Deucravacitinib (BMS-986165) is a deuterated small-molecule TYK2 inhibitor developed for the treatment of numerous autoimmune disorders. While the first-generation discovery chemistry route to access deucravacitinib was concise and sufficient to access kilogram quantities of API, impurity control and cost-of-goods concerns necessitated the design of a new route. Once a new route was identified and demonstrated, each step was optimized for yield, purity, robustness, and sustainability. Key accomplishments include (1) the development of a novel cyclocondensation under mild conditions to afford a methylated 1,2,4-triazole with excellent regiocontrol, (2) the development of safe, homogeneous conditions to quench POCl3 following chlorination of a substrate that is sensitive to nucleophilic and basic conditions, (3) the discovery of a robust, scalable "dual-base" palladium-catalyzed C–N coupling reaction, and (4) mechanistic understanding to inform control strategies for a number of process-related impurities in an API step amidation mediated by EDC. Ultimately, the optimized commercial route was successfully scaled up to afford more than a metric ton of deucravacitinib for clinical and commercial use.

The reaction optimization of an alkylation to enable the production of the penultimate intermediate of an HIV attachment inhibitor candidate is described. To address the challenges associated with the reactivity and stability of di-tert-butyl(chloromethyl) phosphate (2), and the poor solubility and reactivity of the starting BMS-626529-Li salt (1), strategic selection of Et4NI and 325 mesh K2CO3 as additives, and wet CH3CN as solvent were required. An aqueous workup protocol was also developed to selectively remove an undesired N-6 alkylation isomer. The final processing conditions resulted in the isolation of the penultimate compound 3 in 70% yield with high purity.

A practical, high yielding procedure for the efficient preparation of toluene solutions of ethyl diazoacetate (EDA) from ethyl glycinate is described. The process incorporates extensive safety studies related to the preparation and handling of a carcinogenic and explosive reagent. In addition, a safe neutralization process for the excess EDA and waste streams were developed. EDA was successfully made as a solution in toluene from three 175-kg batches of ethyl glycinate.

A prior study in New York City observed that airborne concentrations of three metals found in steel – iron, manganese, and chromium – are more than 100 times higher in the subway system than in aboveground air. To investigate the potential for health effects of exposure at these levels, we conducted a pilot study of subway workers comparing personal exposures to steel dust with biomarkers of metal exposure, oxidative stress, and DNA damage in blood and urine samples. Workers wore a personal air sampler operating at 4 L/m for one to three work shifts with blood and urine samples collected at the end of the final shift. We found that PM2.5 exposures varied among subway workers on the basis of job title and job activity. The subway workers’ mean time-weighted PM2.5 exposure was 52 μg/m3, with a median of 27 μg/m3, and a range of 6–469 μg/m3. The observed concentrations of PM2.5, iron, manganese, and chromium fell well below occupational standards. Biomarker concentrations among the 39 subway workers were compared with a group of 11 bus drivers, and a group of 25 suburban office workers. Concentrations of DNA–protein crosslinks and chromium in plasma were significantly higher in subway workers than in bus drivers, but no significant difference was observed for these biomarkers between subway workers and office workers. Urinary isoprostane concentrations were significantly correlated with the number of years working in the subway system, and were detected at higher, though not significantly higher, concentrations in subway workers than in bus drivers or office workers. At the group level, there was no consistent pattern of biomarker concentrations among subway workers significantly exceeding those of the bus drivers and office workers. At the individual level, steel dust exposure was not correlated with any of the biomarkers measured.

Arsenic is a prevalent contaminant at US Superfund sites where remediation by pump and treat systems is often complicated by slow desorption of As from Fe and Al (hydr)oxides in aquifer solids. Chemical amendments that either compete with As for sorption sites or dissolve Fe and Al (hydr)oxides can increase As mobility and improve pump and treat remediation efficiency. The goal of this work was to determine optimal amendments for improving pump and treat at As contaminated sites such as the Vineland Chemical Co. Superfund site in southern New Jersey. Extraction and column experiments were performed using As contaminated aquifer solids (81 ± 1 mg/kg), site groundwater, and either phosphate (NaH(2)PO(4)·H(2)O) or oxalic acid (C(2)H(2)O(4)·2H(2)O). In extraction experiments, phosphate mobilized between 11% and 94% of As from the aquifer solids depending on phosphate concentration and extraction time (1 mM-1 M; 1-24 h) and oxalic acid mobilized between 38 and 102% depending on oxalic acid concentration and extraction time (1-400 mM; 1-24 h). In column experiments, phosphate additions induced more As mobilization in the first few pore volumes but oxalic acid was more effective at mobilizing As overall and at lower amendment concentrations. At the end of the laboratory column experiments, 48% of As had been mobilized from the aquifer sediments with 100 mM phosphate and 88% had been mobilized with 10 mM oxalic acid compared with 5% with ambient groundwater alone. Furthermore, simple extrapolations based on pore volumes suggest that chemical treatments could lower the time necessary for clean up at the Vineland site from 600 a with ambient groundwater alone to potentially as little as 4 a with 10 mM oxalic acid.

The determination of both the normal and tangential components of the total velocity is important in the study of cross- and along-isopycnal transport processes in the ocean. A pattern-matching method is used to determine objectively the total velocity. Sensitivity of this method to pattern and search tile sizes and to correlation threshold also is examined. Three methods for estimating the cross-isopycnal or normal component of the total flow are compared and discussed: Marr-Ullman, optical flow and minimum norm. It is also shown that optical flow and minimum norm are equivalent when the parameter-alpha in the optical flow formulation is set to zero. The direct computation of the tangential component is not possible because it lies in the null-space of the solution set of the basic constraint equations used in velocity estimation methods which are based on the rate of change of image brightness (or temperature). A new method for indirectly estimating the tangential component of the total flow based on vector subtracting of the total flow and the nor-mal component of flow is introduced. Several sequences of satellite images are analysed and the resulting total flow. normal component of flow, and the tangential component determined using this new method are consistent with motion inferred from edge maps. Recommendations are then made for the best normal component of flow to use in the determination of the tangential component.

Iron flocculate or "floc" deposits are commonly observed in groundwater discharge zones downgradient of unlined solid waste landfills. Bright orange in color and composed predominantly of amorphous iron oxyhydroxides, these deposits generally have been regarded as aesthetically undesirable but environmentally benign. In recent years, there has been increased awareness of the widespread occurrence of elevated arsenic in reducing groundwaters. Research carried out at municipal landfills in New England indicates that naturally occurring arsenic exhibits redox-mediated mobility and is frequently associated with reduced iron as a dissolved constituent in leachate-impacted groundwaters. If iron precipitates in discharge zones where reduced groundwaters are exposed to atmospheric oxygen, it follows that arsenic may co-precipitate with iron in these areas. To assess the prevalence of arsenic as a constituent of iron floc deposits, samples were collected at seven landfills and at one natural mineral spring in the lower Hudson Valley of southeastern New York State. At six of seven landfill sites, arsenic concentrations exceeded 33 mg/kg, which represents the "severe effects level" for aquatic life as identified in New York State regulatory guidance for screening contaminated sediments. These results indicate that arsenic contamination is of potential concern for downgradient of landfills wherever iron-stained leachate discharges are observed. Sampling and analysis of iron flocs associated with such leachates could also provide a means of identifying landfills that may present risks of arsenic contamination to downgradient water supply wells, especially in cases where groundwater monitoring wells are not available for sampling.

Maps of mean monthly surface temperature and precipitation for Alaska and adjacent areas of Canada, produced by Oregon State University's Spatial Climate Analysis Service (SCAS) and the Alaska Geospatial Data Clearinghouse (AGDC), were analyzed. Because both sets of maps are generally available and in use by the community, there is a need to document differences between the processes and input data sets used by the two groups to produce their respective set of maps and to identify similarities and differences between the two sets of maps and possible reasons for the differences. These differences do not affect the observed large-scale patterns of seasonal and annual variability. Alaska is divided into interior and coastal zones, with consistent but different variability, separated by a transition region. The transition region has high interannual variability but low long-term mean variability. Both data sets support the four major ecosystems and ecosystem transition zone identified in our earlier work. Differences between the two sets of maps do occur, however, on the regional scale; they reflect differences in physiographic domains and in the treatment of these domains by the two groups (AGDC, SCAS). These differences also provide guidance for an improved observational network for Alaska. On the basis of validation with independent in situ data, we conclude that the data set produced by SCAS provides the best spatial coverage of Alaskan long-term mean monthly surface temperature and precipitation currently available.

The United States Clean Air Act Amendments of 1990 reflected increasing concern about potential effects of low-level airborne metal exposure on a wide array of illnesses. Here we summarize results demonstrating that the New York City (NYC) subway system provides an important microenvironment for metal exposures for NYC commuters and subway workers and also describe an ongoing pilot study of NYC transit workers' exposure to steel dust. Results from the TEACH (Toxic Exposure Assessment, a Columbia and Harvard) study in 1999 of 41 high-school students strongly suggest that elevated levels of iron, manganese, and chromium in personal air samples were due to exposure to steel dust in the NYC subway. Airborne concentrations of these three metals associated with fine particulate matter were observed to be more than 100 times greater in the subway environment than in home indoor or outdoor settings in NYC. While there are currently no known health effects at the airborne levels observed in the subway system, the primary aim of the ongoing pilot study is to ascertain whether the levels of these metals in the subway air affect concentrations of these metals or related metabolites in the blood or urine of exposed transit workers, who due to their job activities could plausibly have appreciably higher exposures than typical commuters. The study design involves recruitment of 40 transit workers representing a large range in expected exposures to steel dust, the collection of personal air samples of fine particulate matter, and the collection of blood and urine samples from each monitored transit worker.

The behaviors of dissolved arsenic and iron are significantly decoupled in groundwaters beneath a closed landfill in southern Maine and in laboratory experiments using these groundwaters. At this site naturally-occurring arsenic is mobilized from the glacial sediments under reducing conditions induced and promoted by landfill leachate. Differences in arsenic and iron behavior were seen in laboratory titration experiments which progressively oxidize groundwater from this site and in field data for groundwater composition in the area surrounding this former landfill. The persistence of elevated levels of dissolved arsenic in groundwaters where dissolved iron is relatively low provides direct indication of the difficulty of preventing transport of arsenic from this type of site.

Measurements of natural and man-made radionuclides have been used >,o trace fine-grained sediment accumulation throv?,ghout the Hudson River system. The results, when combined with measurements of particle-associated pollutants, such as P^Bs, chlorinated hydrocarbon pesticides, and trace metals, provide information on the sources, transport, distribution, history, and fate of these contaminants. This technique has proven quite useful for monitoring contaminant levels in natural water systems and assessing the effect of various remedial actions, particularly the "no-action" alternative.