Process R&D of Eravacycline: The First Fully Synthetic Fluorocycline in Clinical Development

Abstract

Process research and development of the first fully synthetic broad spectrum 7-fluorotetracycline in clinical development is described. The process utilizes two key intermediates in a convergent approach. The key transformation is a Michael–Dieckmann reaction between a suitable substituted aromatic moiety and a key cyclohexenone derivative. Subsequent deprotection and acylation provide the desired active pharmaceutical ingredient in good overall yield.

Natural Products as Platforms To Overcome Antibiotic Resistance

“…Chemists at Tetraphase quickly developed a synthetic route to prepare sufficient material for distribution. 160 Eravacycline ( 155 ) was found to overcome the most prevalent tetracycline resistance mechanisms, including TetM, a ribosomal protection protein, and several efflux pumps, including TetA, TetB, and TetK. 161 Only against the relatively rare tetX (degradation via oxidation) was tigecycline more active than eravacycline.…”

Process Research and Development of an Enantiomerically Enriched Allyic Amine, One of the Key Intermediates for the Manufacture of Synthetic Tetracyclines

“…As part of our ongoing program to develop an efficient manufacturing approach to enone 1, a key intermediate in the manufacture of fully synthetic tetracyclines, including our lead candidate eravacycline, 1 we have devoted significant efforts to develop manufacturing routes to intermediates 2 and 3. These two key intermediates are used as building blocks for the convergent synthesis of enone 1 (Figure 1).…”

Evaluation of Eravacycline: A Novel Fluorocycline

“…Eravacycline includes four cyclic rings categorized as (A, B, C, and D) synthesized utilizing the original pharmacophore of TETs with the carbons, C‐1, C‐3, C‐10, C‐11, C‐12, and C‐12a substituted with oxygen atoms . In concordance with the readily recognizable TET structuring, the C‐4 site is branded by the placement of a dimethylamine group . The alpha‐stereochemical conformation, naturally occurring at C‐4a and 12‐a, as well as the keto‐enol system present at C‐11 and 12; in close proximity of the D and A rings (comprising the minimum TET pharmacophore) are maintained as they are required for optimal bacterial eradication .…”

“…18 The C-2 amide remains intact as its removal reduces activity; similar to the presence of the cis A/B ring fusion and bß-hydroxyl group at the C-12a. 17,18 The novelty in ERV structuring is characterized by the implementation of a fluorine atom at the C-7 position, and the [2-(pyrrolidine-1-yl)ethanamido] group at the C-9 site, optimizing antibacterial activity and oral bioavailability (Figure 1). 19 The simplest TET that represents detectable antibacterial activity is the minimum TET pharmacophore or 6-deoxy-6-demethyl TET.…”

“…In concordance with the readily recognizable TET structuring, the C‐4 site is branded by the placement of a dimethylamine group . The alpha‐stereochemical conformation, naturally occurring at C‐4a and 12‐a, as well as the keto‐enol system present at C‐11 and 12; in close proximity of the D and A rings (comprising the minimum TET pharmacophore) are maintained as they are required for optimal bacterial eradication . The C‐2 amide remains intact as its removal reduces activity; similar to the presence of the cis A/B ring fusion and βß‐hydroxyl group at the C‐12a .…”