Recent evidence suggests that blocking aberrant hedgehog pathway signaling may be a promising therapeutic strategy for the treatment of several types of cancer. Cyclopamine, a plant Veratrum alkaloid, is a natural product antagonist of the hedgehog pathway. In a previous report, a seven-membered D-ring semisynthetic analogue of cyclopamine, IPI-269609 (2), was shown to have greater acid stability and better aqueous solubility compared to cyclopamine. Further modifications of the A-ring system generated three series of analogues with improved potency and/or solubility. Lead compounds from each series were characterized in vitro and evaluated in vivo for biological activity and pharmacokinetic properties. These studies led to the discovery of IPI-926 (compound 28), a novel semisynthetic cyclopamine analogue with substantially improved pharmaceutical properties and potency and a favorable pharmacokinetic profile relative to cyclopamine and compound 2. As a result, complete tumor regression was observed in a Hh-dependent medulloblastoma allograft model after daily oral administration of 40 mg/kg of compound 28.

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The evolution of the synthesis of Halaven ® (E7389, INN eribulin mesylate) from a medicinal chemistry process to the execution of the final process on pilot scale is described. The completion of the synthesis of Halaven ® from C1-C13 ester and C14-C35 sulfone alcohol involves a series of chemo-, regio-, and stereoselective transformations. Furthermore, a high-dilution macrocyclization presented a number of challenges for industrial-scale manufacture (throughput, processing time, and side reactions). This paper describes studies at Eisai leading to an understanding, optimization, and control of the chemistry that realized the reproducible commercial production of Halaven ® .Amongst the synthetic issues to be addressed in order to provide the necessary quantities of Halaven ® (1) 1-3 for full clinical evaluation are: (i) procurement of the fragments 3 (C14-C35) 4 and 4 (C1-C13), 5 (ii) stereo-and chemoselective coupling of these fragments, (iii) carbon-carbon bond formation to generate the macrocycle, and (iv) controlled establishment of the polycyclic ketal and amino alcohol functionalities. This paper describes the current status of synthetic studies at Eisai which address these issues and have enabled commercial supply of 1 in a totally synthetic manner (Scheme 1). The synthesis of 1 from C14-C35 sulfone 3 and C1-C13 ester 4 is depicted in Scheme 2. The synthesis begins with DIBAL reduction of 4 in toluene solution at -78 °C. Aldehyde 5 is isolated in 93% yield following quench with methanol, workup, and chromatographic purification for removal of the overreduction byproduct. The aldehyde is prone to oxidation to the carboxylic acid during isolation and storage, which had previously been managed by careful handling of the neat preparation or solutions under inert atmospheres, usually argon. However, after several sampling cycles, the carboxylic acid impurity had increased and repurification of the aldehyde was required. Addition of 0.5-1 wt% 3,5-di-tert-butyl-4-hydroxytoluene (BHT) to the reaction mixture and to chromatographic fractions prior to concentration inhibits the oxidation of the aldehyde. The aldehyde is then readily stored and delivered as a solution for the coupling with 3.

Multikilogram manufacturing process of the Halaven ® C14-C35 fragment is described. The synthesis features convergent assembly of subunits by iterative asymmetric Ni/Cr-mediated coupling executed in fixed equipment. Halaven ® (1; E7389, INN eribulin mesylate) is a fully synthetic analogue of the structurally complex marine natural product halichondrin B. 1 Eribulin has been recently approved by the FDA for the treatment of certain patients with metastatic breast cancer. 2,3 The Halaven ® C14-C35 fragment 2 constitutes a major structural element of 1, in which 10 of the 19 stereogenic centers contained in Halaven ® are incorporated. 4 The overall approach toward 2 mirrors that used by Kishi and co-workers to construct the halichondrin C14-C38 fragment: 3a Namely, Ni(II)/Cr(II)-mediated coupling (Nozaki-Hiyama-Kishi reaction) of the C27-C35 aldehyde 3 and the sulfonate-containing nucleophile 4 followed by Williamson cyclic etherification was anticipated to form the pyran-containing C14-C35 subunit (Scheme 1). 5 The conciseness of this approach and the functional-group tolerance of the Ni/Cr process were attractive features for future manufacturing. Nevertheless, there were concerns about scaling up the overall process due to the somewhat labile nature of the C23 sulfonate substrate 4 and the fact that a Ni/Cr coupling had not previously been demonstrated on kilogram scale in fixed equipment. At the same time, we considered that in principle a similar strategy could be employed to construct the tetrahydrofuran-containing C14-C26 subunit. A strategic advantage of utilizing a Ni/Cr C19-C20 coupling-cyclic etherification sequence for the preparation of 4 would be the opportunity to demonstrate the feasibility of the Nozaki-Hiyama-Kishi reaction in fixed equipment on a much less costly and presumably more stabile system. Thus, establishment of a firm foundation for the overall synthesis of eribulin which used not only a C26-C27 Ni/Cr-mediated coupling, but also a later-stage C13-C14 Ni/Cr-mediated macrocyclization could be accomplished by carefully studying and then demonstrating the viability of C19-C20 Ni/Cr 'model system' on kilogram scale in our pilot plant.

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