- Asymmetric Synthesis of (S)-2-(6-methoxy-2-naphthyl)propanoic Acid
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For the synthesis of the title compound of 60 percent ee, a new method is established which involves cyanation of an acetal derived from 1-(6-methoxy-2-naphthyl)ethanone and (S,S)-2,4-pentanediol, alkaline hydrolysis, and finally hydrogenolysis with palladium catalyst.
- Hiyama, Tamejiro,Saito, Kumi,Sato, Ken-ichi,Wakasa, Noriko,Inoue, Masuo
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- Disposition of naproxen, naproxen acyl glucuronide and its rearrangement isomers in the isolated perfused rat liver
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1. An isolated perfused rat liver (IPRL) preparation was used to investigate separately the disposition of the non-steroidal anti-inflammatory drug (NSAID) naproxen (NAP), its reactive acyl glucuronide metabolite (NAG) and a mixture of NAG rearrangement isomers (isoNAG), each at 30 μg NAP equivalents ml-1 perfusate (n = 4 each group). 2. Following administration to the IPRL, NAP was eliminated slowly in a log-linear manner with an apparent elimination half-life (t1/2) of 13.4 ± 4.4 h. No metabolites were detected in perfusate, while NAG was the only metabolite present in bile in measurable amounts (3.9 ± 0.8% of the dose). Following their administration to the IPRL, both NAG and isoNAG were rapidly hydrolysed (t1/2 in perfusate = 57 ± 3 and 75 ± 14 min respectively). NAG also rearranged to isoNAG in the perfusate. Both NAG and isoNAG were excreted intact in bile (24.6 and 14.8% of the NAG and isoNAG doses, respectively). 3. Covalent NAP-protein adducts in the liver increased as the dose changed from NAP to NAG to isoNAG (0.20 to 0.34 to 0.48% of the doses, respectively). Similarly, formation of covalent NAP-protein adducts in perfusate were greater in isoNAG-dosed perfusions. The comparative results suggest that isoNAG is a better substrate for adduct formation with liver proteins than NAG.
- Lo,Addison,Hooper,Dickinson
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- New synthesis of optically active α-arylpropanoic acid: The asymmetric hydrogenation of atropic acid over cinchona-modified Pd/Fe2O3 catalysts
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The first satisfactory application of the heterogeneous cinchona-modified Pd/Fe2O3 catalyst system in the synthesis of optically active α-arylpropanoic acid, namely, the highly enantioselective (up to 87% ee) hydrogenation of atropic acid to S-(+)-naproxen is described.
- Ma,Wang,Shi
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- Catalytically distinct antibodies prepared by the reactive immunization versus transition state analogue hapten manifolds
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This report describes the first direct comparison between the reactive immunization and transition state analogue hapten manifolds for catalytic antibody production. In an initial communication (Janda et al J. Am. Chem. Soc. 1997, 119, 10251) we described the use of a phosphonate diester hapten 5, in a reactive immunization approach, that elicited a panel of proficient biocatalysts for the hydrolysis of S-(+)-naproxen p-methylsulfonylphenyl ester (3b) [k(cat)(3b)/k(uncat)(3b) = 0.05-6.60 x 105]. However, only moderate enantioselectivity was obtained when the panel of antibody catalysts was studied in a kinetic resolution of rac-3a, the best result leading to S- (+)-4a in 90% ee for 35% conversion of rac-3a. This report details a transition state analogue hapten approach to elicit antibody catalysts for this same process by employment of phosphonate monoester 6. This strategy has yielded a library of catalysts with excellent turnover numbers [k(cat)(3b)/k(uncat)(3b) = 0.14-19.0 x 105] and enantioselectivities. Three of these catalysts, 6G6, 12C8, and 12D9, perform a useful kinetic resolution of rac-3a, generating S-(+)-naproxen 4a in >98% ee with up to 50% conversion. Comparing the two hapten strategies reveals that the antibodies, although elicited for the same reaction with the same substrate, exhibit quite different catalytic behavior. The transition state analogue approach has furnished better catalysts, in terms of turnover numbers and enantiomeric discrimination, but which possess varying degrees of product inhibition by phenol 9. Thermodynamic evaluation reveals that their catalytic power is derived almost entirely as a function of differential stabilization of the transition state over the ground state: K(m)(3b)/K(i)(8). By contrast, the reactive immunization approach has elicited more proficient biocatalysts that couple an efficient 'catalytic' mechanism and improved substrate recognition with no product inhibition.
- Datta, Anita,Wentworth Jr., Paul,Shaw, Joanne P.,Simeonov, Anton,Janda, Kim D.
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- Fabrication of a nano-drug delivery system based on layered rare-earth hydroxides integrating drug-loading and fluorescence properties
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We demonstrate the first example of intercalation of naproxen (abbr. NPX) into layered europium hydroxide (LEuH) and investigate the structure, chemical composition, thermostability, morphology, luminescence properties, cytotoxic effect, and controlled-release behaviors. Different deprotonation degrees lead to NPX-LEuH composites with diverse structures (horizontal or vertical arrangement), and the thermal stability of organics is enhanced after intercalation. The Eu3+ luminescence in NPX-LEuH composites is enhanced, especially for the NPX-LEuH-1: 0.5 composite. The content of naproxen in the intercalation material can be confirmed by HPLC. The cytotoxic effect of LEuH is observed with a sulforhodamine B (SRB) colorimetric assay, which reveals that the LEuH has low cytotoxic effects on most cells. In addition, the NPX-LEuH nanocomposites can control the release of NPX in Na2HPO4-NaH2PO4 buffer solution at pH 6.86 and 37 °C, and the complete release needs about 200 min. The release mechanism can be ascribed to the ion-exchange reaction between NPX and HPO42-/H2PO4- in bulk solution. The ion-exchange velocity is fast at the beginning and slows down gradually with the exchange reaction. The construction of LRH composites with drug molecules provides a beneficial pathway for preparing a nano-drug delivery system based on LRHs integrating drug-loading and fluorescence properties.
- Gu, Qingyang,Chen, Wen,Duan, Fei,Ju, Ruijun
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- Efficient resolution of naproxen by inclusion crystallization with N-octyl-glucamine and structure characterization of the inclusion complex
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(S)-(+)-Naproxen was directly resolved from the racemate with high enantiopurity (>95% e.e.) by inclusion crystallization using N-octyl-D-(-)-glucamine as the chiral host. The crystal structure of the inclusion complex was determined.
- Yuan, Xuejun,Li, Jiguo,Tian, Yunqi,Lee, Gene-Hsiang,Peng, Xie-Ming,Zhu, Rongguang,You, Xiaozeng
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- Asymmetric dihydroxylation in an approach to the enantioselective synthesis of 2-arylpropanoic acid non-steroidal anti-inflammatory drugs
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Naproxen ((S)-2-(6-methoxy-2-naphthyl)propanoic acid) and flurbiprofen ((S)2-3 -fluoro-4-phenylphenyl) propanoic acid) have been synthesised in high en antiomeric excess. The synthetic strategy employed waste introduce asymmetry into the molecules by Sharpless asymmetric dihydroxylation of the appropriate methyl styrenes. The resultant diols were then converted into optically active epoxides and the required stereogenic centre was assembled by catalytic hydrogenolysis of the introduced benzylic epoxide oxygen bond, followed by oxidation of the derived optically active primary alcohol.
- Griesbach, Robert C.,Hamon, David P. G.,Kennedy, Rebecca J.
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- Polymer-supported chiral catalysts with positive support effects
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In this paper, we discuss the rational design of polymeric catalysts and the positive effect of polymer supports on the catalytic asymmetric reactions. The attachment of chiral catalysts to soluble polymers, particularly dendritic polymers, offered a potential combination of the advantages of homogeneous and heterogeneous asymmetric catalysis.
- Fan, Qing-Hua,Wang, Rui,Chan, Albert S.C
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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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- ASYMMETRIC COUPLING OF ARYLMAGNESIUM BROMIDES WITH ALLYLIC ESTERS
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Arylmagnesium bromides were allowed to react with 3-penten-2-yl (or 2-buten-1-yl) acetate (pivaloate, carbonate, or methyl ether) in the presence of NiCl2 catalyst to afford (R)-4-aryl-2-pentene (or 3-aryl-1-butene) in high chemical and optical yields.
- Hiyama, Tamejiro,Wakasa, Noriko
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- Scalable synthesis of a new enantiomerically pure π-extended rigid amino indanol
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A convenient route to a benzo-fused amino indanol chiral controller is disclosed. The synthesis is based on a newly optimized entry to 3H-benz(e)indene that can be performed on decagram scale with no purification of intermediates. Subsequent oxidation, classical resolution, and Ritter steps give the target synthon in >98% ee. The resolution features (S)-naproxen as an inexpensive and highly crystalline resolving agent. Conversion of the amino alcohol to its bis(oxazolinyl)-propane is also reported. A solid state structure of the CuCl2-box complex shows preservation of the distorted square planar geometry found in the parent CuCl2(indanyl-box) despite greater steric crowding by the blocking groups.
- Rendina, Victor L.,Goetz, Samantha A.,Neitzel, Angelika E.,Kaplan, Hilan Z.,Kingsbury, Jason S.
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- Improvement of catalytic properties of Candida Rugosa lipase by sol-gel encapsulation in the presence of magnetic calix[4]arene nanoparticles
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Candida rugosa lipase (CRL) was encapsulated within a chemically inert sol-gel support prepared by polycondensation with tetraethoxysilane (TEOS) and octyltriethoxysilane (OTES) in the presence of N-methylglucamine based calix[4]arene magnetic nanoparticles. The results indicate that the magnetic calix[4]arene based encapsulated lipase particularly has shown high conversion and enantioselectivity. It has also been noticed that the magnetic calix[4]arene based encapsulated lipase has excellent enantioselectivity (E = 460) as compared to the free enzyme (E = 166) with an ee value of >98% for S-Naproxen.
- Sayin, Serkan,Yilmaz, Elif,Yilmaz, Mustafa
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- Nickel-catalyzed asymmetric reductive cross-coupling of α-chloroesters with (hetero)aryl iodides
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An asymmetric reductive cross-coupling of α-chloroesters and (hetero)aryl iodides is reported. This nickel-catalyzed reaction proceeds with a chiral BiOX ligand under mild conditions, affording α-arylesters in good yields and enantioselectivities. The reaction is tolerant of a variety of functional groups, and the resulting products can be converted to pharmaceutically-relevant chiral building blocks. A multivariate linear regression model was developed to quantitatively relate the influence of the α-chloroester substrate and ligand on enantioselectivity.
- Cleary, Leah,DeLano, Travis J.,Dibrell, Sara E.,Lacker, Caitlin R.,Pancoast, Adam R.,Poremba, Kelsey E.,Reisman, Sarah E.,Sigman, Matthew S.
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- Enantioselective synthesis of (S)-naproxen using immobilized lipase on chitosan beads
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S-naproxen by enantioselective hydrolysis of racemic naproxen methyl ester was produced using immobilized lipase. The lipase enzyme was immobilized on chitosan beads, activated chitosan beads by glutaraldehyde, and Amberlite XAD7. In order to find an appropriate support for the hydrolysis reaction of racemic naproxen methyl ester, the conversion and enantioselectivity for all carriers were compared. In addition, effects of the volumetric ratio of two phases in different organic solvents, addition of cosolvent and surfactant, optimum pH and temperature, reusability, and inhibitory effect of methanol were investigated. The optimum volumetric ratio of two phases was defined as 3:2 of aqueous phase to organic phase. Various water miscible and water immiscible solvents were examined. Finally, isooctane was chosen as an organic solvent, while 2-ethoxyethanol was added as a cosolvent in the organic phase of the reaction mixture. The optimum reaction conditions were determined to be 35?°C, pH?7, and 24?h. Addition of Tween-80 in the organic phase increased the accessibility of immobilized enzyme to the reactant. The optimum organic phase compositions using a volumetric ratio of 2-ethoxyethanol, isooctane and Tween-80 were 3:7 and 0.1% (v/v/v), respectively. The best conversion and enantioselectivity of immobilized enzyme using chitosan beads activated by glutaraldehyde were 0.45 and 185, respectively.
- Gilani, Saeedeh L.,Najafpour, Ghasem D.,Heydarzadeh, Hamid D.,Moghadamnia, Aliakbar
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- Photo-controllable molecular hydrogels for drug delivery
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A photocleavable nitrobenzyl ester group was introduced in the backbone of self-assembling peptides using standard Fmoc-peptide systhesis. The nitrobenzyl ester group could be used as a cleavable linker to connect a gelator and a hydrophilic group. Photo-irradiation would lead to the generation of the molecular gelator and the formation of a molecular hydrogel. The nitrobenzyl ester group could also be used as one part of hydrophobic capping group for short peptides to produce molecular hydrogelators. In this case, photo-irradiation would lead to the release of hydrophobic anti-imflammatory drug of Naproxen and the gel-sol phase transition. The application of photocleavable group in molecular self-assembly would lead to photo-controllable self-assembly materials for controlled drug release, tissue engineering, and regenerative medicine. Copyright
- Liu, Hanxia,Song, Zhijian,Chen, Xuemei
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- Metal-based scaffolds of Schiff bases derived from naproxen: Synthesis, antibacterial activities, and molecular docking studies
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We report here the synthesis, characterization, and antibacterial evaluation of transition metal complexes of Ni, Cu, Co, Mn, Zn, and Cd (6a–f), using a Schiff base ligand (5) derived from naproxen (an anti-inflammatory drug) and 5-bromosalicylaldehyde by a series of reactions. The ligand and the synthesized complexes were characterized by elemental analysis, UV-Visible, FTIR, and XRD techniques. The ligand 5 behaves as a bidentate donor and coordinates with metals in square planar or tetrahedral fashion. In order to evaluate its bioactivity profile, we screened the Schiff base ligand and its metal complexes (6a–f) against different species of bacteria and the complexes were found to exhibit significant antibacterial activity. The complexes showed more potency against Bacillus subtilis as compared to the other species. Moreover, we modeled these complexes’ binding affinity against COX1 protein using computational docking.
- Shaheen, Muhammad Ashraf,Feng, Shanshan,Anthony, Mehwish,Tahir, Muhammad Nawaz,Hassan, Mubashir,Seo, Sung-Yum,Ahmad, Saeed,Iqbal, Mudassir,Saleem, Muhammad,Lu, Changrui
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- Biocatalyzed irreversible esterification in the preparation of S-naproxen
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Dimethyl carbonate was used as alcohol donor in the esterification of naproxen in the presence of immobilised lipase B from Candida antarctica (Novozym 435). The conjugation of hydrolysis of dimethyl carbonate and esterification of acid, created irreversible operative conditions so permitting the recovery of S-naproxen in high ee (>98%). The adopted procedure has a general use.
- Morrone,D'Antona,Lambusta,Nicolosi
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- Improvement of catalytic activity of lipase in the presence of wide rim substituted calix[4]arene carboxylic acid-grafted magnetic nanoparticles
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Candida rugosa lipase immobilized on calix[4]arene carboxylic acid-grafted magnetic nanoparticles using a sol-gel encapsulation technique was tested for activity, which was assessed both in the enantioselective hydrolysis of racemic Naproxen methyl ester and that of p-nitrophenylpalmitate. It has also been noticed that, compared to the free enzyme (E = 137) with an ee value of [98 %, S-Naproxen calix[4]arene carboxylic acid-grafted magnetic nanoparticles based on encapsulated lipase (Calix-1-MN and Calix-2-MN) offer excellent enantioselectivity (E = 373 and E = 381). Moreover, the results indicated that after the fifth reuse in the enantioselective reaction, the encapsulated lipase (Calix-2-MN) still retained about 43 % of its conversion power. Springer Science+Business Media Dordrecht 2013.
- Akceylan, Ezgi,Sahin, Ozlem,Yilmaz, Mustafa
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- Continuous Liquid Vapor Reactions Part 2: Asymmetric Hydroformylation with Rhodium-Bisdiazaphos Catalysts in a Vertical Pipes-in-Series Reactor
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Asymmetric hydroformylation (AHF) of 2-vinyl-6-methoxynaphthalene demonstrates important design characteristics of a vertical pipes-in-series plug flow reactor (PFR). The regio- and enantioselectivity of the AHF reaction provide a chemical probe of gas-liquid mixing in a flow reactor for comparison with well-stirred batch reactors. Results obtained with the flow reactor compare favorably to those obtained in batch. Thus, AHF provides an efficient, in-flow enantioselective synthesis of (S)-Naproxen.
- Abrams, M. Leigh,Buser, Jonas Y.,Calvin, Joel R.,Johnson, Martin D.,Jones, Bradley R.,Lambertus, Gordon,Landis, Clark R.,Martinelli, Joseph R.,May, Scott A.,McFarland, Adam D.,Stout, James R.
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- OPTICALLY ACTIVE NAPROXEN BY KINETIC RESOLUTION
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Optically active naproxen is prepared from it's racemic precursor by kinetic resolution via the anhydride and it's reaction with optically active 1-(4-pyridyl)ethanol in high chemical and optical yield.
- Franck, Amelie,Ruechardt, Christoph
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- Asymmetric transformation of the second kind of racemic naproxen
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Several chiral derivatives of racemic naproxen were subjected to asymmetric transformations. Notably, asymmetric transformation of the second kind of a mixture of 2b and 3b gave a diastereomeric excess (d.e.) over 90% in favor of 2b. This d.e. was increased to over 99% after recrystallization.
- Lopez, Francisco J.,Ferrino, Sergio A.,Reyes, Mario S.,Roman, Ruth
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- Surface-mounted MOF templated fabrication of homochiral polymer thin film for enantioselective adsorption of drugs
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A self-polymerized chiral monomer 3,4-dihydroxy-l-phenylalanine (l-DOPA) has been introduced into the pores of an achiral surface-mounted metal organic framework (SURMOF), and then the homochiral poly(l-DOPA) thin film has been successfully formed after UV light irradiation and etching of the SURMOF. Remarkably, such a poly(l-DOPA) thin film exhibited enantioselective adsorption of naproxen. This study opened a SURMOF-templated approach for preparing porous polymer thin films.
- Gu, Zhi-Gang,Fu, Wen-Qiang,Liu, Min,Zhang, Jian
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- Chiral mannitol as auxiliary in synthesis of optical active 2-arylpropanoic acids by 1,2-aryl enantioselective migrations
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(S)-(+)-2-(6′-methoxy-2-naphthyl) propanoic acid has been prepared from (6-methoxy-2-naphthyl)-1-propanone and D-mannitol with ZnCl2 catalysis by 1,2-aryl enantioselective migration in high yields.
- Wang,Ma,Shi
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- Synthesis of diastereomeric anhydrides of (RS)-ketorolac and (RS)-etodolac, semi-preparative HPLC enantioseparation, establishment of molecular asymmetry and recovery of pure enantiomers
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Herein, enantioseparation of two anti-inflammatory drugs, namely, (RS)-ketorolac and (RS)-etodolac, commonly marketed and administered as racemates, was achieved by RP-HPLC. This method provided very low limit of detection values (3.69 and 3.02 ng mL-1 for diastereomeric derivatives of (R)- and (S)-Ket, respectively) as compared to those reported in literature. (S)-Naproxen benzotriazole ester, which was used as a chiral reagent, was synthesized and characterized by UV, IR, and 1H NMR spectroscopies, elemental analysis, and polarimetry. The diastereomeric derivatives were synthesized via microwave irradiation, separated on an analytical scale by RP-HPLC, and then isolated by preparative HPLC. The use of a mobile phase containing methanol and aqueous triethylamine phosphate (TEAP) in the isocratic mode was found to be successful for the separation of diastereomeric derivatives, and the separation conditions with respect to pH, flow rate, and buffer concentration were optimized. The diastereomeric derivatives were characterized, and their absolute configuration was established. Hydrolysis of the derivatives provided native enantiomers under mild reaction conditions. This study describes the successful enantioseparation of the above mentioned two analytes by semi-preparative HPLC with easy recovery of the native enantiomers without racemization and with the establishment of molecular asymmetry.
- Malik, Poonam,Bhushan, Ravi
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- Separation of naproxen enantiomers using hollow fiber molecularly imprinted membrane chromatography
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In this paper, the use of molecularly imprinted membrane (MIM) for chromatographic separation is described. Poly(vinylidene fluoride) hollow-fiber membranes were grafted on an imprinted polymer layer by using 4-vinylpyridine and trimethylolpropane triacrylate as monomer and crosslinker and were applied as the chromatographic media. During separation, naproxen enantiomers were separated efficiently, and the separation factor was 2.36. Molecularly imprinted membrane chromatography (MIMC) showed an apparently opposite transport behavior compared to molecularly imprinted polymer (MIP)-packed chromatography.
- Bing, Nai Ci,Tian, Zhen,Jin, Hai Ying,Wang, Li Jun,Zhu, Lu Ping,Xu, Zhen Liang
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- In vitro regioselective stability of β-1-O- and 2-O-acyl glucuronides of naproxen and their covalent binding to human serum albumin
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β-1-O- (NAG) and 2-O-glucuronides (2-isomer) of (S)-naproxen (NA) were prepared to determine which positional isomer(s) of the acyl glucuronide of NA is responsible for forming covalent adducts with human serum albumin (HSA). Their comparative stability and covalent binding adduct formation with HSA were investigated at pH 7.4 and at 37 °C. NA and its acyl glucuronides were simultaneously determined by HPLC. Three positional isomers were formed successively after incubation of NAG in the buffer only. However, when NAG was incubated with HSA (30 mg/mL), isomers other than the 2-isomer were formed in little or negligible quantities. In HSA solution, NAG (k(d) = 2.08 ± 0.08 h-1) was four times less stable than 2-isomer (k(d) 0.51 ± 0.02 h-1). NAG was degraded by hydrolysis (k(hyd) = 1.01 ± 0.10 h-1) and isomerization (k(iso) 1.07 ± 0.07 h-1) to the same extent; however, hydrolysis was predominant for the 2-isomer (k(d) = 0.51 ± 0.02 h-1). The incubation of both NAG and 2-isomer with HSA led to the formation of a covalent adduct; however, the adduct formation from the 2-isomer proceeded more slowly than that from NAG. The present results suggest that the covalent binding of NA to HSA via its acyl glucuronides proceeds through both transacylation (direct nucleophilic displacement) and glycation mechanisms; NAG rapidly forms an adduct that may be unstable, and the protein adduct from the 2-O-acyl glucuronide is as important for the covalent binding as those from the 1-O-acyl glucuronides.
- Iwaki, Masahiro,Ogiso, Taro,Inagawa, Shinako,Kakehi, Kazuaki
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- Molecularly imprinted uniform-sized polymer-based stationary phase for naproxen
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A molecularly imprinted uniform-sized polymer-based stationary phase for (S)-naproxen has been prepared using 4-vinylpyridine and ethylenedimethacrylate as a host functional monomer and cross-linker, respectively. The imprinted polymer material could separate naproxen enantiomers with separation factor of 1.74. Further, the materials showed high selectivity for naproxen and moderate selectivity for other 2-arylpropionic acid derivatives. On the other hand, the imprinted polymer material showed little selectivity for other acidic, basic and neutral compounds.
- Haginaka, Jun,Takehira, Hisako,Hosoya, Ken,Tanaka, Nobuo
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- Asymmetric Synthesis of Naproxen by a New Heterogeneous Catalyst
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A new heterogeneous, asymmetric catalyst is described.The catalyst is a modified version of the supported aqueous-phase catalyst reported previously (Wan and Davis, J.Catal. 148,1(1994)); ethylene glycol is used in place of water as the hydrophilic phase.Both the enantioselectivity and the activity of this new heterogeneous catalyst are comparable to the homogeneous analogue in neat methanol (or ethylene glycol); e.e.'s are 95.7percent vs 96.1percent and t.o.f.'s are 40.7 hr-1 vs 131.0 hr-1, respectively.Recycling of the catalyst is possible without leaching of ruthenium at a detection limit of 32 ppb.
- Wan, Kam T.,Davis, Mark E.
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- Enantioselective hydrolysis of naproxen ethyl ester catalyzed by monoclonal antibodies
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This report described that a hapten of racemic phosphonate 3 designed as the mimic of the transition state of hydrolysis of naproxen ethyl ester was successfully synthesized from easily available 2-acetyl-6-methoxy-naphthalene 5. Then BALB/C mice were immunized and one of the monoclonal catalytic antibodies, N116-27, which enantioselectively accelerated the hydrolysis of the R-(-)-naproxen ethyl ester was given. The Michaelis-Menton parameter for the catalyzed reaction was KM=6.67 mM and kcat/kuncat=5.8×104. This enantioselective result was explained by the fact that the R-isomer of rac-hapten was more immunogenic than the S-isomer.
- Shi, Zhen-Dan,Yang, Bing-Hui,Zhao, Jing-Jing,Wu, Yu-Lin,Ji, Yong-Yong,Yeh, Ming
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- Design and synthesis of Janus-type chiral dendritic diphosphanes and their applications in asymmetric hydrogenation
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A series of chiral diphosphane-functionalized Janus dendrimers (up to 16 BINAP units) have been readily synthesized by using liquid-phase organic synthesis with the third-generation Frechet-type poly(aryl ether) dendron as the soluble support. The resulting dendritic ligands were purified by simple solvent precipitation without the need for chromatographic separation at the end of reaction. Complete functionalization of the dendrimers with BINAP moieties was confirmed by 1H NMR, MALDI-TOF mass spectroscopy, and elemental analyses. Their ruthenium complexes were applied to the asymmetric hydrogenation of 2-arylacrylic acids. It was found that only slightly lower enantioselectivities were achieved than the corresponding small-molecular Ru catalyst. Interestingly, a clear increase in activity of the dendritic catalysts was observed on going to the higher generations. In addition, the third-generation catalyst could be recycled without significant loss of catalytic activity or enantioselectivity before the fifth catalytic run. A new kind of easily available Janus dendritic diphosphane ligand has been synthesized and their metal complexes were applied to the asymmetric hydrogenation of 2-arylacrylic acids. Interestingly, a clear increase in activity of the dendritic catalysts was observed on going to the higher generations. Furthermore, the third-generation catalyst could be recycled at least five times. Copyright
- Liu, Ji,Feng, Yu,Ma, Baode,He, Yan-Mei,Fan, Qing-Hua
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- Preparation of (S)-naproxen by enantioselective hydrolysis of racemic naproxen amide with resting cells of Rhodococcus erythropolis MP50 in organic solvents
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Racemic naproxen amide (RS)-1 was hydrolyzed to enantiomerically pure naproxen (S)-2 in water-saturated organic solvents with log P values between 2.0 and 0.17 using immobilized resting cells of the bacterial strain Rhodococcus erythropolis MP50. Alkyl acetates are the most suitable solvents concerning solubility of (RS)-1 and enzyme activity. In butyl acetate with 3 vol% DMSO as cosolvent and an increased water content of the immobilized cells the rate of hydrolysis was an optimum. Under these reaction conditions a preparative scale application gave after 45 h, at a conversion rate of 48%, (S)-2 with >99% ee and an isolated yield of 84%.
- Effenberger, Franz,Graef, Bernd Walter,Osswald, Steffen
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- A simple catalytic route to naproxen
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We report herein the asymmetric synthesis of naproxen involving catalytic enantioselective methylation for the first time. The reaction is conducted in a solid-liquid biphasic system using chiral quaternary ammonium salts.
- Kumar, Sanjeev,Ramachandran, Uma
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- Synthesis, comparative docking, and pharmacological activity of naproxen amino acid derivatives as possible anti-inflammatory and analgesic agents
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Background and aim: Naproxen is a member of the Nonsteroidal anti-inflammatory drugs (NSAIDs). This work aimed to synthesize a safe NSAID agent based on a peptide derivative. Methods: The structure of compounds 5–20 was established on the basis of spectral data. Frontier molecular orbitals and chemical reactivity were discussed to clarify inter-and intramolecular interactions among tested compounds. We applied competitive molecular docking using polynomial logarithms to identify the most accurate algorithm for pharmacological activity prediction for the tested compounds. The docking protocol with the lowest RMSD was selected for analyzing binding affinity. Results: Docking results illustrated that the binding interaction increased after introduction of an acidic fragment to the parent compound. These compounds were selected for additional study against adsorption, distribution, metabolism, excretion, and toxicity (ADMET) in silico. The compounds tested had good oral bioavailability without any carcinogenesis effect; no marked health effects were observed via rodent toxicity. Compounds passed through docking and ADMET profiles for them (5–16) were examined as anti-inflammatory and analgesic agents. Compounds 8 and 16 showed higher anti-inflammatory potency than the reference drug and tested compounds. Compounds 8, 10, and 14 exhibited the highest analgesic potency compared to the other tested compounds. Conclusion: The tested compounds have shown negligible ulcerogenic effects, and may be considered safer drugs than naproxen for treating inflammatory conditions.
- Elhenawy, Ahmed A.,Al-Harbi,Moustafa, Gaber O.,El-Gazzar,Abdel-Rahman, Rehab F.,Salim, Abd Elhamid
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- Synthesis of optical active 2-arylpropionic acids
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(S)-2-(6′-methoxyl-α-naphthyl)propionic acid ((S)-Naprofen, ee%=99) has been prepared by starting from (6-methoxyl-α-naphthyl)propan-1-one and D-sorbitol under ZnCl2 catalysis.
- Wang,Ma
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Read Online
- Asymmetric hydrogenation of 2-arylacrylic acids catalyzed by immobilized Rn-BINAP complex in 1-n-butyl-3-methylimidazolium tetrafluoroborate molten salt
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The [RuCl2-(S)-BINAP]2.NEt3 catalyst precursor dissolved in 1-n-butyl-3-methylimidazolium tetrafluoroborate molten salt is able-to hydrogenate 2-arylacrylic acids (aryl=Ph or 6-MeO-naphthyl) with enantioselectivities similar or higher than those obtained in homogeneous media. Moreover, the hydrogenated products can be quantitatively separated from the reaction mixture and the recovered ionic liquid catalyst solution can be reused several times without any significant changes in the catalytic activity or selectivity.
- Monteiro, Adriano L.,Zinn, Fabiano K.,De Souza, Roberto F.,Dupont, Jairton
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Read Online
- Enantioselective Synthesis of Chiral Carboxylic Acids from Alkynes and Formic Acid by Nickel-Catalyzed Cascade Reactions: Facile Synthesis of Profens
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We report a stereoselective conversion of terminal alkynes to α-chiral carboxylic acids using a nickel-catalyzed domino hydrocarboxylation-transfer hydrogenation reaction. A simple nickel/BenzP* catalyst displayed high activity in both steps of regioselective hydrocarboxylation of alkynes and subsequent asymmetric transfer hydrogenation. The reaction was successfully applied in enantioselective preparation of three nonsteroidal anti-inflammatory profens (>90 % ees) and the chiral fragment of AZD2716.
- Fu, Kaiyue,Ma, Yu,Sun, Yaxin,Tang, Bo,Yang, Guang,Yang, Peng,Yue, Jieyu,Zhang, Li,Zhou, Jianrong Steve
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- Reshaping the active pocket of esterase Est816 for resolution of economically important racemates
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Bacterial esterases are potential biocatalysts for the production of optically pure compounds. However, the substrate promiscuity and chiral selectivity of esterases usually have a negative correlation, which limits their commercial value. Herein, an efficient and versatile esterase (Est816) was identified as a promising catalyst for the hydrolysis of a wide range of economically important substrates with low enantioselectivity. We rationally designed several variants with up to 11-fold increased catalytic efficiency towards ethyl 2-arylpropionates, mostly retaining the initial substrate scope and enantioselectivity. These variants provided a dramatic increase in efficiency for biocatalytic applications. Based on the best variant Est816-M1, several variants with higher or inverted enantioselectivity were designed through careful analysis of the structural information and molecular docking. Two stereoselectively complementary mutants, Est816-M3 and Est816-M4, successfully overcame and even reversed the low enantioselectivity, and several 2-arylpropionic acid derivatives with highEvalues were obtained. Our results offer potential industrial biocatalysts for the preparation of structurally diverse chiral carboxylic acids and further lay the foundation for improving the catalytic efficiency and enantioselectivity of esterases.
- Fan, Xinjiong,Fu, Yao,Liu, Xiaolong,Zhao, Meng
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p. 6126 - 6133
(2021/09/28)
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- Asymmetric Markovnikov Hydroaminocarbonylation of Alkenes Enabled by Palladium-Monodentate Phosphoramidite Catalysis
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A palladium-catalyzed asymmetric Markovnikov hydroaminocarbonylation of alkenes with anilines has been developed for the atom-economical synthesis of 2-substituted propanamides bearing an α-stereocenter. A novel phosphoramidite ligand L16 was discovered which exhibited very high reactivity and selectivity in the reaction. This asymmetric Markovnikov hydroaminocarbonylation employs readily available starting materials and tolerates a wide range of functional groups, thus providing a facile and straightforward method for the regio- and enantioselective synthesis of 2-substituted propanamides under ambient conditions. Mechanistic studies revealed that the reaction proceeds through a palladium hydride pathway.
- Yao, Ya-Hong,Yang, Hui-Yi,Chen, Ming,Wu, Fei,Xu, Xing-Xing,Guan, Zheng-Hui
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- PHOTOLYTIC COMPOUNDS AND TRIPLET-TRIPLET ANNIHILATION MEDIATED PHOTOLYSIS
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The invention provides novel photolytic compounds and prodrugs, nanoparticles and compositions thereof, and methods of conducting photolysis mediated by triplet-triplet annihilation.
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Paragraph 0026
(2021/04/17)
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- Method for dynamic kinetic resolution of alpha-aryl-alpha-alkyl carboxylic ester and application
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The invention discloses a method for dynamic kinetic resolution of alpha-aryl-alpha-alkyl carboxylic ester and application, and belongs to the technical field of organic synthesis. Pentafluorophenol ester and benzhydrol are taken as reactants, a dynamic kinetic resolution reaction is carried out under the nitrogen-oxygen catalysis of chiral DMAP derived from diphenylmethylamine to obtain alpha-aryl-alpha-alkyl ester, and (S)-naproxen, (S)-ibuprofen, (S)-ketoprofen, (S)-fenopolfen and (S)-flurbiprofen are synthesized. According to the chiral DMAP nitrogen-oxygen catalyst, oxygen atoms in pyridine nitrogen-oxygen serve as nucleophilic sites to participate in a dynamic kinetic resolution reaction, and meanwhile hydrogen in catalyst molecules also plays a key role. The method has the advantages of good yield, high enantioselectivity and the like.
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Paragraph 0075-0077
(2021/07/17)
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- Palladium-Catalyzed Asymmetric Markovnikov Hydroxycarbonylation and Hydroalkoxycarbonylation of Vinyl Arenes: Synthesis of 2-Arylpropanoic Acids
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Asymmetric hydroxycarbonylation is one of the most fundamental yet challenging methods for the synthesis of carboxylic acids. Herein, we reported the development of a palladium-catalyzed highly enantioselective Markovnikov hydroxycarbonylation of vinyl arenes with CO and water. A monodentate phosphoramidite ligand L6 plays vital role in the reaction. The reaction tolerates a range of functional groups, and provides a facile and atom-economical approach to an array of 2-arylpropanoic acids including several commonly used non-steroidal anti-inflammatory drugs. The catalytic system has also enabled an asymmetric Markovnikov hydroalkoxycarbonylation of vinyl arenes with alcohols to afford 2-arylpropanates. Mechanistic investigations suggested that the hydropalladation is irreversible and is the regio- and enantiodetermining step, while hydrolysis/alcoholysis is probably the rate-limiting step.
- Guan, Zheng-Hui,Ren, Zhi-Hui,Wang, Yuan,Yang, Hui-Yi,Yao, Ya-Hong,Zou, Xian-Jin
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supporting information
p. 23117 - 23122
(2021/09/18)
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- Cobalt-Catalyzed Deprotection of Allyl Carboxylic Esters Induced by Hydrogen Atom Transfer
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A brief, efficient method has been developed for the removal of the allyl protecting group from allyl carboxylic esters using a Co(II)/TBHP/(Me2SiH)2O catalytic system. This facile strategy displays excellent chemoselectivity, functional group tolerance, and high yields. This transformation probably occurs through the hydrogen atom transfer process, and a Co(III)-six-membered cyclic intermediate is recommended.
- Li, Nan,Gui, Yizhen,Chu, Mengqi,You, Mengdi,Qiu, Xiaohan,Liu, Hejia,Wang, Shiang,Deng, Meng,Ji, Baoming
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supporting information
p. 8460 - 8464
(2021/11/13)
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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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- Oxidation of Alkynyl Boronates to Carboxylic Acids, Esters, and Amides
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A general efficient protocol was developed for the synthesis of carboxylic acids, esters, and amides through oxidation of alkynyl boronates, generated directly from terminal alkynes. This protocol represents the first example of C(sp)?B bond oxidation. This approach displays a broad substrate scope, including aryl and alkyl alkynes, and exhibits excellent functional group tolerance. Water, primary and secondary alcohols, and amines are suitable nucleophiles for this transformation. Notably, amino acids and peptides can be used as nucleophiles, providing an efficient method for the synthesis and modification of peptides. The practicability of this methodology was further highlighted by the preparation of pharmaceutical molecules.
- Li, Chenchen,Li, Ruoling,Zhang, Bing,Zhao, Pei,Zhao, Wanxiang
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p. 10913 - 10917
(2020/05/25)
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- Deracemizing α-Branched Carboxylic Acids by Catalytic Asymmetric Protonation of Bis-Silyl Ketene Acetals with Water or Methanol
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We report a highly enantioselective catalytic protonation of bis-silyl ketene acetals. Our method delivers α-branched carboxylic acids, including nonsteroidal anti-inflammatory arylpropionic acids such as Ibuprofen, in high enantiomeric purity and high yields. The process can be incorporated in an overall deracemization of α-branched carboxylic acids, involving a double deprotonation and silylation followed by the catalytic asymmetric protonation.
- Mandrelli, Francesca,Blond, Aurélie,James, Thomas,Kim, Hyejin,List, Benjamin
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p. 11479 - 11482
(2019/07/18)
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- Iron-catalysed enantioselective Suzuki-Miyaura coupling of racemic alkyl bromides
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The first iron-catalysed enantioselective Suzuki-Miyaura coupling reaction has been developed. In the presence of catalytic amounts of FeCl2 and (R,R)-QuinoxP?, lithium arylborates are cross-coupled with tert-butyl α-bromopropionate in an enantioconvergent manner, enabling facile access to various optically active α-arylpropionic acids including several nonsteroidal anti-inflammatory drugs (NSAIDs) of commercial importance. (R,R)-QuinoxP? is specifically able to induce chirality when compared to analogous P-chiral ligands that give racemic products, highlighting the critical importance of transmetalation in the present asymmetric cross-coupling system.
- Iwamoto, Takahiro,Okuzono, Chiemi,Adak, Laksmikanta,Jin, Masayoshi,Nakamura, Masaharu
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supporting information
p. 1128 - 1131
(2019/01/28)
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- Enantioselective Copper-Catalyzed Methylboration of Alkenes
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An enantioselective Cu-catalyzed borylative cross-coupling reaction of alkenes, bis(pinacolato)diboron (B2(pin)2), and methyl iodide is reported. Alkenes including styrenes, β-substituted styrenes, and challenging aliphatic olefins were smoothly transferred to the desired methylboration products with excellent diastereoselectivities (dr up to >99:1) and enantioselectivities (er up to 99:1). The utility of this process was demonstrated by the synthesis of naproxen and formal synthesis of two natural products.
- Chen, Bin,Cao, Peng,Liao, Yang,Wang, Min,Liao, Jian
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supporting information
p. 1346 - 1349
(2018/03/09)
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- Two stereocentered HKR of anti -β,β′-diphenylpropanoxirane and anti -3-phenylethyloxiranes catalysed by Co(iii)(salen)-OAc complex: Enantioselective synthesis of (+)-sertraline and (+)-naproxen
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The Co(III)(salen)OAc-catalyzed two stereocentered hydrolytic kinetic resolution (HKR) of anti-β,β′-diphenylmethyloxirane and anti-3-phenylethyloxiranes affords the corresponding anti-1,2-diols and oxiranes in high enantiomeric excess. The synthetic potential of this methodology is demonstrated by the enantioselective synthesis of (+)-sertraline, an antidepressant drug, and (+)-naproxen, an anti-inflammatory drug.
- Kamble, Rohit B.,Devalankar, Dattatraya,Suryavanshi, Gurunath
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p. 10414 - 10420
(2018/06/18)
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- Acylguanidine derivatives of zanamivir and oseltamivir: Potential orally available prodrugs against influenza viruses
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Zanamivir (ZA) and guanidino-oseltamivir carboxylic acid (GOC) are very potent inhibitors against influenza neuraminidase (NA). The guanidinium moiety plays an important role in NA binding; however, its polar cationic nature also hinders the use of ZA and GOC from oral administration. In this study, we investigated the use of ZA and GOC acylguanidine derivatives as possible orally available prodrugs. The acylguanidine derivatives were prepared by coupling with either n-octanoic acid or (S)-naproxen. The lipophilic acyl substituents were verified to improve cell permeability, and may also improve the bioavailability of acylguanidine compounds. In comparison, the acylguanidines bearing linear octanoyl chain showed better NA inhibitory activity and higher hydrolysis rate than the corresponding derivatives having bulky branched naproxen moiety. Our molecular docking experiments revealed that the straight octanoyl chain could extend to the 150-cavity and 430-cavity of NA to gain extra hydrophobic interactions. Mice receiving the ZA octanoylguanidine derivative survived from influenza infection better than those treated with ZA, whereas the GOC octanoylguanidine derivative could be orally administrated to treat mice with efficacy equal to oseltamivir. Our present study demonstrates that incorporation of appropriate lipophilic acyl substituents to the polar guanidine group of ZA and GOC is a feasible approach to develop oral drugs for influenza therapy.
- Hsu, Peng-Hao,Chiu, Din-Chi,Wu, Kuan-Lin,Lee, Pei-Shan,Jan, Jia-Tsrong,Cheng, Yih-Shyun E.,Tsai, Keng-Chang,Cheng, Ting-Jen,Fang, Jim-Min
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p. 314 - 323
(2018/05/29)
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- Reagent-free continuous thermal tert-butyl ester deprotection
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Continuous processing enables the use of non-standard reaction conditions such as high temperatures and pressures while in the liquid phase. This expands the chemist's toolbox and can enable previously unthinkable chemistry to proceed with ease. For a series of amphoteric amino acid derivatives, we have demonstrated the ability to hydrolyze the tert-butyl ester functionality in protic solvent systems. Using a continuous plug flow reactor at 120–240 °C and 15–40 min reaction times, no pH modification or additional reagents are needed to achieve the desired transformation. The method was then expanded to encompass a variety of more challenging substrates to test selectivity and racemization potential. The acid products were generally isolated as crystalline solids by simple solvent exchange after the deprotection reaction in good to high yield and purity.
- Cole, Kevin P.,Ryan, Sarah J.,Groh, Jennifer McClary,Miller, Richard D.
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supporting information
p. 6209 - 6217
(2017/09/30)
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- Method for synthesizing arylpropionic acid-like nonsteroidal antiinflammatory agent
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The invention discloses a method for synthesizing an arylpropionic acid-like nonsteroidal antiinflammatory agent. The method comprises that an aryl acetonitrile compound as a substrate, an amine borane complex and N, N-dimethylformamide as a solvent undergo a methylation reaction under basic conditions to produce an aryl propionitrile compound, and the aryl propionitrile compound is hydrolyzed under strong basic conditions to form the arylpropionic acid-like nonsteroidal antiinflammatory agent. The method creatively uses the amine borane complex and N, N-dimethylformamide as methylation reagents so that bis-methylation and large toxicity caused by the traditional methylation reagents such as methyl iodide and dimethyl sulfate are avoided. The method is simple and is easy to operate. The arylpropionic acid-like nonsteroidal antiinflammatory agent has a high yield and high purity. Compared with the existing method using a metal catalyst system, the method utilizes anon-metallic system so that the use of transition metals is avoided. The method provides a novel approach for preventing metal residues in synthetic drugs.
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Paragraph 0021; 0023-0025
(2017/10/27)
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- Ultrafast chiral separations for high throughput enantiopurity analysis
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Recent developments in fast chromatographic enantioseparations now make high throughput analysis of enantiopurity on the order of a few seconds achievable. Nevertheless, routine chromatographic determinations of enantiopurity to support stereochemical investigations in pharmaceutical research and development, synthetic chemistry and bioanalysis are still typically performed on the 5-20 min timescale, with many practitioners believing that sub-minute enantioseparations are not representative of the molecules encountered in day to day research. In this study we develop ultrafast chromatographic enantioseparations for a variety of pharmaceutically-related drugs and intermediates, showing that sub-minute resolutions are now possible in the vast majority of cases by both supercritical fluid chromatography (SFC) and reversed phase liquid chromatography (RP-LC). Examples are provided illustrating how such methods can be routinely developed and used for ultrafast high throughput analysis to support enantioselective synthesis investigations.
- Barhate, Chandan L.,Joyce, Leo A.,Makarov, Alexey A.,Zawatzky, Kerstin,Bernardoni, Frank,Schafer, Wes A.,Armstrong, Daniel W.,Welch, Christopher J.,Regalado, Erik L.
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supporting information
p. 509 - 512
(2017/01/13)
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- Temperature-Controlled Bidirectional Enantioselectivity in Asymmetric Hydrogenation Reactions Utilizing Stereodynamic Iridium Complexes
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Stereochemically flexible 2,2(-bis(diphenylphosphino)biphenyl (BIPHEP) ligands were modified with chiral α-substituted carboxylic acid auxiliaries in the 3- and 3′-position. The resulting central-to-axial chirality transfer to the stereochemically flexible chiral axis of the BIPHEP core was investigated as well as complexation of these diastereomeric ligands to iridium(I). Solid-state structures of both ligand diastereomers and a diastereomerically pure iridium(I) BIPHEP complex were obtained. Thermal equilibration of the resulting iridium(I) complexes was studied to investigate the stereodynamic properties of the BIPHEP ligands. The iridium(I) complexes without and after pre-catalysis warming in solution - which induces a shift of the diastereomeric ratio - were applied for asymmetric hydrogenation of a prochiral α-substituted acrylic acid, resulting in temperature-controlled bidirectional enantioselectivity of iridium catalysts for the first time. In both cases, enantioenriched (R)-naproxen as well as (S)-naproxen - after re-equilibration of the catalyst at elevated temperatures - was obtained by using the same catalyst.
- Siebert, Max,Storch, Golo,Rominger, Frank,Trapp, Oliver
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supporting information
p. 3485 - 3494
(2017/07/27)
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- A Stability-Indicating RP-HPLC-UV Method for Determination and Chemical Hydrolysis Study of a Novel Naproxen Prodrug
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A new naproxen amide prodrug was synthesized and spectrally characterized and a simple, precise, and accurate stability-indicating RP-HPLC method was developed and validated for determination and chemical hydrolysis study of the prodrug. Forced degradation studies were conducted as per the International Conference on Harmonization (ICH) guidelines to establish the stability-indicating power of the method. Separations were performed on a C18 column (150 × 4.6 mm i.d., 5 μm p.s.). The mobile phase consisted of acetonitrile and phosphate buffer pH 4.0 in the ratio 60: 40. The flow rate and injection volume were 1.0 mL/min and 15 μL, respectively. The peaks were monitored at 272 nm. The average retention time is 5.136 min. The linearity of the method was investigated in the range of 10-50 μg/mL and r2 was found to be larger than 0.9987. The LOD and LOQ were found to be 1.853 and 5.615 μg/mL, respectively. Results indicated that the degradants are well resolved and separated from the prodrug. Hydrolysis kinetics studies were carried out in buffer solutions (pH 1.2, 5.5 and 7.4) to establish the fate of the prodrug. The half-lives in the respective buffers were 23.5, 262, and 334 hours indicating sufficient stability to attain the goal of oral delivery.
- Hamid, Mohamed H.M.,Elsaman, Tilal
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- Efficient resolution of profen ethyl ester racemates by engineered Yarrowia lipolytica Lip2p lipase
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Enzyme-catalyzed enantiomer discrimination is still a great challenge for the development of industrial pharmaceutical processes. For the resolution of ibuprofen, naproxen and ketoprofen racemates, three major anti-inflammatory drugs, only lipases from Candida rugosa present a high selectivity if solvent and surfactant use is discarded. However, their catalytic activities are too low. In the present work, we demonstrate that the lipase Lip2p from the yeast Yarrowia lipolytica has a higher catalytic activity than C. rugosa lipases to hydrolyze the ethyl esters of ibuprofen, naproxen and ketoprofen, but its selectivity is not sufficient [E?=?52 (S); 11 (S) and 1.5 (R) respectively]. The enantioselectivity was further improved by site-directed mutagenesis, targeted at the substrate binding site and guided by molecular modelling studies. By investigating the binding modes of the (R)- and (S)-enantiomers in the active site, two amino acid residues located in the hydrophobic substrate binding site of the lipase, namely residues 232 and 235, were identified as crucial for enantiomer discrimination and enzyme activity. The (S) enantioselectivity of Lip2p towards ethyl ibuprofen esters was rendered infinite (E???300) by replacing V232 by an A or C residue. Substitution of V235 by C, M, S, or T amino acids led to a great increase in the (S)-enantioselectivity (E???300) towards naproxen ethyl ester. Finally, the variant V232F enabled the efficient kinetic resolution of ethyl ketoprofen ester enantiomers [(R)-enantiopreference; E???300]. In addition to the increase in selectivity, a remarkable increase in velocity by 2.6, 2.7 and 2.5?times, respectively, was found for ibuprofen, naproxen and ketoprofen ethyl esters.
- Gérard, Doriane,Guéroult, Marc,Casas-Godoy, Leticia,Condoret, Jean-Stéphane,André, Isabelle,Marty, Alain,Duquesne, Sophie
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p. 433 - 441
(2017/03/24)
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- NNN ligand, metal complexes thereof, preparation methods and application
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The invention discloses an NNN ligand, metal complexes thereof, preparation methods and application, and particularly provides an NNN ligand 1, a metal complex 2 of the NNN ligand, a metal complex 3 of the NNN ligand and preparation methods of the NNN ligand 1 and the metal complexes, as well as application of the metal complex 3 of the NNN ligand to catalysis on hydroboration reaction of bis-substituted olefin, especially application of the metal complex 3 to catalysis on asymmetric hydroboration reaction of 1, 1-bis-substituted olefin. The metal complex 3 of the NNN ligand has good catalytic activity in the hydroboration reaction of the bis-substituted olefin, especially asymmetric hydroboration reaction of the 1, 1-bis-substituted olefin, has excellent regioselectivity and enantioselectivity, and is high in yield and mild in reaction conditions; besides, the preparation methods of the NNN ligand and the metal complexes thereof are simple, environment-friendly, mild in reaction conditions, relatively high in yield, and simple in post-processing, and the raw materials are low in cost and easy to obtain, so that the preparation methods are suitable for industrial production. (The formulas of the NNN ligand 1, metal complex 2 and metal complex 3 are shown in the description).
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- Facile one-pot preparation of chiral monoliths with a well-defined framework based on the thiol-ene click reaction for capillary liquid chromatography
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A novel chiral cyclodextrin (CD) monolith was easily prepared via a one-pot process based on the thiol-ene click reaction of allyl-β-CD with pentaerythritol tetra-(3-mercaptopropionate) in a fused-silica capillary. The effects of both the composition of prepolymerization solution and reaction temperature on the morphology, permeability, and selectivity of the β-CD chiral monolith were investigated in detail. The conditions were optimized to fabricate a homogeneous and permeable chiral monolith. In this study, the β-CD monolith was used as the stationary phase of capillary liquid chromatography for the chiral separation of several pharmaceutical enantiomers including flavanone, flurbiprofen, naproxen, synephrine, isoprenaline sulfate, ketoprofen, and atropine sulfate monohydrate. Compared to the previously reported two-step method, this one-pot method for the preparation of a β-CD chiral monolith is simple and time-saving. Moreover, good resolutions were obtained for chiral isomers in a shorter analysis time compared to that reported in the literatures. These results indicate that the thiol-ene click chemistry provides a simple and robust method for the preparation of a chiral β-CD monolith.
- Zhang, Peng,Wang, Jiannan,Yang, Haiguan,Su, Linjing,Xiong, Yuhao,Ye, Fanggui
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p. 24835 - 24842
(2016/03/22)
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- Asymmetric Hydrogenation of α-Substituted Acrylic Acids Catalyzed by a Ruthenocenyl Phosphino-oxazoline-Ruthenium Complex
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Asymmetric hydrogenation of various α-substituted acrylic acids was carried out using RuPHOX-Ru as a chiral catalyst under 5 bar H2, affording the corresponding chiral α-substituted propanic acids in up to 99% yield and 99.9% ee. The reaction could be performed on a gram-scale with a relatively low catalyst loading (up to 5000 S/C), and the resulting product (97%, 99.3% ee) can be used as a key intermediate to construct bioactive chiral molecules. The asymmetric protocol was successfully applied to an asymmetric synthesis of dihydroartemisinic acid, a key intermediate required for the industrial synthesis of the antimalarial drug artemisinin.
- Li, Jing,Shen, Jiefeng,Xia, Chao,Wang, Yanzhao,Liu, Delong,Zhang, Wanbin
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supporting information
p. 2122 - 2125
(2016/06/01)
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- Ferrocenyl chiral bisphosphorus ligands for highly enantioselective asymmetric hydrogenation via noncovalent ion pair interaction
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A new class of ferrocenyl chiral bisphosphorus ligand, Wudaphos, was developed, and exhibits excellent ee and activity (ee up to 99%, TON up to 20000) for the asymmetric hydrogenation of both 2-aryl and 2-alkyl acrylic acids through ion pair noncovalent interaction under base free and mild reaction conditions. Well-known anti-inflammatory drugs such as naproxen and ibuprofen together with the intermediate for the preparation of Roche ester and some bioactive compounds were also efficiently obtained with excellent ee. Control experiments were conducted and revealed that the ion pair noncovalent interaction and chain length played important roles.
- Chen, Caiyou,Wang, Heng,Zhang, Zhefan,Jin, Shicheng,Wen, Songwei,Ji, Jianjian,Chung, Lung Wa,Dong, Xiu-Qin,Zhang, Xumu
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p. 6669 - 6673
(2016/10/31)
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- HYDROGEN SULFIDE PRECURSORS AND CONJUGATES THEREOF
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The present invention provides methods of forming hydrogen sulfide. The methods include contacting a precursor compound with an unmasking agent; wherein the precursor compound comprises a hydrogen sulfide releasing moiety and a masked nucleophile; and wherein the contacting is conducted under conditions sufficient for cyclization of the precursor compound via lactone or lactam formation; thereby releasing hydrogen sulfide from the precursor compound. Hydrogen sulfide precursor compounds according to Formula (I) are also described, as well as methods for treating diseases and conditions using hydrogen sulfide precursors.
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Paragraph 0213; 0214
(2017/01/31)
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- 2-ARYL-ZINC-PROPIONATE CATALYST AND PREPARATION METHOD AND USE THEREOF
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The present invention belongs to the technical field of chemical catalysts, and particularly relates to a zinc 2-arylpropionate catalyst, a preparation method therefor and use thereof The structural formula of the zinc 2-arylpropionate catalyst of the present invention is one of the following structures. The catalyst can be used for homogeneous catalysis of a 1,2-aryl rearrangement reaction of α-haloarylketal, and especially for synthesis of high yield and environmentally friendly 2-arylpropanonic acid non-steroidal anti-inflammatory analgesic drugs, such as, ibuprofen, ketoprofen, loxoprofen, flurbiprofen, fenoprofen, or naproxen and the like.
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Paragraph 0020
(2016/11/28)
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- METHOD FOR THE PRODUCTION OF PRAZIQUANTEL AND PRECURSORS THEREOF
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The present invention relates to methods for the production of enantiopure or enantioenriched Praziquantel precursors and to methods for the production of enantiopure or enantioenriched Praziquantel comprising the methods for the production of the Praziquantel precursors. The present invention further relates to compounds or intermediates useful in such methods.
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Page/Page column 27-28
(2016/06/15)
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- Improvement of catalytic activity of Candida rugosa lipase in the presence of calix[4]arene bearing iminodicarboxylic/phosphonic acid complexes modified iron oxide nanoparticles
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In the present study, iron oxide magnetite nanoparticles, prepared through a co-precipitation method, were coated with phosphonic acid or iminodicarboxylic acid derivatives of calix[4]arene to modulate their surfaces with different acidic groups. Candida rugosa lipase was then directly immobilized onto the modified nanoparticles through sol-gel encapsulation. The catalytic activities and enantioselectivities of the two encapsulated lipases in the hydrolysis reaction of (R/S)-naproxen methyl ester and (R/S)-2-phenoxypropionic acid methyl ester were assessed. The results showed that the activity and enantioselectivity of the lipase were improved when the lipase was encapsulated in the presence of calixarene-based additives; the encapsulated lipase with the phosphonic acid derivative of calix[4]arene had an excellent rate of enantioselectivity against the (R/S)-naproxen methyl and (R/S)-2-phenoxypropionic acid methyl esters, with E = 350 and 246, respectively, compared to the free enzyme. The encapsulated lipases (Fe-Calix-N(COOH)) and (Fe-Calix-P) showed good loading ability and little loss of enzyme activity, and the stability of the catalyst was very good; they only lost 6-11% of the enzyme's activity after five batches.
- Ozyilmaz, Elif,Bayrakci, Mevlut,Yilmaz, Mustafa
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- Chiral diphosphine ligand in asymmetric hydrogenation thereof and related application of the catalyst in the reaction (by machine translation)
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The invention discloses a chiral diphosphine ligand based on ferrocene skeleton in asymmetric hydrogenation thereof and related application of the catalyst in the reaction. This kind of novel chiral diphosphine ligand has as the general formula I The structure of the shown, wherein R 1 can be is methyl, phenyl, tert-butyl, hydroxy, etc.. R 2 can be ethyl, phenyl, cyclohexyl, methyl phenyl, tert-butyl, 3,5-dimethyl phenyl, 3,5-di-tert-butyl phenyl, 3,5-di-tert-butyl-4-methoxybenzene, 2,6-dimethoxyphenyl, 2,6-dimethyl phenyl, anthryl. At the same time, two phosphine atom bridged between the can is phenyl, naphthyl, alkyl or the like. At the same time, this invention has disclosed this kind of novel chiral diphosphine ligand synthesis and in preparation of chiral pharmaceutical ibuprofen and a naproxen, and the like. (by machine translation)
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Paragraph 0104; 0108; 0109
(2016/10/09)
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- Simple azo dyes provide access to versatile chiroptical switches
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Azo dyes have played an important role in the development of the chemical industry for 150 years. The azo-core of these dyes can undergo trans to cis photoisomerization, which allows azobenzene derivatives to act as light triggered molecular switches. Here, we showed that simple derivatization of Sudan I provides access to chiroptical molecular switches, and that the properties of these switches can be readily tuned by modification of the molecular structure. The synthesis, characterization, photoisomerization, thermal stability, chiral HPLC resolution, determination of absolute configuration and chiroptical properties of chiroptical switches based on Sudan I are reported. ortho-difluorinated Sudan I derivatives have improved thermal stabilities and switching properties compared to switches based on Sudan I itself. Transfer of stereochemical information from a non-racemic chiral unit to the π-conjugated system of the dye and exciton-coupled circular dichroism are both observed. The chiral unit influences the geometry and hence the spectra of cis and trans-isomers differently, which is the mechanistic basis of chiroptical switching. The azo-core of dyes can undergo trans to cis photoisomerization, which allows azobenzene derivatives to act as light triggered molecular switches. Simple derivatization of Sudan I using a chiral auxiliary provides access to chiroptical molecular switches. The properties of these switches can be readily tuned by modification of the molecular structure.
- Anger, Emmanuel,Fletcher, Stephen P.
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p. 3651 - 3655
(2015/06/16)
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- Engineered hydrophobic pocket of (S)-selective arylmalonate decarboxylase variant by simultaneous saturation mutagenesis to improve catalytic performance
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A bacterial arylmalonate decarboxylase (AMDase) catalyzes asymmetric decarboxylation of unnatural arylmalonates to produce optically pure (R)-arylcarboxylates without the addition of cofactors. Previously, we designed an AMDase variant G74C/C188S that displays totally inverted enantioselectivity. However, the variant showed a 20,000-fold reduction in activity compared with the wild-type AMDase. Further studies have demonstrated that iterative saturation mutagenesis targeting the active site residues in a hydrophobic pocket of G74C/C188S leads to considerable improvement in activity where all positive variants harbor only hydrophobic substitutions. In this study, simultaneous saturation mutagenesis with a restricted set of amino acids at each position was applied to further heighten the activity of the (S)-selective AMDase variant toward α-methyl-α-phenylmalonate. The best variant (V43I/G74C/A125P/V156L/M159L/C188G) showed 9,500-fold greater catalytic efficiency kcat/Km than that of G74C/C188S. Notably, a high level of decarboxylation of α-(4-isobutylphenyl)-α-methylmalonate by the sextuple variant produced optically pure (S)-ibuprofen, an analgesic compound which showed 2.5-fold greater activity than the (R)-selective wild-type AMDase.
- Yoshida, Shosuke,Enoki, Junichi,Kourist, Robert,Miyamoto, Kenji
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p. 1965 - 1971
(2015/11/24)
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- PROTEIN COMPLEX CAPABLE OF CATALYZING ASYMMETRIC OXIDATION REACTION AND METHOD FOR PRODUCING SAME
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Provided are: a protein complex capable of selectively and asymmetrically oxidizing one of enantiomers of a secondary alcohol without adding a coenzyme and having an asymmetric oxidation activity in a water-soluble solvent system in the presence of oxygen; a method for producing the same; and a production method relating to coating of the protein complex with a high molecular compound. A method for producing a protein complex capable of catalyzing an asymmetric oxidation reaction, said method being characterized by comprising: a first step that comprises a treatment for enclosing a crude water-soluble protein derived from an animal or plant in a gel, a treatment for air-oxidizing the gel, and a treatment for eluting the protein complex from the gel into an aqueous solution; and a second step that comprises a treatment for applying gravity to the aqueous solution of the protein complex to concentrate and precipitate the protein complex, a treatment for redissolving the protein complex precipitate in an aqueous glycine sodium hydroxide solution of about 0.5 mM and allowing the same to homogeneously coexist with a high molecular compound, and a treatment for re-precipitating the coexistence solution and dehydrating and drying the same to give the protein complex coated with the high molecular compound.
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Page/Page column 50
(2015/11/10)
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- Iron-Catalyzed Enantioselective Cross-Coupling Reactions of α-Chloroesters with Aryl Grignard Reagents
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The first iron-catalyzed enantioselective cross-coupling reaction between an organometallic compound and an organic electrophile is reported. Synthetically versatile racemic α-chloro- and α-bromoalkanoates were coupled with aryl Grignard reagents in the presence of catalytic amounts of an iron salt and a chiral bisphosphine ligand, giving the products in high yields with acceptable and synthetically useful enantioselectivities (er up to 91:9). The produced α-arylalkanoates were readily converted to the corresponding α-arylalkanoic acids with high optical enrichment (er up to >99:1) via simple deprotections/recrystallizations. The results of radical probe experiments are consistent with a mechanism that involves the formation of an alkyl radical intermediate, which undergoes subsequent enantioconvergent arylation in an intermolecular manner. The developed asymmetric coupling offers not only facile and practical access to various chiral α-arylalkanoic acid derivatives, which are of significant pharmaceutical importance, but also a basis of controlling enantioselectivity in an iron-catalyzed organometallic transformation. (Chemical Equation Presented).
- Jin, Masayoshi,Adak, Laksmikanta,Nakamura, Masaharu
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supporting information
p. 7128 - 7134
(2015/06/25)
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- Laccase-Mediator System for Alcohol Oxidation to Carbonyls or Carboxylic Acids: Toward a Sustainable Synthesis of Profens
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By combining two green and efficient catalysts, such as the commercially available enzyme laccase from Trametes versicolor and the stable free radical 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO), the oxidation in water of some primary alcohols to the corresponding carboxylic acids or aldehydes and of selected secondary alcohols to ketones can be accomplished. The range of applicability of bio-oxidation is widened by applying the optimized protocol to the oxidation of enantiomerically pure 2-arylpropanols (profenols) into the corresponding 2-arylpropionic acids (profens), in high yields and with complete retention of configuration.
- Galletti, Paola,Pori, Matteo,Funiciello, Federica,Soldati, Roberto,Ballardini, Alberto,Giacomini, Daria
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p. 2684 - 2689
(2016/12/23)
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- Cobalt-catalyzed enantioselective hydroboration of 1,1-disubstituted aryl alkenes
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We report the synthesis of cobalt complexes of novel iminopyridine-oxazoline (IPO) ligands and their application to the asymmetric hydroboration of 1,1-disubstituted aryl alkenes. The new catalysts afforded α-alkyl-β-pinacolatoboranes with exclusive regioselectivity in high yields with up to 99.5% ee. Furthermore, we have applied this method to an efficient synthesis of naproxen.
- Zhang, Lei,Zuo, Ziqing,Wan, Xiaolong,Huang, Zheng
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p. 15501 - 15504
(2014/12/11)
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- Crystal structures of two Bacillus carboxylesterases with different enantioselectivities
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Naproxen esterase (NP) from Bacillus subtilis Thai I-8 is a carboxylesterase that catalyzes the enantioselective hydrolysis of naproxenmethylester to produce S-naproxen (E > 200). It is a homolog of CesA (98% sequence identity) and CesB (64% identity), both produced by B. subtilis strain 168. CesB can be used for the enantioselective hydrolysis of 1,2-O-isopropylideneglycerol (solketal) esters (E > 200 for IPG-caprylate). Crystal structures of NP and CesB, determined to a resolution of 1.75 A and 2.04 A, respectively, showed that both proteins have a canonical α/β hydrolase fold with an extra N-terminal helix stabilizing the cap subdomain. The active site in both enzymes is located in a deep hydrophobic groove and includes the catalytic triad residues Ser130, His274, and Glu245. A product analog, presumably 2-(2-hydroxyethoxy)acetic acid, was bound in the NP active site. The enzymes have different enantioselectivities, which previously were shown to result from only a few amino acid substitutions in the cap domain. Modeling of a substrate in the active site of NP allowed explaining the different enantioselectivities. In addition, Ala156 may be a determinant of enantioselectivity as well, since its side chain appears to interfere with the binding of certain R-enantiomers in the active site of NP. However, the exchange route for substrate and product between the active site and the solvent is not obvious from the structures. Flexibility of the cap domain might facilitate such exchange. Interestingly, both carboxylesterases show higher structural similarity to meta-cleavage compound (MCP) hydrolases than to other α/β hydrolase fold esterases.
- Rozeboom, Henriette J.,Godinho, Luis F.,Nardini, Marco,Quax, Wim J.,Dijkstra, Bauke W.
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p. 567 - 575
(2014/02/14)
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- ANTIVIRAL COMPOSITIONS DIRECTED AGAINST THE INFLUENZA VIRUS NUCLEOPROTEIN
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A pharmaceutical composition for treating viral infections by an influenza type A virus, includes a compound capable of acting as an inhibitor of the binding of the viral RNA to the nucleoprotein of influenza type A viruses, and capable of binding to the viral-RNA-binding domain on the nucleoprotein. A pharmaceutical composition for treating viral infections by an orthomyxovirus, includes a compound capable of acting as an inhibitor of the binding of the viral RNA to the nucleoprotein of orthomyxoviruses, and capable of binding to the viral-RNA-binding domain on the nucleoprotein of the viruses. A compound acting as an inhibitor of the binding of the viral RNA to the nucleoprotein of influenza type A viruses, and binding to the viral-RNA-binding domain on the nucleoprotein of influenza type A viruses and a method for identifying such a compound having these properties are also described.
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Page/Page column
(2014/06/24)
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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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supporting information
p. 3911 - 3915
(2013/07/26)
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- Characterization of a new thermophilic and acid tolerant esterase from Thermotoga maritima capable of hydrolytic resolution of racemic ketoprofen ethyl ester
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A gene coding for a putative thermostable esterase (Tm1160) from the hyperthermophilic bacterium Thermotoga maritima was cloned and expressed in Escherichia coli. The purified enzyme displayed optimal activity at 70 °C and had a half-life of 60 min at 90 °C. It was stable over a range of pHs from 5.0 to 7.5 with an optimum around 5.0-5.5. The enzyme was found to have high acid tolerance and maintained about 50% of its activity even after 60 min of treatment at pH 4.5 and 70 °C. Furthermore, the enzyme exhibited the highest specific activity with p-nitrophenyl butyrate (318 ± 7 s -1 mM-1). Under native conditions, Tm1160 forms a ～74 kDa dimer in solution. In addition, the esterase Tm1160 could enantioselectively hydrolyze the racemic ketoprofen ethyl ester and with an enantiomeric excess (eep) of 91.4% at a conversion of 41.1%, which makes it as a promising biocatalyst for the chiral resolution of (S)-ketoprofen.
- Wei, Tao,Feng, Shengxue,Mao, Duobin,Yu, Xuan,Du, Congcong,Wang, Xihua
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