A series of R-SMS-Phos ligands was evaluated in the Rh(I)-catalyzed hydrogenation of a set of olefins showing a marked influence of the cyclic nature and structure of the R groups. Overall, cPen- and ...Cy-SMS-Phos performed efficiently, while Ph- and Bn-SMS-Phos exhibited slower kinetics and furnished lower ee’s also compared with C6F5CH2-SMS-Phos. The Rh(I)-(Cy-SMS-Phos) catalyst was screened under mild conditions displaying excellent enantioselectivities and high TOFs. Cases of catalysis under catalyst or substrate control were identified.
A series of enantiopure P-stereogenic 1,2-bis(o-RO-phenyl)(phenyl)phosphinoethane (R-SMS-Phos) ligands wherein R= i-Pr, i-Bu, t-Bu, 3-Pen, and CH2TMS was assessed in the Rh(I)-catalyzed hydrogenation ...of an indicative set of olefins. The best performing t-Bu-SMS-Phos ligand was screened against a wide range of representative classes of standard and new olefinic substrates such as dehydroamido esters, dehydro-α-amido-phosphonates, enamides, itaconates, acrylates, enol acetates, α-phosphonovinyl benzoates, α-(2-pyridyl N-oxide)styrenes, and α-(1-hydroxyliminoethyl)styrenes. Excellent enantioselectivities and high TOFs were attained under mild conditions.
Despite the fact that it was put on the market more than 60 years ago, hydrochlorothiazide (HCT) is still one of the most important antihypertensive drugs. Due to its chemical structure, which ...contains the secondary aryl-alkyl-amino moiety, it is vulnerable to the formation of N-nitrosamine drug substance-related impurity (NDSRI) N-nitroso-hydrochlorothiazide (NO-HCT). In our study, we reveal that NO-HCT degrades rapidly at pH values 6 to 8. The main degradation products identified are formaldehyde, thiatriazine, and aminobenzenesulfonic acid derivative. Interestingly, degradation of NO-HCT at pH values from 5 to 1 is significantly slower and provides a different impurity profile when compared to the profile generated between pH 6 and 8. Specifically, between pH 1 and 5, HCT is observed as one of the key degradation products of NO-HCT in addition to formaldehyde and aminobenzenesulfonic acid. Moreover, at pH 1, the aminobenzenesulfonic acid derivative is transformed to the corresponding diazonium salt in approximately 3% yield with the nitrosyl cation, which is released during the decomposition of NO-HCT to HCT. This diazonium is highly unstable above pH 5. To verify that degradation of NO-HCT does not produce the corresponding diazonium salt that could be formed via metabolic activation of NO-HCT, this diazonium salt and its hydrolytic and reduction degradation products were synthesized and used as standards for the identification of species formed during the degradation of NO-HCT. This enabled us to confirm that the corresponding aryl diazonium salt, which would be obtained from metabolic activation of NO-HCT, is not observed in the NO-HCT degradation pathway. Our study also demonstrates that this diazonium salt is stable only in the presence of a large excess of strong mineral acid under anhydrous conditions. In the presence of water, it is instantaneously converted to an aminobenzenesulfonic acid derivative. These findings suggest that the NO-HCT should not be considered as a typical compound belonging to the cohort of the concern.
The nature of the starting material (SM) and the presence of (potentially) mutagenic impurities (PMIs) can correlate strongly, since many syntheses involve the use of potentially mutagenic ...electrophilic (alkylating) agents as SMs. Since the regulatory guidelines are far from clear and straightforward, selection of the appropriate SMs is a very challenging task for pharmaceutical companies. Here, the principal criteria for the selection of SMs have been identified based on the existing guidelines. Three SMs in the synthesis of vortioxetine drug substance were selected and justified on the basis of their incorporation into the structure of the API, on whether they have defined chemical properties and structure or not, on the number of synthetic steps between the SM and the API, on commercial availability and formation of impurities, and their control. Determination of a theoretical purge factor (TPF) was successful in evaluating the risk of using potentially mutagenic SM 1 and SM 3, with their related impurities, and the effect of a nonmutagenic SM 2 on the quality and safety of the API. This approach enables the use of selected SMs to be justified.
Determination of theoretical purge factors for the evaluation of risk of carryover of potential mutagenic impurities (MIs) into the final active pharmaceutical ingredient (API) has been discussed as ...a possible approach to demonstrate efficient purification of potential MIs (Substances I, II, III, and IV) in the synthesis of the vortioxetine drug substance. Theoretical purge factors for the four potential MIs were determined based on the physicochemical properties of an MI in relation to processing conditions. Compared to depletion studies of I and III, the calculated purge factors were very conservative in predicting impurities reduction. However, even a conservatively calculated purge factor correctly predicted high purging capability of the process to eliminate substance I. This novel approach could help pharmaceutical companies to focus on those impurities that are more likely to be carried over into the final API, thus obviating the use of analytical testing where not necessary.
•Critical evaluation of model reduction techniques.•Approaches for automatic reduction in Modelica are selected and adopted.•Development and implementation of the toolbox on the equation ...level.•Development and implementation of the toolbox on the component diagram level.•Critical evaluation of the implementation on the example of a suspension system.
Object-oriented modelling of cyber-physical systems with Modelica and similar environments has brought many advantages, especially the efficient re-use of models and thus the possibility of creating powerful multi-domain libraries. Unfortunately, the models have become highly complex, which causes serious problems during processing and execution. Consequently, verification and debugging is becoming an increasingly challenging task. The continuous investigation of simplifications and reductions in all phases of model developments is thus urgent.
The present paper deals with reduction methods based on metric ranking and preserve realisation, which means that the structure and the parameters of the model remain physically interpretable. Two model-reduction methods are described and implemented in Open Modelica. The first operates on a set of differential-algebraic equations, and the second is based on modified bond-graphs-reduction techniques. The latter approach is suitable for component-based models in Modelica that are usually represented graphically with object diagrams. The paper briefly describes the research area, the problems of the adoption of the developed model reduction techniques to the Modelica environments, and the final implementation. Both proposed approaches are tested on the model of a car suspension system and briefly discussed.
This paper deals with the adaptation of energy-based realization-preserving model-reduction techniques for object-oriented models implemented in Modelica. An approach originally developed for bond ...graphs, where energy-related heuristics were used to identify the components contributing the most to the model’s salient dynamics, was extended to more heterogeneously formulated models in Modelica. A prototype toolbox was developed inside the modeling environment OpenModelica. Its applicability was demonstrated with two examples. Although the model-reduction tool cannot reduce the model completely automatically, it may still offer many useful insights and hints to the user.
Most of today’s modelling and simulation concepts originate from the times and methods of analog computers. Usually, it is assumed that the model must be expressed in an explicit state-space form. ...Consequently, the topology of the system gets lost and any future extension and reuse of the model is tedious and error-prone. In other words, it is the modeller’s task to consider the computational order of the operations during a simulation.
In this paper we discuss the re-implementation of a passive-solar- building simulator in an object-oriented environment; it was originally built in the non-object-oriented simulation environment of
Matlab–Simulink. The former simulator was designed to resemble a real physical test chamber with regard to the thermal and solar radiation flows. However, due to the lack of object orientation in
Matlab–Simulink it was very difficult to apply any configuration modifications and extensions.
We start with a brief description of the mathematical modelling which includes thermal dynamics and solar radiation. Then the implementation in
Modelica is presented. So, a much superior environment in comparison with
Matlab-Simulink was obtained, giving us the possibility of high-level modular and object-oriented modelling. The model is also extremely efficient in multidisciplinary projects in which control-engineering specialists (our group) cooperate with specialists from civil engineering, because civil engineers can more easily understand graphical and textual models in
Modelica than schemes in
Simulink.
We expect that such a model will fulfil and significantly improve several model properties in comparison to the
Matlab–Simulink implementation, i.e., a better understanding of the influences of thermal and radiation flows on comfortable living conditions, a model-based control-system design, which will enable the harmonization of active and passive energy resources, important energy savings, and a very suitable environment for education in modelling, simulation and control.
For the purposes of this paper, computer-aided physical modelling means a type of modelling in which a computer-aided approach is used, with the basic aim being to maintain the physical structure of ...a real system or its topology as much as possible in the model. Bond graphs represent a very efficient and traditional approach. However, new, object-oriented and multi-domain tools based on the Modelica language are more appropriate for industrial staff or for the people who do not have a deep insight into modelling and simulation. In this paper we describe several educational and industrial application projects in the Dymola–Modelica environment: a process-systems library, two mechanical systems (an inverted pendulum and a laboratory helicopter), a model of thermal and radiation flows in buildings and two models of processes in mineral-wool production, i.e., a pendulum system and a recuperator system. We describe some experiences from these projects, but also from a more general use of the Matlab–Simulink and Dymola–Modelica environments over many years. One simple conclusion is that we need to educate with two approaches: a more physical and advanced acausal Modelica-like approach, but also a more traditional causal or block-oriented approach according to the historical CSSL standard. The important advantages and disadvantages of both approaches are described. The Modelica-based approach enables true ‘physical’ modelling with fully reusable components. However, there is a particular danger, i.e., users occasionally forget some basic modelling principles when using sophisticated libraries. The result is a very complex modelling structure that is relatively inefficient for the simulation and sometimes has many numerical problems. It is usually very difficult to detect the real reasons for that.
A diversified family of enantiopure P-stereogenic "R-SMS-Phos" {R-SMS-Phos = 1,2-bis(o-RO-phenyl)(phenyl)phosphinoethane} ligands wherein R = branched or heteroatom-substituted alkyl, aralkyl, silyl, ...acyl, sulfonyl, etc. was screened for the Rh(I)-catalyzed hydrogenation of a representative set of olefinic substrates. This systematic and detailed investigation revealed a marked beneficial impact on enantioselectivity and catalyst activity in comparison to Knowles' ultimate DiPAMP {DiPAMP = 1,2-bis(o-anisyl)(phenyl)phosphinoethane} design. Mutant ligands with highly enhanced properties possessing particular features wherein the DiPAMP structure is found embedded were identified.
