Process Development and Scale-up of Fully Synthetic Tetracycline TP-2758: A Potent Antibacterial Agent with Excellent Oral Bioavailability

Abstract

Process research and development of the fully synthetic broad spectrum tetracycline TP-2758, with a chiral pyrrolidine side chain at the C-8 position, is described. The process utilizes two key intermediates, 7 and 10, in a convergent approach that allows for manufacturing of sufficient quantities of API to supply preclinical and early clinical development. The pyrrolidine moiety was introduced into the left-hand piece (LHP) 10 with high enantioselectivity using Ellman’s sulfinamide chemistry, and the absolute configuration was confirmed by X-ray crystal structure analysis.

Leaks in the Pipeline: a Failure Analysis of Gram-Negative Antibiotic Development from 2010 to 2020

“…This approach produced one clinically approved antibiotic (eravacycline) and two other phase 1 candidates (TP-271 and TP-6076). TP-2758, with a chiral 8-pyrrolidinyl substitution, was discovered while generating a series of novel 7-methoxy-8-heterocyclyl tetracycline analogs ( 48 ). Derivatives of tetracyclines, called glycylcyclines, were developed to combat the rise of tetracycline resistance.…”

A Scalable High‐Yielding and Selective Oxidative Heck Cross‐Coupling – A Key Step for the Synthesis of trans‐Stilbenes

“…From route C, we observed that neither BuLi nor i PrMgClLiCl operated for the carboxylation. However, according to the literature, [31] an exchange Br‐Metal could avoid the formation of undesired side products. The reaction was performed using 1 mmol of the starting material with either BuLi or with i PrMgClLiCl.…”

“…Using the organolithium base, no product was observed, whereas with the organomagnesium base, a yield of 41 % of target product was obtained. Attempt to scale‐up (10 mmol) this reaction step, a yield of only 8 % of target product was isolated [31] …”

“…Attempt to scale-up (10 mmol) this reaction step, a yield of only 8 % of target product was isolated. [31] Method B Since our attempt to scale-up the approach using CO 2 failed, we had to consider other alternative methods. In this context, a palladium-catalysed hydroxyl carbonylation involving gaseous CO was implemented (unfortunately, we could not fulfil the goal of entry 4 of Table 1).…”

Arynes and Cyclic Alkynes as Synthetic Building Blocks for Stereodefined Quaternary Centers

“…Having developed the racemic arylation/alkenylation reaction, we turned our attention to the discovery of a diastereoselective variant to access enantioenriched products (Table ). Thus, a series of enantioenriched chiral amines, readily prepared using Ellman auxiliary chemistry (i.e., 18 – 24 ), , were condensed with ketoester 9 to access enamines 17 . Subsequent arylation under the conditions depicted in Figure furnished 12 in enantioenriched form.…”