Synthesis of Rovafovir Etalafenamide (Part III): Evolution of the Synthetic Process to the Phosphonamidate Fragment

Abstract

Phosphonamidate 1 is a key fragment in the assembly of rovafovir etalafenamide, a novel nucleotide reverse transcriptase inhibitor under development at Gilead Sciences for the treatment of HIV infection. An early manufacturing route, relying on simulated moving bed (SMB) chromatography for the separation of phosphorus diastereomers, was executed on scale to produce multiple batches of 1. However, developing alternative synthetic conditions became desirable in consideration of the high production cost, long lead time, and high process mass intensity (PMI) associated with SMB. Several strategies to improve these factors are described herein, including epimerization and recycling of the undesired (R)-phosphorus diastereomer, design of stereoselective approaches to establish the desired (S)-configuration at phosphorus, and identification of conditions or derivatives to allow for selective crystallization. Ultimately, a second-generation route to 1 was developed and demonstrated on scale. The new route achieves the separation of phosphorus diastereomers by means of selective crystallization, does not require SMB, and offers lower PMI, cost, and lead time.

Synthesis of Rovafovir Etalafenamide (Part I): Active Pharmaceutical Ingredient Process Development, Scale-Up, and Impurity Control Strategy

“…Iodine was of ACS reagent grade containing ≤0.005% each of chlorine and bromine. Starting materials 3 and 5 were prepared according to the procedures described in the associated publications. , …”

“…Starting materials 3 and 5 were prepared according to the procedures described in the associated publications. 12,13 Instrumentation. HPLC analyses were performed on a Waters ACQUITY H-Class UPLC system equipped with a quaternary pump, refrigerated sample chamber, flow-through needle autosampler/injector operating in partial loop needle overfill mode, column heater, and photodiode array detector.…”

“…Purification of crude 1 by silica gel chromatography and subsequent crystallization as the citrate salt then yielded the desired API 1a . The synthesis and impurity control strategies of the starting materials 3 and 5 are addressed in the later parts of this series. , …”

“…The synthesis and impurity control strategies of the starting materials 3 and 5 are addressed in the later parts of this series. 12,13 It was seen early in the development of this route that protection of the adenine NH 2 was required prior to the iodoetherification reaction in order to suppress the competing iodoamination reaction. Additionally, the protected adenine moiety is significantly less prone to formation of the N-oxide at N-1 when treated with Oxone compared to the corresponding, unprotected adenine.…”

Synthesis of Rovafovir Etalafenamide (Part IV): Evolution of the Synthetic Process to the Fluorinated Nucleoside Fragment

“…Fluorinated nucleosides and nucleotides, in particular, have received attention as the incorporation of fluorine into these structures can improve their biological activity and stability. , Rovafovir etalafenamide ( 2 , Scheme ), a fluorinated nucleotide analogue of 2′,3′-didehydro-2′,3′-dideoxy adenosine (d4AP), maintains the anti-HIV activity of the nonfluorinated analogue while exhibiting lower mitochondrial toxicity and is being developed for the treatment of HIV . The accompanying articles in this issue describe the synthesis of 2 via a convergent synthesis which combines the fluorinated nucleoside core 1 and the phosphonamidate ester 3 . The development of a manufacturing process for the nucleoside core is described herein.…”