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Christopher J Welch

Publications and source records attributed to Christopher J Welch.

16 recordsLinked to original sources
PubMed2007

Fast methods of enantiopurity determination for the Soai reaction: towards a general enantioenrichment detector?

The Soai reaction system possesses a remarkable combination of characteristics (enantioselective autocatalysis, strong positive nonlinearity leading to asymmetric amplification, ability to be triggered by wide variety of exogenous enantioenriched materials) that make it a potential starting point for a generalized detector for enantioenrichment. In this study we apply standard approaches used in pharmaceutical process research to the problem of developing a rapid method for analysis of the enantiopurity of the Soai reaction product. Several methods for rapid analysis (<1 min per sample) are described, including an approach using chiral supercritical fluid chromatography (SFC) and an approach using achiral chromatography with circular dichroism (CD) detection. Some thoughts on incorporation into a device for generalized enantioenrichment detection are presented.

Chromatography, High Pressure Liquid↗
PubMed2007

Investigation of the stability of Chiralpak AD chiral stationary phase under various solvent conditions and development of a method to identify stationary phase-derived polymer contamination.

The stability of Chiralpak AD chiral stationary phase under various solvent conditions was investigated. An analytical method for the detection of the presence of solubilized Chiralpak AD coating was developed using CD spectroscopy (CD signal at 245 nm). In addition, NMR analysis of the solubilized polymer revealed a characteristic signal for the 3,5-dimethylphenyl carbamate methyl protons at around 2.5 ppm. Both of these methods may be helpful in detecting contamination by the Chiralpak AD polymer or in the study of CSP solvent compatibility.

Journal Article↗
PubMed2007

Solving multicomponent chiral separation challenges using a new SFC tandem column screening tool.

A tool for improved tandem column chiral supercritical fluid chromatography (SFC) method development screening was prepared by modification of a commercial analytical SFC instrument with two different software-controllable, six position high-pressure column selection valves, each controlling a bank of five different columns and a pass through line. The resulting instrument, which has the ability to screen 10 different individual columns and 25 different tandem column arrangements, is a useful tool for facilitating the screening of tandem column SFC arrangements for separation of complex mixtures of stereoisomers or other multicomponent mixtures. Strategies for optimal use of the instrument are discussed, and several examples of the use of the instrument in developing tandem SFC methods for resolution of multicomponent mixtures are presented.

Chromatography, Supercritical Fluid↗
PubMed2006

Determination of the enantiomeric excess of an M3 antagonist drug substance by chemometric analysis of the IR spectra of different guest-host complexes.

A novel approach for the potential on-line determination of the enantiomeric excess (ee) of an M3 antagonist drug substance combining attenuated total reflectance infrared (ATR-IR) spectroscopy, guest-host complexes, and chemometric data analysis is described. Chiral recognition through a formation of diastereomeric complexes was measured by ATR-IR. Small changes on the IR spectra reflect the interaction between the guest (M3) and host (chiral selector). These changes are measured as a function of M3 enantiomer excess. The standard error of prediction is 1.3 ee%. The prediction results based on the IR method were in good agreement with the gravimetric method. The robustness of the calibration model was evaluated by varying the concentration of the chiral selector, the pH of the solution, and the organic solvents. The stability of the calibration model was also demonstrated through measuring different sets of samples on different days.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2006

Identification and characterization of isomeric intermediates in a catalyst formation reaction by means of speciation analysis using HPLC-ICPMS and HPLC-ESI-MS.

Information on chemical speciation is much needed in mechanistic and kinetic studies on catalyst formation processes in pharmaceutical research. Speciation analysis was applied to the identification and quantification of various rhodium species involved in a ligand exchange process leading to formation of catalyst dirhodium(II) tetrakis[methyl 2-oxopyrrolidin-5(S)-carboxylate]. Inductively coupled plasma mass spectrometry (ICPMS) was used as an element-specific detector following species separation by reversed-phase high-performance liquid chromatography (RP-HPLC), and electrospray ionization mass spectrometry (ESI-MS) was used for species identification and confirmation. A novel interface between the HPLC and ICPMS, which consisted of an eluent splitter, a desolvation unit, and the ICPMS built-in peristaltic pump, enabled the use of RP-HPLC with gradient elution and up to 100% organic components in the LC eluent without organic loading in the plasma. A variety of reaction intermediates were identified and quantified along the pathway to formation of the desired product, including isomeric di-, tri-, and tetrasubstituted species previously believed to be absent. This has provided new insights into the mechanism and kinetics of the reaction. The combination of HPLC-ICPMS and HPLC-ESI-MS has proven to be a valuable tool for the investigation of species evolution in catalyst formation process.

Catalysis↗
PubMed2006

Multiparallel chiral method development screening using an 8-channel microfluidic HPLC system.

The Eksigent Express 800 8-channel microfluidic HPLC system was investigated for carrying out multiparallel screening and development of fast normal phase chiral separations. In contrast to the familiar automated sequential chiral method development approaches that often afford a next day result, the multiparallel approach offers the exciting possibility of near "real time" method development, often affording an optimized method in less than 1 h. In this study, four column types (300 microm i.d.) with two different mobile phases are screened using a universal standard gradient approach. Interestingly, parallel method optimization following initial screening was shown to sometimes lead to surprising and unanticipated outcomes, emphasizing the value of the multiparallel screening approach. A variety of standard test racemates were analyzed, with optimized separation methods for most in the 1- to 2-min range. These results compare favorably with results obtained on a single channel conventional HPLC system using 4.6-mm i.d. columns. In addition, isocratic methods developed on the microbore columns are readily translated to the larger column format.

Benzoin↗
PubMed2005

Determination of enantiomeric composition of (-)-(R)-2-tert-butyltetrahydroimidazolidin-4-one by polarimetry, 1H NMR, and chiral SFC.

Partial resolution of rac-2-tert-butyltetrahydroimidazolidin-4-one was carried out by recrystallization of diastereomeric salts. The enantiomeric composition of enriched samples was estimated by polarimetry, (1)H NMR, and chiral SFC. Enantiomeric composition estimated by polarimetry or by (1)H NMR was directly proportional to that estimated by chiral SFC. The occurrence of solute self-association in chloroform was detected through measurements of optical and specific rotation at variable concentration of (-)-(R)-2-tert-butyltetrahydroimidazolidin-4-one. Our data suggest that solute self-association in chloroform might be independent of enantiomeric composition.

Chromatography, Liquid↗
PubMed2004

Species differential stereoselective oxidation of a methylsulfide metabolite of MK-0767 [(+/-)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethyl)phenyl]methyl]benzamide], a peroxisome proliferator-activated receptor dual agonist.

MK-0767 [(+/-)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethyl)phenyl]methyl]benzamide], a thiazolidinedione (TZD)-containing peroxisome proliferator-activated receptor agonist, is a rapidly interconverting racemate that possesses a chiral center at the five position of the TZD ring. M25 is a methyl sulfide metabolite generated from MK-0767 following CYP3A4-mediated TZD ring opening and subsequent methylation of the sulfide intermediate M22. M25, a major in vitro and in vivo metabolite, was further metabolized in liver microsomes to the methyl sulfoxide amide (M16) with two chiral centers and the methyl sulfone amide (M20) with one chiral center. Previous studies demonstrated that both CYP3A4 and flavin monooxygenase-3 (FMO3) catalyzed the formation of M16, whereas M20 was formed exclusively by CYP3A4. The relative contribution of CYP3A4 and FMO3 in the formation of M16 in human and preclinical species was evaluated by chiral analysis using supercritical fluid chromatography. No stereoselectivity was observed in incubations of M25 with human and rhesus liver and recombinant CYP3A4 microsomes, whereas a high degree of stereoselectivity (63 to >99% enantiomeric excess) was observed in rat and dog liver and human recombinant FMO3 microsomes. Also, polyclonal anti-rat CYP3A2 antibody and cytochrome P450 (P450) chemical inhibitors did not inhibit the oxidation of M25 in rat liver microsomes. Furthermore, M25 oxidation was more sensitive to heat inactivation at pH 8 and 8.7 in rat and dog liver microsomes than in human and monkey liver microsomes, consistent with the species difference in involvement of FMOs. Collectively, these results indicated that S-oxidation of M25 was catalyzed primarily by P450 enzymes in human and monkey liver microsomes and by FMO enzymes in rat and dog liver microsomes.

Animals↗
PubMed2004

Effective use of preparative chiral HPLC in a preclinical drug synthesis.

Access to a key 3-aryl-delta-lactone intermediate in enantiopure form using preparative chiral chromatography allowed expedited preparation of an important drug discovery target. A preclinical drug discovery strategy that combines rapid route discovery with effective use of preparative chiral chromatography can result in significant savings of both time and labor.

Amides↗
PubMed2003

Reactive resin facilitated preparation of an enantiopure fluorobicycloketone.

A facile preparation of enantiopure ethyl (1S,5S,6S)-6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylate is described. The key feature of the synthesis involves copper-catalyzed enantioselective intramolecular cyclopropanation of a diazoketone to form endo-fluorocyclopropane in a single operation. Removal of a problematic chloroketone impurity using a reactive resin treatment enabled a high throughput enantiopurity upgrade by chiral HPLC. The development of a scalable synthesis of is presented, including details of the selection of catalyst and ligand optimization, incorporation of a reactive resin treatment and selection of chiral HPLC media and conditions.

Journal Article↗
PubMed2003

Is it possible to estimate the enantioselectivity of a chiral catalyst from its racemic mixture?

The evaluation of a racemic catalyst was investigated in the case of oxazaborolidine (OAB)-catalyzed borane reduction of 1,5-diphenyl-1,5-pentanedione, giving the corresponding diol. On the basis of the diastereoselectivity of the diols, it is possible to estimate the enantioselectivity (ee) of the first step, which correlates well with the ee in the reaction of the structurally similar phenyl n-pentyl ketone with enantiopure OAB catalyst. The measure of diastereoselectivity could be a tool for screening racemic catalysts without the need for resolving the individual enantiomers, if in the second step of the process there is no substrate control and no catalyst scrambling.

Journal Article↗
PubMed2003

Efficient synthesis of NK(1) receptor antagonist aprepitant using a crystallization-induced diastereoselective transformation.

An efficient stereoselective synthesis of the orally active NK(1) receptor antagonist Aprepitant is described. A direct condensation of N-benzyl ethanolamine with glyoxylic acid yielded a 2-hydroxy-1,4-oxazin-3-one which was activated as the corresponding trifluoroacetate. A Lewis acid mediated coupling with enantiopure (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol afforded a 1:1 mixture of acetal diastereomers which was converted into a single isomer via a novel crystallization-induced asymmetric transformation. The resulting 1,4-oxazin-3-one was converted via a unique and highly stereoselective one-pot process to the desired alpha-(fluorophenyl)morpholine derivative. Interesting and unexpected [1,2]-Wittig and [1,3]-sigmatropic rearrangements were identified during the optimization of these key steps. In the final step, a triazolinone side chain was appended to the morpholine core. The targeted clinical candidate was thus obtained in 55% overall yield over the longest linear sequence.

Aprepitant↗
PubMed2003

Studies on the racemization of a stereolabile 5-aryl-thiazolidinedione.

The enantiomers of the stereolabile peroxisome proliferator-activated receptor (PPAR) agonist, 1, were isolated by preparative chiral chromatography and their absolute configuration established using a combination of chromatographic and NMR methods. Enantiomer interconversion was investigated under a variety of conditions, with rapid racemization being observed in most solvents, including all aqueous systems studied, irrespective of pH. Rapid racemization in both dog and human plasma was confirmed by chiral HPLC with MS detection.

Animals↗
PubMed2002

Asymmetric synthesis of 1,2,3-trisubstituted cyclopentanes and cyclohexanes as key components of substance p antagonists.

An efficient asymmetric synthesis of 1,2,3-trisubstituted cyclopentanes and cyclohexanes is described. Three methods were developed for the preparation of the 2,3-disubstituted cyclopentenones and cyclohexenones, which are key achiral building blocks. These intermediates are reduced catalytically with (R)-2-methyloxazaborolidine in high yield (82-98%) and excellent ee (89-96%). Directed reduction of the chiral allylic alcohols using Red-Al gives exclusively the 1,2-anti stereochemistry (>99:1). Epimerization of the ester center followed by saponification/crystallization affords the desired hydroxyacids in good yield (65-70%) and in high enantiomeric excess (>99%).

Catalysis↗
PubMed2002

Liquid chromatographic resolution of racemic amines, amino alcohols and related compounds on a chiral crown ether stationary phase.

A chiral stationary phase (CSP) based on diphenyl-substituted 1,1'-binaphthyl crown ether was applied in resolving various racemic amines, amino alcohols and alpha-aminocarbonyl compounds including pharmaceutically important compounds such as amphetamine analogues, mexiletine, norepinephrine and norephedrine. The resolution was quite successful. In order to find out the effects of mobile phase additives on the chromatographic resolution behaviors, four selected racemic compounds were resolved on the CSP with the variation of the type and content of organic, acidic and cationic modifiers in aqueous mobile phase and with the variation of column temperature. The resolution behaviors were quite dependent on the type and the content of organic, acidic and cationic modifiers in aqueous mobile phase and on column temperature.

Alcohols↗