The asymmetric hydrogenation of tetrasubstituted α,β-unsaturated ketones has been accomplished using an in situ formed rhodium-Josiphos catalyst. The reaction is enhanced by addition of catalytic ...zinc(II) triflate, which significantly improves turnover frequency while suppressing epimerization of the products.
This article describes the development and optimization of chemical reactions and subsequent multikilogram preparation of the glucokinase activator (R)-1 to fund clinical evaluation as a potential ...therapeutic for type II diabetes. The major process developments presented here are a Wittig olefination isomerization based synthesis of an E-acrylic acid, an optimized enantioselective hydrogenation of the E-acrylic acid, and a challenging final amide coupling.
A pilot-plant scale desymmetrization of the cyclic meso-epoxide 4b, using a chiral lithium amide prepared from symmetrical diamine 17, was designed and implemented to provide allylic alcohol 3b in ...high yield and greater than 99% ee. This chiral alcohol was converted to ketone 2b, a key intermediate in a new asymmetric synthesis of LY459477. Chiral diamine 17 was prepared from a readily available chiral precursor, (R)-α-methylbenzylamine, and could be recovered from the reaction mixture and reused. Studies performed to probe the mechanism of the rearrangement reaction of epoxide 4b showed that diamine 17 provided an optimal combination of selectivity and scaleability for this process.
A fully continuous process including an asymmetric hydrogenation reaction operating at 70 bar hydrogen, aqueous extraction, and crystallization was designed, developed, and demonstrated at pilot ...scale. This paper highlights safety, quality, and throughput advantages of the continuous reaction and separations unit operations. Production of 144 kg of product was accomplished in laboratory fume hoods and a laboratory hydrogenation bunker over two continuous campaigns. Maximum continuous flow vessel size in the lab hoods was 22 L glassware, and maximum plug flow tube reactor (PFR) size in the bunker was 73 L. The main safety advantages of running the hydrogenation reaction continuous rather than batch were that the flow reactor was smaller for the same throughput and, more importantly, the tubular hydrogenation reactor ran 95% liquid filled at steady state. Therefore, the amount of hydrogen in the reactor at any one time was less than that of batch. A two-stage mixed suspension–mixed product removal (MSMPR) cascade was used for continuous crystallization. Impurity rejection by continuous crystallization was superior to that by batch because scalable residence time and steady-state supersaturation enabled robust and repeatable control of enantiomer rejection in a kinetic regime, although this is a nonstandard approach, debatable as an impurity control strategy. The fully continuous wet-end process running in a laboratory infrastructure achieved the same weekly throughput that would be expected from traditional batch processing in a plant module with 400 L vessels.
