Синтез та N-алкілування діетил 4,7-дигідроазоло[1,5-a]піримідин-5,6-дикарбоксилатів

It has been shown that the ternary condensation of oxaloacetic ester (diethyl 2-oxosuccinate), aromatic aldehydes and 3-amino-1,2,4-triazole or 5-aminotetrazole in dimethylformamide results in formation of the corresponding diethyl 7-aryl-4,7-dihydroazolo[1,5-a]pyrimidin-5,6-dicarboxylates. By 1H NMR spectroscopy (according to the data of the chemical shifts of C(2)H-protons for the corresponding N(4)H- and N(4)-methylderivatives of 7-phenyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-5,6-dicarboxylate) it has been found that alkylation of 4,7-dihydro[1,2,4]azolo[1,5-a]pyrimidin-5,6-dicarboxylates in the acetonitrile–saturated water alkali system leads selectively to formation of N(4)-alkyl derivatives. Both the starting compounds obtained and their N(4)-methylsubstituted analogues together with relative diethyl 4-aryl-3,4-dihydropyrimidin-2(1H)-on-5,6-dicarboxylates, 6-unsubstituted 4-aryl-3,4-dihydropyrimidin-2(1H)-on-5-dicarboxylates and the derivatives of 6-COR-7-aryl-4,7-dihydro[1,2,4] triazolo[1,5-a]pyrimidines are the promising objects for studying benzyl C(7)-functionalization of 4,7-dihydroazolo 1,5-a]pyrimidines, as well as of reactions associated with the presence of double C=C-bonds activated by two electron withdrawing groups. Obtaining of the key N(4)H- and N(4)Me-derivatives of 7-phenyl-4,7-dihydro[1,2,4] triazolo- and tetrazolo[1,5-a]pyrimidin-5,6-dicarboxylates also opens the way to the research of biological properties of the compounds of this class. It is noteworthy that being a three-component one the reaction studied, without any doubts, are appropriate for the synthesis of the derivatives of 7-aryl-4,7-dihydro[1,2,4]triazolo- and tetrazolo[1,5-a]pyrimidines containing two electron withdrawing substituents in positions 5 and 6.Показано, что трехкомпонентная конденсация щавелевоуксусного эфира (диэтил 2-оксосукцината), ароматических альдегидов и 3-амино-1,2,4-триазола или 5-аминотетразола в диметилформамиде приводит к образованию соответствующих диэтил 7-арил-4,7-дигидроазоло[1,5-a]пиримидин-5,6-дикарбоксилатов. С помощью 1Н ЯМР-спектроскопии (по данным химических сдвигов сигналов протонов С(2)H для соответствующих N(4)H- и N(4)Ме-производных диэтил 7-фенил-4,7-дигидро[1,2,4]триазоло[1,5-a] пиримидин-5,6-дикарбоксилата) установлено, что алкилирование 7-арил-4,7-дигидроазоло[1,5-a]пиримидин-5,6-дикарбоксилатов в системе ацетонитрил-насыщенная водная щелочь селективно приводит к образованию N(4)-алкилпроизводных. Как полученные исходные соединения, так и их N(4)-метилзамещенные аналоги наряду с родственными диэтил 4-арил-3,4-дигидропиримидин-2(1Н)-он-5,6-дикарбоксилатами, 6-незамещенными этил 4-арил-3,4-дигидропиримидин-2(1Н)-он-5-карбоксилатами и производными 6-COR-7-арил-4,7-дигидро[1,2,4]триазоло[1,5-a]пиримидинов являются перспективными объектами для изучения бензильной С(7)-функционализации 4,7-дигидроазоло[1,5-a]пиримидинов, а также реакций, связанных с наличием двойной C=C-связи, активированной двумя акцепторными группами. Получение ключевых N(4)H- и N(4)Ме-производных 7-фенил-4,7-дигидро[1,2,4]триазоло- и тетразоло[1,5-a]пиримидин-5,6-дикарбоксилатов также открывает путь к биологическим исследованиям соединений этого класса. Заметим, что исследованная реакция, являясь трехкомпонентной, безусловно подходит для синтеза и исследования комбинаторных библиотек производных 7-арил-4,7-дигидро[1,2,4]триазоло- и тетразоло[1,5-a]пиримидинов, содержащих два электроноакцепторных заместителя в положениях 5 и 6.Показано, що трикомпонентна конденсація щавлевооцтового естеру (діетил 2-оксосукцинату), ароматичних альдегідів та 3-аміно-1,2,4-триазолу або 5-амінотетразолу в диметилформаміді призводить до утворення відповідних діетил 4,7-дигідроазоло[1,5-a]піримідин-5,6-дикарбоксилатів. За допомогою 1Н ЯМР-спектроскопії (за даними про хімічні зсуви сигналів протонів С(2)Н для відповідних N(4)H- та N(4)Me-похідних діетил 7-феніл-4,7-дигідро[1,2,4]триазоло[1,5-a]піримідин-5,6-дикарбоксилатів) вста-новлено, що алкілування 4,7-дигідроазоло[1,5-a]піримідин-5,6-дикарбоксилатів у системі ацетонітрилнасичений водний луг селективно призводить до утворення N(4)-алкілпохідних. Як отримані вихідні сполуки, так і їхні N(4)-метилзаміщені аналоги поряд зі спорідненими діетил 4-арил-3,4-дигідропіримідин-2(1Н)-он-5,6-дикарбоксилатами, 6-незаміщеними етил 4-арил-3,4-дигідропіримідин-2(1Н)-он-5-карбоксилатами та похідними 6-COR-7-арил-4,7-дигідро[1,2,4]триазоло[1,5-a]піримідинів є перспективними об’єктами для вивчення бензильної С(7)-функціоналізації 4,7-дигідроазоло[1,5-a]піримідинів, а також реакцій, пов’язаних з наявністю подвійного C=C-зв’язку, активованого двома акцепторними групами. Отримання ключових N(4)H- і N(4)Ме-похідних 7-феніл-4,7-дигідро[1,2,4]триазоло- та тетразоло[1,5-a]піримідин-5,6-дикарбоксилатів також відкриває шлях до біологічних досліджень сполук цього класу. Відзначимо, що досліджена реакція, будучи трикомпонентною, безумовно підходить для синтезу та дослідження комбінаторних бібліотек похідних 7-арил-4,7-дигідро[1,2,4]триазоло- та тетразоло[1,5-a]піримідинів, що містять два електроноакцепторні замісники у положеннях 5 та 6

Evaluating Filtration and Thermal Stability of Water-Based Mud Using Green Synthesized Zinc Oxide Nanoparticles

   Nanoparticles (NPs) have unique capabilities that make them an eye-opener opportunity for the upstream oil industry. Their nano-size allows them to flow within reservoir rocks without the fear of retention between micro-sized pores. Incorporating NPs with drilling and completion fluids has proved to be an effective additive that improves various properties such as mud rheology, filtration, thermal conductivity, and wellbore stability. However, the biodegradability of drilling fluid chemicals is becoming a global issue as the discharged wetted cuttings raise toxicity concerns and environmental hazards. Therefore, it is urged to utilize chemicals that tend to break down and susceptible to biodegradation. This research presents the practical application of bio-based Zinc Oxide nanoparticles (ZnO NPs) prepared chemically from celery leaf plant extract as green additive in water-based mud drilling fluid (WBM). The study aimed to evaluate the filtration and thermal stability of WBM using green-synthesized ZnO NPs. The results showed that the ZnO NPs have minimal effect of mud density, but significant improvement in mud thermal stability and filtration properties were attained with concentrations lower than 1g. The fluid loss rate was reduced by 33% with 0.45g of ZnO nanoparticles, and the thinnest mud cake was obtained as well. In terms of thermal stability, the bio-based ZnO NPs greatly enhanced the rheological properties of WBM at elevated temperatures. The rate of increment in plastic viscosity (PV) or decrement in yield point (YP) and gel strength occurred in a controllable manner compared to the rheological properties of base mud at high temperatures reaching 90°C. This study provides insight into the effect of green-synthesized ZnO nanoparticles on the performance of water-based mud and highlights their potential as an effective and environmentally friendly additive for the oil and gas industry

Correlation between circulating tumour DNA and metabolic tumour burden in metastatic melanoma patients

Background: Circulating tumour DNA (ctDNA) may serve as a measure of tumour burden and a useful tool for non-invasive monitoring of cancer. However, ctDNA is not always detectable in patients at time of diagnosis of metastatic disease. Therefore, there is a need to understand the correlation between ctDNA levels and the patients\u27 overall metabolic tumour burden (MTB). Methods: Thirty-two treatment naïve metastatic melanoma patients were included in the study. MTB and metabolic tumour volume (MTV) was measured by 18F-fluoro-D-glucose positron emission tomography/computed tomography (FDG PET/CT). Plasma ctDNA was quantified using droplet digital PCR (ddPCR). Results: CtDNA was detected in 23 of 32 patients. Overall, a significant correlation was observed between ctDNA levels and MTB (

Subnormothermic perfusion with h2s donor ap39 improves dcd porcine renal graft outcomes in an ex vivo model of kidney preservation and reperfusion

This is the final published version, also available from MDPI via the DOI in this record.Cold preservation is the standard of care for renal grafts. However, research on alterna-tives like perfusion at higher temperatures and supplementing preservation solutions with hydrogen sulfide (H2S) has gained momentum. In this study, we investigated whether adding H2S donor AP39 to porcine blood during subnormothermic perfusion at 21 °C improves renal graft outcomes. Porcine kidneys were nephrectomized after 30 min of clamping the renal pedicles and treated to 4 h of static cold storage (SCS) on ice or ex vivo subnormothermic perfusion at 21 °C with autologous blood alone (SNT) or with AP39 (SNTAP). All kidneys were reperfused ex vivo with autologous blood at 37 °C for 4 h. Urine output, histopathology and RNAseq were used to evaluate the renal graft function, injury and gene expression profiles, respectively. The SNTAP group exhibited significantly higher urine output than other groups during preservation and reperfusion, along with significantly lower apoptotic injury compared to the SCS group. The SNTAP group also exhibited differential pro-survival gene expression patterns compared to the SCS (downregulation of pro-apoptotic genes) and SNT (downregulation of hypoxia response genes) groups. Subnormothermic perfusion at 21 °C with H2S-supplemented blood improves renal graft outcomes. Further research is needed to facilitate the clinical translation of this approach.Medical Research Council (MRC)Physicians Services Incorporated (PSI) FoundationLawson Research Institut

Detection of clinical progression through plasma ctDNA in metastatic melanoma patients: A comparison to radiological progression

Background The validity of circulating tumour DNA (ctDNA) as an indicator of disease progression compared to medical imaging in patients with metastatic melanoma requires detailed evaluation. Methods Here, we carried out a retrospective ctDNA analysis of 108 plasma samples collected at the time of disease progression. We also analysed a validation cohort of 66 metastatic melanoma patients monitored prospectively after response to systemic therapy. Results ctDNA was detected in 62% of patients at the time of disease progression. For 67 patients that responded to treatment, the mean ctDNA level at progressive disease was significantly higher than at the time of response (P \u3c 0.0001). However, only 30 of these 67 (45%) patients had a statistically significant increase in ctDNA by Poisson test. A validation cohort of 66 metastatic melanoma patients monitored prospectively indicated a 56% detection rate of ctDNA at progression, with only two cases showing increased ctDNA prior to radiological progression. Finally, a correlation between ctDNA levels and metabolic tumour burden was only observed in treatment naïve patients but not at the time of progression in a subgroup of patients failing BRAF inhibition (N = 15). Conclusions These results highlight the low efficacy of ctDNA to detect disease progression in melanoma when compared mainly to standard positron emission tomography imaging

Detection of metastases using circulating tumour DNA in uveal melanoma

Background: Approximately 50% of uveal melanoma (UM) patients will develop metastatic disease depending on the genetic features of the primary tumour. Patients need 3–12 monthly scans, depending on their prognosis, which is costly and often non-specific. Circulating tumour DNA (ctDNA) quantification could serve as a test to detect and monitor patients for early signs of metastasis and therapeutic response. Methods: We assessed ctDNA as a biomarker in three distinct UM cohorts using droplet-digital PCR: (A) a retrospective analysis of primary UM patients to predict metastases; (B) a prospective analysis of UM patients after resolution of their primary tumour for early detection of metastases; and (C) monitoring treatment response in metastatic UM patients. Results: Cohort A: ctDNA levels were not associated with the development of metastases. Cohort B: ctDNA was detected in 17/25 (68%) with radiological diagnosis of metastases. ctDNA was the strongest predictor of overall survival in a multivariate analysis (HR = 15.8, 95% CI 1.7–151.2, p = 0.017). Cohort C: ctDNA monitoring of patients undergoing immunotherapy revealed a reduction in the levels of ctDNA in patients with combination immunotherapy. Conclusions: Our proof-of-concept study shows the biomarker feasibility potential of ctDNA monitoring in for the clinical management of uveal melanoma patients

Синтез та N-алкілування діетил 4,7-дигідроазоло[1,5-a]піримідин-5,6-дикарбоксилатів

It has been shown that the ternary condensation of oxaloacetic ester (diethyl 2-oxosuccinate), aromatic aldehydes and 3-amino-1,2,4-triazole or 5-aminotetrazole in dimethylformamide results in formation of the corresponding diethyl 7-aryl-4,7-dihydroazolo[1,5-a]pyrimidin-5,6-dicarboxylates. By 1H NMR spectroscopy (according to the data of the chemical shifts of C(2)H-protons for the corresponding N(4)H- and N(4)-methylderivatives of 7-phenyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-5,6-dicarboxylate) it has been found that alkylation of 4,7-dihydro[1,2,4]azolo[1,5-a]pyrimidin-5,6-dicarboxylates in the acetonitrile–saturated water alkali system leads selectively to formation of N(4)-alkyl derivatives. Both the starting compounds obtained and their N(4)-methylsubstituted analogues together with relative diethyl 4-aryl-3,4-dihydropyrimidin-2(1H)-on-5,6-dicarboxylates, 6-unsubstituted 4-aryl-3,4-dihydropyrimidin-2(1H)-on-5-dicarboxylates and the derivatives of 6-COR-7-aryl-4,7-dihydro[1,2,4] triazolo[1,5-a]pyrimidines are the promising objects for studying benzyl C(7)-functionalization of 4,7-dihydroazolo 1,5-a]pyrimidines, as well as of reactions associated with the presence of double C=C-bonds activated by two electron withdrawing groups. Obtaining of the key N(4)H- and N(4)Me-derivatives of 7-phenyl-4,7-dihydro[1,2,4] triazolo- and tetrazolo[1,5-a]pyrimidin-5,6-dicarboxylates also opens the way to the research of biological properties of the compounds of this class. It is noteworthy that being a three-component one the reaction studied, without any doubts, are appropriate for the synthesis of the derivatives of 7-aryl-4,7-dihydro[1,2,4]triazolo- and tetrazolo[1,5-a]pyrimidines containing two electron withdrawing substituents in positions 5 and 6.Показано, что трехкомпонентная конденсация щавелевоуксусного эфира (диэтил 2-оксосукцината), ароматических альдегидов и 3-амино-1,2,4-триазола или 5-аминотетразола в диметилформамиде приводит к образованию соответствующих диэтил 7-арил-4,7-дигидроазоло[1,5-a]пиримидин-5,6-дикарбоксилатов. С помощью 1Н ЯМР-спектроскопии (по данным химических сдвигов сигналов протонов С(2)H для соответствующих N(4)H- и N(4)Ме-производных диэтил 7-фенил-4,7-дигидро[1,2,4]триазоло[1,5-a] пиримидин-5,6-дикарбоксилата) установлено, что алкилирование 7-арил-4,7-дигидроазоло[1,5-a]пиримидин-5,6-дикарбоксилатов в системе ацетонитрил-насыщенная водная щелочь селективно приводит к образованию N(4)-алкилпроизводных. Как полученные исходные соединения, так и их N(4)-метилзамещенные аналоги наряду с родственными диэтил 4-арил-3,4-дигидропиримидин-2(1Н)-он-5,6-дикарбоксилатами, 6-незамещенными этил 4-арил-3,4-дигидропиримидин-2(1Н)-он-5-карбоксилатами и производными 6-COR-7-арил-4,7-дигидро[1,2,4]триазоло[1,5-a]пиримидинов являются перспективными объектами для изучения бензильной С(7)-функционализации 4,7-дигидроазоло[1,5-a]пиримидинов, а также реакций, связанных с наличием двойной C=C-связи, активированной двумя акцепторными группами. Получение ключевых N(4)H- и N(4)Ме-производных 7-фенил-4,7-дигидро[1,2,4]триазоло- и тетразоло[1,5-a]пиримидин-5,6-дикарбоксилатов также открывает путь к биологическим исследованиям соединений этого класса. Заметим, что исследованная реакция, являясь трехкомпонентной, безусловно подходит для синтеза и исследования комбинаторных библиотек производных 7-арил-4,7-дигидро[1,2,4]триазоло- и тетразоло[1,5-a]пиримидинов, содержащих два электроноакцепторных заместителя в положениях 5 и 6.Показано, що трикомпонентна конденсація щавлевооцтового естеру (діетил 2-оксосукцинату), ароматичних альдегідів та 3-аміно-1,2,4-триазолу або 5-амінотетразолу в диметилформаміді призводить до утворення відповідних діетил 4,7-дигідроазоло[1,5-a]піримідин-5,6-дикарбоксилатів. За допомогою 1Н ЯМР-спектроскопії (за даними про хімічні зсуви сигналів протонів С(2)Н для відповідних N(4)H- та N(4)Me-похідних діетил 7-феніл-4,7-дигідро[1,2,4]триазоло[1,5-a]піримідин-5,6-дикарбоксилатів) вста-новлено, що алкілування 4,7-дигідроазоло[1,5-a]піримідин-5,6-дикарбоксилатів у системі ацетонітрилнасичений водний луг селективно призводить до утворення N(4)-алкілпохідних. Як отримані вихідні сполуки, так і їхні N(4)-метилзаміщені аналоги поряд зі спорідненими діетил 4-арил-3,4-дигідропіримідин-2(1Н)-он-5,6-дикарбоксилатами, 6-незаміщеними етил 4-арил-3,4-дигідропіримідин-2(1Н)-он-5-карбоксилатами та похідними 6-COR-7-арил-4,7-дигідро[1,2,4]триазоло[1,5-a]піримідинів є перспективними об’єктами для вивчення бензильної С(7)-функціоналізації 4,7-дигідроазоло[1,5-a]піримідинів, а також реакцій, пов’язаних з наявністю подвійного C=C-зв’язку, активованого двома акцепторними групами. Отримання ключових N(4)H- і N(4)Ме-похідних 7-феніл-4,7-дигідро[1,2,4]триазоло- та тетразоло[1,5-a]піримідин-5,6-дикарбоксилатів також відкриває шлях до біологічних досліджень сполук цього класу. Відзначимо, що досліджена реакція, будучи трикомпонентною, безумовно підходить для синтезу та дослідження комбінаторних бібліотек похідних 7-арил-4,7-дигідро[1,2,4]триазоло- та тетразоло[1,5-a]піримідинів, що містять два електроноакцепторні замісники у положеннях 5 та 6

Impact of inverter controller-based grid-connected pv system in the power quality

In a Grid-Connected Photovoltaic System (GCPS), the inverters are applied for integration with the power grid. This integration brings some issues at the connection point. Therefore, grid-tied inverter control performs a vital role in feeding the power system with good power quality. This study presents a current-controlled Voltage Source Inverter (VSI) strategy for large-scale GCPS generates 1000 kW rated of power. The methodology and structure of the control system are presented. The power quality issues such as harmonics, voltage fluctuation, voltage unbalance, and power factor are limited at the interfacing point into the required limits as imposed by the standards. This study also discusses the controller design and the simulation results are introduced to show its effectiveness. Furthermore, the values obtained may be used to evaluate the power supply quality of various inverter controllers

Review of the Estimation Methods of Energy Consumption for Battery Electric Buses

In the transportation sector, electric battery bus (EBB) deployment is considered to be a potential solution to reduce global warming because no greenhouse gas (GHG) emissions are directly produced by EBBs. In addition to the required charging infrastructure, estimating the energy consumption of buses has become a crucial precondition for the deployment and planning of electric bus fleets. Policy and decision-makers may not have the specific tools needed to estimate the energy consumption of a particular bus network. Therefore, many state-of-the-art studies have proposed models to determine the energy demand of electric buses. However, these studies have not critically reviewed, classified and discussed the challenges of the approaches that are applied to estimate EBBs’ energy demands. Thus, this manuscript provides a detailed review of the forecasting models used to estimate the energy consumption of EBBs. Furthermore, this work fills the gap by classifying the models for estimating EBBs’ energy consumption into small-town depot and big-city depot networks. In brief, this review explains and discusses the models and formulations of networks associated with well-to-wheel (WTW) assessment, which can determine the total energy demand of a bus network. This work also reviews a survey of the most recent optimization methods that could be applied to achieve the optimal pattern parameters of EBB fleet systems, such as the bus battery capacity, charger rated power and the total number of installed chargers in the charging station. This paper highlights the issues and challenges, such as the impact of external factors, replicating real-world data, big data analytics, validity index, and bus routes’ topography, with recommendations on each issue. Also, the paper proposes a generic framework based on optimization algorithms, namely, artificial neural network (ANN) and particle swarm optimization (PSO), which will be significant for future development in implementing new energy consumption estimation approaches. Finally, the main findings of this manuscript further our understanding of the determinants that contribute to managing the energy demand of EBBs networks

Correlation between circulating tumour DNA and metabolic tumour burden in metastatic melanoma patients

Abstract Background Circulating tumour DNA (ctDNA) may serve as a measure of tumour burden and a useful tool for non-invasive monitoring of cancer. However, ctDNA is not always detectable in patients at time of diagnosis of metastatic disease. Therefore, there is a need to understand the correlation between ctDNA levels and the patients’ overall metabolic tumour burden (MTB). Methods Thirty-two treatment naïve metastatic melanoma patients were included in the study. MTB and metabolic tumour volume (MTV) was measured by 18F-fluoro-D-glucose positron emission tomography/computed tomography (FDG PET/CT). Plasma ctDNA was quantified using droplet digital PCR (ddPCR). Results CtDNA was detected in 23 of 32 patients. Overall, a significant correlation was observed between ctDNA levels and MTB (p < 0.001). CtDNA was not detectable in patients with an MTB of ≤10, defining this value as the lower limit of tumour burden that can be detected through ctDNA analysis by ddPCR. Conclusions We showed that ctDNA levels measured by ddPCR correlate with MTB in treatment naïve metastatic melanoma patients and observed a limit in tumour size for which ctDNA cannot be detected in blood. Nevertheless, our findings support the use of ctDNA as a non-invasive complementary modality to functional imaging for monitoring tumour burden