Development of a convergent synthesis of omarigliptin (MK-3102) suitable for commercial manufacture is described. The target molecule is assembled through a diastereoselective reductive amination of a highly functionalized pyranone with a mesylated pyrazole followed by deprotection of a Boc group. The synthesis of the pyranone relies on three Ru-catalyzed reactions, 1) a DKR reduction of a rac-α-aminoketone to set the two contiguous stereogenic centers, 2) a cycloisomerization of a bis-homopropargylic alcohol to a dihydropyran, and finally 3) a Ru-catalyzed oxidation of a pyranol to the desired pyranone. A regioselective synthesis of an N-Boc-1-mesyl pyrazole fragment was achieved via a base promoted mesyl group isomerisation to afford 30:1 selectivity. A highlight of the endgame process development is telescoping a Boc deprotection and reductive amination followed by direct crystallization of the penultimate from the reaction mixture. This avoids handling of an unstable, mutagenic 1-mesylpyrazole BSA salt used in the earlier multi-kilogram deliveries, and improved the overall diastereoselectivity and efficiency of the route.
SUMMARY: The synthesis of a new liquid crystalline block copolymer consisting of a polystyrene block and a side-chain liquid crystalline siloxane block is reported. The synthetic approach described is based on the anionic polymerization of styrene and cyclic ~m e~y l~v i n y l~s i l o x a n e monomers, followed by functionalization of the siloxane block with side chain mesogens. The siloxane block has a Tg well below 25°C and is designed to exhibit a chiral smectic C* phase at room temperature. These block copolymers are the first sidechain liquid crystalline block copolymers which contain both a high Tg glassy block and a low Tg liquid crystalline block. Int~ductionBlock copolymers with a side-chain liquid crystalline block and an amorphous glassy block are novel materials that present a structurally rich environment in which morphology influences liquid crystalline alignment and phase behaviori4). These materials are of practical interest because the ability to orient mesogens with mechanical and electrical fields combined with the mechanical properties of block copolymers may lead to applications such as electro-optic free standing thin films, mechano-optic materials, and piezoelectric elastomers. We have previously synthesized and c h~a c~~z e d liquid crystalline block copolymers with ferroelectric mesogens using polystyrene-polymethacrylate systems5). Other researchers have also begun to explore the ferroelectric liquid crystalline phase behavior of smectic C*-amorphous block copolymers6S7).In this paper, we report the synthesis of a liquid crystalline block copolymer consisting of a polystyrene block and a side-chain liquid crystalline siloxane block. These are the first block copolymer systems to have a high Tg amorphous block (polystyrene) coupled to a low Tg liquid crystalline block (polysiloxane). It is anticipated that the electro-optical behavior of these systems will be influenced by the block copolymer morphology and the liquid crystalline phase behavior. Because the siloxane block has a low Tg, we hope to access room temperature ferroelectric properties while maintaining mechanical integ-A synthetic scheme developed in our labs and concurrently in the Netherl~ds*) allows for the synthesis of siloxane liquid crystalline polymers by anionic polymerization techniques. We apply this technique to make block copolymers of polystyrene and a side-chain liquid crystalline siloxane. Scheme 1 illustrates the synthetic route for rity.the block copolymers and Scheme 2 gives the synthetic scheme for the mesogens which are attached to the siloxme backbone following synthesis of the block copolymer. Experimental part ~nstrum~n~ationGel permeation chromatography (GPC) was used to determine molecular weight distributions relative to polystyrene standards. Tetrahydrofuran (THF) was the mobile phase. The GPC system consists of a Waters 440 UV absorbance detector set to 254 nm, a Waters 746 Data Module, a Waters 515 HPLC pump, and 3 styragel columns. Thermal transitions were measured with a Perkin Elmer DSC-7. All hea...
Process analytical technologies (PATs) have played an important role in process development and optimization throughout the pharmaceutical industry. Recent new PATs, including in-process video microscopy (PVM), a new generation of focused-beam reflectance measurement (FBRM), miniature process IR spectroscopy, and a flow IR sensor, have been evaluated, demonstrated, and utilized in the process development of many drug substances. First, PVM has filled a technical gap by providing the capability to study morphology for particle engineering by visualizing particles in real time without compromising the integrity of sample. Second, the new FBRM G series has closed gaps associated with the old S series with respect to probe fouling, bearing reliability, data analysis, and software integration. Third, a miniaturized process IR analyzer has brought forth the benefits of increased robustness, enhanced performance, improved usability, and ease of use, especially at scale-up. Finally, a miniaturized flow IR sensor has provided process flow chemistry development with a smaller, faster-performing, less expensive analytical tool.
NEW HYPNOTICS 243 the green solid. In the Liebermann reaction a dark green color is imparted to the sulfuric acid.
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