A scalable process for the manufacture of a Hsp90 inhibitor was developed and optimized. Key features in the seven-step process include a selective SNAr reaction followed by an Ullmann-type coupling of indazolone to an aryl halide. This improved process afforded 65% yield over two critical steps compared to 25% following the Medicinal Chemistry route.

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A scalable process for the manufacture of a potassium ion channel blocker was developed and optimized. Key features of the process include an optimized Grignard reaction, a direct cyanation of the intermediate trityl alcohol derivative, and an improved nitrile hydrolysis protocol, relative to the original acidic hydrolysis conditions, to generate the crude active pharmaceutical ingredient (API) with >95% HPLC purity. The Grignard and the cyanation reactions could be telescoped, resulting in an improved throughput compared to the original four-step process. An effective recrystallization of the API was also developed and the process scaled up to manufacture multiple batches at the pilot scale.

(+)-Methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate hydrochloride (CTDP 31,446) is known as a dopamine reuptake inhibitor. This cocaine analogue lacking the tropane skeleton is being considered for potential treatment of cocaine addiction. Herein we report the development of a scalable process for the preparation of this compound. This study was mainly aimed at improving the process throughput, eliminating chromatographic purifications for the separation of (±)-6-cis isomer from (±)-6-trans isomer, and developing a robust crystallization for isolation of pure (±)-6-cis in a single crop with a good mass recovery. The process development work also highlights an efficient recycle of (±)-6-trans via a kinetic epimerization followed by crystallization of the resulting (±)-6-cis isomer. The resolution of (±)-6-cis and the crystallization of the final HCl salt were optimized and implemented to afford CTDP-31,446 with high purity and good mass recovery.

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