The invention of a commercial route to the Bruton's tyrosine kinase inhibitor branebrutinib (BMS-986195) in four total chemical steps is described. The execution of high-throughput experimentation (HTE) coupled with a first-principles approach across the proposed synthetic route enabled the identification of a novel indolization reaction that rapidly generated high synthetic complexity, as the centerpiece of the synthesis. A parallel HTE strategy during route design enabled the efficient and rapid evaluation of multiple options within a short timeframe to complete rigorous process development while mitigating the risks associated with implementing new chemistry featuring an aggressive disconnection strategy.

The SPYDR lab visit program is a key component in the Chemical and Synthetic Developments campaign on `Safety as Part of Your Daily Routine' (SPYDR) at Bristol-Myers Squibb. This program was initiated in 2013, which has all the senior leaders in Chemical and Synthetic Development organization visiting laboratories to engage in a safety focused discussion with the laboratory occupants. These meetings are not laboratory inspections per se, but are conversations designed to meet with the laboratory scientists in their working environment, to solicit their safety concerns and to engage the scientists in personal discussions. The visits are scheduled on the calendar three times a year, with each senior leader visiting 4-6 laboratories per year. The participation rate is very high (>90%) and feedback from the staff is consistently positive. An innovative online survey system was set-up for the visitor to easily convey the concerns he/she receives, as well as provide an assessment of the laboratory's focus on safety. The Safety Culture Team meets monthly to review the survey results and take action on the concerns. The accomplishments from this initiative are beneficial to resolving many specific safety concerns, facilitating access to safety resources, and dramatically improving the safety culture of our organization.

This final communication, of a nine part publication series, details the process development history for the final synthetic step to prepare the drug substance BMS-663068 tris(hydroxymethyl)aminomethane (TRIS) salt. The challenge of developing a robust commercial process to prepare BMS-663068-TRIS salt (active pharmaceutical ingredient, API) was achieved by studying the underlying mechanisms that governed key processing characteristics. Eliminating a slurry-to-slurry transformation results in predictable reaction kinetics and control of impurity formation. Key powder property aspects, such as specific surface area and bulk density, were controlled by examining the impact of seed age, crystallization relative supersaturation (RSS), and particle attrition due to agitation during drying. Ultimately, the processing parameters established for preparation of this drug substance resulted in the generation of the target compound with consistent quality, powder properties, and yield across multiple batches.

The incorporation of sodium from sodium fluoride in single-crystal CuInSe2 (CIS) is investigated to provide insight into the intra-granular aspects of sodium incorporation in CIS-based thin films. Sodium was incorporated by evaporating NaF onto two CIS crystals of varying compositions and defect structures followed by heating under vacuum. Diffusion profiles show a near-surface reaction before a deeper diffusion zone which follows a complementary error function, confirming Na diffusion into the crystals. Transmission electron microscopy analysis indicates that dislocations do not control the diffusion process. The activation energy of diffusion is ∼0.7 eV for both crystals. This low activation energy suggests that Na diffusion occurs rapidly through the bulk at temperatures as low as 300 °C and helps explain the uniform Na concentration often observed in grain interiors of polycrystalline Cu(InGa)Se2 thin films.

The Na content of (Ag,Cu)(In,Ga)Se2 films was cyclically adjusted using a novel method involving cycles of water rinsing at 60 °C followed by heating in air at 200 °C to remove Na and evaporation of NaF to re-introduce Na back into the film. The low temperatures and short heating times ensure that Na is removed only from grain boundaries while leaving grain interiors unaffected. Cross-grain conductivity and Seebeck coefficient were measured during this removal procedure and both measurements decreased when Na was removed and both recovered upon the re-addition of Na, consistent with an increase in compensating donor defects in the absence of Na. These results demonstrate that Na reversibly affects the electrical properties of grain boundaries. We propose that Na reversibly passivates donor-like defects such as InCu double donors at grain boundaries.

A robust and efficient non-precious metal catalyst for hydrogen evolution reaction is one of the key components for carbon dioxide-free hydrogen production. Here we report that a hierarchical nanoporous copper-titanium bimetallic electrocatalyst is able to produce hydrogen from water under a mild overpotential at more than twice the rate of state-of-the-art carbon-supported platinum catalyst. Although both copper and titanium are known to be poor hydrogen evolution catalysts, the combination of these two elements creates unique copper-copper-titanium hollow sites, which have a hydrogen-binding energy very similar to that of platinum, resulting in an exceptional hydrogen evolution activity. In addition, the hierarchical porosity of the nanoporous copper-titanium catalyst also contributes to its high hydrogen evolution activity, because it provides a large-surface area for electrocatalytic hydrogen evolution, and improves the mass transport properties. Moreover, the catalyst is self-supported, eliminating the overpotential associated with the catalyst/support interface.

The sluggish kinetics of methanol oxidation reaction (MOR) is a major barrier to the commercialization of direct methanol fuel cells (DMFCs). In this work, we report a facile synthesis of platinum-ruthenium nanotubes (PtRuNTs) and platinum-ruthenium-coated copper nanowires (PtRu/CuNWs) by galvanic displacement reaction using copper nanowires as a template. The PtRu compositional effect on MOR is investigated; the optimum Pt/Ru bulk atomic ratio is about 4 and surface atomic ratio about 1 for both PtRuNTs and PtRu/CuNWs. Enhanced specific MOR activities are observed on both PtRuNTs and PtRu/CuNWs compared with the benchmark commercial carbon-supported PtRu catalyst (PtRu/C, Hispec 12100). X-ray photoelectron spectroscopy (XPS) reveals a larger extent of electron transfer from Ru to Pt on PtRu/CuNWs, which may lead to a modification of the d-band center of Pt and consequently a weaker bonding of CO (the poisoning intermediate) on Pt and a higher MOR activity on PtRu/CuNWs.

Electrochemical CO2 reduction is a key reaction for CO2 conversion to valuable fuels and chemicals. Because of the high stability of the CO2 molecule, a catalyst is typically required to minimize the energy input and improve reaction rates needed for device level commercialization. In this paper, we report a nanostructured Zn dendrite catalyst that is able to electrochemically reduce CO2 to CO in an aqueous bicarbonate electrolyte with greatly enhanced properties. The catalytic activity is over an order of magnitude higher than that of bulk Zn counterparts, with a CO faradaic efficiency around 3-fold higher. The stability of the Zn electrode under realistic CO2 electrolysis conditions was explored using scanning electron microscopy and in situ/operando X-ray absorption spectroscopy techniques. The results clearly demonstrate that nanostructured and bulk Zn catalysts are structurally stable at potentials more negative than -0.7 V versus RHE, whereas severe chemical oxidation occurs at more positive potentials.

Despite numerous studies, there is still no definitive explanation on how Na improves Cu(In,Ga)Se2 (CIGS) device efficiency. This paper investigates how the electrical transport properties of CIGS films are affected by the amount of Na at grain boundaries. The controlled removal of Na from CIGS grain boundaries is achieved by rinsing in a water bath at 70°C. Periodically during the rinse, the in-plane conductance and the Seebeck coefficient are measured, and both are found to decrease as Na is removed by the bath. Assuming carrier mobility remains unaffected, a simultaneous decrease in conductivity and Seebeck effect can only be caused by an increase in compensating donor-like defects.

Molybdenum (Mo) coated soda‐lime glass is a commonly used substrate for Cu(InGa)Se 2 solar cells as it also acts as the sodium (Na) source, which improves the efficiency of these devices. In this work, we investigate how oxygen controls the segregation and accumulation of Na on the Mo surface. A direct relationship between the concentration of surface oxygen and the amount of Na accumulation is showed. Values for the surface segregation ratio and grain boundary diffusion coefficient for Na in Mo are obtained by fitting diffusion data at several temperatures to a model for grain boundary diffusion. The results of this model reveal that surface oxygen controls the Na saturation level through its effect on the surface segregation of Na. An activation energy for grain boundary diffusion of Na is estimated and is similar to that of MoO bond dissociation in MoO 3 suggesting the involvement of this bond during Na transport. © 2014 American Institute of Chemical Engineers AIChE J , 60: 2365–2372, 2014

Polarization curves of hydrogen oxidation on a Pt disk, electroplated Ni and CoNiMo multimetallic layer.

The incorporation of Na into Cu(InGa)Se2 (CIGS) based absorber layers is critical for fabricating high efficiency photovoltaic devices. In the present study we show that Na transport through Mo and CIGS from soda-lime glass substrates takes place through the grain boundaries with oxygen playing a critical role. Device performance drops as the Na level in CIGS is reduced but recovers by mild air heat treatment implying that Na plays a major role at the junction and at CIGS grain boundaries within the depletion region. Finally, we present results on the use of NaF as a post-deposition Na source.

The development of low-cost processes for hydrogen production from renewable energy is of tremendous importance for a truly sustainable hydrogen-based energy system. In this article, we demonstrate the ability to utilize sunlight to produce hydrogen from a potentially low-cost and abundant biomass derivative, glucose, using a WO3-based tandem photoelectrochemical cell (PEC). Thin film WO3 photoelectrodes are shown to exhibit excellent photocatalytic activity towards the oxidation of a variety of complex oxygenates, with photocurrents that are nearly equal to those achieved in the presence of simple alcohols such as methanol and ethanol. This result indicates that WO3-based PEC reactors can be used as a feedstock-flexible technology. High performance liquid chromatography and gas chromatography were utilized to analyze glucose degradation and product formation, respectively, showing that glucose is ultimately oxidized to a mixture of CO and CO2 that depends on reaction conditions. These results suggest that the photoelectrode surface and operating conditions may be adjusted to optimize the production of either H-2 or syngas (H-2 + CO). In addition to half-cell measurements, unassisted electrolysis of glucose was demonstrated with a tandem cell device consisting of a WO3 photoelectrode, CdTe bottom cell, and WC counter electrode. Using this tandem configuration, a stable short-circuit current density of 1.38 mA cm(-2) was recorded under outdoor illumination in 0.33 M H2SO4/0.1 M glucose. This PEC device utilizes no precious metal catalysts and shows great potential as a low-temperature pathway towards H-2 and/or syngas production from renewable energy.

The partial hydrogenation of soybean oil was carried out in a novel piston oscillating monolith reactor (POMR). POMR performance was studied under the application of low frequency (0-17.5 Hz) and amplitude (2.5 mm) vibrations at 110 degrees C and 0.41 MPa H-2 using a Pd/Al2O3 monolith catalyst. Results show observed rate improvements of up to 220% for 17.5 Hz, 2.5 mm piston oscillations over low frequency pulsing conditions. For comparison purposes, the reaction was also carried out in a stirred tank reactor using the monolith catalyst. The POMR showed better activity at an equivalent power per unit volume when compared to a stirred tank. With the monolith catalyst, both external and internal mass transfer limitations exist. Using standard diffusion-reaction calculations and measurements over a range of particle sizes it was shown that the vibrations improve external mass transfer rates as well as internal transport within the washcoat. The POMR showed equal or better serial pathway selectivity than a stirred tank, except at the highest frequency, but gave higher trans fatty acid formation.

The catalytic partial hydrogenation of soybean oil and the oxydesulfurization of simulated number 2 diesel were carried out in a novel piston oscillating monolith reactor (POMR). The POMR uses low frequency oscillations to alternate liquidand gas-rich environments in the reactor channels of catalyst monoliths. Even application of low frequency (0-20 Hz) and amplitude (2.5 mm) vibrations results in significant increases in the observed rates of such reactions, well above what can be obtained in stirred tanks operated at equivalent power/volume ratios. A theory of oscillating transport in membranes is employed to explain the results.

Current materials for high temperature H2S removal from gasifier effluents are Znand Ca-based sorbents. These work at temperatures less than typical gasifier (especially biogasifier) effluent temperatures. We are examining sorbents based on Ce/La/M (M = transition metal) oxides and Ce/La/RE (RE = a rare earth) oxide. Reduced Ce/La oxides adsorb H2S at temperatures of 600°C and above, and are regenerable in O2 mixtures. But addition of group VII-VIII transition metals to Ce/LaOx increases the sulfur removal capacity significantly. Addition of oxides such as ZrO2 or a third rare earth oxide increases surface area, sintering resistance of CeOx/La2O3 at high temperatures, and sulfur capacity. These sorbents can be regenerated at temperatures near the operating conditions of gasifiers. They can also be used as tar cracking catalysts for tars formed in the gasifier. The results of some characterization tests, including H2S adsorption / TPD, are presented.