Cleanability of Surfaces from Active Pharmaceutical Ingredient Surrogate Riboflavin by Falling Film

Falling films in wash down process are of major interest for pharmaceutical isolators, which are used for processing of highly potent pharmaceutical products. In this study multiple process parameters were examined with common materials of isolator systems. The importance of material and surface finish in respect of cleanability and complete wetting as well as a combination of process parameters are presented and discussed. For cleaning validation an effect of high interest was discovered: swab sampling areas changed their properties over many repeated cycles and showed decreased cleanability.     

Low‐Temperature Chemical Synthesis of High‐Purity Diacylglycerols (DAG) from Monoacylglycerols (MAG)

A chemical method was developed for low‐temperature synthesis of DAG from MAG followed by an easy purification procedure in order to obtain high‐purity DAG. Solvent‐assisted and solvent‐free reaction conditions were used, combined with different catalysts (sodium methoxide, p‐toluenesulfonic acid, methanesulfonic acid, and sulfuric acid). All reactions were performed at 35 and 70 °C. By increasing both acidity and polarity of the catalyst the equilibrium shifts towards the formation of DAG. When using sulfuric acid in solvent‐assisted condition at 70 °C, 88 % conversion was obtained after 20 min of reaction (77 % w/w DAG in the reaction mixture after evaporation of the solvent). After purifying by means of column chromatography, 96 % pure DAG were obtained. The overall yield of DAG was 81 %.     

Microwave Setup Design for Continuous Fine‐Chemicals Synthesis

A feasibility study in state‐of‐the‐art multi‐ and monomode microwave cavities was conducted to outline important functionalities necessary in a microwave setup for continuous fine‐chemicals synthesis. For multimode operation, the heating efficiency depends on the position as well as on the volume distribution of the load. For monomode operation, the heating efficiency does not depend on the axial position and has a maximum with respect to the load diameter. Based on this study, a microwave setup consisting of four cavities was designed and constructed. The setup provided a defined microwave field pattern and allowed focusing of the microwave power. A near‐uniform distribution of microwave energy in all four cavities of the setup was achieved at reduced grid to applicator losses.     

A Highly Active 4‐Siloxyproline Catalyst for Asymmetric Synthesis

trans‐4‐tert‐Butyldimethylsiloxy‐L ‐proline displays a greater catalytic activity than the parent proline without compromising the enantioselectivity, which widens the substrate scope in the α‐aminoxylation of carbonyl compounds, as well as O‐nitroso‐aldol/Michael, and Mannich reactions.     

Microwave‐Assisted Synthesis of Magnetic Hydroxyapatite for Removal of Heavy Metals from Groundwater

A simple, fast, and economic methodology to fabricate a highly efficient superparamagnetic Fe₃O₄/hydroxyapatite nanocomposite (MHAP) was successfully developed. Hydroxyapatite was functionalized with magnetite nanoparticles through coprecipitation‐assisted microwave processes to improve the magnetic properties. The synthesized magnetic hybrid adsorbent matrix was investigated by different methods. Transmission electron microscopy demonstrated a good impregnation of Fe₃O₄ on the hydroxyapatite matrix with uniform morphology. Magnetic hysteresis measurement revealed that MHAP nanocomposites exhibit excellent strong, soft‐magnetic properties. The synergistic effect was an evidence for iron and manganese ion removal, enlightening their potentialities in treatment of polluted ground water.     

Sulfur‐Assisted and 1,8‐Diazabicyclo[5.4.0]undec‐7‐ene (DBU)‐Catalyzed Cyclization of 2‐Alkynylanilines for the Metal‐Free Synthesis of Indole Derivatives

A sulfur‐assisted and 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU)‐catalyzed cyclization of 2‐alkynylanilines for the metal‐free synthesis of indole derivatives is reported. As a result of the metal‐free process, the ready availability of the starting materials and the simple and convenient operation, the type of reaction presented here has potential utility in organic synthesis. A 10‐gram scale preparation may demonstrate the possibility of its application in the environmentally friendly synthesis of indole derivatives.     

Potassium tert‐Butoxide‐Promoted Synthesis of 1‐Aminoisoquinolines from 2‐Methylbenzonitriles and Benzonitriles under Catalyst‐Free Conditions

Herein a practical and efficient protocol for preparing a range of aminoisoquinolines is reported. Various aminoisoquinolines were prepared in moderate to good yields from the corresponding 2‐methylbenzonitriles and benzonitriles upon treatment with potassium tert‐butoxide.

     

Synthesis of Tung‐Oil‐Based Reactive Diluents

Three new reactive diluents were prepared from tung oil using a Diels‐Alder reaction. The dienophiles were methacryloxypropyl trimethoxysilane (MAS), 2,2,2‐trifluoroethyl methacrylate (TFM) and triallyl ether acrylate (TAEA). The chemical structures were evaluated using ¹H NMR, ¹³C NMR, FT‐IR, GPC and MALDI‐TOF‐MS. Spectra evidence (NMR, MS) indicated that a six‐member ring were formed in all three reactions indicating a Diels‐Alder adduct. The reactive diluents were formulated with a soya‐based alkyd to evaluate viscosity reduction and drying time. The viscosity of alkyd was reduced up to 70% using the reactive diluents. The drying time for the autoxidative reactive diluents with alkyds were 1.8‐1‐7 times faster than alkyd alone.

     

Efficient and Selective Synthesis of E‐Vinylamines via Tungsten(0)‐Catalyzed Hydroamination of Terminal Alkynes

The hydroamination of terminal alkynes (RCCH=phenylacetylene, 4‐methylphenylacetylene, 4‐fluorophenylacetylene, 1‐hexyne, methyl 2‐propynyl ether, prop‐2‐yn‐1‐ol) with secondary amines (piperidine, pyrrolidine, morpholine, piperazine, methylpiperazine, 4‐methylpiperidine and 3‐methylpiperidine) was achieved in high yield (up to 99%), regioselectivity (only anti‐Markovnikov product) and stereoselectivity (only E‐isomers) within a maximum of 5 h in reactions catalyzed by the tungsten tetracarbonyl complex cis‐[W(CO)₄(piperidine)₂] at 90 °C without any additional solvent.

     

Peptide Bioconjugates of Electron‐Poor Metallocenes: Synthesis,Characterization, and Anti‐Proliferative Activity

We report the synthesis of metallocene compounds Cp₂M with two different electron‐withdrawing substituents on both cyclopentadienyl rings (hexafluoroacetone (HFA) and chlorobenzoyl ( 1 – 5 ); HFA and COOH ( 6 and 7 ), M=Fe or Ru). The COOH‐containing derivatives were used to synthesize peptide bioconjugates with enkephalin ( 8 and 9 ) and neurotensin ( 10 and 11 ) as well as fluorescein‐labeled neurotensin ( 12 ). All the molecules were fully characterized, including X‐ray structures for 6 and 7 . The physicochemical properties (lipophilicity and electrochemistry) and cytotoxicity on MCF‐7, HT‐29, and PT‐45 cancer cells were evaluated for selected compounds. Electrochemical investigation by cyclic voltammetry revealed that all bis‐substituted metallocenes are up to 300 mV harder to oxidize compared to the monosubstituted 2‐ferrocenylhexafluoropropan‐2‐ol (FcHFA: Δ${E{{{\rm f}\hfill \atop 0\hfill}}}$ =214 mV; disubstituted derivatives: up to Δ${E{{{\rm f}\hfill \atop 0\hfill}}}$ =512 mV; both vs. FcH^0/+). For the bis‐substituted compounds, log P determinations by RP‐HPLC showed increased lipophilicity in comparison to the monosubstituted FcHFA and RcHFA. Cellular uptake was investigated by fluorescence microcopy, and this revealed endosomal entrapment for 12 .     

Fast synthesis of 1,3‐DAG by Lecitase® Ultra‐catalyzed esterification in solvent‐free system

Lecitase® Ultra, a phospholipase, was explored as an effective biocatalyst for direct esterification of glycerol with oleic acid to produce 1,3‐DAG. Experiments were carried out in batch mode, and optimal reaction conditions were evaluated. In comparison with several organic solvent mediums, the solvent‐free system was found to be more beneficial for this esterification reaction, which was further studied to investigate the reaction conditions including oleic acid/glycerol mole ratio, temperature, initial water content, enzyme load, and operating time. The results showed that Lecitase® Ultra catalyzed a fast synthesis of 1,3‐DAG by direct esterification in a solvent‐free medium. Under the optimal reaction conditions, a short reaction time 1.5 h was found to achieve the fatty acid esterification efficiency of 80.3 ± 1.2% and 1,3‐DAG content of 54.8 ± 1.6 wt% (lipid layer of reaction mixture mass). The reusability of Lecitase® Ultra was evaluated via recycling the excess glycerol layer in the reaction system. DAG in the upper lipid layer of reaction mixture was purified by molecular distillation and the 1,3‐DAG‐enriched oil with a purity of about 75 wt% was obtained. Practical applications: The new Lecitase® Ultra catalyzed process for production of 1,3‐DAG from glycerol and oleic acid described in this study provides several advantages over conventional methods including short reaction time, the absence of a solvents and a high product yield.     

Synthesis of Fatty Acetoacetates Under Microwave Irradiation Catalysed by Sulfamic Acid in a Solvent-Free System

The 1,3‐dicarbonyl compounds are important building blocks to obtain products with various biological activities and technological applications. In this work, we used a simple transesterification method to develop fatty acetoacetates in a solvent‐free medium using a green catalyst, sulfamic acid (NH₂SO₃H), under microwave irradiation. The experimental results demonstrate good yields in a short reaction time (13 min), which makes this method an efficient approach to synthesize fatty acetoacetates from a wide range of saturated, unsaturated, and polyunsaturated long chain fatty alcohols, and ricinoleic derivatives. Experiments of recycling of the catalyst were performed and no decrease in catalytic activity of sulfamic acid was observed.     

Solvent‐Free Non‐Covalent Organocatalysis: Enantioselective Addition of Nitroalkanes to Alkylideneindolenines as a Flexible Gateway to Optically Active Tryptamine Derivatives

A catalytic asymmetric addition of nitroalkanes to alkylideneindolenines, generated in situ from arylsulfonylindoles, is presented. Despite the weakness of the non‐covalent H‐bond interactions between catalyst and substrates, the performance of the bifunctional organocatalyst used was found to be essentially unaffected by the polarity of the reaction medium. Nitroalkanes, mostly used in nearly stoichiometric amounts, could thus function both as solvents and reagents, resulting in a truly solvent‐free reaction. The broad substrate scope shown by the present transformation allowed the preparation of some optically active tryptamine precursors that are not accessible through the previous catalytic asymmetric methods.     

Catalytic Asymmetric Inverse‐Electron‐Demand (IED) [4+2] Cycloaddition of Salicylaldimines: Preparation of Optically Active 4‐Aminobenzopyran Derivatives

The catalytic asymmetric inverse‐electron‐demand (IED) [4+2] cycloaddition of various salicylaldehyde‐derived N‐arylimines with electron‐rich alkenes in the presence of chiral BINOL‐derived phosphoric acid catalysts has been studied with the aim of obtaining optically active 4‐aminobenzopyran derivatives. Dienophiles such as 2,3‐dihydro‐2H‐furan, benzyl N‐vinylcarbamate and 2‐vinylindole have been employed.     

Microwave‐Assisted Facile Synthesis of Furo[3,2‐b]indole Derivatives via Silver(I)‐Mediated [3+2] Cycloaddition

A robust one‐pot process has been developed for the synthesis of a variety of furo[3,2‐b]indoles from readily available o‐propargylaminoacetophenones via silver(I)‐mediated [3+2] cycloaddition.     

Synthesis of Benzoxazole and Benzimidazole Derivatives via Ligand‐Free Copper(I)‐Catalyzed Cross‐Coupling Reaction of o‐Halophenols or o‐Haloanilines with Carbodiimides

A novel and efficient synthesis of benzoxazole and benzimidazole derivatives via a ligand‐free, copper(I)‐catalyzed, one‐pot cascade process has been developed. A variety of carbodiimides coupled with o‐halophenols or o‐haloanilines to give the products in moderate to excellent yields under the mild conditions.     

Asymmetric One‐Pot Synthesis of 1,4‐Dihydroquinolines via an Organocatalytic Aza‐Michael/Michael Cascade Strategy

A synthetic method for the construction of fully substituted enantioenriched 1,4‐dihydroquinolines using an organocatalytic aza‐Michael/Michael cascade reaction has been developed. The asymmetric reaction of 2‐(tosylamino)phenyl α,β‐unsaturated ketones with alkynyl aldehydes, promoted by diphenylprolinol O‐TMS ether as an organocatalyst, generated chiral 1,4‐dihydroquinolines in good to high yields with excellent enantioselectivities (up to 97 % ee).

     

Co‐composting an animal fatty‐proteinaceous waste with a solid lignocellulosic by‐product from the olive oil industry (‘alperujo’)

BACKGROUND: The production of biodegradable wastes and their disposal cause a major financial problem in many industrial activities. Co‐composting was thought to be a feasible alternative for disposing of a strongly alkaline waste from the pharmaceutical industry (AW), mainly consisting of animal fats and partially hydrolysed proteins in a stable emulsion. The AW was added gradually, during the early phase of the composting process, to a substrate made up of ‘alperujo’ (AL), the wet, lignocellulosic, solid by‐product of the olive oil industry, and fresh horse manure, which was added to improve the physical structure of the composting substrate. RESULTS: The addition of AW reduced organic matter degradation during composting, enriched the amount of organic compounds in the water‐ and alkali‐soluble fractions and increased mineral salt contents. Thus, significantly higher electrical conductivity, humification indices and contents of organic matter, P, K and Na were recorded in the end‐composts resulting from AW treatments. However, the application of one AW‐based compost led to soil N immobilisation, as revealed by an incubation experiment, which must be considered in order to avoid potential N starvation in the short term. CONCLUSION: According to these results, composting can be used as a disposal alternative for AW, leading to end‐products with potential uses as organic amendments or fertilisers for agricultural systems. In addition, these composts could be used to produce alternative liquid organic fertilisers, based on the extraction of their humic‐like fraction. Copyright © 2009 Society of Chemical Industry     

Utilizing Mor‐DalPhos/Palladium‐Catalyzed Monoarylation in the Multicomponent One‐Pot Synthesis of Indoles

The application of a Mor‐DalPhos/palladium catalyst system in the one‐pot, multicomponent assembly of substituted indoles from ortho‐chlorohaloarenes, alkyl ketones (including acetone), and primary amines is reported. The described protocols offer improved substrate scope in all three reaction components, under more mild conditions and without the need for an additional drying agent. Also reported are the first examples of such multicomponent reactions where all reactants are combined at the start of the reaction, without the need for inert atmosphere reaction conditions.