Strategies in API Scale Up - Pharmaceutical Technology

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PharmTech Europe

Strategies in API Scale Up
Process chemists employ a variety of approaches to improve yield, purity, and stereoselectivity.

Pharmaceutical Technology
Volume 37, Issue 1, pp. 52-54

Synthetic organic chemists in the pharmaceutical and fine-chemical industries seek advances to help improve yield, purity, and stereoselectivity of intermediates and APIs. This goal takes route in a multitude of ways from general advances in organic chemistry to reaction-specific gains. Advances in asymmetric synthesis are of particular importance given the prevalence of chiral compounds as potential drug candidates and the attendant interest in producing single enantiomers. This objective has to be met with the ability to scale up any given stereoselective synthesis for commercial manufacture, and several interesting developments have made in this area. Production economics also are a consideration as well in scaling up reactions to commercial levels. A cost-effective route to the antimalarial drug artemisinin, and a biocatalytic route for aromatic nitration reactions are some recent developments.

Asymmetric synthesis

Patricia Van Arnum
Enantioselective imine-cyanation/Strecker reaction. Researchers at the Institute of Chemical and Engineering Sciences, a national research institute under Singapore's Agency for Science, Technology and Research, recently reported on a robust new catalyst that selectively generates amino-acid precursors from cyanide at room temperature at an industrial scale. Specifically, they reported on a new catalyst more amenable to scale-up in the asymmetric Strecker reaction, a heterogeneous self-supported chiral titanium cluster (SCTC) catalyst in the enantioselective imine–cyanation/Strecker reaction used in both batch and continuous processes (1, 2). A limitation in the asymmetric Strecker reaction is the lack of availability of efficient and reusable heterogeneous catalysts that work at room temperature. The researchers took advantage of the hydrolyzable nature of titanium alkoxide to synthesize a SCTC catalyst by the controlled hydrolysis of a preformed chiral titanium–alkoxide complex (2). The researchers reported that the isolated SCTC catalysts were stable and showed up to 98% enantioselectivity with complete conversion of the imine within two hours for a wide variety of imines at room temperature. Moreover, the heterogeneous catalysts were recyclable more than 10 times without any loss in activity or selectivity (2).

The researchers reported that the catalyst was used in a packed-bed reactor to carry out the cyanation under continuous flow with up to 97 % enantioselectivity under optimized flow conditions at room temperature in the case of benzhydryl imine. A three-component Strecker reaction also was performed under continuous flow by using the corresponding aldehydes and amines instead of the preformed imines under which good product distribution was obtained for the formation of amino nitriles with enantioselectivity values of up to 98% (2).


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