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Chemical reaction data in journal articles, patents, and even electronic laboratory notebooks are currently stored in various formats, often unstructured, which presents a significant barrier to downstream applications, including the training of machine-learning models. We present the Open Reaction Database (ORD), an open-access schema and infrastructure for structuring and sharing organic reaction data, including a centralized data repository. The ORD schema supports conventional and emerging technologies, from benchtop reactions to automated high-throughput experiments and flow chemistry. The data, schema, supporting code, and web-based user interfaces are all publicly available on GitHub. Our vision is that a consistent data representation and infrastructure to support data sharing will enable downstream applications that will greatly improve the state of the art with respect to computer-aided synthesis planning, reaction prediction, and other predictive chemistry tasks.
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We have devised a room temperature process for the cyclopropanation of electron-poor olefins using unstabilised diazo compounds, generated under continuous flow conditions. This protocol was applied to a wide range of different diazo species to generate functionalised cyclopropanes which are valuable 3D building blocks.
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Compostos Azo/síntese química , Ciclopropanos/química , Compostos Azo/química , Estrutura MolecularRESUMO
A copper-catalyzed coupling reaction between flow-generated unstabilized diazo compounds and terminal alkynes provides di- and trisubstituted allenes. This extremely mild and rapid transformation is highly tolerant of several functional groups.
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Alcadienos/síntese química , Alcinos/química , Cobre/química , Compostos de Diazônio/química , Alcadienos/química , Catálise , Metano/análogos & derivados , Metano/química , TemperaturaRESUMO
Performing reactions in flow can offer major advantages over batch methods. However, laboratory flow chemistry processes are currently often limited to single steps or short sequences due to the complexity involved with operating a multi-step process. Using new modular components for downstream processing, coupled with control technologies, more advanced multi-step flow sequences can be realized. These tools are applied to the synthesis of 2-aminoadamantane-2-carboxylic acid. A system comprising three chemistry steps and three workup steps was developed, having sufficient autonomy and self-regulation to be managed by a single operator.
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Amantadina/análogos & derivados , Ácidos Carboxílicos/síntese química , Técnicas de Química Sintética/instrumentação , Amantadina/síntese química , Amantadina/química , Ácidos Carboxílicos/química , Desenho de EquipamentoRESUMO
Here we describe the use of a new open-source software package and a Raspberry Pi(®) computer for the simultaneous control of multiple flow chemistry devices and its application to a machine-assisted, multi-step flow preparation of pyrazine-2-carboxamide - a component of Rifater(®), used in the treatment of tuberculosis - and its reduced derivative piperazine-2-carboxamide.
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This work presents a generalizable computer vision (CV) and machine learning model that is used for automated real-time monitoring and control of a diverse array of workup processes. Our system simultaneously monitors multiple physical outputs (e.g., liquid level, homogeneity, turbidity, solid, residue, and color), offering a method for rapid data acquisition and deeper analysis from multiple visual cues. We demonstrate a single platform (consisting of CV, machine learning, real-time monitoring techniques, and flexible hardware) to monitor and control vision-based experimental techniques, including solvent exchange distillation, antisolvent crystallization, evaporative crystallization, cooling crystallization, solid-liquid mixing, and liquid-liquid extraction. Both qualitative (video capturing) and quantitative data (visual outputs measurement) were obtained which provided a method for data cross-validation. Our CV model's ease of use, generalizability, and non-invasiveness make it an appealing complementary option to in situ and real-time analytical monitoring tools and mathematical modeling. Additionally, our platform is integrated with Mettler-Toledo's iControl software, which acts as a centralized system for real-time data collection, visualization, and storage. With consistent data representation and infrastructure, we were able to efficiently transfer the technology and reproduce results between different labs. This ability to easily monitor and respond to the dynamic situational changes of the experiments is pivotal to enabling future flexible automation workflows.
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We present an automated droplet reactor platform possessing parallel reactor channels and a scheduling algorithm that orchestrates all of the parallel hardware operations and ensures droplet integrity as well as overall efficiency. We design and incorporate all of the necessary hardware and software to enable the platform to be used to study both thermal and photochemical reactions. We incorporate a Bayesian optimization algorithm into the control software to enable reaction optimization over both categorical and continuous variables. We demonstrate the capabilities of both the preliminary single-channel and parallelized versions of the platform using a series of model thermal and photochemical reactions. We conduct a series of reaction optimization campaigns and demonstrate rapid acquisition of the data necessary to determine reaction kinetics. The platform is flexible in terms of use case: it can be used either to investigate reaction kinetics or to perform reaction optimization over a wide range of chemical domains.
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We present a systematic approach for predicting the best solvents for selective extraction of components with unknown structure from complex mixtures (e.g., natural products)-a tool promising dramatic simplification of extraction process optimization. Its key advantage is that identification of the component(s) is unnecessary-prediction is based on a small set of experimental distribution coefficients (obtained using a combination of shake-flask extraction and chromatographic analysis) rather than structure-based descriptors. The methodology is suitable for the very common situations in practice where the desired compound needs to be separated from unknown impurities (i.e., selectively extracted from the mixture), as well as for large-scale and high-throughput work. The proof-of-concept methodology was developed and evaluated using an extensive set of experimental distribution data of lignin-related compounds obtained in this work.
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Stability studies of pharmaceutical drug products and pharmaceutical active substances are important to research and development in order to fully understand and maintain product quality and safety throughout its shelf-life. Oxidative forced degradation studies are among the different types of stability studies performed by the pharmaceutical industry in order to understand the intrinsic stability of drug molecules. We have been comparing the use of electrochemistry as an alternative oxidative forced degradation method to traditional forced degradation and accelerated stability studies. Using the electrochemical degradation approach the substrate oxidation takes place in a commercially available electrochemical cell and the effluent of the cell can be either a) directly infused into the mass spectrometer or b) injected in a chromatographic column for separation of the different products formed prior to the mass spectrometry analysis. To enable the study of large numbers of different experimental conditions and molecules we developed a new dual pump automated electrochemical screening platform. This system used a HPLC pump and autosampler to load and wash the electrochemical cell and deliver the oxidized sample plug to a second injection loop. This system enabled the automatic sequential analyses of large numbers of different solutions under varied experimental conditions without need for operator intervention during the run sequence. Here we describe the system and evaluate its performance using a test molecule with well characterized stability and compare results to those obtained using an off-line electrochemistry approach.
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Estabilidade de Medicamentos , Técnicas Eletroquímicas/métodos , Soluções Farmacêuticas/análise , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida/métodos , Espectrometria de Massas/métodos , Oxirredução , Soluções Farmacêuticas/metabolismoRESUMO
Formaldehyde and formic acid are reactive impurities found in commonly used excipients and can be responsible for limiting drug product shelf-life. Described here is the use of activated carbon in drug product packaging to attenuate formaldehyde-induced and formic acid-induced drug degradation in tablets and cross-linking in hard gelatin capsules. Several pharmaceutical products with known or potential vulnerabilities to formaldehyde-induced or formic acid-induced degradation or gelatin cross-linking were subjected to accelerated stability challenges in the presence and absence of activated carbon. The effects of time and storage conditions were determined. For all of the products studied, activated carbon attenuated drug degradation or gelatin cross-linking. This novel use of activated carbon in pharmaceutical packaging may be useful for enhancing the chemical stability of drug products or the dissolution stability of gelatin-containing dosage forms and may allow for the 1) extension of a drug product's shelf-life when the limiting attribute is a degradation product induced by a reactive impurity, 2) marketing of a drug product in hotter and more humid climatic zones than currently supported without the use of activated carbon, and 3) enhanced dissolution stability of products that are vulnerable to gelatin cross-linking.
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Carvão Vegetal/química , Formas de Dosagem , Formaldeído/química , Formiatos/química , Gelatina/química , Cápsulas , Reagentes de Ligações Cruzadas , Contaminação de Medicamentos , Embalagem de Medicamentos , Estabilidade de Medicamentos , Excipientes , Comprimidos , Vareniclina/químicaRESUMO
The work takes advantage of an important feature of flow chemistry, whereby the generation of a transient species (or reactive intermediate) can be followed by a transfer step into another chemical environment, before the intermediate is reacted with a coupling partner. This concept is successfully applied to achieve a room temperature sp2-sp3 cross coupling of boronic acids with diazo compounds, these latter species being generated from hydrazones under flow conditions using MnO2 as the oxidant.
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Applications of aerobic oxidation methods in pharmaceutical manufacturing are limited in part because mixtures of oxygen gas and organic solvents often create the potential for a flammable atmosphere. To address this issue, limiting oxygen concentration (LOC) values, which define the minimum partial pressure of oxygen that supports a combustible mixture, have been measured for nine commonly used organic solvents at elevated temperatures and pressures. The solvents include acetic acid, N-methylpyrrolidone, dimethyl sulfoxide, tert-amyl alcohol, ethyl acetate, 2-methyltetrahydrofuran, methanol, acetonitrile, and toluene. The data obtained from these studies help define safe operating conditions for the use of oxygen with organic solvents.
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The aim of this study was to evaluate the use of electrochemistry to generate oxidative degradation products of a model pharmaceutical compound. The compound was oxidized at different potentials using an electrochemical flow-cell fitted with a glassy carbon working electrode, a Pd/H2 reference electrode and a titanium auxiliary electrode. The oxidative products formed were identified and structurally characterized by LC-ESI-MS/MS using a high resolution Q-TOF mass spectrometer. Results from electrochemical oxidation using electrolytes of different pH were compared to those from chemical oxidation and from accelerated stability studies. Additionally, oxidative degradation products predicted using an in silico commercially available software were compared to those obtained from the various experimental methods. The electrochemical approach proved to be useful as an oxidative stress test as all of the final oxidation products observed under accelerated stability studies could be generated; previously reported reactive intermediate species were not observed most likely because the electrochemical mechanism differs from the oxidative pathway followed under accelerated stability conditions. In comparison to chemical degradation tests electrochemical degradation has the advantage of being much faster and does not require the use of strong oxidizing agents. Moreover, it enables the study of different operating parameters in short periods of time and optimisation of the reaction conditions (pH and applied potential) to achieve different oxidative products mixtures. This technique may prove useful as a stress test condition for the generation of oxidative degradation products and may help accelerate structure elucidation and development of stability indicating analytical methods.
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Simulação por Computador , Técnicas Eletroquímicas , Modelos Químicos , Preparações Farmacêuticas/química , Tecnologia Farmacêutica/métodos , Química Farmacêutica , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Técnicas Eletroquímicas/instrumentação , Eletrodos , Desenho de Equipamento , Concentração de Íons de Hidrogênio , Estrutura Molecular , Oxirredução , Software , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Tecnologia Farmacêutica/instrumentação , Fatores de TempoRESUMO
[reaction: see text] Conformational analysis, van der Waals attractions, and transition structure calculations are combined to design an asymmetric Lewis acid-catalyzed Diels-Alder reaction for simple acyclic alpha,beta-unsaturated ketones and alpha,beta-unsaturated acid chlorides, giving up to 83 and 92% ee, respectively. The two-point-binding chiral recognition mechanism, Lewis acid-Lewis base coordination with boron and a van der Waals attraction with the naphthyl group, uses the inherent enone unit of simple alpha,beta-unsaturated carbonyl compounds, ending the need for auxiliary oxygen binding sites on the dienophile.
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A sustainable flow chemistry process for the hydration of nitriles, whereby an aqueous solution of the nitrile is passed through a column containing commercially available amorphous manganese dioxide, has been developed. The product is obtained simply by concentration of the output stream without any other workup steps. The protocol described is rapid, robust, reliable, and scalable, and it has been applied to a broad range of substrates, showing a high level of chemical tolerance.
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Amidas/síntese química , Compostos de Manganês/química , Nitrilas/química , Óxidos/química , Amidas/química , Catálise , Técnicas de Química Combinatória , Estrutura Molecular , Água/químicaRESUMO
A flow chemistry Meerwein-Ponndorf-Verley (MPV) reduction procedure using partially hydrated zirconium oxide via a machine-assisted approach is reported. The heterogeneous reductive system could be applied to a wide range of functionalized substrates, allowing clean and fast delivery of the alcohol products within a few minutes (6-75 min). In three examples the system was scaled to deliver 50 mmol of product.
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Álcoois/química , Aldeídos/química , Cetonas/química , Zircônio/química , Catálise , Hidrogenação , EstereoisomerismoRESUMO
A flow chemistry process for the Oppenauer oxidation of benzylic secondary alcohols using partially hydrated zirconium oxide and a simple carbonyl containing oxidant such as acetone, cyclohexanone, and neopentanal is reported. The heterogeneous oxidative system could be applied to a wide range of functionalized alcohol substrates, allowing clean and fast delivery of ketone products within a few minutes between 40 and 100 °C.
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Álcoois Benzílicos/química , Álcoois Benzílicos/síntese química , Zircônio/química , Catálise , Estrutura Molecular , OxirreduçãoRESUMO
High-yielding Heck reactions are demonstrated using 0.05 mol % Pd(OAc)2 without phosphine ligands. These reactions are run in a mesoscale flow reactor which allows precise control of reaction times and temperatures. Profiling yield and selectivity versus Pd loading shows 500 ppm to be optimal for aryl iodides; higher loadings favor side reactions caused by Pd(II) species. Aryl halides are examined via concise Design of Experiment to expand the scope and optimize conditions.
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Acetatos/química , Hidrocarbonetos Bromados/química , Hidrocarbonetos Iodados/química , Paládio/química , Catálise , Ligantes , Estrutura Molecular , TemperaturaRESUMO
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) has been found to catalyze the amidation of acyl imidazoles. The rate acceleration is especially evident with traditionally unreactive, electron-deficient anilines. DBU is readily available and offers safety and cost advantages over more commonly employed catalysts such as 1-hydroxybenzotriazole.