- 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
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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
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- Improvement of dissolution and suppository release characteristics of flurbiprofen by inclusion complexation with heptakis(2,6-di-O-methyl)-β-cyclodextrin
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The inclusion behavior of methylated β-cyclodextrins, heptakis(2,6-di-O-methyl)-β-cyclodextrin (2), and heptakis-(2,3,6-tri-O-methyl)-β-cyclodextrin (3) in solution and the solid state was compared with that of natural β-cyclodextrin (1) using an anti-inflammatory drug, flurbiprofen, as a guest molecule. Stability constants were determined by the solubility method at various temperatures, and the thermodynamic parameters were calculated for inclusion complex formation in aqueous solution. The solid complexes were obtained in a molar ratio of 1:1, and their dissolution behavior and release from suppository bases were examined. The data suggest that the inclusion mode of the complex with 3 is somewhat different from that of the complexes with 1 and 2. From a practical point of view, 2 seems to be particularly useful for improving the pharmaceutical properties of flurbiprofen in various dosage forms.
- Uekama,Imai,Maeda,Irie,Hirayama,Otagiri
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- Method for determination of optical purity of 2-arylpropanoic acids using urea derivatives based on a 1,1′-binaphthalene skeleton as chiral NMR solvating agents: Advantages and limitations thereof
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Five optically active urea derivatives (1-5) were used as NMR solvating agents for analysis of the optical purity of different 2-arylpropanoic acids commonly used as nonsteroidal anti-inflammatory drugs. These novel chiral solvating agents were more efficient at discriminating the respective enantiomers of targets than the chiral solvating agents known so far, without the need to add a base for achieving the signal splitting. The advantages and limits of the use of these novel chiral solvating agents were studied.
- Cu?ínová, Petra,Hájek, Peter,Jank?, Kristyna,Holakovsky, Roman
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- An efficient method for the lipase-catalysed resolution and in-line purification of racemic flurbiprofen in a continuous-flow reactor
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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
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- Direct enantioselective HPLC monitoring of lipase-catalyzed kinetic resolution of flurbiprofen
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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
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- Resolution of (R,S)-flurbiprofen catalysed by dry mycelia in organic solvent
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Mycelia of Aspergillus oryzae display high enantioselectivity towards (R)-flurbiprofen and can be efficiently used in pure organic solvent for the resolution of (R,S)-flurbiprofen through esterification. The use of the lyophilized mycelia facilitates the separation process so that in one step the two enantiomers of flurbiprofen, which are both valuable for pharmaceutical applications, can be easily separated. The biotransformation can be carried out in different apolar solvents using different primary alcohols as nucleophiles under very mild conditions.
- Spizzo, Patrizia,Basso, Alessandra,Ebert, Cynthia,Gardossi, Lucia,Ferrario, Valerio,Romano, Diego,Molinari, Francesco
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- A Highly Enantioselective Alkene Methoxycarbonylation Enables a Concise Synthesis of (S)-Flurbiprofen
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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.
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- Enantioseparation of Racemic Flurbiprofen by Aqueous Two-Phase Extraction With Binary Chiral Selectors of L-dioctyl Tartrate and L-tryptophan
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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.
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- Different in vitro activity of flurbiprofen and its enantiomers on human articular cartilage
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The 2-arylpropionic acid derivatives or 'profens' are an important group of non-steroidal anti-inflammatory drugs that have been used for the symptomatic treatment of various forms of arthritis. These compounds are chiral and the majority of them are stil
- Panico,Cardile,Vittorio,Ronsisvalle,Scoto,Parenti,Gentile,Morrone,Nicolosi
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- 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
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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
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- An efficient method for the synthesis of (S)-flurbiprofen by 1,2-rearrangement of the aryl group
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(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
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- 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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supporting information
(2021/11/22)
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- Deracemization through photochemical E/Z isomerization of enamines
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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
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p. 869 - 874
(2022/03/07)
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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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- Preparation method of flurbiprofen
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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.
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Paragraph 0064; 0076-0077
(2021/05/12)
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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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- Preparation method of high-optical-purity 2S-(+)-flurbiprofen axetil
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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.
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Paragraph 0025; 0026
(2021/02/06)
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- Preparation method of flurbiprofen
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The invention relates to a preparation method of flurbiprofen. The method comprises the following steps: (1) reacting 2-fluoro-4-brominated biphenyl with metal magnesium at the temperature of 40-65 DEG C to prepare (2-fluorine-[1,1'-biphenyl]-4-yl) magnesium bromide; (2) reacting (2-fluorine-[1,1'-biphenyl]-4-yl) magnesium bromide and ethyl 2-bromopropionate under the action of a nickel catalyst to prepare flurbiprofen ethyl ester; (3) hydrolyzing the flurbiprofen ethyl ester to prepare the flurbiprofen sodium; and (4) dissolving flurbiprofen sodium in water, adding acid to adjust the pH value, and separating out flurbiprofen. According to the preparation method, use of high-risk reagents is avoided, and used chemical reagents are cheap and easy to obtain; the preparation method has the advantages of being simple and convenient to operate, safe, controllable, good in reproducibility, high in product yield, high in purity, safe, environmentally friendly, low in cost, and suitable for industrial production and the like.
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Paragraph 0050-0061
(2021/05/12)
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- Catalytic α-Deracemization of Ketones Enabled by Photoredox Deprotonation and Enantioselective Protonation
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This study reports the catalytic deracemization of ketones bearing stereocenters in the α-position in a single reaction via deprotonation, followed by enantioselective protonation. The principle of microscopic reversibility, which has previously rendered this strategy elusive, is overcome by a photoredox deprotonation through single electron transfer and subsequent hydrogen atom transfer (HAT). Specifically, the irradiation of racemic pyridylketones in the presence of a single photocatalyst and a tertiary amine provides nonracemic carbonyl compounds with up to 97% enantiomeric excess. The photocatalyst harvests the visible light, induces the redox process, and is responsible for the asymmetric induction, while the amine serves as a single electron donor, HAT reagent, and proton source. This conceptually simple light-driven strategy of coupling a photoredox deprotonation with a stereocontrolled protonation, in conjunction with an enrichment process, serves as a blueprint for other deracemizations of ubiquitous carbonyl compounds.
- Chen, Shuming,Gao, Anthony Z.,Ivlev, Sergei I.,Meggers, Eric,Nie, Xin,Ye, Chen-Xi,Zhang, Chenhao
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supporting information
p. 13393 - 13400
(2021/09/03)
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- Intermediate for preparing S-flurbiprofen, preparation method and application thereof
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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.
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Paragraph 0123-0126
(2021/07/01)
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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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supporting information
p. 85 - 91
(2021/01/12)
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- Visible-light photoredox-catalyzed selective carboxylation of C(sp3)?F bonds with CO2
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It is highly attractive and challenging to utilize carbon dioxide (CO2), because of its inertness, as a nontoxic and sustainable C1 source in the synthesis of valuable compounds. Here, we report a novel selective carboxylation of C(sp3)?F bonds with CO2 via visible-light photoredox catalysis. A variety of mono-, di-, and trifluoroalkylarenes as well as α,α-difluorocarboxylic esters and amides undergo such reactions to give important aryl acetic acids and α-fluorocarboxylic acids, including several drugs and analogs, under mild conditions. Notably, mechanistic studies and DFT calculations demonstrate the dual role of CO2 as an electron carrier and electrophile during this transformation. The fluorinated substrates would undergo single-electron reduction by electron-rich CO2 radical anions, which are generated in situ from CO2 via sequential hydride-transfer reduction and hydrogen-atom-transfer processes. We anticipate our finding to be a starting point for more challenging CO2 utilization with inert substrates, including lignin and other biomass.
- Bo, Zhi-Yu,Chen, Lin,Gao, Tian-Yu,Jing, Ke,Lan, Yu,Liu, Shi-Han,Luo, Shu-Ping,Yan, Si-Shun,Yu, Bo,Yu, Da-Gang
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supporting information
p. 3099 - 3113
(2021/11/16)
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- Preparation method of flurbiprofen
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The invention relates to a preparation method of flurbiprofen, and belongs to the technical field of medicine synthesis. In order to solve the problems of poor safety and low yield of the existing route, the invention provides a preparation method of flurbiprofen. The method comprises the following steps: under the action of Lewis acid, carrying out acylation reaction on o-fluoroaniline or N-substituted o-fluoroaniline and 2-halogenated propionyl halide to obtain an intermediate compound as shown in formula II; under the action of a ketal catalyst, carrying out ketal reaction on the compound as shown in the formula II and a carbonyl protection reagent to obtain a ketal substance; in the presence of an acidic catalyst, carrying out a rearrangement reaction on the ketal to obtain a compoundas shown in a formula IV; under an acidic or alkaline condition, carrying out hydrolysis reaction to obtain a compound as shown in a formula V; under the action of a diazotization catalyst and a phasetransfer catalyst, mixing a compound as shown in a formula V, benzene and nitrite under an acid condition, carrying out diazotization reaction, and carrying out hydrolysis reaction after the diazotization reaction is finished, so as to obtain the corresponding product flurbiprofen as shown in a formula I. The method has the effects of high reaction safety and high yield.
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- Preparation method of flurbiprofen
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The invention discloses a preparation method of flurbiprofen. The method comprises the following steps: adding 2-(3-fluoro-4-bromophenyl)propionic acid and phenylboronic acid into a water-system solvent under alkaline conditions, and carrying out a palladium-carbon catalyzed coupling reaction to obtain flurbiprofen. The method has the advantages that operation is simpler, the prepared flurbiprofenis higher in purity, industrialized production is facilitated.
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- Synthesis of a TNF inhibitor, flurbiprofen and an: I -Pr analogue in enantioenriched forms by copper-catalyzed propargylic substitution with Grignard reagents
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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
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supporting information
p. 9906 - 9909
(2021/12/07)
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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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supporting information
p. 10913 - 10917
(2020/05/25)
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- Bidentate phosphine-phosphine oxide ligand and intermediate, preparation method and application thereof
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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.
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Paragraph 0431-0434; 0439-0442
(2020/11/10)
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- Cobalt-Catalyzed Asymmetric Hydrogenation of α,β-Unsaturated Carboxylic Acids by Homolytic H2 Cleavage
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The asymmetric hydrogenation of α,β-unsaturated carboxylic acids using readily prepared bis(phosphine) cobalt(0) 1,5-cyclooctadiene precatalysts is described. Di-, tri-, and tetra-substituted acrylic acid derivatives with various substitution patterns as well as dehydro-α-amino acid derivatives were hydrogenated with high yields and enantioselectivities, affording chiral carboxylic acids including Naproxen, (S)-Flurbiprofen, and a d-DOPA precursor. Turnover numbers of up to 200 were routinely obtained. Compatibility with common organic functional groups was observed with the reduced cobalt(0) precatalysts, and protic solvents such as methanol and isopropanol were identified as optimal. A series of bis(phosphine) cobalt(II) bis(pivalate) complexes, which bear structural similarity to state-of-the-art ruthenium(II) catalysts, were synthesized, characterized, and proved catalytically competent. X-band EPR experiments revealed bis(phosphine)cobalt(II) bis(carboxylate)s were generated in catalytic reactions and were identified as catalyst resting states. Isolation and characterization of a cobalt(II)-substrate complex from a stoichiometric reaction suggests that alkene insertion into the cobalt hydride occurred in the presence of free carboxylic acid, producing the same alkane enantiomer as that from the catalytic reaction. Deuterium labeling studies established homolytic H2 (or D2) activation by Co(0) and cis addition of H2 (or D2) across alkene double bonds, reminiscent of rhodium(I) catalysts but distinct from ruthenium(II) and nickel(II) carboxylates that operate by heterolytic H2 cleavage pathways.
- Chirik, Paul J.,Shevlin, Michael,Zhong, Hongyu
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- Deoxygenative α-alkylation and α-arylation of 1,2-dicarbonyls
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Construction of C-C bonds at the α-carbon is a challenging but synthetically indispensable approach to α-branched carbonyl motifs that are widely represented among drugs, natural products, and synthetic intermediates. Here, we describe a simple approach to generation of boron enolates in the absence of strong bases that allows for introduction of both α-alkyl and α-aryl groups in a reaction of readily accessible 1,2-dicarbonyls and organoboranes. Obviation of unselective, strongly basic and nucleophilic reagents permits carrying out the reaction in the presence of electrophiles that intercept the intermediate boron enolates, resulting in two new α-C-C bonds in a tricomponent process. This journal is
- Arman, Hadi D.,Dang, Hang T.,Haug, Graham C.,Jin, Shengfei,Larionov, Oleg V.,Nguyen, Viet D.
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p. 9101 - 9108
(2020/09/17)
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- Exploration of New Biomass-Derived Solvents: Application to Carboxylation Reactions
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A range of hitherto unexplored biomass-derived chemicals have been evaluated as new sustainable solvents for a large variety of CO2-based carboxylation reactions. Known biomass-derived solvents (biosolvents) are also included in the study and the results are compared with commonly used solvents for the reactions. Biosolvents can be efficiently applied in a variety of carboxylation reactions, such as Cu-catalyzed carboxylation of organoboranes and organoboronates, metal-catalyzed hydrocarboxylation, borocarboxylation, and other related reactions. For many of these reactions, the use of biosolvents provides comparable or better yields than the commonly used solvents. The best biosolvents identified are the so far unexplored candidates isosorbide dimethyl ether, acetaldehyde diethyl acetal, rose oxide, and eucalyptol, alongside the known biosolvent 2-methyltetrahydrofuran. This strategy was used for the synthesis of the commercial drugs Fenoprofen and Flurbiprofen.
- Gevorgyan, Ashot,Hopmann, Kathrin H.,Bayer, Annette
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p. 2080 - 2088
(2020/02/20)
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- Preparation of optically pure flurbiprofen via an integrated chemo-enzymatic synthesis pathway
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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
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p. 135 - 142
(2019/02/14)
-
- 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
-
supporting information
p. 1128 - 1131
(2019/01/28)
-
- Enantioselective Palladium-Catalyzed Cross-Coupling of α-Bromo Carboxamides and Aryl Boronic Acids
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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)
-
- 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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- Nickel nanoparticle-catalyzed carboxylation of unsaturated hydrocarbon with CO2 using sulfur-modified Au-supported nickel material
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A hydrocarboxylation reaction of alkyne or styrene derivatives with CO2 proceeded smoothly by using an air-stable nano-sized nickel catalyst supported on sulfur-modified gold (SANi), giving functionalized acrylic acids and phenylpropionic acids including an anti-inflammatory drug, Flurbiprofen. Notably, SANi could be recycled several times without a significant decrease of the yield.
- Taniguchi, Takahisa,Saito, Nozomi,Doi, Ryohei,Kimoto, Arato,Hoshiya, Naoyuki,Fujiki, Katsumasa,Shuto, Satoshi,Fujioka, Hiromichi,Arisawa, Mitsuhiro,Sato, Yoshihiro
-
supporting information
p. 1406 - 1409
(2019/11/05)
-
- LiCl-Accelerated multimetallic cross-coupling of aryl chlorides with aryl triflates
-
While the synthesis of biaryls has advanced rapidly in the past decades, cross-Ullman couplings of aryl chlorides, the most abundant aryl electrophiles, have remained elusive. Reported here is the first general cross-Ullman coupling of aryl chlorides with aryl triflates. The selectivity challenge associated with coupling an inert electrophile with a reactive one is overcome using a multimetallic strategy with the appropriate choice of additive. Studies demonstrate that LiCl is essential for effective cross-coupling by accelerating the reduction of Ni(II) to Ni(0) and counteracting autoinhibition of reduction at Zn(0) by Zn(II) salts. The modified conditions tolerate a variety of functional groups on either coupling partner (42 examples), and examples include a three-step synthesis of flurbiprofen.
- Huang, Liangbin,Ackerman, Laura K. G.,Kang, Kai,Parsons, Astrid M.,Weix, Daniel J.
-
supporting information
p. 10978 - 10983
(2019/08/07)
-
- Palladium-Catalyzed α-Arylation of Carboxylic Acids and Secondary Amides via a Traceless Protecting Strategy
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A novel traceless protecting strategy is presented for the long-standing challenge of conducting the palladium-catalyzed α-arylation of carboxylic aids and secondary amides with aryl halides. Both of the presented coupling processes occur with a variety of carboxylic acids and amides and with a variety of aryl bromides containing a broad range of functional groups, including base-sensitive functionality like acyl, alkoxycarbonyl, nitro, cyano, and even hydroxyl groups. Five commercial drugs were prepared through this method in one step in 81-96% yield. Gram-scale synthesis of medication Naproxen and Flurbiprofen with low palladium loading further highlights the practical value of this method.
- He, Zhi-Tao,Hartwig, John F.
-
supporting information
p. 11749 - 11753
(2019/08/26)
-
- Photocarboxylation of Benzylic C-H Bonds
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The carboxylation of sp3-hybridized C-H bonds with CO2 is a challenging transformation. Herein, we report a visible-light-mediated carboxylation of benzylic C-H bonds with CO2 into 2-arylpropionic acids under metal-free conditions. Photo-oxidized triisopropylsilanethiol was used as the hydrogen atom transfer catalyst to afford a benzylic radical that accepts an electron from the reduced form of 2,3,4,6-tetra(9H-carbazol-9-yl)-5-(1-phenylethyl)benzonitrile generated in situ. The resulting benzylic carbanion reacts with CO2 to generate the corresponding carboxylic acid after protonation. The reaction proceeded without the addition of any sacrificial electron donor, electron acceptor or stoichiometric additives. Moderate to good yields of the desired products were obtained in a broad substrate scope. Several drugs were successfully synthesized using the novel strategy.
- Meng, Qing-Yuan,Schirmer, Tobias E.,Berger, Anna Lucia,Donabauer, Karsten,K?nig, Burkhard
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p. 11393 - 11397
(2019/08/20)
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- CpRhIII-Catalyzed Allyl-Aryl Coupling of Olefins and Arylboron Reagents Enabled by C(sp3)-H Activation
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Herein, we present a mild CpRhIII-catalyzed Suzuki-Miyaura-type allyl-aryl coupling of readily accessible arylboron reagents with a broad range of olefins. Allylic arylation was achieved without the need for prefunctionalized alkenes, and the general Heck-type reactivity between olefins and arenes was not observed. Mechanistic studies indicate that the reaction was enabled through the fast generation of a RhIII-allyl species via undirected C(sp3)-H activation. Moreover, the developed protocol was applied to the highly concise synthesis of the anti-inflammatory drug flurbiprofen.
- Knecht, Tobias,Pinkert, Tobias,Dalton, Toryn,Lerchen, Andreas,Glorius, Frank
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p. 1253 - 1257
(2019/01/21)
-
- 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.
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p. 1067 - 1078
(2018/08/01)
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- Selective α-Monomethylation by an Amine-Borane/N,N-Dimethylformamide System as the Methyl Source
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A new and practical α-monomethylation strategy using an amine-borane/N,N-dimethylformamide (R3N-BH3/DMF) system as the methyl source was developed. This protocol has been found to be effective in the α-monomethylation of arylacetonitriles and arylacetamides. Mechanistic studies revealed that the formyl group of DMF delivered the carbon and one hydrogen atoms of the methyl group, and R3N-BH3 donated the remaining two hydrogen atoms. Such a unique reaction pathway enabled controllable assemblies of CDH2-, CD2H-, and CD3- units using Me2NH-BH3/d7-DMF, Me3N-BD3/DMF and Me3N-BD3/d7-DMF systems, respectively. Further application of this method to the facile synthesis of anti-inflammatory flurbiprofen and its varied deuterium-labeled derivatives was demonstrated.
- Xia, Hui-Min,Zhang, Feng-Lian,Ye, Tian,Wang, Yi-Feng
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p. 11770 - 11775
(2018/09/10)
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- Preparation method of flurbiprofen and preparation method of flurbiprofen axetil
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The invention relates to the field of pharmaceutical chemical synthesis, in particular to a preparation method of flurbiprofen and a preparation method of flurbiprofen axetil. The preparation method of the flurbiprofen comprises the steps of carrying out a Grignard reaction by using 4-bromine-2-fluorine biphenyl as a raw material, carrying out a coupling reaction, and acidizing to obtain the flurbiprofen; the yield is 90%, and the purity is 99.5%; then, the flurbiprofen axetil is prepared by using the flurbiprofen, obtained by the method, as a raw material, the yield reaches up to 90%, and thepurity reaches up to 99.5%. The preparation methods are high in quality controllability and industrial reproducibility.
- -
-
Paragraph 0007; 0029; 0030-0032; 0044
(2018/10/19)
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- METHOD FOR PRODUCING OPTICALLY ACTIVE 2-(2-FLUOROBIPHENYL-4-YL) PROPANOIC ACID
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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 0384-0386
(2018/10/21)
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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.
-
supporting information
p. 509 - 512
(2017/01/13)
-
- Enantioselective potential of polysaccharide-based chiral stationary phases in supercritical fluid chromatography
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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
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supporting information
p. 239 - 246
(2017/05/29)
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- A preparing method of flurbiprofen
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A preparing method of flurbiprofen is disclosed and belongs to the technical field of medicine preparation. A Suzuki coupling reaction is adopted. 2-(3-fluoro-4-chloro-phenyl)-propionic acid and a phenylboronic acid reagent are subjected to the palladium catalyzed Suzuki coupling reaction in an organic solvent under existence of an alkali to obtain the flurbiprofen, wherein the mole ratio of the 2-(3-fluoro-4-chloro-phenyl)-propionic acid to the phenylboronic acid reagent is 1:(0.9-1.1). The method is simple. The prepared flurbiprofen is high in yield and high in purity.
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-
Paragraph 0037; 0038; 0039; 0062; 0063; 0064
(2017/08/28)
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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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-
-
- Flurbiprofen synthesis method
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The invention relates to a flurbiprofen synthesis method and belongs to the technical field of pharmaceutical synthesis. According to the flurbiprofen synthesis method, Suzuki coupling reaction is utilized, the flurbiprofen can be obtained from 2-(3-fluoro-4-bromophenyl) propionic acid and phenyl boron reagent in organic solvent in the alkali condition through palladium catalytic Suzuki coupling reaction; the mole ratio between the 2-(3-fluoro-4-bromophenyl) propionic acid and the phenyl boron reagent is 1: (0.9 to 1.1). The synthesis method is simple, and the obtained flurbiprofen is high in yield and high in purity.
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Paragraph 0049-0052; 0061-0064; 0073-0076; 0085-0088
(2017/08/28)
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- Photochemically Controlled Drug Dosing from a Polymeric Scaffold
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Purpose: To develop the first photoactive biomaterial coating capable of controlled drug dosing via inclusion of synthesised drug-3,5-dimethoxybenzoin (DMB) conjugates in a poly(2-methyoxyethyl acrylate) (pMEA) scaffold. Methods: Flurbiprofen- and naproxen-DMB conjugates were prepared via esterification and characterised via NMR spectroscopy and mass spectrometry following chromatographic purification. Conjugate photolysis was investigated in acetonitrile solution and within the pMEA matrix following exposure to low-power 365?nm irradiation. Photo-liberation of drug from pMEA into phosphate buffered saline was monitored using UV-vis spectroscopy. Results: The synthetic procedures yielded the desired drug conjugates with full supporting characterisation. Drug regeneration through photolysis of the synthesised conjugates was successful in both acetonitrile solution and within the pMEA scaffold upon UV irradiation. Conjugates were retained within the pMEA scaffold with exclusive drug liberation following irradiation and increased drug dose with increasing exposure. Multi-dosing capacity was demonstrated though the ability of successive irradiation periods to generate further bursts of drug. Conclusion: This study demonstrates the first application of photochemically controlled drug release from a biomaterial coating and the feasibility of using pMEA as a scaffold for housing the photoactive drug-DMB conjugates.
- Donnelly, Louise,Hardy, John G.,Gorman, Sean P.,Jones, David S.,Irwin, Nicola J.,McCoy, Colin P.
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p. 1469 - 1476
(2017/06/05)
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- C(sp2)-H Borylation of Fluorinated Arenes Using an Air-Stable Cobalt Precatalyst: Electronically Enhanced Site Selectivity Enables Synthetic Opportunities
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Cobalt catalysts with electronically enhanced site selectivity have been developed, as evidenced by the high ortho-to-fluorine selectivity observed in the C(sp2)-H borylation of fluorinated arenes. Both the air-sensitive cobalt(III) dihydride boryl 4-Me-(iPrPNP)Co(H)2BPin (1) and the air-stable cobalt(II) bis(pivalate) 4-Me-(iPrPNP)Co(O2CtBu)2 (2) compounds were effective and exhibited broad functional group tolerance across a wide range of fluoroarenes containing electronically diverse functional groups, regardless of the substitution pattern on the arene. The electronically enhanced ortho-to-fluorine selectivity observed with the cobalt catalysts was maintained in the presence of a benzylic dimethylamine and hydrosilanes, overriding the established directing-group effects observed with precious-metal catalysts. The synthetically useful selectivity observed with cobalt was applied to an efficient synthesis of the anti-inflammatory drug flurbiprofen.
- Obligacion, Jennifer V.,Bezdek, Máté J.,Chirik, Paul J.
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p. 2825 - 2832
(2017/03/08)
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- Arylmalonate Decarboxylase-Catalyzed Asymmetric Synthesis of Both Enantiomers of Optically Pure Flurbiprofen
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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
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p. 916 - 921
(2016/03/15)
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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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- Method for preparing S-(+)-flurbiprofen axetil high in optical purity
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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%.
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Paragraph 0033
(2017/03/25)
-
- Preparation method of 2-(2--fluoro-4-biphenylyl) propionic acid
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The invention discloses a preparation method of 2-(2--fluoro-4-biphenylyl) propionic acid, and belongs to the technical fields of chemical synthesis and medicines. A zinc reagent is prepared from trimethyl-chlorosilane as a zinc powder activating agent; with 4-bromo-2-fluoro biphenyl as a raw material, 2-(2-fluoro-4-biphenyl) ethyl propionate is obtained by reaction under the action of the zinc reagent and a catalyst-ligand; and the 2-(2-fluoro-4-biphenylyl) propionic acid is obtained through hydrolysis. The method is simple in process, simple and convenient to operate and short in reaction time; the product is high in yield, few in impurity, simple in post-treatment, high in equipment utilization rate and suitable for large-scale industrial production and application. Particularly, by a metal nickel-ligand catalyst system, the catalyst is high in activity and low in dosage; and the yield of the product can be effectively improved.
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Paragraph 0034; 0068; 0069
(2016/11/02)
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- Potent multitarget FAAH-COX inhibitors: Design and structure-activity relationship studies
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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
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p. 216 - 237
(2016/01/16)
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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 0024
(2016/11/28)
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