Absolute Configuration Determination of Retroflexanone Using the Advanced Mosher Method and Application of HPLC-NMR (original) (raw)
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Journal of Organic Chemistry, 2018
The determination of the absolute configuration of chiral alcohols and amines is typically carried out with modified Mosher methods involving a doublederivatization strategy. On the other hand, the number of robust and reliable methods to accomplish that goal using a single derivatization approach is much less abundant and mainly limited to secondary alcohols or primary amines. Herein, we report a conceptually novel strategy to settle the most likely absolute configuration of a wide variety of substrates and chiral derivatizing agents following a singlederivatization experiment coupled with quantum calculations of NMR shifts and DP4+ analysis. Using an ambitious set of 114 examples, our methodology succeeded in setting the correct absolute configuration of the substrates in 96% of the cases. The classification achieved with secondary alcohols, secondary amines, and primary amines herein studied was excellent (100%), whereas more modest results (89%) were observed for primary and tertiary alcohols. Moreover, a new DP4+ integrated probability was built to strengthen the analysis when the NMR data of the two possible diastereoisomers are available. The suitability of these methods in solving the absolute configuration of two relevant cases of stereochemical misassignment ((+)-erythro-mefloquine and angiopterlactone B) is also provided. f1 substrate and CDA (Figure 1). 49 Since the pioneering work of Mosher in 1973 (introducing 50 the so-called Mosher reagent, methoxytrifluoromethylphenyl-51 acetic acid, MTPA), 6 the number of CDAs and methodologies 52 has increased significantly. 4 Nowadays, robust and reliable 53 methods are available for primary, secondary, and tertiary 54 alcohols, diols, thiols, primary and secondary amines, 55 carboxylic acids, and sulfoxides, among others. 4
European Journal of Pharmaceutical Sciences, 2013
In the frame of increasingly stringent quality assessment required by the regulators, the pharmaceutical industry has to face increasingly sophisticated counterfeiting practices. Counterfeits based on deliberate copying of processes or on the infringement of current patents for generic medicines are not straightforward to detect, unless the molecular probe is the active molecule itself. In this context, impurity profiling is limited. A tool based on the determination of intramolecular isotopic profiles has been developed to provide manufacturers of APIs (Active Pharmaceutical Ingredients) with a new solution to meet this double requirement. Stable isotope analyses by NMR gives direct access to site-specific isotope content at natural abundance. In this report, it is shown how both 2 H and 13 C NMR spectrometry can provide complementary and valuable information that could be applied to link APIs to their manufacturing source. Isotopic 13 C NMR offers additional benefits over 2 H NMR in using robust adiabatic polarization transfer methods, leading to a tremendous reduction in experimental time. Two approaches are illustrated. Firstly, the use of 2 H and single pulse 13 C NMR spectra obtained on 20 commercial ibuprofen samples from different origins show that this combined strategy leads to (i) a unique intramolecular isotope identification and (ii) a preliminary classification of the samples according to the synthetic pathways of the main industrial processes. An approach employing polarization transfer methods applied to 11 commercial naproxen samples, for which 2 H and single pulse 13 C NMR spectra are not exploitable and/or are not accessible in reasonable time. The relative and partial intramolecular 13 C distribution obtained on naproxen by applying this methodology is sufficiently informative to allow the same conclusions as for ibuprofen. The additional benefits that these approaches should bring to API manufacturers are discussed.
Determination of the configuration of substituted 1,4:3,6‐dianhydrohexitols by 13C NMR spectroscopy
Organic Magnetic Resonance, 1978
The configurations of 1,4:3,6‐dianhydro‐2,5‐di‐O‐mesyl‐D‐mannitol, 1,4:3,6‐dianhydro‐2,5‐di‐O‐mesyl‐D‐glucitol, 1,4:3,6‐dianhydro‐2,5‐di‐O‐mesyl‐L‐iditol, 1,4:3:6‐dianhtydro‐2‐deoxy‐2‐iodo‐5‐O‐mesyl‐D‐mannitol, 1,4:3:6‐dianhtydro‐2‐deoxy‐2‐iodo‐5‐O‐mesyl‐D‐glucitol, 1,4:3,6‐dianhydro‐2‐deoxy‐2‐iodo‐5‐O‐mesyl‐L‐iditol, 1,4:3,6‐dianhydro‐2,5‐dideoxy‐2,5‐diiodo‐D‐glucitol and 1,4:3,6‐dianhydro‐2,5‐dideoxy‐2,5‐diiodo‐L‐iditol were determined by 13C NMR spectroscopy, by invoking the field‐effect.
Analysis of pharmaceutical and natural compounds and newer drugs is commonly used in all the stages of drug discovery and development process. HPTLC is an advanced type of planar chromatography used extensively in the recent years for fingerprinting of medicinal plants, products and for screening lichen substances. Major advantages include precise sample application, wide choice of stationary phases, simultaneous processing of standards, simultaneous scanning in different light sources and excellent documentation facility. It is more sensitive and possible to run more samples in a short period of time, by using small amount of solvent. It is one of the sophisticated instrumental techniques based on the full capabilities of thin layer chromatography. In the present review brief discussion is presented with regard to type of instrument used in HPTLC, its entire methodology and how this technique is better than TLC. This concise information consists of salient points showing immense use in the practical analysis of HPTLC. This article consists of compilation of 63 formulations in total, out of which 38 containing one active substances and 25 containing dual active substances are shown in separate Tables (Table 1 and 2). The names of products, solvent system, details of plates to be used and details of quantitation showing densitometric evaluation are shown against each formulation.
Tetrahedron-asymmetry, 2000
Examples in which Mosher's method does not allow a safe con®gurational assignment of absolute con-®guration are presented. This situation occurs when: (a) L 1 and L 2 show identical signs of Ád SR ; (b) when both positive and negative Ád SR values coexist for the same substituent; (c) only NMR data from one substituent of L 1 or L 2 is available; and (d) when polyalcohols are treated like monoalcohols. The requirements for the correct application of this method are discussed. #
Journal of Pharmaceutical and Biomedical Analysis, 2018
The application of various techniques (FT-IR, PXRD, ssNMR) in the analysis of solid dosage forms with low concentration of an API (17--estradiol hemihydrate, EBHH) was tested. PXRD analysis of Estrofem Mite tablets (EMT) confirmed the presence of the main crystalline excipient, ␣-lactose monohydrate. In the PXRD pattern of EMT the strong background from polycrystalline excipients, i.e. hydroxypropylmethylcellulose and corn starch was observed. FT-IR spectra were characterized by the broad peaks in the 3000-3600 cm −1 region of the O H stretching modes coming from multiple hydrogen bonds that are present in the structures of the excipients (␣-lactose monohydrate, corn starch) and API. The only technique which unambiguously confirmed the presence of an API in the EMT was solid state NMR. Despite the tabletting process each of the EMT component retained its characteristic features like relaxation time and T 1 I. Due to the possibility of the manipulation in the experimental registration parameters like recycle delay (RD), evolution time () and contact time (CT) it was possible to perform multiple experiments on the same sample of EMT. The most valuable were the inversion recovery CP experiments in which, by setting the proper values of , it was possible to selectively observe the signals of the chosen component of the drug formulation. In this study the great potential of solid state NMR in the analysis of solid dosage forms, as the unique technique that combines the possibility of selective observation of the chosen signals with the non destructive character that enables further analysis of the same sample, was confirmed.
International Journal of Applied Pharmaceutics, 2021
Objective: Statistically designed and Box-Behnken design (BBD) assisted reversed-phase high-performance liquid chromatography-ultraviolet (HPLC-UV) method was developed and validated for the identification of an antipsychotic medication Olanzapine and its organic impurities in pure drug along with forced degradation studies. Methods: The present developed method employed BBD optimized chromatographic conditions comprising of an Inertsil ODS 3V analytical column with dimension 250 mm x 4.6 mm and particle size 5µ. The isocratic mobile phase was used as a mixture of monobasic sodium phosphate buffer (0.01 M, pH 6), methanol and acetonitrile in the proportion of 40/30/30, v/v. The mobile phase flow rate and UV λmax was 1 ml/min and 260 nm, respectively. The method was optimized by Box-Behnken design using design expert software, comprising of three factors for Olanzapine for instance flow rate (A), mobile phase composition (B) and pH (C) while resolution between Olanzapine related compound A and Olanzapine related compound B (Y1) and tailing of Olanzapine (Y2) were taken as a response. Results: Application of BBD yielded statistically designed method with excellent quality parameters achieved in terms of linearity with the coefficient of correlation (R2>0.9999), limit of detection (LOD, 0.0023-0.16 µg/ml), the limit of quantification (LOQ, 0.007-0.39 µg/ml), accuracy (99-100%) and precision ((2%, relative standard deviation (%RSD) were evaluated as per latest available procedures. Conclusion: Forced degradation conditions were carried out, demonstrated that the optimized method was stable and no any interfering peaks eluting at the similar retention time of the studied compounds. The method was found to be stable, easy, rugged and robust, could be applied for the similar types of the pure drug.