Digitization of multistep organic synthesis in reactionware for on-demand pharmaceuticals

Chemical manufacturing is often done at large facilities that require a sizable capital investment and then produce key compounds for a finite period. We present an approach to the manufacturing of fine chemicals and pharmaceuticals in a self-contained plastic reactionware device. The device was designed and constructed by using a chemical to computer-automated design (ChemCAD) approach that enables the translation of traditional bench-scale synthesis into a platform-independent digital code. This in turn guides production of a three-dimensional printed device that encloses the entire synthetic route internally via simple operations. We demonstrate the approach for the γ-aminobutyric acid receptor agonist, (±)-baclofen, establishing a concept that paves the way for the local manufacture of drugs outside of specialist facilities

3D designed and printed chemical generators for on demand reagent synthesis

Modern science has developed well-defined and versatile sets of chemicals to perform many specific tasks, yet the diversity of these reagents is so large that it can be impractical for any one lab to stock everything they might need. At the same time, isssues of stability or limited supply mean these chemicals can be very expensive to purchase from specialist retailers. Here, we address this problem by developing a cartridge -oriented approach to reactionware-based chemical generators which can easily and reliably produce specific reagents from low-cost precursors, requiring minimal expertise and time to operate, potentially in low infrastructure environments. We developed these chemical generators for four specific targets; transition metal catalyst precursor tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3], oxidising agent Dess-Martin periodinane (DMP), protein photolinking reagent succinimidyl 4,4’-azipentanoate (NHS-diazirine), and the polyoxometalate cluster {P8W48}. The cartridge synthesis of these materials provides high-quality target compounds in good yields which are suitable for subsequent utilization

The Effects of the Acupuncture Treatment for Smoking Cessation in High School Student Smokers

The use of alternative medicine for smoking cessation have been increasing steadily in recent years. A series of clinical group studies was performed to clarify the effect, outcome and success rate of an acupuncture treatment for smoking cessation. This study was conducted for four weeks using 238 smoking students at 2 high schools. The subjects were separated into two groups: 159 students were treated with acupuncture on the anti-smoking acupoints of the ear, which is known to be effective for cessation of smoking (case group), and 79 students were treated at other sites of the ear (control group). The acupuncture treatment was alternately administered at each side of the ears on a weekly basis for 4 weeks. The smoking cessation success was only 1 case (0.6%) in the case group and none in the control group after 4 weeks. The change in the taste of tobacco and the intensity of the desire to smoke were not significantly different between the case and control groups, but the case group showed a tendency of reduction in the taste of tobacco and the intensity of the desire to smoke. In addition, the reduction in cigarette consumption was not significant, but the tendency of reduction in the study group was significant. It is believed that the site of auricular acupuncture for smoking cessation is not important. However, there was a significant tendency in terms of the reduction in cigarette consumption, the taste of tobacco and the intensity of the desire to smoke in the case group, indicating that auricular acupuncture in smoking cessation has some effect

Catalyst Decomposition during Olefin Metathesis Yields Isomerization-Active Ruthenium Nanoparticles

The second‐generation Grubbs catalyst, RuCl2(H2IMes)(PCy3) (=CHPh) [GII ; H2IMes=1,3‐bis(2,4,6‐trimethylphenyl)‐4,5‐dihydroimidazol‐2‐ylidene, Cy=cyclohexyl], is shown to decompose during olefin metathesis to generate Ru nanoparticles (RuNPs). These RuNPs appear to contribute significantly to competing isomerization during metathesis. Larger, partially oxidized RuNPs are also observed in commercial GII , but these exhibit modest isomerization activity. Removal of RuNPs from the precatalyst does not prevent isomerization, because new, more reactive NPs are generated by catalyst decomposition during metathesis

Convergence of multiple synthetic paradigms in a universally programmable chemical synthesis machine

Although the automatic synthesis of molecules has been established, each reaction class uses bespoke hardware. This means that the connection of multi-step syntheses in a single machine to run many different protocols and reactions is not possible, as manual intervention is required. Here we show how the Chemputer synthesis robot can be programmed to perform many different reactions, including solid-phase peptide synthesis, iterative cross-coupling and accessing reactive, unstable diazirines in a single, unified system with high yields and purity. Developing universal and modular hardware that can be automated using one software system makes a wide variety of batch chemistry accessible. This is shown by our system, which performed around 8,500 operations while reusing only 22 distinct steps in 10 unique modules, with the code able to access 17 different reactions. We also demonstrate a complex convergent robotic synthesis of a peptide reacted with a diazirine-a process requiring 12 synthetic steps

A simple hand-held magnet array for efficient and reproducible SABRE hyperpolarisation using manual sample shaking

Signal amplification by reversible exchange (SABRE) is a hyperpolarisation technique that catalytically transfers nuclear polarisation from parahydrogen, the singlet nuclear isomer of H2, to a substrate in solution. The SABRE exchange reaction is carried out in a polarisation transfer field (PTF) of tens of gauss before transfer to a stronger magnetic field for nuclear magnetic resonance (NMR) detection. In the simplest implementation, polarisation transfer is achieved by shaking the sample in the stray field of a superconducting NMR magnet. Although convenient, this method suffers from limited reproducibility and cannot be used with NMR spectrometers that do not have appreciable stray fields, such as benchtop instruments. Here, we use a simple hand-held permanent magnet array to provide the necessary PTF during sample shaking. We find that the use of this array provides a 25% increase in SABRE enhancement over the stray field approach, while also providing improved reproducibility. Arrays with a range of PTFs were tested, and the PTF-dependent SABRE enhancements were found to be in excellent agreement with comparable experiments carried out using an automated flow system where an electromagnet is used to generate the PTF. We anticipate that this approach will improve the efficiency and reproducibility of SABRE experiments carried out using manual shaking and will be particularly useful for benchtop NMR, where a suitable stray field is not readily accessible. The ability to construct arrays with a range of PTFs will also enable the rapid optimisation of SABRE enhancement as function of PTF for new substrate and catalyst systems

SABRE hyperpolarization enables high-sensitivity 1H and 13C benchtop NMR spectroscopy

Benchtop NMR spectrometers operating with low magnetic fields of 1-2 T at sub-ppm resolution show great promise as analytical platforms that can be used outside the traditional laboratory environment for industrial process monitoring. One current limitation that reduces the uptake of benchtop NMR is associated with the detection fields' reduced sensitivity. Here we demonstrate how para-hydrogen (p-H2) based signal amplification by reversible exchange (SABRE), a simple to achieve hyperpolarization technique, enhances agent detectability within the environment of a benchtop (1 T) NMR spectrometer so that informative 1H and 13C NMR spectra can be readily recorded for low-concentration analytes. SABRE-derived 1H NMR signal enhancements of up to 17000-fold, corresponding to 1H polarization levels of P = 5.9%, were achieved for 26 mM pyridine in d4-methanol in a matter of seconds. Comparable enhancement levels can be achieved in both deuterated and protio solvents but now the SABRE-enhanced analyte signals dominate due to the comparatively weak thermally-polarized solvent response. The SABRE approach also enables the acquisition of 13C NMR spectra of analytes at natural isotopic abundance in a single scan as evidenced by hyperpolarized 13C NMR spectra of tens of millimolar concentrations of 4-methylpyridine. Now the associated signal enhancement factors are up to 45500 fold (P = 4.0%) and achieved in just 15 s. Integration of an automated SABRE polarization system with the benchtop NMR spectrometer framework produces renewable and reproducible NMR signal enhancements that can be exploited for the collection of multi-dimensional NMR spectra, exemplified here by a SABRE-enhanced 2D COSY NMR spectrum

THE ABSENCE OF UNFIED ORDER OF INTERNATIONAL CONCILIATION AGREEMENTS ENFORCEMENT

В статье анализируется проблема отсутствия на международном уровне достаточного регулирования, позволяющего обеспечить беспрепятственное приведение в исполнение международных мировых соглашений, заключенных в медиации, а также приводится возможный способ решения существующей проблемы путем приведения национального законодательства в соответствие с существующими рамочными международными документами.= This article analyzes the problem of absence on international level enough legal regulation for unobstructed enforcement of international conciliation agreements, concluded in mediation, as well as contains the possible way of solving the problem through adjustment of domestic law with international framework