field of carbon dioxide immobilization and conversion, and particularly discloses a method for synthesizing aryl propionic acid by metal-free catalysis of carbon dioxide carboxylation. The method comprises the following steps: stirring a mixed solution of a diselenide catalyst and a styrene compound in a carbon dioxide atmosphere, adding hydrogen peroxide, and stirringto react, thereby obtaining the aryl propionic acid. Styrene is directly used as a raw material, diselenide is used as a catalyst to realize a carboxylation reaction of olefin and carbon dioxide, andcompared with metal catalyst residues or halogen-containing byproducts in a traditional synthesis method, the byproducts in the method only contain water, and small molecular diselenide is used as the catalyst to replace the traditional metal catalyst, and metal residuals are avoided.
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Paragraph 0065-0067
(2021/02/10)
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- Cobalt-Catalyzed Asymmetric Hydrogenation of α,β-Unsaturated Carboxylic Acids by Homolytic H2 Cleavage
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The asymmetric hydrogenation of α,β-unsaturated carboxylic acids using readily prepared bis(phosphine) cobalt(0) 1,5-cyclooctadiene precatalysts is described. Di-, tri-, and tetra-substituted acrylic acid derivatives with various substitution patterns as well as dehydro-α-amino acid derivatives were hydrogenated with high yields and enantioselectivities, affording chiral carboxylic acids including Naproxen, (S)-Flurbiprofen, and a d-DOPA precursor. Turnover numbers of up to 200 were routinely obtained. Compatibility with common organic functional groups was observed with the reduced cobalt(0) precatalysts, and protic solvents such as methanol and isopropanol were identified as optimal. A series of bis(phosphine) cobalt(II) bis(pivalate) complexes, which bear structural similarity to state-of-the-art ruthenium(II) catalysts, were synthesized, characterized, and proved catalytically competent. X-band EPR experiments revealed bis(phosphine)cobalt(II) bis(carboxylate)s were generated in catalytic reactions and were identified as catalyst resting states. Isolation and characterization of a cobalt(II)-substrate complex from a stoichiometric reaction suggests that alkene insertion into the cobalt hydride occurred in the presence of free carboxylic acid, producing the same alkane enantiomer as that from the catalytic reaction. Deuterium labeling studies established homolytic H2 (or D2) activation by Co(0) and cis addition of H2 (or D2) across alkene double bonds, reminiscent of rhodium(I) catalysts but distinct from ruthenium(II) and nickel(II) carboxylates that operate by heterolytic H2 cleavage pathways.
- Chirik, Paul J.,Shevlin, Michael,Zhong, Hongyu
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supporting information
(2020/03/13)
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- Method for preparing naproxen intermediate
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A technical scheme of the invention provides a method for preparing a naproxen intermediate represented by a chemical structural formula I. Preparation reactions are as follows: 6-methoxy-2-acetonaphthone and trimethyl sulfonium hydrogen sulfate are subjected to an epoxidation reaction in the presence of alkali so as to prepare 2-(6-methoxynaphthyl)-1,2-epoxypropane, the 2-(6-methoxynaphthyl)-1,2-epoxypropane is subjected to catalyzed rearrangement through silica gel or FeCl3 and then reacts with hydroxylamine hydrochloride, thereby preparing an intermediate, i.e., 2-(6-methoxy-2-naphthyl)propyl oxime (I) in one step. Naproxen is prepared by employing a one-pot method through a key intermediate, i.e., 2-(6-methoxy-2-naphthyl)propyl oxime.
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- Deoxygenative α-alkylation and α-arylation of 1,2-dicarbonyls
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Construction of C-C bonds at the α-carbon is a challenging but synthetically indispensable approach to α-branched carbonyl motifs that are widely represented among drugs, natural products, and synthetic intermediates. Here, we describe a simple approach to generation of boron enolates in the absence of strong bases that allows for introduction of both α-alkyl and α-aryl groups in a reaction of readily accessible 1,2-dicarbonyls and organoboranes. Obviation of unselective, strongly basic and nucleophilic reagents permits carrying out the reaction in the presence of electrophiles that intercept the intermediate boron enolates, resulting in two new α-C-C bonds in a tricomponent process. This journal is
- Arman, Hadi D.,Dang, Hang T.,Haug, Graham C.,Jin, Shengfei,Larionov, Oleg V.,Nguyen, Viet D.
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p. 9101 - 9108
(2020/09/17)
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- Preparation method of aryl propionic acid compound
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The invention provides a preparation method of an aryl propionic acid compound, wherein the preparation method comprises the following steps: carrying out acetylation reaction on substituted aryl benzene to obtain aryl acetophenone; carrying out hydrogenation reduction reaction on alpha-substituted aryl ethyl ketone to obtain alpha-substituted aryl ethanol; and in an acidic solution, introducing carbon monoxide gas into the alpha-substituted aryl ethanol, and carrying out a carbonylation reaction under the co-catalytic action of a main catalyst and a cocatalyst to obtain the aryl propionic acid compound, wherein the cocatalyst has the following structural formula described in the specification, R1 is one of hydrogen and a substituted carboxylic acid group, and R2 is one of hydrogen, halogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C12 naphthenic base, substituted carbonyl containing C6-C24 aryl or substitutedaryl, substituted carbonyl containing C3-C12 heterocyclic radical or substituted heterocyclic radical, phenyl, substituted phenyl, naphthyl and substituted naphthyl.
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Paragraph 0121-0125
(2020/10/04)
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- Iridium-Catalyzed α-Methylation of α-Aryl Esters Using Methanol as the C1 Source
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IrCl(cod)2]/dppe-catalyzed α-methylation of aryl esters using methanol as the C1 source was developed. This methylation process is useful in several fields including organic chemistry, biochemistry, and medicinal chemistry. Readily available methanol as methylation reagent was successfully adapted. The reaction processed high atom economy and efficient. By applying the reaction system, the synthesis method of naproxen was provided.
- Tsukamoto, Yuya,Itoh, Satoshi,Kobayashi, Masaki,Obora, Yasushi
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supporting information
p. 3299 - 3303
(2019/05/10)
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- Organocatalyzed Aerobic Oxidation of Aldehydes to Acids
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The first example organocatalyzed aerobic oxidation of aldehydes to carboxylic acids in both organic solvent and water under mild conditions is developed. As low as 5 mol % N-hydroxyphthalimide was used as the organocatalyst, and molecular O2 was used as the sole oxidant. No transition metals or hazardous oxidants or cocatalysts were involved. A wide range of carboxylic acids bearing diverse functional groups were obtained from aldehydes, even from alcohols, in high yields.
- Dai, Peng-Fei,Qu, Jian-Ping,Kang, Yan-Biao
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supporting information
p. 1393 - 1396
(2019/02/26)
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- Electrogenerated Sm(II)-Catalyzed CO2 Activation for Carboxylation of Benzyl Halides
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Sm(II)-catalyzed carboxylation of benzyl halides is reported through the electrochemical reduction of CO2. The transformation proceeds under mild reaction conditions to afford the corresponding phenylacetic acids in good to excellent yields. This user-friendly and operationally simple protocol represents an alternative to traditional strategies, which usually proceeds through the C(sp3)-halide activation pathway.
- Bazzi, Sakna,Schulz, Emmanuelle,Mellah, Mohamed
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p. 10033 - 10037
(2019/12/24)
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- Synthetic process of DL-naproxen
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The invention discloses a synthetic process of DL-naproxen. The synthetic process comprises the steps of with 6-methoxy-2-propionylnaphthalene as a raw material, reacting with dihydric alcohol A and copper chloride so as to obtain ketal A, and carrying out rearrangement reaction on purified or unpurified ketal A, so as to obtain an esterified product A; or carrying out acidic hydrolysis on ketal Aso as to obtain 2-chloro-propan-1-one, carrying out ketalation by virtue of 2-chloro-propan-1-one and purified or unpurified dihydric alcohol B so as to obtain ketal B, carrying out rearrangement reaction on ketal B so as to obtain an esterified product B, hydrolyzing the esterified product A and the esterified product B under a strongly basic condition, and carrying out acidification, so as to obtain DL-naproxen; or reacting by virtue of the esterified product A or the esterified product B and carboxylate and the like under a proper basic condition so as to obtain an esterified product, hydrolyzing the esterified product under a strongly basic condition, and carrying out acidification, so as to obtain DL-naproxen. Compared with the prior art, the synthetic process has the advantages thata chlorination ketal one-pot method is adopted, an ethanol solvent with a low boiling point is not used, a chlorination agent is regenerated and circulated, and links of separation and the like are reduced; and the process route is environment-friendly and high in synthetic efficiency, and the raw materials are cheaper than the raw materials in the prior art in China.
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- Synthesis method of D,L-naproxen
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The invention provides a synthesis method of D,L-naproxen. The synthesis method is characterized by comprising the step of removing bromine: taking D,L-2-(5-bromo-6-methoxyl-naphthyl)-sodium propionate as a raw material, and taking water and dioxane as solvents, adding a catalyst under alkaline conditions and nitrogen protection, reacting under 80-90 DEG C, filtering after the reaction is completed, and regulating the pH (Potential of hydrogen) of filtrate by acid to obtain a final product, wherein the catalyst is one of tetrakis(triphenylphosphine)palladium or diacetatobis(triphenylphosphine)palladium(II) or palladium chloride taking triphenylphosphine as a ligand. According to the synthesis method, through optimizing the synthesis method of naproxen, the tetrakis(triphenylphosphine)palladium and the diacetatobis(triphenylphosphine) palladium(II) as well as the palladium chloride taking the triphenylphosphine as the ligand are adopted as the catalyst to remove the bromine on a benzene ring; hydrogenation and high pressure are not needed; the reaction is safe and reliable; the yield is high; the synthesis method is suitable for industrial production.
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- Synthesis method of novel DL-naproxen
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The invention discloses a synthesis method of novel DL-naproxen. According to the synthesis method, 6-methoxy-2-acetyl naphthalene is adopted as a raw material and is synthesized to prepare the DL-naproxen through halogenating reaction, ketalation reaction, rearrangement reaction and hydrolytic acidification. The synthesis method specifically include: adopting the 6-methoxy-2-acetyl naphthalene as the raw material, synthesizing the 6-methoxy-2-acetyl naphthalene into 2-halogen-1-(6-methoxy-2-naphthyl)propan-1-ketone by directly using a halogenating agent in an appropriate condition, synthesizing into ketal after purification or non-purification, rearranging, hydrolyzing and acidizing to obtain the DL-naproxen. The synthesis method of the novel DL-naproxen is less in synthesis steps and raw materials and simpler in technological processes, and the obtained DL-naproxen is less in impurities, high in content and better in color.
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Paragraph 0025-0029
(2019/10/04)
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- Photocarboxylation of Benzylic C-H Bonds
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The carboxylation of sp3-hybridized C-H bonds with CO2 is a challenging transformation. Herein, we report a visible-light-mediated carboxylation of benzylic C-H bonds with CO2 into 2-arylpropionic acids under metal-free conditions. Photo-oxidized triisopropylsilanethiol was used as the hydrogen atom transfer catalyst to afford a benzylic radical that accepts an electron from the reduced form of 2,3,4,6-tetra(9H-carbazol-9-yl)-5-(1-phenylethyl)benzonitrile generated in situ. The resulting benzylic carbanion reacts with CO2 to generate the corresponding carboxylic acid after protonation. The reaction proceeded without the addition of any sacrificial electron donor, electron acceptor or stoichiometric additives. Moderate to good yields of the desired products were obtained in a broad substrate scope. Several drugs were successfully synthesized using the novel strategy.
- Meng, Qing-Yuan,Schirmer, Tobias E.,Berger, Anna Lucia,Donabauer, Karsten,K?nig, Burkhard
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p. 11393 - 11397
(2019/08/20)
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- D, L-naproxen one-pot synthesis method
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The invention provides a D, L-naproxen one-pot synthesis method which is characterized by including the preparation steps: (1) adding xylene into a reaction vessel, performing reaction with phenyl trimethyl ammonium tribromide and 6-methoxyl-2-propionyl naphthalene to obtain xylene solution; (2) heating the xylene solution to boil and remove water, cooling the xylene solution, adding neopentyl glycol and p-toluenesulfonic acid and then continuing reflux water distribution reaction; (3) adding zinc acetate or zinc oxide into last-step reaction liquid and performing heating reflux reaction; (4) adding sodium hydroxide or potassium hydroxide solution into residues obtained by drying by distillation and dissolution in the last step, performing hydrolysis and collecting water solution for stand-by application of next-step reaction; (5) adding Raney nickel into the water solution and performing hydrogenation reaction to obtain a product. Total yield reaches 73%, one-pot synthesis is performed in whole operation, a technology is simplified, and an industrial route is environmentally friendly.
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Paragraph 0029-0030; 0035-0036; 0041-0042; 0047
(2019/10/04)
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- Palladium-Catalyzed α-Arylation of Carboxylic Acids and Secondary Amides via a Traceless Protecting Strategy
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A novel traceless protecting strategy is presented for the long-standing challenge of conducting the palladium-catalyzed α-arylation of carboxylic aids and secondary amides with aryl halides. Both of the presented coupling processes occur with a variety of carboxylic acids and amides and with a variety of aryl bromides containing a broad range of functional groups, including base-sensitive functionality like acyl, alkoxycarbonyl, nitro, cyano, and even hydroxyl groups. Five commercial drugs were prepared through this method in one step in 81-96% yield. Gram-scale synthesis of medication Naproxen and Flurbiprofen with low palladium loading further highlights the practical value of this method.
- He, Zhi-Tao,Hartwig, John F.
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supporting information
p. 11749 - 11753
(2019/08/26)
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- Nickel-Catalyzed Cyanation of Benzylic and Allylic Pivalate Esters
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A nickel-catalyzed cyanation reaction of benzylic and allylic pivalate esters is reported using an air-stable Ni(II) precatalyst and substoichiometric quantities of Zn(CN)2. Alkene additives were found to inhibit catalysis, suggesting that avoiding β-hydride elimination side reactions is essential for productive catalysis. An enantioenriched allylic ester undergoes enantiospecific cross-coupling to produce an enantioenriched allylic nitrile. This method was applied to an efficient synthesis of (±)-naproxen from commercially available starting materials.
- Michel, Nicholas W. M.,Jeanneret, Alexandria D. M.,Kim, Hyehwang,Rousseaux, Sophie A. L.
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p. 11860 - 11872
(2018/10/02)
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- Visible-Light-Driven External-Reductant-Free Cross-Electrophile Couplings of Tetraalkyl Ammonium Salts
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Cross-electrophile couplings between two electrophiles are powerful and economic methods to generate C-C bonds in the presence of stoichiometric external reductants. Herein, we report a novel strategy to realize the first external-reductant-free cross-electrophile coupling via visible-light photoredox catalysis. A variety of tetraalkyl ammonium salts, bearing primary, secondary, and tertiary C-N bonds, undergo selective couplings with aldehydes/ketone and CO2. Notably, the in situ generated byproduct, trimethylamine, is efficiently utilized as the electron donor. Moreover, this protocol exhibits mild reaction conditions, low catalyst loading, broad substrate scope, good functional group tolerance, and facile scalability. Mechanistic studies indicate that benzyl radicals and anions might be generated as the key intermediates via photocatalysis, providing a new direction for cross-electrophile couplings.
- Liao, Li-Li,Cao, Guang-Mei,Ye, Jian-Heng,Sun, Guo-Quan,Zhou, Wen-Jun,Gui, Yong-Yuan,Yan, Si-Shun,Shen, Guo,Yu, Da-Gang
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p. 17338 - 17342
(2019/01/04)
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- A Ligand-Directed Catalytic Regioselective Hydrocarboxylation of Aryl Olefins with Pd and Formic Acid
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An effective Pd-catalyzed hydrocarboxylation of aryl olefins with Ac2O and formic acid is described. A variety of 2- and 3-arylpropanoic acids can be regioselectively formed by the judicious choice of ligand without the use of toxic CO gas.
- Liu, Wei,Ren, Wenlong,Li, Jingfu,Shi, Yuan,Chang, Wenju,Shi, Yian
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supporting information
p. 1748 - 1751
(2017/04/11)
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- Site-Selective Catalytic Carboxylation of Unsaturated Hydrocarbons with CO2 and Water
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A catalytic protocol that reliably predicts and controls the site-selective incorporation of CO2 to a wide range of unsaturated hydrocarbons utilizing water as formal hydride source is described. This platform unlocks an opportunity to catalytically repurpose three abundant, orthogonal feedstocks under mild conditions.
- Gaydou, Morgane,Moragas, Toni,Juliá-Hernández, Francisco,Martin, Ruben
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supporting information
p. 12161 - 12164
(2017/09/12)
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- SYNTHESIS OF ISOFLAVANES AND INTERMEDIATES THEREOF
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Subject of the invention is a method for enantioselective production of an isoflavane from an isoflavone, comprising the steps: (a) selectively reducing the isoflavone, such that the 4-keto group of the isoflavone is converted to a 4-hydroxy group, and the 2,3-double bond of the isoflavone is converted to a 2,3-single bond, thereby obtaining a 4-hydroxy intermediate, and (b) reacting the 4-hydroxy intermediate with a chiral reagent, such that a chiral group is covalently attached to the C4-position of the 4-hydroxy intermediate, thereby obtaining a chiral intermediate. The invention also relates to intermediates of formulae (IV), (V), (VI) and (VII) obtainable in the inventive process.
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Page/Page column 24
(2016/04/20)
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- Pd-Catalyzed Regiodivergent Hydroesterification of Aryl Olefins with Phenyl Formate
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An effective Pd-catalyzed regiodivergent hydroesterification of aryl olefins with phenyl formate is described. Either linear or branched phenyl arylpropanoates can be obtained in good yields with high regioselectivities by the judicious choice of ligand without the use of toxic CO gas.
- Ren, Wenlong,Chang, Wenju,Wang, Yang,Li, Jingfu,Shi, Yian
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supporting information
p. 3544 - 3547
(2015/07/28)
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- A novel synthesis of (4aS,7aS)-Octahydro-1H-pyrrolo[3,4-b]pyridine:An intermediate of Moxifloxacin Hydrochloride
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A novel synthesis of (4aS, 7aS)-octahydro-1H-pyrrolo[3,4-b]pyridine (1) is demonstrated alongwith recovery and reuse of chiral auxiliary naproxen. Further to this alternative stereoselective reduction procedures on 6-benzyl-5H- pyrrolo[3,4-b]pyridine-5,7(6H)-dione 3 enabling the desired chirality in the nonane 1 is demonstrated.
- Reddy, G. Prashanth,Bandichhor, Rakeshwar
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p. 8701 - 8707
(2013/11/06)
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- Laboratory evolution of enantiocomplementary Candida antarctica lipase B mutants with broad substrate scope
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Candida antarctica lipase B (CALB) is a robust and easily expressed enzyme used widely in academic and industrial laboratories with many different kinds of applications. In fine chemicals production, examples include acylating kinetic resolution of racemic secondary alcohols and amines as well as desymmetrization of prochiral diols (or the reverse hydrolytic reactions). However, in the case of hydrolytic kinetic resolution of esters or esterifying kinetic resolution of acids in which chirality resides in the carboxylic acid part of the substrate, rate and stereoselectivity are generally poor. In the present study, directed evolution based on iterative saturation mutagenesis was applied to solve the latter problem. Mutants with highly improved activity and enantioselectivity relative to wild-type CALB were evolved for the hydrolytic kinetic resolution of p-nitrophenyl 2-phenylpropanoate, with the selectivity factor increasing from E = 1.2 (S) to E = 72 (S) or reverting to E = 42 (R) on an optional basis. Surprisingly, point mutations both in the acyl and alcohol pockets of CALB proved to be necessary. Some of the evolved CALB mutants are also efficient biocatalysts in the kinetic resolution of other chiral esters without performing new mutagenesis experiments. Another noteworthy result concerns the finding that enantiocomplementary CALB mutants for α-substituted carboxylic acid esters also show stereocomplementarity in the hydrolytic kinetic resolution of esters derived from chiral secondary alcohols. Insight into the source of stereoselectivity was gained by molecular dynamics simulations and docking experiments.
- Wu, Qi,Soni, Pankaj,Reetz, Manfred T.
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supporting information
p. 1872 - 1881
(2013/08/24)
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- Enantioselective Grignard addition to nitroolefin
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A novel synthesis of naproxen utilizing nitroaldol, 1,4-addition and Nef reaction is demonstrated where the desired S-enantiomer is achieved by resolution. Further to this first enantioselective 1,4-addition of Grignard reagent to nitroolefin is demonstrated to synthesize derivatives of naproxen.
- Reddy, Prashanth,Bandichhor, Rakeshwar
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p. 3911 - 3915
(2013/07/26)
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- Pd-catalyzed decarboxylative cross-couplings of potassium malonate monoesters with aryl halides
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An efficient catalytic protocol for Pd-catalyzed decarboxylative cross-coupling of potassium malonate monoesters and derivatives with aryl bromides and chlorides are described. Because of its broad applicability, this new catalytic system provides an alternative method for the preparation of diverse aryl acetic acids and derivatives.
- Feng, Yi-Si,Wu, Wei,Xu, Zhong-Qiu,Li, Yan,Li, Ming,Xu, Hua-Jian
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supporting information; experimental part
p. 2113 - 2120
(2012/03/26)
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- One-pot synthesis of phthalazines and pyridazino-aromatics: A novel strategy for substituted naphthalenes
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A new one-pot strategy for the synthesis of phthalazines and pyridazino-aromatics starting from aromatic aldehydes has been developed. A variety of substituents ranging from electron withdrawing to donating is tolerated furnishing the desired 1,2-diazine in good to excellent yields. The products have been applied to the bidentate Lewis acid catalyzed inverse electron-demand Diels-Alder (IEDDA) reaction opening a novel two-step entry into substituted naphthalenes, such as Naproxen.
- Kessler, Simon N.,Wegner, Hermann A.
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supporting information; experimental part
p. 3268 - 3271
(2012/08/28)
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- Highly enantioselective direct alkylation of arylacetic acids with chiral lithium amides as traceless auxiliaries
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A direct, highly enantioselective alkylation of arylacetic acids via enediolates using a readily available chiral lithium amide as a stereodirecting reagent has been developed. This approach circumvents the traditional attachment and removal of chiral auxiliaries used currently for this type of transformation. The protocol is operationally simple, and the chiral reagent is readily recoverable.
- Stivala, Craig E.,Zakarian, Armen
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supporting information; experimental part
p. 11936 - 11939
(2011/09/19)
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- Kinetic resolution of α-substituted alkanoic acids promoted by homobenzotetramisole
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A new method for catalytic nonenzymatic kinetic resolution of α-substituted alkanoic acids has been developed, which relies on their activation with DCC followed by enantioselective alcoholysis of the intermediate symm-anhydrides in the presence of the amidine-based catalyst homobenzotetramisole (HBTM). Moderate to excellent selectivity factors (s=5-96) have been obtained in the case of several classes of substrates, namely, α-aryl-, α-aryloxy/alkoxy-, α-halo-, α-azido-, and α-phthalimido-alkanoic acids. Under similar conditions, α-(arylthio/alkylthio)-alkanoic acids undergo dynamic kinetic resolution providing corresponding esters in up to 92 % ee and up to 93 % yield. Copyright
- Yang, Xing,Birman, Vladimir B.
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supporting information; experimental part
p. 11296 - 11304
(2011/10/19)
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- One-step oxidation of 2-arylpropanols to 2-arylpropionic acids: Improving sustainability in the synthesis of profens
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Three oxidation procedures were evaluated for the synthesis of optically pure 2-arylpropionic acids. Efficient, mild, and eco-friendly conditions were obtained with the system comprising TEMPO, NaClO, and NaClO2. Thus a series of profens were obtained in good to excellent yields. Georg Thieme Verlag Stuttgart New York.
- Galletti, Paola,Pori, Matteo,Giacomini, Daria
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experimental part
p. 2644 - 2648
(2010/11/18)
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- Palladium complexes of bulky ortho-trifluoromethylphenyl-substituted phosphines: Unusually regioselective catalysts for the hydroxycarbonylation and alkoxycarbonylation of alkenes
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The reactions of the very bulky phosphine ligands containing both tert-butyl and ortho-trifluoromethylphenyl substituents with [PdCl 2(PhCN)2] have been studied, in order to assess the impact of steric and electronic effects on a ligand's coordination ability. The palladium complexes of tert-butyl(ortho-trifluoromethylphenyl)methyl phosphine and tert-butyl(ortho-trifluoromethylphenyl)(n-butyl)phosphine were characterised by X-ray crystallography and shown to be good precatalysts for the hydroxy- and alkoxycarbonylation of alkenes relative to Pd complexes of tricyclohexylphosphine and triphenylphosphine. A notable feature of Pd complexes of tert-butyl(ortho-trifluoromethylphenyl)methyl phosphine is significantly enhanced regioselectivity relative to previous state-of-the-art catalysts in the hydroxycarbonylation of styrene, even if lithium chloride co-catalysts are not used. These catalysts derived from large cone angle ligands consistently give higher regioselectivity in the alkoxycarbonylation of styrene using ethanol, n-propanol, and i-propanol as nucleophiles. These Pd complexes are also active in the Suzuki coupling of activated aryl chlorides, and in both carbonylation and Suzuki reactions, tert-butyl(ortho-trifluoromethylphenyl)methyl phosphine gives more productive catalysts than its bulkier analogues.
- Grabulosa, Arnald,Frew, Jamie J.R.,Fuentes, José A.,Slawin, Alexandra M.Z.,Clarke, Matthew L.
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experimental part
p. 18 - 25
(2010/12/20)
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- Water-promoted cascade synthesis of α-arylaldehydes from arylalkenes using N-halosuccinimides: An avenue for asymmetric oxidation using Cinchona organocatalysis
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The direct oxidation of arylalkenes into α-arylaldehydes is achieved for the first time in water without relying on transition metal catalysts, and a novel organocatalytic enantioselective approach is also explored to provide up to 30% ee in initial investigations.
- Sharma, Abhishek,Sharma, Naina,Kumar, Rakesh,Sharma, Upendra K.,Sinha, Arun K.
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supporting information; experimental part
p. 5299 - 5301
(2010/01/31)
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- A novel synthetic route to 2-arylalkanoic acids by a ruthenium-catalyzed chemoselective oxidation of furan rings
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An efficient two-step synthesis of 2-arylalkanoic acids from 1-arylalkanols is described. Firstly, 1-arylalkylfuran derivatives were synthesized in high yields by the metal triflate catalyzed Friedel-Crafts alkylation of 2-methylfuran with 1-arylalkanols without employing anhydrous conditions. The chemoselective oxidation of the furan ring in 1-arylalkylfurans to carboxylic acid was then investigated. In a solvent system of hexane-EtOAc/H2O (1:3:4), the furan ring was selectively oxidized with 7 equivalents of NaIO 4 by using 0.5 mol% RuCl3 as catalyst to give 2-arylalkanoic acids in good yields. The selectivity of ruthenium oxidation was controlled by the solvent ratio of hexane-EtOAc. Georg Thieme Verlag Stuttgart.
- Noji, Masahiro,Sunahara, Haruka,Tsuchiya, Ken-Ichi,Mukai, Toru,Komasaka, Ayako,Ishii, Keitaro
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experimental part
p. 3835 - 3845
(2009/07/04)
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- Facile and selective deallylations of esters under 'aqueous' free-radical conditions
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The conversion of allyl esters into carboxylic acids using radical initiators has been achieved in high yields in aqueous media. Georg Thieme Verlag Stuttgart.
- Perchyonok, V. Tamara,Ryan, Sarah J.,Langford, Steven J.,Hearn, Milton T.,Tuck, Kellie L.
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body text
p. 1233 - 1235
(2009/04/05)
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- A great improvement of the enantioselectivity of lipase-catalyzed hydrolysis and esterification using co-solvents as an additive
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Addition of co-solvents such as tetrahydrofuran resulted in a great improvement of the enantioselectivity of lipase-catalyzed hydrolysis of butyl 2-(4-substituted phenoxy)propanoates in an aqueous buffer solution. On the other hand, lipase lyophilized from an aqueous solution containing the co-solvents catalyzed highly enantioselective esterification of 2-(4-substituted phenoxy)propionic acids, 2-(4-isobutylphenyl)propionic acid (ibuprofen), and 2-(6-methoxy-2-naph-thyl)propionic acid (naproxen) in an organic solvent. An increase in the E value up to two orders of magnitude was observed for some substrates. The origin of the enantioselectivity enhancement caused by the co-solvent addition was mainly attributed to a significant deceleration in the initial reaction rate for the incorrectly binding enantiomer, as compared with that for the correctly binding enantiomer. From the results of FT-1R, CD, and ESR spectra, the co-solvent addition was also found to bring about a partial destruction of the tertiary structure of lipase.
- Nishigaki, Tomohiro,Yasufuku, Yoshitaka,Murakami, Sayuri,Ebara, Yasuhito,Ueji, Shin-Ichi
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experimental part
p. 617 - 622
(2009/04/11)
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- Metal complexes-catalyzed hydrolysis and alcoholysis of organic substrates and their application to kinetic resolution
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Metal complexes-catalyzed hydrolysis and alcoholysis of organic substrates such as alkenyl esters, alkenyl ethers, and azlactones (oxazol-5(4H)-ones) are described. These reactions were applied for kinetic resolution of chiral compounds and high selectivities were achieved with vinyl ethers of 2-substituted cyclohexanols, 1,1′-bi-2-naphthols, 1,1′-bi-2-phenols, and 4,4-disubstituted azlactones. Oxidative carbon-carbon bond cleavage reactions, which were found in the course of the study of asymmetric hydrolysis were also described.
- Tokunaga, Makoto,Aoyama, Hiroshi,Kiyosu, Junya,Shirogane, Yuki,Iwasawa, Tetsuo,Obora, Yasushi,Tsuji, Yasushi
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p. 472 - 480
(2008/02/06)
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- α-(1H-Imidazol-1-yl)alkyl (IMIDA) carboxylic acid esters as prodrugs of carboxylic acid containing drugs
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Synthesis of α-(1H-imidazol-1-yl)alkyl (IMIDA) carboxylic acid esters have been reported in 2-3 simple steps. α-(1H-Imidazol-1-yl)alkyl (IMIDA) carboxylic acid esters were found to be chemically labile and thus serve as novel prodrugs of carboxylic acids.
- Majumdar, Susruta,Spaeth, Maren Mueller,Sivendran, Sashikala,Juntunen, Juha,Thomas, Joshua D.,Sloan
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p. 4609 - 4611
(2008/02/06)
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- Influence of {single bond}OR ester group length on the catalytic activity and enantioselectivity of free lipase and immobilized in membrane used for the kinetic resolution of naproxen esters
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Lipases are suitable catalysts for the kinetic resolution of racemic mixtures due to their ability to discriminate between enantiomers. For this reason, they have been studied largely to develop reactors for the production of optically pure enantiomers. The main problem in these productive systems is enzyme stability and enantiocatalytic selectivity as a function of time. In this work, the enantiocatalytic properties of lipase as a function of the {single bond}OR group length were studied. The methyl, butyl, and octyl esters of naproxen were synthesized and used as reagents. The lipase was used as a free agent and immobilized in a polymeric membrane reactor. The results show that selectivity and stability of the enzyme improved while catalytic activity decreased with the {single bond}OR length group. The immobilized enzyme had higher activity compared with the free enzyme.
- Giorno,D'Amore,Drioli,Cassano,Picci
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p. 194 - 200
(2008/03/12)
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- Expanding the substrate scope of enzymes: Combining mutations obtained by CASTing
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In a previous paper, the combinatorial active-site saturation test (CAST) was introduced as an effective strategy for the directed evolution of enzymes toward broader substrate acceptance. CASTing comprises the systematic design and screening of focused libraries around the complete binding pocket, but it is only the first step of an evolutionary process because only the initial libraries of mutants are considered. In the present study, a simple method is presented for further optimization of initial hits by combining the mutational changes obtained from two different libraries. Combined lipase mutants were screened for hydrolytic activity against six notoriously difficult substrates (bulky carboxylic acid esters) and improved mutants showing significantly higher activity were identified. The enantioselectivity of the mutants in the hydrolytic kinetic resolution of two substrates was also studied, with the best mutant-substrate combination resulting in a selectivity factor of E=49. Finally, the catalytic profile of the evolved mutants in the hydrolysis of simple nonbranched carboxylic acid esters, ranging from acetate to palmitate, was studied for theoretical reasons.
- Reetz, Manfred T.,Carballeira, Jose Daniel,Peyralans, Jerome,Hoebenreich, Horst,Maichele, Andrea,Vogel, Andreas
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p. 6031 - 6038
(2007/10/03)
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- Process for the preparation of 2-aryl propionic acids
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The present invention provides for the preparation of 2-aryl propionic acids, which comprises the steps of: reacting an aryl compound selected from an arylalkyl halide having general formula I, aryl alcohol having general formula II or aryl substituted olefins having general formula III, as shown in the accompanying drawings, wherein, R1 is aryl, substituted aryl, naphthyl or substituted naphthyl groups, R2, R3, R4 and R5 are independently hydrogen, alkyl, aryl, arylalkyl or cycloaliphatic groups with or without substituents and X is other a halogen atom selected from chlorine, bromine, iodine with a halide promoter, an organic acid, water and a palladium catalyst in an organic solvent selected from ketones or cyclic ethers in carbon monoxide atmosphere under homogeneous conditions, at a temperature ranging between 30 to 130° C., for a period ranging between 0.3 to 4 hrs, at pressures ranging between 50 to 1500 psig, cooling the reaction mixture to ambient temperature, flushing the reaction vessel with inert gas, removing the solvent by conventional methods, and separating the catalyst and isolating 2 aryl propionic acid having formula IV as shown in the accompanying drawings, wherein, R1 is aryl, substituted aryl, naphthyl or substituted naphthyl groups, R2, R3, R4 and R5 are independently hydrogen, alkyl, aryl, arylalkyl, cycloaliphatic groups with or without substituents.
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Page/Page column 4
(2008/06/13)
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- Electrosynthesis of 2-arylpropionic acids from α-methylbenzyl chlorides and carbon dioxide by [Co(Salen)]
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The electrochemical synthesis of the 2-arylpropionic acid group of nonsteroidal anti-inflammatory agents such as ibuprofen, naproxen, indoprofen, biprofen, cicloprofen, and fenoprofen has been carried out in dimethylformamide (DMF) containing tetra-n-butylammonium perchlorate (nBu4NClO 4) by electrochemical carboxylation of α-methylbenzyl chlorides catalyzed by a schiff-base complex [Co(salen)] in an undivided cell equipped with a platinum cathode and magnesium anode under constant current density of 10 mA/cm2 in good yields. Cyclic voltammetric studies have also been carried out to investigate the mechanism by which [Co(salen)] catalyzes the cathodic reaction of α-methylbenzyl chlorides in presence of CO 2 by taking α-phenylethylchloride as the model compound. Copyright Taylor & Francis, Inc.
- Damodar,Krishna Mohan,Khaja Lateef,Jayarama Reddy
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p. 1143 - 1150
(2007/10/03)
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- Hydrolysis of Alkenyl Esters and Ethers Catalyzed by Metal Complexes
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(Equation presented) Various kinds of transition metals catalyzed the hydrolysis of alkenyl esters and ethers under buffer-free, high concentration conditions compared to usual biocatalysts. Hydrolytic kinetic resolution of cis-2-tert-butylcyclohexyl vinyl ether was achieved by chiral (salen)Co complexes with good selectivity (krel = 10.0).
- Aoyama, Hiroshi,Tokunaga, Makoto,Hiraiwa, Shin-Ichiro,Shirogane, Yuki,Obora, Yasushi,Tsuji, Yasushi
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p. 509 - 512
(2007/10/03)
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- Process for the preparation of 2-aryl propionic acids
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The present invention provides an improved process for the preparation of 2-aryl propionic acid which by subjecting an aryl compound selected from an aryl alcohol or aryl halide or an aryl olefin to carbonylation in the presence of a halide source, a protonic acid, water and a heterogeneous metal and a phosphine ligand as a catalyst in an organic solvent.
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Page column 70
(2008/06/13)
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- Prodrugs of non-steroidal anti-inflammatory and carboxylic acid containing compounds
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Compounds of the formula: RC(O)O-spacer-OC(O)R′, wherein (i) RC(O)— is the acyl residue of an NSAID or other pharmaceutically active agent bearing a carboxylic acid function, (ii) spacer is Cn alkyl, (iii) n is from 1 to 6, and (iv) R′ is substituted or unsubstituted heteroaryl or heterocycle, and pharmaceutical compositions thereof.
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