The
development of an entirely crystallization-based synthetic
route to the antimalarial BRD5018 is described, which assembles a
structurally complex bicyclic azetidine scaffold adorned with five
stereogenic centers without the need for any chromatographic separations.
A diastereoselective glycine ester Claisen rearrangement, diastereomeric
salt resolution, and diastereoselective iodo-lactonization are utilized
to provide an efficient access to three contiguous stereogenic centers
on an acyclic template with the desired relative and absolute configurations.
A tandem aziridine ring-opening/azetidine ring-closure on the derived
2-amino-1,4-diol template was developed to efficiently establish the
all-cis trisubstituted azetidine scaffold with the
proper ancillary functionality for end-game maneuvers. d-Ribose-2,3-acetonide
provided a conveniently differentiated vicinal syn-diol suitable for the planned reductive amination/periodate cleavage/Staudinger-aza-Wittig
sequence to form the eight-membered diazocene ring. An early quantitative
installation of the diaryl acetylene moiety via a Sonogashira coupling
on an electronically matched methyl 4-bromocinnamate circumvented
a low-yielding, late-stage reaction in the first-generation synthesis.
Multiple crystalline intermediates enabled the complete removal of
chromatography from the synthesis resulting in a substantially reduced
cost and waste generation with enhanced throughput and quality control.
Complex permittivity (ε', ε'') of soil sample of Western Rajasthan region is measured at 9.385 GHz for various moisture content at a temperature of 200c. The dielectric constant of dry soil is found in good agreement with literature values. The dielectric constant and dielectric loss of moist soil increases with increase in moisture content in soil. The dielectric data is used to calculate ac conductivity and emissivity.
Anti-Wolbachia therapy has been clinically proven
to be a safe approach for the treatment of onchocerciasis and lymphatic
filariasis. AWZ1066S, a first-in-class highly specific anti-Wolbachia drug candidate developed for a short-course treatment
of human filariasis, has advanced into clinical development. An improved,
cost-efficient, and scalable process for the manufacture of this clinical
candidate is described. Presented herein is the process development
work for the active pharmaceutical ingredient (API) and its two key
starting materials [2-(trifluoromethyl)-3-pyridyl]methanamine and
(S)-3-methylmorpholine, starting from 2,4-dichloropyrido[2,3-d]pyrimidine, which is capable of delivering high-purity
(>99%) API consistently. The optimized production route was used
in
the manufacture of the clinical candidate at the kilogram scale to
support the ongoing clinical development.
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