Classical Resolution Research Articles

The First Large-Scale Synthesis of MK-4305: A Dual Orexin Receptor Antagonist for the Treatment of Sleep Disorder

A new synthetic route to drug candidate 1, a potent and selective dual orexin antagonist for the treatment of sleep disorders, has been developed. The key acyclic precursor 10 was prepared in a one-step process in 75% isolated yield from commercially available starting materials using novel chemistry to synthesize 2-substituted benzoxazoles. A reductive amination was followed by a classical resolution to afford chiral diazepane (R)-11. Finally, coupling of (R)-11 with acid 5 furnished the desired drug candidate 1.

Practical Syntheses of a CXCR3 Antagonist

Two new, reliable syntheses of a pyrido[2,3-d]-pyrimidine inhibitor of the CXCR3 receptor are described. A nine-step synthesis of the CXCR3 inhibitor (1) from 2-aminonicotinic acid was demonstrated on a multikilogram scale and incorporates a classic resolution to deliver the enantioenriched active pharmaceutical ingredient (API). A second synthesis of the CXCR3 inhibitor starts from (+)-(D)-Boc alanine and 2-chloronicotinic acid and utilizes a Goldberg coupling. This second synthesis, performed on a gram scale, intersects the former route at a common intermediate thereby completing a formal synthesis of the enantioenriched API in higher overall yield without the need for a resolution.

NO Relaxation Approach (NORA) to predict thermal NO in combustion chambers

In combustion models employing tabulated or global kinetics, the prediction of thermal NO is usually performed by either the direct resolution of Zel’dovich mechanism or the tabulation of the NO reaction rate using a laminar flamelet database and a progress variable representative of the fuel oxidation reactions, for instance temperature or a linear combination of major products mass fractions. It is known that the first method lacks accuracy if radical species such as N or O appearing in the NO reaction rate are not correctly estimated. The second method cannot lead to accurate predictions because NO reactions take place essentially when the fuel oxidation is over, therefore the NO reaction rate shows a very weak correlation with the progress variable. In this paper a new approach called NO Relaxation Approach (NORA), is proposed for the modeling of thermal NO. It allows a high accuracy when coupled with this type of combustion models. With NORA, the NO reaction rate is written as a linear relaxation towards the equilibrium value Y NO eq with a characteristic time τ. Both parameters are tabulated as functions of equivalence ratio, pressure, temperature and dilution mass fraction. NORA is first validated on homogeneous internal combustion engine cases, where it closely fits the complex chemistry results. It is then integrated into the turbulent combustion model ECFM3Z dedicated to piston engine applications. In this model a mixed tabulated (TKI) and global kinetics (CORK) approach is used to describe turbulent combustion. First applications on eight Diesel engine operating points show a good improvement with NORA compared to a classical resolution of Zel’dovich mechanism.

Asymmetric Synthesis of (S)‐2‐Indolinecarboxylic Acid by Combining Biocatalysis and Homogeneous Catalysis

(S)-2-Indolinecarboxylic acid, an intermediate for ACE inhibitors, was until recently produced by Fischer indole synthesis and classical resolution in seven steps. However, Perkin condensation to form ortho-chlorocinnamic acid, which is converted to (S)-ortho-chlorophenylalanine using the enzyme phenylalanine ammonia lyase prior to copper-catalyzed ring closure thereof delivers the enantiopure product in just three steps.

Classical design structure of orthogonal designs with six to eight factors and sixteen runs

AbstractMost two‐level fractional factorial designs used in practice involve independent or fully confounded effects (so‐called regular designs). For example, for 16 runs and 6 factors, the classical resolution IV design with defining relation I = ABCE = BCDF = ADEF has become the de facto gold standard. Recent work has indicated that non‐regular orthogonal designs could be preferable in some circumstances. Inhibiting a wider usage of these non‐regular designs seems to be a combination of inertia/status quo and perhaps the general resistance and suspicion to designs that are computer generated to achieve ‘X–Y–Z’ optimality. In this paper each of the orthogonal non‐isomorphic two‐level, 16 run designs with 6, 7, or 8 factors (both regular and non‐regular) are shown to have a classical‐type construction with a 24 or a replicated 23 starting point. Additional factor columns are defined either using the familiar one‐term column generators or generators using weighted sums of effects. Copyright © 2010 John Wiley & Sons, Ltd.

Beyond the lateral resolution limit by phase imaging

We present a theory to extend the classical Abbe resolution limit by introducing a spatially varying phase into the illumination beam of a phase imaging system. It allows measuring lateral and axial distance differences between point sources to a higher accuracy than intensity imaging alone. Various proposals for experimental realization are debated. Concretely, the phase of point scatterers' interference is experimentally visualized by high numerical aperture (NA = 0.93) digital holographic microscopy combined with angular scanning. Proof-of-principle measurements are presented by using sub-wavelength nanometric holes on an opaque metallic film. In this manner, Rayleighs classical two-point resolution condition can be rebuilt. With different illumination phases, enhanced bandpass information content is demonstrated, and its spatial resolution is theoretically shown to be potentially signal-to-noise ratio limited.

Synthesis of LY503430

LY503430 is a neuroprotective agent that reduces brain damage caused by 6-hydroxydopamine or the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). It is a lead for the treatment of Parkinson’s and ­Alzheimer’s disease, depression and schizophrenia. For a kg-scale synthesis of LY503430 based on a classical resolution, see: N. A. Magnus et al. Org. Process Res. Dev. 2005, 9, 621.

Rational Screening Approach for Classical Chiral Resolution under Thermodynamic Equilibrium: A Case Study of Diphenyl-Substituted N-Methyl-Piperazine

Separation of racemic mixtures by the formation and crystallization of diastereomeric salts (classical resolution) is an important process in the pharmaceutical industry. We have developed and implemented a high-throughput screening workflow to effectively guide the development and optimization of a thermodynamically favored resolution process. A case study is presented for optical resolution of a diphenyl-substituted N-methyl-piperazine derivative, a racemic compound with a eutectic point of 60% ee. Through a rational screening approach, the effect of equilibrium solubility on resolution efficiency was systematically evaluated with regards to resolving agent, solvent composition, resolving agent stoichiometry, and racemate concentration. An isothermal solubility phase diagram was obtained, and solid-state characterization was performed on the diastereomeric salts to understand their phase behaviors under the optimal resolution conditions. The highest resolution efficiency was achieved when the diastereom...

Parallel or classical kinetic resolution of a planar chiral ferrocenylketone through asymmetric reductions

Racemic 1-acetyl-2-methoxymethylferrocene, (±)- 1 was subjected to asymmetric reduction with two different methodologies and complementary results were obtained. When the reduction of (±)- 1 was carried out in the presence of CBS-oxazaborolidine catalyst and BH 3·Me 2S as the hydrogen source, both enantiomers of the substrate were converted with comparable reaction rates and selectivities. The corresponding diastereoisomeric ferrocenylalcohols 3a and 3b were obtained in a 1:1 ratio and >90% enantiomeric excess; this reaction profile being related with a parallel kinetic resolution with high ds 1 and ds 2 diastereofacial selectivities. On the contrary, the transfer hydrogenation of (±)- 1 with HCOOH/triethylamine in the presence of ( R, R)-Noyori’s catalyst proceeded via classical kinetic resolution, so that the formed (−)- 3b or unreacted (+)- 1 could be obtained in highly enantiopure form before or beyond 50% of the substrate conversion, respectively. Alcohol 3b with an (1 R p , S)- or (1 S p , R)-configuration is not easily accessible by the diastereoselective metallation/electrophilic quenching sequence routinely applied in the synthesis of planar chiral ferrocenes. As a result, the described procedures provide a valuable access to this useful starting material for the synthesis of homochiral related derivatives.

Direct enantio-convergent transformation of racemic substrates without racemization or symmetrization

Asymmetric reactions that transform racemic mixtures into enantio-enriched products are in high demand, but classical kinetic resolution produces enantiopure compounds in <50% yield even in an ideal case. Many deracemization processes have thus been developed including dynamic kinetic resolution and dynamic kinetic asymmetric transformation, which can provide enantio-enriched products even after complete conversion of the racemic starting materials. However, these dynamic processes require racemization or symmetrization of the substrates or intermediates. We demonstrate a direct chemical enantio-convergent transformation without a racemization or symmetrization process. Copper(I)-catalysed asymmetric allylic substitution of a racemic allylic ether afforded a single enantiomer of an α-chiral allylboronate with complete conversion and high enantioselectivity (up to 98% enantiomeric excess). One enantiomer of the substrate undergoes an anti-S(N)2'-type reaction whereas the other enantiomer reacts via a syn-S(N)2' pathway. The products, which cannot be prepared by dynamic procedures, have been used to construct all-carbon quaternary stereocentres.

ChemInform Abstract: Hydrolases in Organic Synthesis: Preparation of Enantiomerically Pure Compounds

Esterhydrolases ( Esterases , Lipases ) are highly ( chemo-, regio- and enantio- ) selective biocatalysts for the transformation of racemic and achiral substrates into enantiomerically pure compounds. Numerous examples for their application in the preparation of synthetically useful chiral auxiliaries and building blocks for flavour compounds, pheromones and several pharmaceuticals including 8- adrenergic blockers, antidepressants and ACE inhibitors are presented. The close relationship between biological activity and absolute configuration both in natural products and synthetic materials ( e.g. drugs , agrochemicals ) has prompted considerable efforts regarding the synthesis of enantiomerically pure compounds. They are widely used as - chiral building blocks for biologically active compounds, - auxiliaries and stationary phases for analytical purposes or - chiral ligands for the design of enantioselective catalysts Next to other methods , e.g. classical resolutions via diastereoisomers, asymmetric and I' chiral pool syn- theses enzymes - nature's chiral catalysts - have emerged as highly effective 'I reagents for their prepa- ration. They display highly attractive properties for the solution of synthetic organic problems, some of which are summarized in Fig 1.

Superresolution with seismic arrays using empirical matched field processing

Scattering and refraction of seismic waves can be exploited with empirical-matched field processing of array observations to distinguish sources separated by much less than the classical resolution limit. To describe this effect, we use the term ‘superresolution’, a term widely used in the optics and signal processing literature to denote systems that break the diffraction limit. We illustrate superresolution with Pn signals recorded by the ARCES array in northern Norway, using them to identify the origins with 98.2 per cent accuracy of 549 explosions conducted by closely spaced mines in northwest Russia. The mines are observed at 340–410 km range and are separated by as little as 3 km. When viewed from ARCES many are separated by just tenths of a degree in azimuth. This classification performance results from an adaptation to transient seismic signals of techniques developed in underwater acoustics for localization of continuous sound sources. Matched field processing is a potential competitor to frequency–wavenumber (FK) and waveform correlation methods currently used for event detection, classification and location. It operates by capturing the spatial structure of wavefields incident from a particular source in a series of narrow frequency bands. In the rich seismic scattering environment, closely spaced sources far from the observing array nonetheless produce distinct wavefield amplitude and phase patterns across the small array aperture. With observations of repeating events, these patterns can be calibrated over a wide band of frequencies (e.g. 2.5–12.5 Hz) for use in a power estimation technique similar to frequency-wavenumber analysis. The calibrations enable coherent processing at high frequencies at which wavefields normally are considered incoherent under a plane-wave model.

Coherence versus interferometric resolution

We examine the relation between second-order coherence and resolution in the interferometric detection of phase shifts. While for classical thermal light resolution and second-order coherence are synonymous, we show that for quantum light beams reaching optimum precision second-order coherence and resolution become antithetical.

Kilogram Synthesis of a LFA-1/ICAM Inhibitor

The process development and the kilogram-scale synthesis of BMS-587101 (1) are described. The synthesis features a [3 + 2] azomethine ylide cycloaddition to efficiently build the spirocyclic core in a diastereoselective fashion followed by a classical resolution which affords the desired enantiomer in >98% enantiomeric excess. The target was prepared in four steps in an overall yield of 22%.

Multiscale multiagent architecture validation by virtual instruments in molecular dynamics experiments

A multiagent architecture is proposed in order to build a physics laboratory in virtual reality. Thermodynamics experiments are used for its validation. Classical numerical resolution of thermodynamics problems comes up against the number and variability of boundary conditions. Based on molecular dynamics, a multiagent approach is proposed, resting upon agent spatial and temporal autonomy. This approach grants each particle a capacity to identify its environment using both its own clock and perceptive area. Individual molecular properties are injected into thermal and mechanical models, and macroscopic gas behaviors can be detected and quantified by 3D virtual instruments, created in order to involve the user into the simulation. In order to assess its ability to simulate thermodynamic experiments, our method is applied to classical situations, such as the Joule-Gay Lussac experiment or the maxwellian relaxation in a hard-sphere gas. The simulated gas behavior is in good agreement with theoretical results for gases without interaction. Taking into account the volume of the molecules, our method also allows to quantify the mean free path and the average collision time for Neon and Xenon hard-sphere gases at equilibrium. Dynamic speed relaxation from uniform to maxwellian distribution is simulated successfully, and molecular covolume are also measured with such virtual gases.

Application of Classical Resolution for Separation of DL‐Serine

AbstractFor resolution of chiral compound‐forming substances diastereomeric salt formation is the most important classical separation technique. Diastereomeric salts possess different physical and chemical properties, e.g., solubilities, which facilitate the effective separation via crystallization. A maximum recovery of both diastereomeric salts is usually unachievable when there is a lack of quantitative information regarding solubility and metastable zone width. The present work provides experimental results for the formation of diastereomeric salts of DL‐serine. As basic thermodynamic data binary melting and ternary solubility phase diagrams are shown and discussed. A plan for a series of crystallization processes is suggested for the recovery of both salts in pure form with a maximum possible yield.

An improved synthesis of (1 R,3 S)-3-[( tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid

An improved synthesis of (1 R,3 S)-3-[( tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid from 3-aminobenzoic acid is described utilising milder and more selective conditions. Both a classical salt resolution and an enzymatic approach have been shown to give the desired compound in high selectivity.

Process Development of a Diacyl Glycerolacyltransferase-1 Inhibitor

A synthesis of a selective diacyl glycerolacyltransferase-1 (DGAT-1) inhibitor, 1, is described. The synthesis illustrates a diketone Favorskii reaction on 9 in place of the more common ketoester variant for generation of the dicarboxycyclopentane core, the development of an efficient classical resolution of a key cyclopentyl ketoacid intermediate 4, and an ambient temperature Suzuki−Miyaura coupling which avoids epimerization of the labile aryl ketone of 1.

Convenient Synthesis of Optically Pure 8-Methoxy-2-methyl-1,2,3,4-tetrahydroquinoline and 2-Methyl-1,2,3,4-tetrahydroquinoline

A convenient method was developed to synthesize optically pure 8-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline (2a) and 2-methyl-1,2,3,4-tetrahydroquinoline (2b) by combining the methods of catalytic hydrogenation and classical resolution. the catalytic system ([ru(p-cymene)cl(2)](2)/i(2)) showed high efficiency in preparing racemic 2a and 2b, which were successfully resolved using commercial tartaric acid derivatives, and both enantiomers were obtained in moderate yield with >99% ee.

Subtleties in asymmetric catalyst structure: the resolution of a 6-phospha-2,4,8-trioxa-adamantane and its applications in asymmetric hydrogenation catalysis

An efficient, classical resolution of the versatile P-ligand intermediate 6-phospha-2,4,8-trioxa-adamantane (CgPH) is described and the rhodium complex of the optically pure secondary phosphine beta-CgPH is an active and moderately selective asymmetric hydrogenation catalyst.