The synthesis and "round trip radical cyclization" of 11-iodo-2,7,11-trimethyldodec-6-en-5-one are described. The round trip cyclization is a sequence of 5-exo, 6-endo, and 5-exo cyclizations in which the last radical cyclization occurs at the same carbon atom as the initial radical generation. The key second (6-endo) cyclization produces two stereoisomers, one of which cyclizes efficiently to isogymnomitrene ketone, while the other cyclizes inefficiently to gymnomitrene ketone. Efforts to influence the kinetic or thermodynamic outcome of the second cyclization were not successful, and the results are contrasted with a related cyclization of Jung and Rayle where thermodynamic control was readily established.
Tetrahydroisoquinoline is a ubiquitous structural framework presented in numerous pharmacologically relevant molecules. Although accessible by the Pictet−Spengler cyclization, conditions commonly used for such cyclizations are often difficult to implement on scale. Herein, we report the development of a scaleable approach utilizing Eaton’s reagent for the cyclization of substituted phenylacetamide analogues to tetrahydroisoquinoline-2-one. The development, optimization, and safety hazard evaluations, which outline the benefits and ease of workup of this new process, are discussed.
The genotoxins ethyl chloride (EtCl) and methyl chloride (MeCl) were generated during the preparation of the hydrochloride salts of two tertiary amines in the presence of ethanol and methanol, respectively. In EtOH five batches of a tertiary amine hydrochloride were prepared on 0.3-18 kg scale using 37% aqueous HCl; residual EtCl was detected at less than 10 ppm in each batch. The preparation of the hydrochloride salt of another tertiary amine in MeOH on a 3 kg scale produced salt with 11-12 ppm of MeCl, and these higher levels precipitated investigations into controlling the levels of residual MeCl in batches of the HCl salt of the second amine. Four rework procedures were developed to reduce the level of MeCl in one batch of HCl salt. Generating the salts at a lower temperature (10 °C) was the key parameter to minimize the concentration of these impurities in this drug candidate when HCl was charged as 37% aqueous HCl. Control of the process was demonstrated by preparing a 30 kg batch containing 1 ppm of MeCl without rework processing; this level of MeCl is well within the guideline of e1.5 µg for the daily dosage of this drug candidate. The analytical methods to detect EtCl and MeCl, which were critical for the development of these processes, are also described.
Early process development toward a triple reuptake inhibitor
is described. Three different routes were evaluated; one of them was
optimized and scaled up to generate 470 g of API as this route minimized
the formation of undesired side products. The selected route featured
Eaton’s reagent-mediated cyclization of a phenyl acetamide,
copper-mediated Buchwald–Hartwig coupling to install a morpholine
moiety, and palladium-catalyzed α-arylation of a dihydroisoquinolinone
to construct the core structure.
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