- An efficient method for the synthesis of (S)-flurbiprofen by 1,2-rearrangement of the aryl group
-
(S)-Flurbiprofen (1) is a nonsteroidal anti-inflammatory drug (NSAID) used to relieve pain and inflammation associated with osteoarthritis. Herein a new and practical method for the preparation of 1 from 4-bromo-2-fluorobiphenyl (2) is reported, which achieves a good overall yield (20%) and high enantioselectivity (96%). This method avoids the use of expensive catalysts and affords the possibility of large-scale manufacturing with simple operations.
- Chen, Hua,Dai, Yuhao,Liu, Yu,Luo, Kaihong,Zhang, Yi
-
-
- Enantioselective Synthesis of Chiral Carboxylic Acids from Alkynes and Formic Acid by Nickel-Catalyzed Cascade Reactions: Facile Synthesis of Profens
-
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
-
supporting information
(2021/11/22)
-
- Deracemization through photochemical E/Z isomerization of enamines
-
Catalytic deracemization of a-branched aldehydes is a direct strategy to construct enantiopure a-tertiary carbonyls, which are essential to pharmaceutical applications. Here, we report a photochemical E/Z isomerization strategy for the deracemization of a-branched aldehydes by using simple aminocatalysts and readily available photosensitizers. A variety of racemic a-branched aldehydes could be directly transformed into either enantiomer with high selectivity. Rapid photodynamic E/Z isomerization and highly stereospecific iminium/enamine tautomerization are two key factors that underlie the enantioenrichment. This study presents a distinctive photochemical E/Z isomerization strategy for externally tuning enamine catalysis.
- Huang, Mouxin,Luo, Sanzhong,Pan, Tianrun,Zhang, Long
-
p. 869 - 874
(2022/03/07)
-
- Reshaping the active pocket of esterase Est816 for resolution of economically important racemates
-
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
-
p. 6126 - 6133
(2021/09/28)
-
- Preparation method of high-optical-purity 2S-(+)-flurbiprofen axetil
-
The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of high-optical-purity 2S (+) flurbiprofen axetil, which comprises the following steps: (1) reacting 2S (+) flurbiprofen with 1-bromoethyl acetate under the actions of inorganic alkali, an organic solvent and a phase transfer catalyst, and carrying out suction filtration, washing, drying and vacuum concentration to obtain an oily crude product; and performing column chromatography purification on the oily crude product to obtain a pure product. The product yield reaches 90% or above, the optical purity reaches 99.9% or above, and the product racemization problem in the preparation process is effectively solved.
- -
-
Paragraph 0025; 0026
(2021/02/06)
-
- Palladium-Catalyzed Asymmetric Markovnikov Hydroxycarbonylation and Hydroalkoxycarbonylation of Vinyl Arenes: Synthesis of 2-Arylpropanoic Acids
-
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
-
supporting information
p. 23117 - 23122
(2021/09/18)
-
- Preparation method of flurbiprofen
-
The invention relates to the technical field of medicine synthesis, in particular to a preparation method of flurbiprofen, which comprises the following steps: carrying out Sonogashira coupling reaction on 4-bromo-2-fluorobiphenyl and trimethylsilylacetylene under the catalysis of palladium to obtain 4-trimethylsilylethynyl-2-fluorobiphenyl, removing trimethylsilyl from the product in an alkaline solution without separation, so as to obtain 4-ethynyl-2-fluorobiphenyl; and then taking a complex formed by nickel and a phosphine ligand in situ as a catalyst, taking formic acid as a carboxylation and hydrogenation reagent, carrying out hydrocarboxylation-hydrogenation cascade reaction on the 4-ethynyl-2-fluorobiphenyl, and conducting purifying to obtain flurbiprofen. The method has the advantages of easily available raw material sources, short route, simple operation, mild reaction conditions and high yield. According to the present invention, ethynyl is directly converted into a propionic acid group through the efficient one-pot cascade reaction, and the racemic flurbiprofen, the levorotatory flurbiprofen and the dextrorotatory flurbiprofen can be synthesized only by changing the phosphine ligand type, such that the preparation of the optical pure flurbiprofen through the tedious and low-efficiency splitting of the racemic flurbiprofen is avoided.
- -
-
-
- Intermediate for preparing S-flurbiprofen, preparation method and application thereof
-
The invention discloses an intermediate for preparing S-flurbiprofen, and a preparation method and application thereof. The provided preparation method of S-flurbiprofen comprises the following step: in a solvent and in the presence of alkali, carrying out hydrolysis reaction as shown in the specification on a carboxylic ester compound as shown in a formula IV to obtain the S-flurbiprofen. R and R in the formula IV are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. By adopting the intermediate and the reaction route provided by the invention, the reaction yield of each step is higher, and the yield and the purity of the prepared S-flurbiprofen are higher; the reaction materials in each step are cheap and easily available, and the use of high-price enzymes or asymmetric catalysts is also avoided; the operation is simple, the reaction can be carried out under conventional equipment, the amplification possibility is provided, and industrialization is easy; and the route generates less three wastes, and is good in environmental friendliness.
- -
-
Paragraph 0123-0126
(2021/07/01)
-
- Asymmetric Markovnikov Hydroaminocarbonylation of Alkenes Enabled by Palladium-Monodentate Phosphoramidite Catalysis
-
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
-
supporting information
p. 85 - 91
(2021/01/12)
-
- Synthesis of a TNF inhibitor, flurbiprofen and an: I -Pr analogue in enantioenriched forms by copper-catalyzed propargylic substitution with Grignard reagents
-
The copper-catalyzed substitution reaction of diethyl phosphate derived from TMSCCCH(OH)CH2CH2OTBDPS with 3-c-C5H9-4-MeOC6H3MgBr, followed by several transformations, afforded a tumor necrosis factor inhibitor possessing a Ph-acetylene moiety. The inhibitor was also synthesized from phenylacetylene phosphate PhCCCH(OP(O)(OEt)2)CH2CH2OTBDPS. Furthermore, the substitution of phosphates derived from TMSCCCH(OH)CH3 and TMSCCCH(OH)-i-Pr with 3-F-4-PhC6H3MgBr gave the corresponding substitution products, which were transformed to flurbiprofen and its i-Pr analogue, respectively. The copper-catalyzed substitutions in these syntheses proceeded in a regio- and stereoselective manner. This journal is
- Isogawa, Yukari,Kobayashi, Yuichi,Ogawa, Narihito,Takashima, Yuji,Tsuboi, Atsuki
-
p. 9906 - 9909
(2021/12/07)
-
- Chiral liquid chromatography-mass spectrometry (LC-MS/MS) method development with β-cyclodextrin (β-CD) derivatized chiral stationary phase for the enhanced separation and determination of flurbiprofen enantiomers: Application to a stereoselective pharmacokinetic study
-
A method was developed and validated for the enantioselective determination of flurbiprofen in rat plasma using liquid chromatography/electrospray ionization-tandem mass spectrometry under reversed-phase elution mode. Two polysaccharide derivatized chiral stationary phases and a homemade β-cyclodextrin (β-CD) derivatized based chiral column were evaluated. The latter one, a per-4-chlorophenylcarbamate-β-cyclodextrin bonded chiral stationary phase which was synthesized in our laboratory, enabled the highly sensitive detection and complete separation (resolution 2.0) of the flurbiprofen enantiomers. The assay was carried out after the solid-phase extraction procedure with C18 cartridges, and with R-(-)-ibuprofen used as the internal standard. The developed method has been validated for specificity, linearity, accuracy, precision, recovery, matrix effect, stability, carryover effect and dilution effect. The lower limit of quantification for R-flurbiprofen and S-flurbiprofen was 10 ng mL-1 in rat plasma, respectively. Linearity was confirmed in the range of 10.0-20000.0 ng mL-1 with a correlation coefficient (r2) greater than 0.996. The established method was successfully applied to a stereoselective pharmacokinetic study of flurbiprofen enantiomers in rat plasma following oral administration. This journal is
- Cai, Liangzhao,Guo, Xingjie,Liu, Beibei,Sun, Jiayi,Yu, Jia
-
supporting information
p. 10334 - 10342
(2020/07/14)
-
- Cobalt-Catalyzed Asymmetric Hydrogenation of α,β-Unsaturated Carboxylic Acids by Homolytic H2 Cleavage
-
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
-
-
- Bidentate phosphine-phosphine oxide ligand and intermediate, preparation method and application thereof
-
The invention discloses a bidentate phosphine-phosphine oxide ligand and an intermediate, a preparation method and application thereof. The phosphine oxide compound is shown as a formula I and/or ent-I. The phosphine oxide compound is used as a metal ligand and is applied to Suzuki-Miyaura coupling reaction so that generation of self-coupled by-products is avoided, and an alpha-aryl carbonyl compound is obtained; and the dosages of the ligand and the metal catalyst are less.
- -
-
Paragraph 0431-0434; 0439-0442
(2020/11/10)
-
- Preparation of optically pure flurbiprofen via an integrated chemo-enzymatic synthesis pathway
-
In the synthesis of chiral molecules, the incorporation of enantioselective enzymatic conversions within the synthetic route often presents a useful approach. For the substitution of a chemical step with an enzymatic reaction, however, the complete synthetic route leading to and from this reaction needs to be considered carefully. An integrated approach, taking the possibilities and challenges of both types of conversions into account, can give access to chemo-enzymatic processes with great potential for effective synthesis strategies. We here report on the synthesis of enantiopure flurbiprofen using arylmalonate decarboxylase (AMDase, EC 4.1.1.76) in a chemo-enzymatic approach. Interestingly, practical considerations required shifting the enzymatic step to an earlier position in the synthetic route than previously anticipated. Engineered enzyme variants made it possible to obtain both (R)- and (S)-enantiomers of the target compound in excellent optical purity (>99%ee). The presented results underline that enzymes are most useful when they fit in a synthetic route, and that the optimization of biocatalytic steps and the planning of synthetic routes should be an integrated process.
- Enoki, Junichi,Linhorst, Max,Busch, Florian,Baraibar, álvaro Gomez,Miyamoto, Kenji,Kourist, Robert,Mügge, Carolin
-
p. 135 - 142
(2019/02/14)
-
- Deracemizing α-Branched Carboxylic Acids by Catalytic Asymmetric Protonation of Bis-Silyl Ketene Acetals with Water or Methanol
-
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
-
p. 11479 - 11482
(2019/07/18)
-
- Enantioselective Palladium-Catalyzed Cross-Coupling of α-Bromo Carboxamides and Aryl Boronic Acids
-
We herein report an enantioselective palladium-catalyzed cross-coupling between α-bromo carboxamides and aryl boronic acids, generating a series of chiral α-aryl carboxamides in good yields and excellent enantioselectivities. The development of a chiral P,P=O ligand was critical in overcoming the second transmetalation issue and allows the first asymmetric palladium-catalyzed coupling of α-bromo carbonyl compounds.
- Li, Bowen,Li, Tiejun,Aliyu, Muinat A.,Li, Zhen Hua,Tang, Wenjun
-
supporting information
p. 11355 - 11359
(2019/07/12)
-
- Iron-catalysed enantioselective Suzuki-Miyaura coupling of racemic alkyl bromides
-
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
-
supporting information
p. 1128 - 1131
(2019/01/28)
-
- Evaluation of the Edman degradation product of vancomycin bonded to core-shell particles as a new HPLC chiral stationary phase
-
A modified macrocyclic glycopeptide-based chiral stationary phase (CSP), prepared via Edman degradation of vancomycin, was evaluated as a chiral selector for the first time. Its applicability was compared with other macrocyclic glycopeptide-based CSPs: TeicoShell and VancoShell. In addition, another modified macrocyclic glycopeptide-based CSP, NicoShell, was further examined. Initial evaluation was focused on the complementary behavior with these glycopeptides. A screening procedure was used based on previous work for the enantiomeric separation of 50 chiral compounds including amino acids, pesticides, stimulants, and a variety of pharmaceuticals. Fast and efficient chiral separations resulted by using superficially porous (core-shell) particle supports. Overall, the vancomycin Edman degradation product (EDP) resembled TeicoShell with high enantioselectivity for acidic compounds in the polar ionic mode. The simultaneous enantiomeric separation of 5 racemic profens using liquid chromatography-mass spectrometry with EDP was performed in approximately 3?minutes. Other highlights include simultaneous liquid chromatography separations of rac-amphetamine and rac-methamphetamine with VancoShell, rac-pseudoephedrine and rac-ephedrine with NicoShell, and rac-dichlorprop and rac-haloxyfop with TeicoShell.
- Hellinghausen, Garrett,Lopez, Diego A.,Lee, Jauh T.,Wang, Yadi,Weatherly, Choyce A.,Portillo, Abiud E.,Berthod, Alain,Armstrong, Daniel W.
-
p. 1067 - 1078
(2018/08/01)
-
- METHOD FOR PRODUCING OPTICALLY ACTIVE 2-(2-FLUOROBIPHENYL-4-YL) PROPANOIC ACID
-
A novel process for producing optically active 2-(2-fluorobiphenyl-4-yl)propanoic acid is disclosed. This production process is characterized in that a compound of formula [1] is reacted with magnesium and so forth to prepare an organometallic reagent, which is reacted with a compound of formula [2] in the presence of a catalytic amount of a nickel compound and a catalytic amount of an optically active compound of formula [3] to obtain a compound represented by formula [4] which is subsequently converted to a compound represented by formula [5] or a pharmaceutically acceptable salt thereof.
- -
-
Paragraph 0410-0414; 0422
(2018/10/21)
-
- Ultrafast chiral separations for high throughput enantiopurity analysis
-
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.
-
supporting information
p. 509 - 512
(2017/01/13)
-
- Enantioselective potential of polysaccharide-based chiral stationary phases in supercritical fluid chromatography
-
The enantioselective potential of two polysaccharide-based chiral stationary phases for analysis of chiral structurally diverse biologically active compounds was evaluated in supercritical fluid chromatography using a set of 52 analytes. The chiral selectors immobilized on 2.5?μm silica particles were tris-(3,5-dimethylphenylcarmabate) derivatives of cellulose or amylose. The influence of the polysaccharide backbone, different organic modifiers, and different mobile phase additives on retention and enantioseparation was monitored. Conditions for fast baseline enantioseparation were found for the majority of the compounds. The success rate of baseline and partial enantioseparation with cellulose-based chiral stationary phase was 51.9% and 15.4%, respectively. Using amylose-based chiral stationary phase we obtained 76.9% of baseline enantioseparations and 9.6% of partial enantioseparations of the tested compounds. The best results on cellulose-based chiral stationary phase were achieved particularly with propane-2-ol and a mixture of isopropylamine and trifluoroacetic acid as organic modifier and additive to CO2, respectively. Methanol and basic additive isopropylamine were preferred on amylose-based chiral stationary phase. The complementary enantioselectivity of the cellulose- and amylose-based chiral stationary phases allows separation of the majority of the tested structurally different compounds. Separation systems were found to be directly applicable for analyses of biologically active compounds of interest.
- Kucerova, Gabriela,Kalikova, Kveta,Tesarova, Eva
-
supporting information
p. 239 - 246
(2017/05/29)
-
- A Highly Enantioselective Alkene Methoxycarbonylation Enables a Concise Synthesis of (S)-Flurbiprofen
-
A highly enantioselective synthesis of (S)-flurbiprofen methyl ester in two steps from commercially available 4-bromo-2-fluoro-1,1′-biphenyl is shown. [PdCl2((S)-xylyl-phanephos)] catalyst is used to accomplish both Grignard cross-coupling and the highly enantioselective intermolecular methoxycarbonylation reaction.
- Harkness, Gavin J.,Clarke, Matthew L.
-
supporting information
p. 4859 - 4863
(2017/09/07)
-
- Facile one-pot preparation of chiral monoliths with a well-defined framework based on the thiol-ene click reaction for capillary liquid chromatography
-
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
-
p. 24835 - 24842
(2016/03/22)
-
- Arylmalonate Decarboxylase-Catalyzed Asymmetric Synthesis of Both Enantiomers of Optically Pure Flurbiprofen
-
The bacterial decarboxylase (AMDase) catalyzes the enantioselective decarboxylation of prochiral arylmalonates with high enantioselectivity. Although this reaction would provide a highly sustainable synthesis of active pharmaceutical compounds such as flurbiprofen or naproxen, competing spontaneous decarboxylation has so far prevented the catalytic application of AMDase. Here, we report on reaction engineering and an alternate protection group strategy for the synthesis of these compounds that successfully suppresses the side reaction and provides pure arylmalonic acids for subsequent enzymatic conversion. Protein engineering increased the activity of the synthesis of the (S)-and (R)-enantiomers of flurbiprofen. These results demonstrated the importance of synergistic effects in the optimization of this decarboxylase. The asymmetric synthesis of both enantiomers in high optical purity (>99 %) and yield (>90 %) can be easily integrated into existing industrial syntheses of flurbiprofen, thus providing a sustainable method for the production of this important pharmaceutical ingredient. Optically pure flurbiprofen: A novel deprotection strategy for the preparation of the starting material combined with decarboxylase (AMDase) variants optimized by enzyme engineering allowed the asymmetric synthesis of both enantiomers of the non-steroidal anti-inflammatory drug (NSAID) flurbiprofen in excellent yield and optical purity.
- Ga?meyer, Sarah Katharina,Wetzig, Jasmin,Mügge, Carolin,Assmann, Miriam,Enoki, Junichi,Hilterhaus, Lutz,Zuhse, Ralf,Miyamoto, Kenji,Liese, Andreas,Kourist, Robert
-
p. 916 - 921
(2016/03/15)
-
- Method for preparing S-(+)-flurbiprofen axetil high in optical purity
-
The invention discloses a method for preparing S-(+)-flurbiprofen axetil high in optical purity.The method comprises the steps of 1, making S-(+)-flurbiprofen axetil react with 1-substituted ethyl acetate in the presence of alkali and organic solvent for 3-15 h at the temperature of 0-25 DEG C; 2, extracting and washing a reaction product, and separating out grease; 3, conducting column chromatographic purification on the grease; 4, removing organic solution residues with the solvent coevaporation method, and then conducting vacuum drying to obtain the target product.Inorganic base is not used, organic base highly intersoluble with organic solvent is adopted, a proper solvent ratio is selected to guarantee the proceeding of reaction, and racemization and product breakdown which occur often are avoided during preparation.The total yield of the prepared S-(+)-flurbiprofen axetil can be 80% or more, and optical purity is higher than 99%.
- -
-
Paragraph 0033
(2017/03/25)
-
- Potent multitarget FAAH-COX inhibitors: Design and structure-activity relationship studies
-
Non-steroidal anti-inflammatory drugs (NSAIDs) exert their pharmacological effects by inhibiting cyclooxygenase (COX)-1 and COX-2. Though widely prescribed for pain and inflammation, these agents have limited utility in chronic diseases due to serious mechanism-based adverse events such as gastrointestinal damage. Concomitant blockade of fatty acid amide hydrolase (FAAH) enhances the therapeutic effects of the NSAIDs while attenuating their propensity to cause gastrointestinal injury. This favorable interaction is attributed to the accumulation of protective FAAH substrates, such as the endocannabinoid anandamide, and suggests that agents simultaneously targeting COX and FAAH might provide an innovative strategy to combat pain and inflammation with reduced side effects. Here, we describe the rational design and structure-active relationship (SAR) properties of the first class of potent multitarget FAAH-COX inhibitors. A focused SAR exploration around the prototype 10r (ARN2508) led to the identification of achiral (18b) as well as racemic (29a-c and 29e) analogs. Absolute configurational assignment and pharmacological evaluation of single enantiomers of 10r are also presented. (S)-(+)-10r is the first highly potent and selective chiral inhibitor of FAAH-COX with marked in vivo activity, and represents a promising lead to discover novel analgesics and anti-inflammatory drugs.
- Migliore, Marco,Habrant, Damien,Sasso, Oscar,Albani, Clara,Bertozzi, Sine Mandrup,Armirotti, Andrea,Piomelli, Daniele,Scarpelli, Rita
-
p. 216 - 237
(2016/01/16)
-
- Reversed-phase high-performance liquid chromatographic separation of some 2-arylpropionic acids using vancomycin as chiral stationary phase
-
Abstract A rapid, sensitive and reproducible HPLC method has been developed for enantioseparation of six non-steroidal anti-inflammatory drugs, which are acidic compounds: carprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen and ketoprofen. The effects of the mobile phase composition on retention times and resolutions of the analytes were studied. A column based on vancomycin immobilized by reductive amination to aldehyde functionalised silica was prepared in house and used. The prepared sorbent shows a great stability and selectivity over a range of pH (4-6), and the separation was carried out using the mobile phase composed of a mixture of 40% of methanol in ammonium nitrate buffer (50 mM) at pH 5.0. Another mobile phase consisted of 50% of methanol in phosphate buffer (5A mM) at pH 5.0 was also prepared and tested. The two mobile phases are the optimum conditions obtained. All experiments were conducted at flow rate 0.6 ml/min, using a UV detector wavelength at λ = 254 nm.
- Bouchair, Nabila,Righezza, Michel,Hamdi, Abderrezak
-
p. 921 - 928
(2015/05/05)
-
- Enantioseparation of Racemic Flurbiprofen by Aqueous Two-Phase Extraction With Binary Chiral Selectors of L-dioctyl Tartrate and L-tryptophan
-
A novel method for chiral separation of flurbiprofen enantiomers was developed using aqueous two-phase extraction (ATPE) coupled with biphasic recognition chiral extraction (BRCE). An aqueous two-phase system (ATPS) was used as an extracting solvent which was composed of ethanol (35.0% w/w) and ammonium sulfate (18.0% w/w). The chiral selectors in ATPS for BRCE consideration were L-dioctyl tartrate and L-tryptophan, which were screened from amino acids, β-cyclodextrin derivatives, and L-tartrate esters. Factors such as the amounts of L-dioctyl tartrate and L-tryptophan, pH, flurbiprofen concentration, and the operation temperature were investigated in terms of chiral separation of flurbiprofen enantiomers. The optimum conditions were as follows: L-dioctyl tartrate, 80 mg; L-tryptophan, 40 mg; pH, 4.0; flurbiprofen concentration, 0.10 mmol/L; and temperature, 25 C. The maximum separation factor α for flurbiprofen enantiomers could reach 2.34. The mechanism of chiral separation of flurbiprofen enantiomers is discussed and studied. The results showed that synergistic extraction has been established by L-dioctyl tartrate and L-tryptophan, which enantioselectively recognized R- and S-enantiomers in top and bottom phases, respectively. Compared to conventional liquid-liquid extraction, ATPE coupled with BRCE possessed higher separation efficiency and enantioselectivity without the use of any other organic solvents. The proposed method is a potential and powerful alternative to conventional extraction for separation of various enantiomers. Chirality 27:650-657, 2015.
- Chen, Zhi,Zhang, Wei,Wang, Liping,Fan, Huajun,Wan, Qiang,Wu, Xuehao,Tang, Xunyou,Tang, James Z.
-
p. 650 - 657
(2015/08/25)
-
- PROCESS FOR THE MANUFACTURE OF S-(+)-FLURBIPROFEN
-
There is described a process for the preparation of S-(+)-flurbiprofen, or a salt thereof, which comprises the steps of: (i) treating a solution rich in S-(+)-flurbiprofen, or a salt thereof, with an aqueous wash; said solution comprising a mixture of a water immiscible solvent and a water miscible solvent; and (ii) crystallising and/ or isolating the S-(+)-flurbiprofen, or a salt thereof.
- -
-
-
- Laccase-Mediator System for Alcohol Oxidation to Carbonyls or Carboxylic Acids: Toward a Sustainable Synthesis of Profens
-
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
-
p. 2684 - 2689
(2016/12/23)
-
- SPIROBENZYLAMINE-PHOSPHINE, PREPARATION METHOD THEREFOR AND USE THEREOF
-
The present invention relates to a spirobenzylamine-phosphine, preparation method therefor and use thereof. The compound has a structure represented by formula (I), wherein n=0 to 3; R1, R2, R3, R4, R5, R6, R7, R8 and R9 having a value as defined in claim 1. Starting from the substituted 7-trifluoromesyloxy-7'-diarylphosphino-1, 1'-spiro-dihydroindene, the compound is synthesized in a two-step or three-step reactions. The new spirobenzylamine-phosphine is complexed with an iridium precursor and is subjected to ion exchange, to give an Iridium/spirobenzylamine-phosphine complex comprising various anions. The spiro benzyl amine-phosphine/Iridium complex according to the present invention may be used for catalyzing asymmetry hydrogenation of a variety of alpha-substituted acrylic acids, has high activity and enantio-selectivity, and has a good prospect of industrialization.
- -
-
Paragraph 0067
(2014/07/22)
-
- Spirobenzylamine-Phosphine, Preparation Method Therefor And Use Thereof
-
The present invention relates to a spirobenzylamine-phosphine, preparation method therefor and use thereof. The compound has a structure represented by formula (I), wherein n=0 to 3; R1, R2, R3, R4, R5, R6, R7, R8 and R9 having a value as defined in claim 1. Starting from the substituted 7-trifluoromesyloxy-7′-diarylphosphino-1,1′-spiro-dihydroindene, the compound is synthesized in a two-step or three-step reactions. The new spirobenzylamine-phosphine is complexed with an iridium precursor and is subjected to ion exchange, to give an Iridium/spirobenzylamine-phosphine complex comprising various anions. The spiro benzyl amine-phosphine/Iridium complex according to the present invention may be used for catalyzing asymmetry hydrogenation of a variety of alpha-substituted acrylic acids, has high activity and enantio-selectivity, and has a good prospect of industrialization.
- -
-
Paragraph 0078; 0079
(2014/07/22)
-
- Biotransformation with whole microbial systems in a continuous flow reactor: Resolution of (RS)-flurbiprofen using Aspergillus oryzae by direct esterification with ethanol in organic solvent
-
Cell-bound lipases of dry mycelium of Aspergillus oryzae were used in organic solvent for the resolution of racemic flurbiprofen by direct esterification with ethanol in a flow-chemistry reactor. Under flow conditions a significant reduction of the reaction time and an increase of the enantioselectivity were achieved compared to the batch mode. Moreover, the process was implemented by adding an in-line purification step integrated with the racemization of the unreacted flurbiprofen directly into a polymer-supported resin.
- Tamborini, Lucia,Romano, Diego,Pinto, Andrea,Contente, Martina,Iannuzzi, Maria C.,Conti, Paola,Molinari, Francesco
-
p. 6090 - 6093
(2013/10/22)
-
- Substrate-selective inhibition of cyclooxygenase-2: Development and evaluation of achiral profen probes
-
Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid and the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA). We recently reported that (R)-profens selectively inhibit endocannabinoid oxygenation but not arachidonic acid oxygenation. In this work, we synthesized achiral derivatives of five profen scaffolds and evaluated them for substrate-selective inhibition using in vitro and cellular assays. The size of the substituents dictated the inhibitory strength of the analogs, with smaller substituents enabling greater potency but less selectivity. Inhibitors based on the flurbiprofen scaffold possessed the greatest potency and selectivity, with desmethylflurbiprofen (3a) exhibiting an IC50 of 0.11 μM for inhibition of 2-AG oxygenation. The crystal structure of desmethylflurbiprofen complexed to mCOX-2 demonstrated a similar binding mode to other profens. Desmethylflurbiprofen exhibited a half-life in mice comparable to that of ibuprofen. The data presented suggest that achiral profens can act as lead molecules toward in vivo probes of substrate-selective COX-2 inhibition.
- Windsor, Matthew A.,Hermanson, Daniel J.,Kingsley, Philip J.,Xu, Shu,Crews, Brenda C.,Ho, Winnie,Keenan, Catherine M.,Banerjee, Surajit,Sharkey, Keith A.,Marnett, Lawrence J.
-
supporting information
p. 759 - 763
(2012/10/29)
-
- An efficient method for the lipase-catalysed resolution and in-line purification of racemic flurbiprofen in a continuous-flow reactor
-
The lipase-catalysed kinetic resolution of flurbiprofen was performed in a flow-chemistry reactor allowing for a significant reduction of the reaction time compared to the classical batch method. The process was implemented by adding an in-line purification step of the exiting solution, consisting in a catch and release protocol, which allows easy separation and recovery of both (S)-flurbiprofen and (R)-flurbiprofen butyl ester with an enantiomeric excess ≥90% and a chemical purity >98%.
- Tamborini, Lucia,Romano, Diego,Pinto, Andrea,Bertolani, Arianna,Molinari, Francesco,Conti, Paola
-
-
- Enantioselective hydrogenation of α-substituted acrylic acids catalyzed by iridium complexes with chiral spiro aminophosphine ligands
-
Highly active: Iridium complexes with chiral spiro aminophosphine ligands were synthesized and applied as catalysts for the asymmetric hydrogenation of α-substituted acrylic acids (see scheme). The complexes were highly active catalysts, showing turnover frequencies of up to 6000 h-1, and catalyst loadings could be reduced to 0.01 mol %. Copyright
- Zhu, Shou-Fei,Yu, Yan-Bo,Li, Shen,Wang, Li-Xin,Zhou, Qi-Lin
-
supporting information; experimental part
p. 8872 - 8875
(2012/10/08)
-
- Enantiodifferentiation of ketoprofen by Japanese firefly luciferase from Luciola lateralis
-
Recently, we found that firefly luciferase exhibited (R)-enantioselective thioesterification activity toward 2-arylpropanoic acids. In the case of Japanese firefly luciferase from Luciola lateralis (LUC-H), the E-value for ketoprofen was approximately 20. In this study, we used a spectrophotometric method to measure the catalytic activity of LUC-H. Using this method allowed us to judge the reaction efficiency easily. Our results confirmed that LUC-H exhibits enantioselective thioesterification activity toward a series of 2-arylpropanoic acids. The highest activity was observed with ketoprofen. We also observed high enzymatic activity of LUC-H toward long-chain fatty acids. These results were reasonable because LUC-H is homologous with long-chain acyl-CoA synthetase. To obtain further information about the enantiodifferentiation mechanism of the LUC-H catalyzed thioesterification of ketoprofen, we determined the kinetic parameters of the reaction relative to each of its three substrates: ketoprofen, ATP, and coenzyme A (CoASH). We found that whereas the affinities of each compound are not affected by the chirality of ketoprofen, enantiodifferentiation is achieved by a chirality-dependent difference in the kcat parameter.
- Kato, Dai-Ichiro,Tatsumi, Tomohiro,Bansho, Asami,Teruya, Keisuke,Yoshida, Hiromitsu,Takeo, Masahiro,Negoro, Seiji
-
experimental part
p. 140 - 146
(2012/01/19)
-
- Highly enantioselective direct alkylation of arylacetic acids with chiral lithium amides as traceless auxiliaries
-
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
-
supporting information; experimental part
p. 11936 - 11939
(2011/09/19)
-
- Lipase-catalyzed alcoholytic resolution of (R,S)-flurbiprofenyl azolides for preparation of (R)-NO-flurbiprofen ester prodrugs
-
A lipase-catalyzed alcoholysis of (R,S)-flurbiprofenyl azolide in anhydrous methyl tert-butyl ether (MTBE) has been developed for the preparation of (R)-flurbiprofenyl ester, (S)-flurbiprofenyl azolide and hence (S)-flurbiprofen. On the basis of enzyme en
- Ciou, Jyun-Fen,Wang, Pei-Yun,Wu, An-Chi,Tsai, Shau-Wei
-
p. 960 - 965
(2013/01/09)
-
- High-performance liquid chromatography separation of enantiomers of mandelic acid and its analogs on a chiral stationary phase
-
The enantiomers of mandelic acid and its analogs have been chromatographically separated on a chiral stationary phase (CSP) derived from 4-(3,5-dinitrobenzamido) tetrahydrophenanthrene. The rationale of separations of these compounds is discussed with respect to the method development for determining enantiomeric purity and possibility of obtaining enantiomerically pure materials by high-pressure liquid chromatography. The relationship of analyte structure to the extent of enantiomeric separation has been examined and separation factors (a) are presented for various groups of structurally related compounds. Chiral recognition models have been suggested to account for the observed separations. These models provide mechanistic insights into the chiral recognition process.
- Aneja, Ritu,Luthra, Pratibha Mehta,Ahuja, Satinder
-
experimental part
p. 479 - 485
(2010/08/20)
-
- Spontaneous oscillatory in vitro chiral conversion of simple carboxylic acids and its possible mechanism
-
In earlier studies, we have collected experimental evidence (mostly from thin-layer chromatography and polarimetry) on the spontaneous oscillatory in vitro chiral conversion of simple carboxylic acids dissolved in 70% aqueous ethanol. To elucidate this phenomenon, we developed a simple theoretical model of two linked Templators. Recently, we have obtained additional experimental evidence of the spontaneous condensation of chiral carboxylic acids, based on the biuret test (amino acids), high performance liquid chromatography, and 13C NMR spectroscopy (profens and hydroxy acids). We briefly describe our experimental results in the context of the existing literature and outline an improved theoretical model for these phenomena. Our system resembles in some respects the reported oscillatory condensation of organic silanols. Here, the key reaction is the formation of carboxylic acid-derived enols. Finally, we discuss the importance of the oscillatory chiral conversion of simple carboxylic acids for biochemistry, pharmacology, and related life sciences. Copyright
- Sajewicz, Mieczyslaw,Matlengiewicz, Marek,Leda, Marcin,Gontarska, Monika,Kronenbach, Dorota,Kowalska, Teresa,Epstein, Irving R.
-
scheme or table
p. 1066 - 1073
(2011/07/06)
-
- One-step oxidation of 2-arylpropanols to 2-arylpropionic acids: Improving sustainability in the synthesis of profens
-
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
-
experimental part
p. 2644 - 2648
(2010/11/18)
-
- Chemoenzymatic synthesis of (2S)-2-arylpropanols through a dynamic kinetic resolution of 2-arylpropanals with alcohol dehydrogenases
-
We applied Horse Liver Alcohol Dehydrogenase (HLADH) to the enantioselective synthesis of six (2S)-2-arylpropanols, useful intermediates in the synthesis of Profens. The influence of substrate structure and reaction conditions on yields and enantioselectivity were investigated. The high yields and high enantioselectivity towards the (S)-enantiomer obtained in the bioreduction of 2-arylpropionic aldehydes, clearly indicate the achievement of a DKR process through a combination of an enzyme-catalyzed kinetic reduction with a chemical base-catalyzed racemization of the unreacted aldehydes. The racemization step is represented by the keto-enol equilibrium of the aldehyde and can be controlled by modulating pH and reaction conditions.
- Galletti, Paola,Emer, Enrico,Gucciardo, Gabriele,Quintavalla, Arianna,Pori, Matteo,Giacomini, Daria
-
supporting information; experimental part
p. 4117 - 4123
(2010/10/03)
-
- Enantioselective synthesis of α-methyl carboxylic acids from readily available starting materials via chemoenzymatic dynamic kinetic resolution
-
An enantioselective method for the synthesis of α-methyl carboxylic acids starting from trans-cinnamaldehyde, a readily available and inexpensive compound, has been developed. Allylic alcohol 1 was obtained via a standard Grignard addition to trans-cinnamaldehyde. Dynamic kinetic resolution was applied to allylic alcohol 1 utilizing a ruthenium catalyst and either an (R)-selective lipase or an (S)-selective protease to provide the corresponding allylic esters in high yield and high ee. A copper-catalyzed allylic substitution was then applied to provide the corresponding alkenes with inversion of stereochemistry. Subsequent C-C double bond cleavage afforded pharmaceutically important α-methyl substituted carboxylic acids in high ee and overall yields of up to 76%.
- Thalen, Lisa K.,Sumic, Anna,Bogar, Krisztian,Norinder, Jakob,Persson, Andreas K. Ae.,Baeckvall, Jan-E.
-
supporting information; experimental part
p. 6842 - 6847
(2010/11/24)
-
- METHOD FOR PRODUCING OPTICALLY ACTIVE ESTER AND METHOD FOR PRODUCING OPTICALLY ACTIVE CARBOXYLIC ACID
-
Disclosed is a method for producing an optically active ester by highly selectively esterifying one enantiomer of a racemic carboxylic acid, while producing an optically active carboxylic acid which is the other enantiomer. An optically active ester is produced while producing an optically active carboxylic acid at the same time by reacting a racemic carboxylic acid with a specific alcohol or phenol derivative in the presence of benzoic anhydride or a derivative thereof and a catalyst such as tetramisole or benzotetramisole, thereby selectively esterifying one enantiomer of the racemic carboxylic acid.
- -
-
Page/Page column 14-15
(2010/09/18)
-
- An effective kinetic resolution of racemic α-arylpropanoic acids, α-arylbutanoic acids, and β-substituted-α-arylpropanoic acids with bis(9-phenanthryl)methanol as a new achiral nucleophile in the asymmetric esterification using carboxylic anhydrides and the acyl-transfer catalyst
-
A general method for the kinetic resolution of racemic α-arylalkanoic acids with achiral alcohols is described. It was determined that bis(9-phenanthryl)methanol is a suitable nucleophile which reacts with the intermediary mixed anhydrides generated from aromatic anhydrides with α-arylpropanoic acids or β-substituted-α-arylpropanoic acids in the presence of (+)-benzotetramisole to produce the corresponding optically active esters with high ee's under very mild conditions.
- Nakata, Kenya,Onda, Yu-Suke,Ono, Keisuke,Shiina, Isamu
-
experimental part
p. 5666 - 5669
(2010/11/18)
-
- Iterative saturation mutagenesis accelerates laboratory evolution of enzyme stereoselectivity: Rigorous comparison with traditional methods
-
Efficacy in laboratory evolution of enzymes is currently a pressing issue, making comparative studies of different methods and strategies mandatory. Recent reports indicate that iterative saturation mutagenesis (ISM) provides a means to accelerate directed evolution of stereoselectivity and thermostability, but statistically meaningful comparisons with other methods have not been documented to date. In the present study, the efficacy of ISM has been rigorously tested by applying it to the previously most systematically studied enzyme in directed evolution, the lipase from Pseudomonas aeruginosa as a catalyst in the stereoselective hydrolytic kinetic resolution of a chiral ester. Upon screening only 10 000 transformants, unprecedented enantioselectivity was achieved (E = 594). ISM proves to be considerably more efficient than all previous systematic efforts utilizing error-prone polymerase chain reaction at different mutation rates, saturation mutagenesis at hot spots, and/or DNA shuffling, pronounced positive epistatic effects being the underlying reason.
- Reetz, Manfred T.,Prasad, Shreenath,Carballeira, Jose D.,Gumulya, Yosephine,Bocola, Marco
-
experimental part
p. 9144 - 9152
(2010/08/21)
-
- Direct enantioselective HPLC monitoring of lipase-catalyzed kinetic resolution of flurbiprofen
-
The solvent versatility of Chiralpak IB, a 3,5-dimethylphenylcarbamate derivative of cellulose-based chiral stationary phase, is demonstrated in the direct enantioselective HPLC monitoring of lipase-catalyzed kinetic resolution of flurbiprofen in nonstandard HPLC organic solvents. Nonstandard HPLC organic solvents were used as the reaction media for the lipase-catalysis and in mean time as diluent to dissolve the difficult to dissolve enzyme substrate (the acid) and as eluent for the simultaneous enantioselective HPLC baseline separation of both substrate and product in one run without any further derivatization.
- Ghanem, Ashraf
-
experimental part
p. 597 - 603
(2010/09/18)
-
- Kinetic resolution of racemic α-arylalkanoic acids with achiral alcohols via the asymmetric esterification using carboxylic anhydrides and acyl-transfer catalysts
-
A variety of optically active carboxylic esters are produced by the kinetic resolution of racemic α-substituted carboxylic acids using achiral alcohols, aromatic or aliphatic carboxylic anhydrides, and chiral acyl-transfer catalysts. The combination of 4-methoxybenzoic anhydride (PMBA) or pivalic anhydride with the modified benzotetramisole-type catalyst ((S)-β-Np-BTM) is the most effective for promotion of the enantioselective coupling reaction between racemic carboxylic acids and a novel nucleophile, bis(α-naphthyl) methanol, to give the corresponding esters with high ees. This protocol was successfully applied to the production of nonracemic nonsteroidal anti-inflammatory drugs from racemic compounds utilizing the transacylation process to generate the mixed anhydrides from the acid components with the suitable carboxylic anhydrides.
- Shiina, Isamu,Nakata, Kenya,Ono, Keisuke,Onda, Yu-Suke,Itagaki, Makoto
-
supporting information; experimental part
p. 11629 - 11641
(2010/10/04)
-
- PROCESS FOR THE MANUFACTURE OF RACEMIC 2-ARYL-PROPIONIC ACID
-
There is described a process for the manufacture of a racemic 2-aryl propionic acid compound, or a pharmaceutically acceptable salt thereof, which comprises reacting the S- or R- enantiomer of the corresponding 2-aryl propionic acid compound with a base.
- -
-
Page/Page column 16
(2010/04/03)
-