Development of a novel quality by design–enabled stability-indicating HPLC method and its validation for the quantification of nirmatrelvir in bulk and pharmaceutical dosage forms

A systematic and novel quality by design–enabled, rapid, simple, and economic stability–indicating HPLC method for quantifying nirmatrelvir (NMT) was successfully developed and validated. An analytical target profile (ATP) was established, and critical analytical attributes (CAAs) were allocated to meet the ATP requirements. The method used chromatographic separation using a Purosphere column with a 4.6 mm inner diameter × 250 mm (2.5 μm). The analysis occurred at 50°C with a flow rate of 1.2 mL/min and detection at 220 nm. A 10 μL sample was injected, and the mobile phase consisted of two components: mobile phase A, containing 0.1% formic acid in water (20%), and mobile phase B, containing 0.1% formic acid in acetonitrile (80%). The diluent was prepared by mixing acetonitrile and water at a 90:10 v/v ratio. The retention time for the analyte was determined to be 2.78 min. Accuracy exceeded 99%, and the correlation coefficient was greater than 0.999. The validated HPLC method was characterized as precise, accurate, and robust. Significantly, NMT was found to be susceptible to alkaline, acidic, and peroxide conditions during forced degradation testing. The stability-indicating method developed effectively separated the degradation products formed during stress testing, underlining its effectiveness in stability testing and offering accuracy, reliability, and sensitivity in determining NMT.     

PTSA–catalyzed functionalization of hydroquinones with benzhydryl alcohols in water

An intriguing and operationally simple direct benzylation of hydroquinones with benzhydryl alcohols has been developed using PTSA in water, affording functionalized hydroquinones in good to excellent yields. The advantages of being environmentally benign, metal-free, base-free, easy workup and having a wide substrate scope make it a promising process for the synthesis of symmetrically and unsymmetrically benzylated hydroquinones as well as for industrial applications.     

Total synthesis of the putative structure of the novel triquinane based sesquiterpenoid natural product dichomitol

A total synthesis of the recently reported triquinane natural product dichomitol, isolated from the fermentation broth of Dichomitus squalens, has been accomplished from the commercially available 1,5-cyclooctadiene through a series of unambiguous synthetic steps. A complete mismatch between the spectral characteristics of the synthetic product and that of the natural product warrants a revision of the structure of dichomitol.     

An efficient stereoselective synthesis of (2S,4S,5R)-(−)- and (2R,4R,5S)-(+)-bulgecinine

A short synthetic route to (−)-and (+)-bulgecinine, the amino acid moiety of the bulgecins was achieved from the readily available nonchiral pool starting material cis-2-butene-1,4-diol in which a Claisen orthoester rearrangement and a Sharpless asymmetric dihydroxylation were used as the key steps.     

Multiple time scale dynamics of distance fluctuations in a semiflexible polymer: a one-dimensional generalized Langevin equation treatment

Time-dependent fluctuations in the distance x(t) between two segments along a polymer are one measure of its overall conformational dynamics. The dynamics of x(t), modeled as the coordinate of a particle moving in a one-dimensional potential well in thermal contact with a reservoir, is treated with a generalized Langevin equation whose memory kernel K(t) can be calculated from the time-correlation function of distance fluctuations C(t) identical with x(0)x(t). We compute C(t) for a semiflexible continuum model of the polymer and use it to determine K(t) via the GLE. The calculations demonstrate that C(t) is well approximated by a Mittag-Leffler function and K(t) by a power-law decay on time scales of several decades. Both functions depend on a number of parameters characterizing the polymer, including chain length, degree of stiffness, and the number of intervening residues between the two segments. The calculations are compared with the recent observation of a nonexponential C(t) and a power law K(t) in the conformational dynamics within single molecule proteins [Min et al., Phys. Rev. Lett. 94, 198302 (2005)].     

Vanadium Catalyst for C- and S-Alkylation of Benzhydrols in Water: An Experimental Study and Green Metrics Evaluation

A strategy for the vanadium-catalyzed dehydrative C- and S-alkylation by nucleophilic substitution of benzhydrols with arenes and thiols is reported. The alkylation was achieved with the divanadium oxoperoxo complex [K₃(V⁺⁵)₂(O₂²⁻⁾₄(O²⁻)₂(μ-OH)] in water under air. The newly developed transformation could accommodate a broad substrate scope, including (hetero)arenes and thiols (34 examples). Both the symmetrical and unsymmetrical benzhydrols furnished excellent yields of the alkylated product under mild reaction conditions. The scope of this strategy was further extended to synthesize bis-benzylated arenes (poly-arylated products) in high yields and regioselectivities. The green metrics determination of all the alkylated products suggests the technical and environmental benefits of the present protocol. The longevity experiment reveals the catalytic activity was maintained over seven cycles. To understand the mechanism of the present reaction, spectroscopic and kinetic studies were undertaken. This simple protocol, which affords the desired products with water as the by-product, can be achieved under mild conditions without needing a base or other additives.     

Defining the Determinant-like Function for m by n Matrices Using the Exterior Algebra

In this paper, we present a function called the Determinant-Like Function that generalises the determinant function to m by n matrices using the Clifford algebra C?(V, 0). By definition, this generalisation satisfies the property that the exterior product of its column vectors has a magnitude that equals its determinant-like function if it has more rows than columns. For matrices which have more columns than rows, we make use of another property that the exterior product of its rows has a magnitude that equals the absolute value of its determinant-like function if it has more columns than rows. Defining the sign of this determinant-like function remains an open question.     

On the Determinant-like Function and the Vector Determinant

A generalisation of the determinant to rectangular matrices, known as the determinant-like function, has its magnitude defined previously. In this paper, we show that the determinant-like function is a rotation of the vector determinant.We further propose that this rotation is an identity transformation and thus the determinant-like function is in fact the same as the vector determinant. From this, we derive some properties of the determinant-like function.     

Synthesis of C1–C11 eribulin fragment and its diastereomeric analogues

A practical stereoselective synthesis of the central C1–C10 fragment of eribulin and its two diastereomeric analogues is developed. Our approach relied on the use of l-ascorbic acid as the starting material which allowed accessing a key intermediate with a syn diol moiety (C9 and C10 of eribulin) and a carboxylic ester group. A functionalized six membered lactone having several required hydroxyl groups was then obtained. In a number of steps, the lactone was converted to an intermediate for our key oxa-Michael reaction. A regio- and stereocontrolled intramolecular oxa-Michael reaction completed the synthesis of the C1–11 fragment having a trans-fused tetrahydropyrans with the exact stereochemistry of various hydroxyl groups, as in eribulin.