The widespread application of 1,2,3-triazoles in pharmaceuticals has resulted in substantial interest toward developing efficient postmodification methods. Whereas there are many postmodification methods available to obtain N 1 -substituted 1,2,3-triazoles, developing a selective and convenient protocol to synthesize N 2 -aryl-1,2,3-triazoles has been challenging. We report a catalyst-free and regioselective method to access N 2 -aryl-1,2,3-triazoles in good to excellent yields (66−97%). This scalable postmodification protocol is effective for a wide range of substrates.
This research investigates applying zinc oxide (ZnO) nanoparticles (NPs) as inorganic nanofillers to poly(amide-imide) (PAI) as a polymer matrix via ultrasound technique for the preparation of PAI/ZnO bionanocomposites (BNCs). The surface of ZnO NPs was successfully treated with γ-methacryloxypropyltrimethoxysilane coupling agent (KH570) to decrease the hydrophilicity of NPs. The optically active PAI containing natural L-leucine amino acid was synthesized in a green solvent system which is consisted of tetrabutyl ammonium bromide/triphenyl phosphate. The influences of the ZnO on the structure, morphology, thermal, and optical properties of BNCs were, respectively, characterized by several techniques. All the results indicate that NPs are successfully modified and are compatible with polymer matrix and also proved that there is a homogenous dispersion of ZnO NPs in the polymer matrix in nanoscale.
Lower rim carboxylic acid calix[n]arenes and upper rim phosphonic acid functionalized calix[4]arenes effect selective transport of distinct molecular payloads through a liquid membrane. The secret to this success lies in the attachment of a receptor-complementary handle. We find that the trimethylammonium ethylene group present in choline is a general handle for the transport of drug and drug-like species. Furthermore, neurotransmitters possessing ionizable amine termini are also transported. Some limitations to this strategy have been uncovered as payloads become increasingly lipophilic. These developments reveal new approaches to synthetic receptor-mediated selective small molecule transport in vesicular and cellular systems.
MRTX1719 was identified as a potent inhibitor
of the
PRMT5/MTA complex, designed to selectively target MTAP-deleted cancers. A scalable synthesis of this atropisomeric compound
and an efficient isolation of the desired isomer were required to
support Phase 1 clinical trials, and this was established through
further development of the racemic medicinal chemistry route. In the
key step, the desired (M)-atropisomer of MRTX1719 was amplified from racemic API by combining crystallization (20
°C) and racemization (160 °C, 4 min). Concurrent execution
of these, ostensibly incompatible, operations was enabled by a continuous
flow setup (SPACE = Simultaneous Processing of Antagonistic Chemical Events) providing 98.4%
e.e. of (M)-atropisomer in 75% yield from racemic
API on 12 kg scale. Process development targeting earlier steps of
the API synthesis led to several impactful revisions including desymmetrization
of 4-chlorobenzamide to access the 6-substituted-4-(aminomethyl)phthalazin-1(2H)-one ring system, improved borylation conditions (Suzuki–Miyaura
or photocatalytic), and demonstration of an economically viable route
to the challenging pentasubstituted benzene from 1,4-difluorobenzene
and cyclopropyl methyl ketone.
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