Commercial Manufacture of Halaven®: Chemoselective Transformations En Route to Structurally Complex Macrocyclic Ketones

Abstract

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.

An α-chloroaldehyde-based formal synthesis of eribulin

“…A doubly diastereoselective Corey–Chaykovsky reaction was also critical for both securing the key C27 stereocenter and uniting our two α-chloroaldehyde-derived building blocks: sulfonium salts 22 and 42 and ketone 33 . Overall, these efforts constitute formal syntheses of eribulin that merge with reported routes to this important anticancer agent and reduce the total number of reactions required to produce eribulin to 52, which compares well with that required for either the Eisai (67 steps) 16 or Alphora (73 steps) 22 processes, and reduces the longest linear sequence to 28 steps. While it is difficult to compare processes run on kilogram 16 to gram 22 to milligram (this work) scale, several aspects of the process presented here may prove advantageous, including a decreased reliance on chiral catalysts and chiral chromatography, low temperature (<0 °C) reactions (5 vs. 10), and the obvious benefits derived from overall improvements to step economy 54 .…”

“…Overall, these efforts constitute formal syntheses of eribulin that merge with reported routes to this important anticancer agent and reduce the total number of reactions required to produce eribulin to 52, which compares well with that required for either the Eisai (67 steps) 16 or Alphora (73 steps) 22 processes, and reduces the longest linear sequence to 28 steps. While it is difficult to compare processes run on kilogram 16 to gram 22 to milligram (this work) scale, several aspects of the process presented here may prove advantageous, including a decreased reliance on chiral catalysts and chiral chromatography, low temperature (<0 °C) reactions (5 vs. 10), and the obvious benefits derived from overall improvements to step economy 54 . Perhaps of equal importance, the present syntheses showcase the unique versatility of α-chloroaldehydes as chiral building blocks for constructing the types of oxygen-containing heterocycles that are often encountered in structurally complex polyketide natural products.…”

“…Much of this work is predicated by several generations of halichondrin syntheses reported by Kishi 3,[13][14][15] . In 2013, the Process Research Group at Eisai disclosed their multi-gram synthesis 12 and commercial manufacturing route [16][17][18] for eribulin that involved a latestage union of the sulfone function in 3 and aldehyde in 7 (Fig. 1B) followed by a Nozaki-Hiyama-Kishi (NHK) 19,20 coupling to close the macrocyclic ring.…”

“…The majority (43) of these steps are required to assemble the C14-C35 fragment 3, which contains 10 chiral centers and three densely functionalized tetrahydrofuran/pyrans. Notably, while the four chiral centers found in the C29-C32 tetrahydrofuran derive from D-glucurono-3,6-lactone, controlling both the relative and absolute stereochemistry at the remaining six chiral centers in 3 requires one chiral separation using simulated moving bed chromatography, as well as four separate asymmetric reactions, two with stoichiometric chiral ligand 16 . An alternative process for eribulin production has been reported by the Process Research Group at Alphora and involves the early introduction of the C35 amine group and the advanced intermediate 4, which is converted into eribulin by a process similar to that used in the Eisai synthesis 21,22 .…”

Marine-Sourced Anti-Cancer and Cancer Pain Control Agents in Clinical and Late Preclinical Development

“…The story of the discovery of this compound (a totally synthetic variation on halichondrin B has been given in a variety of formats over the years, from the chapter by the Eisai scientists in Woburn, MA that showed the progression from the synthesis of halichondrin B to the initial synthesis of eribulin [37], to two recent papers on the industrial methodologies that enabled the production of this molecule, certainly the most complex synthetic drug to date [38,39]. …”