Reusable Glucose-Based Crown Ethers Anchored to PVC.

The recovery and reuse of the enantioselective catalysts produced by tedious work are important not only from the perspective of green chemistry, but also from the point of view of productivity. Some of the carbohydrate-based crown ethers prepared in our research group were able to generate significant asymmetric induction in certain cases. However, they were not recoverable after the synthesis. Therefore, we modified the most effective structure with a propargyl group so that it can be attached to a polymer with an azide-alkyne reaction. It was investigated whether the position of the bonding affects the activity of the crown ethers, hence, the propargyl group was introduced either to the side chain, to the anomeric center or to the benzylidene protecting group. To anchor the macrocycles, low molecular weight PVC was modified with azide groups in 4% and 10%, respectively. It was found that glucose-based crown ether bearing the propargyl group on the benzylidene unit and grafted to PVC in 4% has the highest activity regarding the enantioselectivity (77% ee). The catalyst was recoverable in the Michael addition of diethyl acetamidomalonate to nitrostyrene and it could be reused five times without the loss of enantioselectivity.

Synthesis of Novel Crown Ether-Squaramides and Their Application as Phase-Transfer Catalysts.

This work presents the synthesis of six new phase-transfer organocatalysts in which the squaramide unit is directly linked to the nitrogen atom of an aza-crown ether. Four chiral skeletons, namely hydroquinine, quinine, cinchonine (cinchonas), and α-d-glucopyranoside were responsible for the asymmetric construction of an all-carbon quaternary stereogenic center in α-alkylation and Michael addition reactions of malonic esters. We investigated the effects of these different chiral units and that of crown ethers with different sizes on catalytic activity and enantioselectivity. During extensive parameter investigations, both conventional and emerging green solvents were screened, providing valuable α,α-disubstituted malonic ester derivatives with excellent yields (up to 98%).

Synthesis of Methyl 4,6-Di-O-ethyl-α-d-glucopyranoside-Based Azacrown Ethers and Their Effects in Asymmetric Reactions.

Carbohydrate-based crown ethers have been reported to be able to generate asymmetric induction in certain reactions. Previously, it was proved that the monosaccharide unit, the anomeric substituent, and the sidearm could influence the catalytic activity of the monoaza-15-crown-5 macrocycles derived from sugars. In order to gain information about the effect of the flexibility, 4,6-di-O-ethyl-glucoside-based crown compounds were synthesized, and their efficiency was compared to the 4,6-O-benzylidene analogues. It was found that the absence of the two-ring annulation has a negative effect on the enantioselectivity in liquid-liquid two-phase reactions: in the Darzens condensation of 2-chloroacetophenone and in the epoxidation of chalcone. The same trend was observed in the solid-liquid phase Michael addition of diethyl acetamidomalonate. Surprisingly, in the solid-liquid phase cyclopropanation of benzylidenemalononitrile, one of the new catalysts was highly enantioselective (99% ee).

Synthesis of xylal- and arabinal-based crown ethers and their application as asymmetric phase transfer catalysts.

New xylal- and arabinal-based monoaza-15-crown-5 ethers were synthesized starting from l- and d-xylose, and l- and d-arabinose, respectively. These monosaccharide-based chiral macrocycles were tested as phase transfer catalysts in a few asymmetric reactions. The xylal-based crown compounds proved to be efficient catalysts in a few liquid-liquid phase reactions. The epoxidation of trans-chalcone and the Darzens condensation of α-chloroacetophenone with benzaldehyde took place with complete diastereoselectivity and up to 77% ee and 58% ee, respectively. It was found that the substituents in the aromatic ring of the chalcone and the α-chloroacetophenone had an influence on the enantioselectivity. The highest ee values were obtained in the epoxidation of 4-chlorochalcone (81% ee) and in the reaction of a 2-naphthyl analogue (96% ee), while in the Darzens condensation of 4-phenyl-α-chloroacetophenone with benzaldehyde, a maximum ee of 91% was detected. The configuration of the monosaccharide unit in the crown ring influenced the absolute configuration of the epoxyketones synthesized.

Electrospun amorphous solid dispersions of meloxicam: Influence of polymer type and downstream processing to orodispersible dosage forms.

The objectives of this work were to develop meloxicam based amorphous solid dispersion through electrospinning technique and evaluate the effect of the polymeric matrix on the physicochemical properties of the fibers and the downstream processing ability to orodispersible dosage forms. Drug - polymer interactions formed between Eudragit E and meloxicam, confirmed through Raman and 1HNMR spectra, enabled the development of fibers from ethanol, thus allowing an increased production rate compared to PVPk30 where a DMF:THF solvent system was suitable. Microflux dissolution-permeation studies showed a significantly higher diffusion from amorphous solid dispersions compared to crystalline meloxicam. The flux through the membrane was influenced by the polymers only under basic conditions, where the precipitation of Eudragit E limited the complete resolubilization of the active ingredient. This phenomenon was not observed during large volume conventional dissolution testing. The effect of formulation on long term stability could not be highlighted as all products were stable up to 15 months, stored in closed holders at 25 °C ±â€¯2 °C and 50%RH ±â€¯10%. The increased surface area of fibers enabled tablet preparation with low pressures due to favorable bonding between particles during compression. PVPk30 formulation presented higher tabletability and compactability, as higher tensile strength compacts could be prepared. Eudragit E formulation had lower detachment and ejection stress, suggesting a lower sticking tendency during tableting. The presence of HPßCD in PVPk30 formulation offered improved morphological features of the fibers, however no significant effect was observed on dissolution, permeation or mechanical properties. Downstream processing was guided by polymer mechanical properties and solubility, thus PVPk30 fibers could be delivered in the form of orodispersible webs and conventional tablets, whereas Eudragit E fibers as orodispersible tablets.

Data fusion strategies for performance improvement of a Process Analytical Technology platform consisting of four instruments: An electrospinning case study.

The aim of this work was to develop a PAT platform consisting of four complementary instruments for the characterization of electrospun amorphous solid dispersions with meloxicam. The investigated methods, namely NIR spectroscopy, Raman spectroscopy, Colorimetry and Image analysis were tested and compared considering the ability to quantify the active pharmaceutical ingredient and to detect production errors reflected in inhomogeneous deposition of fibers. Based on individual performance the calculated RMSEP values ranged between 0.654% and 2.292%. Mid-level data fusion consisting of data compression through latent variables and application of ANN for regression purposes proved efficient, yielding an RMSEP value of 0.153%. Under these conditions the model could be validated accordingly on the full calibration range. The complementarity of the PAT tools, demonstrated from the perspective of captured variability and outlier detection ability, contributed to model performance enhancement through data fusion. To the best of the author's knowledge, this is the first application of data fusion in the field of PAT for efficient handling of big-analytical-data provided by high-throughput instruments.

Synthesis of d-mannitol-based crown ethers and their application as catalyst in asymmetric phase transfer reactions.

A few new d-mannitol-based monoaza-15-crown-5 type chiral lariat ethers and 18-crown-6 type macrocycles were synthesized. These crown compounds were used as phase transfer catalysts in asymmetric Michael addititons and in a Darzens condensation under mild conditions to afford the corresponding products in a few cases in good to excellent enantioselectivities. In the Michael addition of diethyl acetoxymalonate to trans-chalcone, in the addition of diethyl acetamidomalonate to ß-nitrostyrene, in the reaction of diethyl bromomalonate with benzylidene malononitriles, in the cyclopropanation reaction of diethyl bromomalonate and 2-benzylidene-1,3-indandione, and in the Darzens condensation of α-chloroacetophenone with benzaldehyde, maximum enantioselectivities of 39%, 65%, 99%, 56%, and 62%, respectively, were obtained in the presence of the d-mannitol-based macrocycles as the catalysts.

Synthesis of l-threitol-based crown ethers and their application as enantioselective phase transfer catalyst in Michael additions.

A few new l-threitol-based lariat ethers incorporating a monoaza-15-crown-5 unit were synthesized starting from diethyl l-tartrate. These macrocycles were used as phase transfer catalysts in asymmetric Michael addition reactions under mild conditions to afford the adducts in a few cases in good to excellent enantioselectivities. The addition of 2-nitropropane to trans-chalcone, and the reaction of diethyl acetamidomalonate with ß-nitrostyrene resulted in the chiral Michael adducts in good enantioselectivities (90% and 95%, respectively). The substituents of chalcone had a significant impact on the yield and enantioselectivity in the reaction of diethyl acetoxymalonate. The highest enantiomeric excess (ee) values (99% ee) were measured in the case of 4-chloro- and 4-methoxychalcone. The phase transfer catalyzed cyclopropanation reaction of chalcone and benzylidene-malononitriles using diethyl bromomalonate as the nucleophile (MIRC reaction) was also developed. The corresponding chiral cyclopropane diesters were obtained in moderate to good (up to 99%) enantioselectivities in the presence of the threitol-based crown ethers.

Crystal structure of diethyl 3-(3-chloro-phen-yl)-2,2-di-cyano-cyclo-propane-1,1-di-carboxyl-ate.

In the racemic title compound, C17H15ClN2O4, which has been synthesized and the crystal structure of the solvent-free mol-ecule determined, the angle between the planes of the benzene and cyclo-propane rings is 54.29 (10)°. The mol-ecular conformation is stabilized by two weak intra-molecular C-H⋯Ocarbox-yl inter-actions. In the crystal, C-H⋯O hydrogen bonds form centrosymmetric cyclic R 2 (2)(10) dimers which are linked into chain substructures extending along c. Further C-H⋯Nnitrile hydrogen bonding, including a centrosymmetric cyclic R 2 (2)(14) association, link the chain substructures, forming a two-dimensional layered structure extending across the approximate ab plane. No significant π-π or halogen-halogen inter-molecular inter-actions are present in the crystal.

Crystal structure of diethyl 2-acet-oxy-2-[3-(4-nitro-phen-yl)-3-oxo-1-phenyl-prop-yl]malonate.

In the racemic title compound, C24H25NO9, the dihedral angle between the planes of the two benzene-ring systems is 80.16 (6)°, while the side-chain conformation is stabilized by a methyl-ene-carboxyl C-H⋯O hydrogen bond. Weak inter-molecular C-H⋯O hydrogen bonds form inversion dimers [graph set R 2 (2)(16)] which are linked into chains extending along a. Further C-H⋯O hydrogen bonding extends the structure along b through cyclic R 2 (2)(10) motifs. Although no π-π aromatic ring inter-actions are present in the structure, C-H⋯π ring inter-actions across c generate an overall three-dimensional supra-molecular structure.

Synthesis of ribo-hexopyranoside- and altrose-based azacrown ethers and their application in an asymmetric Michael addition.

The synthesis of four new ribo-hexopyranoside-based chiral lariat ethers of monoaza-15-crown-5 type and two altropyranoside-based crown ethers were elaborated. Our syntheses utilized the regioselective ring opening of the oxiran moiety of the 2,3-anhydro sugars by nucleophilic reagents to afford the key intermediates. The reaction of methyl-2,3-anhydro-4,6-O-benzylidene-α-D-mannopyranoside with ethanolamine is especially of interest to afford a 3-substituted altropyranoside. One of the ribo-hexopyranoside-based lariat ethers with a 4-methoxyphenyl substituent induced an enantioselectivity of 80% when used as catalyst in the Michael addition of diethyl acetamidomalonate to trans-ß-nitrostyrene under phase transfer catalytic conditions.