The primary limitations of the quantitative analysis of thermally labile halogenated compounds by traditional gas chromatography (GC) are the inadequacy of identifying the insufficiently volatile ...impurity (often with a high boiling point) and the difficulty in obtaining a standard substance with a reliable standardized assay. Taking the 4-(Chloromethyl)-5-methyl-1,3-dioxol-2-one (DMDO-Cl, 1) as an example, we reported a triphenylmethanamino-derivatization method to overcome the challenges of the assay determination of such species. During the quantification of 1, the presence of GC-undetectable polymeric impurity 10 poses a critical challenge in assessing the material quality. Moreover, the standard substance of 1 is not available on the market due to its inherent instability during storage and handling, further complicating the quantitative analysis. In this work, a precolumn HPLC-UV derivatization method based on triphenylmethanamino-alkylation was developed to quantitatively analyze 1. The resulting derivative 2 exhibits excellent crystallinity and superior physical and chemical stability and possesses effective chromophores for UV detection. The conversion from analyte 1 to derivative 2 demonstrates desirable reactivity and purity, facilitating quantitative analysis using the external standard method. The chemical derivatization-chromatographic detection method was optimized and validated, demonstrating its high specificity, good linearity, precision, accuracy, and stability. This method offers a valuable alternative to the general quantitative NMR (qNMR) detection technique, which exhibits reduced specificity in the presence of increased levels of impurities in compound 1.
The article presents a process research study of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (1), a crucial intermediate in the synthesis of baloxavir marboxil. The original four-step sequence ...exhibited various limitations, such as low yield (43%), the use of problematic solvents, a large excess of costly reagents, safety concerns, and impurity control difficulties. To address these challenges, process optimization was carried out to achieve the desired goals for large-scale industrial production. Optimization of the enamine 4b synthesis was performed, resulting in the development of an azeotropic removal method for the byproduct methanol. This improvement led to minimized ring-opening impurity 15 and a significant reduction in the consumption of the condensation reagent. Furthermore, a simplified one-pot two-step oxidation sequence was devised to streamline the process for the synthesis of compound 1. This optimization involved controlling the formation of hydrolytic impurity 16 and its downstream aldol condensation form 17. The optimized process was successfully demonstrated on a 600 g scale with a product purity of 99.9%, and the overall yield was substantially improved, rising from 43 to 66%.
Trityl olmesartan ethyl ester (TOEE), a key intermediate of the launched angiotensin II receptor blocker olmesartan medoxomil, was built using two blocks via an N-alkylation reaction, wherein the ...imidazole N-1 isomer of this intermediate was the only isomeric product reported previously. Unexpectedly, from a sample of laboratory trials, an undesired impurity (a level of 0.2–0.3%) sharing the same molecular mass with TOEE was detected and assumed to be an N-3 regioisomeric impurity of TOEE. Accordingly, a five-step lactone ring-opening synthetic route was designed and successfully used to obtain this impurity, whose structure perfectly matched the NMR and mass spectra. Subsequent characterization by SCXRD directly confirmed the initial speculation of it being an N-3 regioisomer, which was reported for the first time. Next, two downstream impurities toward the active pharmaceutical ingredient (API) were synthesized, in which the N-3 impurity of API proved to be inseparable with the API molecule under the European Pharmacopoeia chromatography method, introducing a risk of impurity identification. Sequential investigations focusing on impurity tracing and control strategies of the downstream impurities were conducted to meet the quality control requirements.
The development of noble-metal-free heterogeneous catalysts that can realize the aerobic oxidation of C-H bonds at low temperature is a profound challenge in the catalysis community. Here we report ...the synthesis of a mesoporous Mn0.5Ce0.5Ox solid solution that is highly active for the selective oxidation of hydrocarbons under mild conditions (100-120 °C). Notably, the catalytic performance achieved in the oxidation of cyclohexane to cyclohexanone/cyclohexanol (100 °C, conversion: 17.7%) is superior to those by the state-of-art commercial catalysts (140-160 °C, conversion: 3-5%). The high activity can be attributed to the formation of a Mn0.5Ce0.5Ox solid solution with an ultrahigh manganese doping concentration in the CeO2 cubic fluorite lattice, leading to maximum active surface oxygens for the activation of C-H bonds and highly reducible Mn(4+) ions for the rapid migration of oxygen vacancies from the bulk to the surface.
The conventional enhancement-and-perturbation approach to establishing Gaussian extremal inequalities is refined via a novel monotone path argument in the product probability space. This refined ...approach is illustrated with simplified/corrected proofs of the Liu-Viswanath extremal inequality and a vector generalization of Costa's entropy power inequality. The power of this refinement is further demonstrated by characterizing two information-theoretic limits, namely, the capacity region of the multiple-input multiple-output (MIMO) Gaussian broadcast channel with private and common messages and the rate-distortion-equivocation function of vector Gaussian secure source coding, which have previously resisted the attack of the conventional approach.
In order to reduce the solar absorption of pavement and accelerate the downward heat conduction, two bidirectional heat induced structures were designed, one named G-BHIS (only gradient thermal ...conductivity) and the other named G + R-BHIS (the combination of gradient thermal conductivity and heat reflective layer). Compared with the contrast structure, the heat absorption was reduced by 12.73% for the G-BHIS and 35.02% for the G + R-BHIS, respectively. The heat accumulation within the pavement was reduced by 15.9% for the G-BHIS and 37.6% for the G + R-BHIS, respectively. The coupling effect of the decreased heat absorption and accumulation reduced pavement temperature. The maximum temperature differences, 2.38 °C (for the G-BHIS) and 7.76 °C (for the G + R-BHIS), both appeared at the depth of 4 cm. Rutting results showed that the maximum rutting depth could be reduced by 41.0% for the G-BHIS and 65.0% for the G + R-BHIS, respectively. The two structures are expected to decrease heat accumulation and reduce pavement temperature, and furthermore, reducing rutting.
•The designed structures can prevent heat into the pavement.•They can allow the heat in the pavement fast to conduct to the base layer.•Pavement temperature can get reduced and rutting problem can also be solved.
OBJECTIVE Uncertainty remains regarding the predictive value of various glycemic measures as they relate to the risk of diabetes and its complications. Using the cutoffs recommended by the American ...Diabetes Association’s 2010 criteria, we determined the associations of fasting plasma glucose (FPG), 2-h postload glucose (2h-PG), and HbA1c with the outcomes. RESEARCH DESIGN AND METHODS Baseline medical history, FPG, 2h-PG, and HbA1c were obtained from a population-based cohort of 193,846 adults aged ≥40 years in China during 2011–2012. A follow-up visit was conducted during 2014–2016 in order to assess incident diabetes, cardiovascular disease (CVD), cancer, and mortality. RESULTS We documented 8,063 cases of diabetes, 3,014 CVD-related events, 1,624 cases of cancer, and 2,409 deaths during up to 5 years of follow-up. Multivariable-adjusted risk ratios (95% CIs) of diabetes associated with prediabetes based on FPG of 100–125 mg/dL, 2h-PG of 140–199 mg/dL, or HbA1c of 5.7–6.4% (39–47 mmol/mol) were 1.60 (1.43–1.79), 2.72 (2.43–3.04), and 1.49 (1.36–1.62), respectively. Restricted cubic spline analyses suggested J-shaped associations of FPG, 2h-PG, and HbA1c levels with CVD, cancer, and mortality. Multivariable-adjusted hazard ratios (95% CIs) associated with untreated diabetes based on FPG ≥126 mg/dL, 2h-PG ≥200 mg/dL, or HbA1c ≥6.5% (48 mmol/mol) were 1.18 (1.05–1.33), 1.31 (1.18–1.45), and 1.20 (1.07–1.34) for CVD; 1.10 (0.92–1.32), 1.44 (1.25–1.67), and 1.08 (0.92–1.28) for cancer; and 1.37 (1.20–1.57), 1.57 (1.41–1.76), and 1.33 (1.17–1.52) for mortality, respectively. 2h-PG remained significantly associated with outcomes in models including FPG and HbA1c as spline terms. Furthermore, 2h-PG significantly improved the ability of the C statistic to predict diabetes, CVD, and mortality. CONCLUSIONS 2h-PG remains independently predictive of outcomes in models including FPG and HbA1c. Therefore, in addition to FPG and HbA1c, routine testing of 2h-PG should be considered in order to better assess the risks of outcomes.
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