Optimization of chemical reactions requires a thorough analysis of reaction products and intermediates over a given time course. Chemical reactions are often analyzed by liquid chromatography-mass spectrometry (LC-MS), but generating LC-MS samples and data analysis is time-consuming and produces a significant amount of waste. We sought to remove the sample preparation and data analysis steps by implementing an iChemExplorer/Agilent LC-MS instrument as our reactor and analysis tool, coupled with an automated report generator of reaction progress over time. Herein, we show that our easy-to-use walk-up automated reaction profiling (WARP) system can sample chemical reactions multiple times to produce a data-rich report of reaction progress over time.

By virtue of its role in cellular proliferation, microtubule-associated serine/threonine kinase-like (MASTL) represents a novel target and a first-in-class (FIC) opportunity to provide a new impactful therapeutic agent to oncology patients. Herein, we describe a hit-to-lead optimization effort that resulted in the delivery of two highly selective MASTL inhibitors. Key strategies leveraged to enable this work included structure-based drug design (SBDD), analysis of lipophilic efficiency (LipE) and novel synthesis. The resulting advanced lead compounds enabled a tumor growth inhibition study which was pivotal in assessing the potential value of MASTL as an oncology therapeutic target.

Immune activating agents represent a valuable class of therapeutics for the treatment of cancer. An area of active research is expanding the types of these therapeutics that are available to patients via targeting new biological mechanisms. Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of immune signaling and a target of high interest for the treatment of cancer. Herein, we present the discovery and optimization of novel amino-6-aryl pyrrolopyrimidine inhibitors of HPK1 starting from hits identified via virtual screening. Key components of this discovery effort were structure-based drug design aided by analyses of normalized B-factors and optimization of lipophilic efficiency.

Tube to tube volume difference presents a challenge in obtaining correct external standard quantitative NMR (esqNMR) results. Deuterium (2H) NMR is easily observable, intrinsically quantitative, present in all samples, free of interfering signals, and insensitive to probe tune/match and sample saltiness. These properties make 2H peak integral an ideal parameter in esqNMR for correcting volume differences between the reference standard and analyte. We demonstrate a novel and practical technique abbreviated as “2H SOLCOR” (2H SOLvent CORrected), where the 2H peak integral from the solvent is used as a universal internal standard to correct volume variations in NMR tubes, thereby improving accuracy and precision of esqNMR method. Herein, this simple yet effective technique is described, and practical considerations for successful implementation are presented. 2H SOLCOR can be applied anywhere esqNMR is used, including where precious samples need to be accurately quantified for qualification as an authentic analytical standard.

Indazoles represent a privileged motif in drug discovery. However, the formation of highly substituted indazoles can require the execution of lengthy synthetic routes with minimal opportunities to introduce diversity. In this report, we disclose the development of a late-stage diversification strategy for the 4- and 5-positions of 4,5,6-trisubstituted indazoles. A regioselective C-H functionalization and subsequent nucleophilic aromatic substitution provide two sequential points of diversification. The synthetic sequence delivers rapid access to an array of 4,5,6-trisubstituted indazoles in only four steps from readily available starting materials.

2-Aminophenyl-1H-pyrazole has been identified as a viable directing group to promote copper(II)-mediated ortho-selective sp2 C-H bond tandem alkynylation/annulation of anilides with terminal alkynes to offer arylmethylene isoindolinones. Meanwhile, copper(II)-mediated ortho-selective sp2 C-H hydroxylation of anilides has also been optimized as the major reaction pathway by using Cu(OAc)2 as the promoter and 1,1,3,3-tetramethylguanidine as an organic base. Recovery of the directing group was achieved by hydrazinolysis for arylmethylene isoindolinones and basic hydrolysis for the hydroxylation products.

Lorlatinib (PF-06463922) is a next-generation small-molecule inhibitor of the orphan receptor tyrosine kinase c-ros oncogene 1 (ROS1), which has a kinase domain that is physiologically related to anaplastic lymphoma kinase (ALK), and is undergoing Phase I/II clinical trial investigations for non-small cell lung cancers. An early goal is to measure the concentrations of this drug in brain tumour lesions of lung cancer patients, as penetration of the blood–brain barrier is important for optimal therapeutic outcomes. Here we prepare both 11 C- and 18 F-isotopologues of lorlatinib to determine the biodistribution and whole-body dosimetry assessments by positron emission tomography (PET). Non-traditional radiolabelling strategies are employed to enable an automated multistep 11 C-labelling process and an iodonium ylide-based radiofluorination. Carbon-11-labelled lorlatinib is routinely prepared with good radiochemical yields and shows reasonable tumour uptake in rodents. PET imaging in non-human primates confirms that this radiotracer has high brain permeability.

The sections in this article are 1 Introduction 2 Simple Theory 3 Experimental Results 4 Conclusions 5 Biographical Sketches Related Articles

The title compound, C8H17NO2·C8H8O3, exists as a complex with the base (pregabalin) in the predicted zwitterion form, based on the pKa differences between the acid and base. The asymmetric unit consists of two molecules of each component. The –NH3 group adopts the standard propeller conformation. The structure forms pairs of hydro­phobic and hydro­philic inter­actions along both the a and c axes.

Recently, trans-disubstituted oxo-aryl-piperidines have been identified as small molecule nonpeptide renin inhibitors for the modulation of hypertension. Herein, we report on the discovery and preparation of a new class of novel cis-disubstituted amino-aryl-piperidines as a mixture of enantiomers that are potent in vitro renin inhibitors and also, possess in vivo antihypertensive activity in a double transgenic mouse model.

Base-promoted cyclization of tert-butyl [2-(benzylideneamino)phenyl]acetate (13a) and subsequent C3-alkylation with allyl bromide affords 3-allyl-2-phenyl-2,3-dihydro-1H-indole-3-carboxylic acid, tert-butyl ester (15b) in high yield as a single diastereomer. This result is contrary to prior publications that describe failed cyclization of an analogous ethyl ester (ethyl [2-(4-methoxybenzylideneamino)phenyl]acetate) under strongly basic conditions. N-Acylation, olefin dihydroxylation, and tert-butyl ester cleavage affords the spirocyclic lactone 18 as a pair of diastereomers. Isolation and characterization of individual diastereomers 18a and 18b are described.

The C-13 principal values of the chemical-shift tensor for fluorene, carbazole, dibenzofuran and dibenzothiophene were determined with the FIREMAT and PHORMAT experiments. Theoretical calculations (DFT) of the tensors were used as an aid to spectral assignment of the tensors, particularly in some positions in which the isotropic chemical shifts were accidentally degenerate. The principal values are discussed in terms of the effects of the heterosubstitutions. Copyright (C) 2001 John Wiley & Sons, Ltd.

The principal values of the C-13 chemical shift tensors and the H-1-C-13 separated-local-field patterns are reported for the all-trans structures with long and short T-1 as well as the more and less mobile amorphous segments in polyethylene. It is shown that the principal values of the chemical shift tensor, and the local H-1 field of the tensor, for the all-trans crystalline structures with long and short T-1 are essentially the same, supporting the previous suggestion by Schmidt-Rohr and Spiess that chain diffusion between the amorphous and the crystalline regions in PE is the primary reason for the multiexponential C-13 T-1 relaxation observed for the all-trans peak observed at 33 ppm. The less mobile amorphous component adopts preferably a trans conformation and undergoes a fast rotation dominantly about the molecular axis at a rate larger than the width of the CH2 group dipolar coupling. The motion involved in the mobile amorphous structure approaches isotropic tumbling, but a modest amount of constrained reorientation remains. Consequently, the C-13-H-1 dipolar coupling is averaged out, but the shift tensor is not totally averaged to its isotropic value.

The phase diagram constructed from differential scanning calorimetry data indicates that the binary mixture of dibenzofuran (DBF) and hexamethylbenzene (HMB) forms a simple eutectic system. Comparative studies of proton T1 values for the annealed and quenched samples show the annealed material can be best described as a two-phase mixed crystals, while a rapidly quenched sample is a combination of a metastable one-phase glass and two-phase mixed crystals. It is found that glass formation is the key to the T1 reduction of DBF in the HMB doping technique reported previously. The interesting trends in the T1 and the relative spin population of DBF is explained with the competition between glass formation and crystalline phase separation.

Using the recently-developed 2D PHORMAT experiment, we have measured accurately and assigned the principal values of the thirteen C-13 chemical shift tensors in 2-methoxydibenzofuran, for which there is no published diffraction structure. A prediction of the conformation of the methoxy group, obtained by comparing the experimental principal values with the corresponding shieldings from ab initio calculations, agrees with a prediction based on the principal values of the unsubstituted parent compound dibenzofuran as modified with empirical methoxy substituent parameters. Both approaches indicate that the methoxy group has a cis conformation relative to the C-1 position, showing the potential of using chemical shift principal values to identify certain structural features of polycrystalline organic samples.

A practical method is described for measuring the principal values of the chemical shift tensors in compounds with very long proton spin-lattice relaxation times (T-1). This technique involves shortening the effective proton T-1 by mixing a compound of interest with another compound having a much shorter T-1 value. The doped mixture, partly consisting of a monophasic glass, allows efficient intermolecular spin diffusion between the two compounds. Using a slow magic-angle turning (MAT) experiment, we have successfully used such mixtures to measure the principal values of the chemical shift tensors of all the carbons in dibenzofuran in just four days. Without using this technique the experimental time required for the pure compound would have been several months.

The magic-angle-turning (MAT) technique introduced by Gan employs slow (approximately 30 Hz) rotation of a powdered sample at the magic angle, in concert with pulses synchronized to 1/3 of the rotor period, to obtain isotropic-shift information in one dimension of a 2D spectrum. The other dimension displays a slow-spinning-sideband powder pattern which, at the low rotor frequencies employed, resembles the stationary-sample powder pattern. The MAT method is very effective for measuring chemical-shift principal values in compounds where spectral overlap precludes the use of 1D methods. Previous MAT implementations are reviewed, and it is shown how a new phase-corrected MAT (PHORMAT) pulse sequence overcomes many of their limitations. This new pulse sequence produces a spinning-sideband-free isotropic-shift spectrum directly as a projection onto the evolution axis with no spectral shearing. Only two purging operations are employed, resulting in a higher signal-to-noise ratio. Pure absorption-absorption-phased 2D spectra are produced. Flat 2D baseplanes result from an echo sequence which delays acquisition until after probe ring down and receiver recovery. The technique used for synchronizing the pulses to 1/3 the rotor period without relying on absolute rotor-frequency stability is described. The PHORMAT spectrum of methyl-α-D-glucopyranoside is presented. The data are analyzed with an emphasis on the quantitative accuracy of the experiment in measuring chemical-shift-tensor principal values and determining the relative number of spins of each type present. The FID data from the spectrometer acquisition are fitted with numerical simulations that employ a banded-matrix method for calculating spinning-sideband amplitudes. The chemical-shift principal values, measured in methyl-α-D-glucopyranoside with the PHORMAT method, are compared with those from a single-crystal determination of the full chemical-shift tensors. The two measurements differ by an RMS-average distance of only 0.57 ppm.

One of the important contributions of high resolution {sup 13}C CP/MAS to coal science is the measurement of the structural parameters of coal. It has been demonstrated that the structural parameters directly derived from {sup 13}C CP/MAS experiments can be utilized to predict the details of coal devolatilization and char formation processes. One of the advantages of spinning a solid sample at the magic angle is the reduction of the line broadening contributions due to the chemical shift anisotropy (CSA). The chemical shift anisotropy is proportional to the strength of the external magnetic field and the CSA of aromatic carbons (200-240 ppm) is greater than that of the aliphatic carbons (20-100 ppm). When the sample is spun at the magic angle the CSA induced powder patterns break up into spinning sidebands and, in order to obtain a {sup 13}C CP/MAS spectrum in which the aromatic carbon sidebands do not overlap the aliphatic carbon signals, it is necessary to spin the sample at approximately 4 KHz at a magnetic field of 2.35 Tesla. At a higher magnetic field strength a greater spinning rate is required. High speed magic angle spinning not only reduces the contributions of the spinning side bands butmore » it also destroys very useful information on the local electronic environment that is embedded in the principal values of the CSA tensors.« less

The overall goal of our work during the last five years has been the non-destructive elucidation of molecular structure in coal and coal-derived materials. Special emphasis has been placed on determining the concentration and molecular forms of organic sulfur in coal. Our approach has been to use the naturally occurring unpaired electrons in coal as reporters of their environment, making use of electron magnetic resonance (EMR) spectroscopy to develop a detailed picture of the types and arrangements of atoms {open_quotes}seen{close_quote} by the electrons. During this period, we constructed the first 95 GHz (W-band) EMR spectrometer in the USA (and the second in the world). With this advanced spectrometer, we were the first to discover that the aromatic sulfur in coal produced a unique EMR signature. Extensive experimental and theoretical work on model aromatic sulfur compounds in the thiophene series (thiophene, benzothiophene, dibenzothiophene, etc.) has enabled us to develop a detailed understanding of the relationships between the molecular and electronic structure of these compounds and their EMR spectra This new basic scientific knowledge in turn allowed us accurately to analyze the W-band EMR spectra from coal, desulfurized coal, and a variety of coal derived materials. We developed an automated computer programmore » (based on spin quantum mechanics) which can analyze the EMR spectra and which reports the aromatic sulfur content of the coal as well as key spectral parameters. This analysis method has been tested on coal blends of know sulfur content as well as on a variety of coals from the IBCSP and elsewhere.« less