A Stereoselective Process for the Manufacture of a 2′-Deoxy-β‑d‑Ribonucleoside Using the Vorbrüggen Glycosylation

Abstract

A practical and scalable process for the manufacture of cladribine (<b>1</b>) is described. Vorbrüggen glycosylation of doubly silylated 2-chloroadenine <b>2</b> with protected 1-<i>O</i>-acetyl-2-deoxy-α,β-d-ribofuranose <b>3</b> under reversible conditions in the presence of 20 mol % triflic acid in a solvent that selectively precipitated the desired β-anomer β-<b>4a</b> whilst leaving the unwanted α-anomer α-<b>4a</b> in solution to isomerise allowed good overall stereoselectivity with exclusive regioselectivity. An aging step allowed anomerisation of α-<b>4a</b> to β-<b>4a</b>, thereby improving the isolable yield of the β-anomer. Direct filtration of the product mixture without a catalyst quench or aqueous workup furnished the crude β-anomer β-<b>4a</b> in good yield (up to 68%) and purity (>95% by HPLC) with no regioisomers detected and only ∼1–3% (by HPLC) of the undesired α-anomer. Deprotection of the crude, unpurified intermediate β-<b>4a</b> followed by recrystallisation provided drug-grade cladribine (<b>1</b>). The process includes three isolation steps and was demonstrated on kilogram scales using cGMP providing 99.8–99.9% pure cladribine in up to an overall 43% yield based on 2-chloroadenine (<b>5</b>). In contrast to previous methods, column chromatography and/or bulky directing groups were not required in the glycosylation step, a high pressure vessel was not needed in the deprotection step, and only one dedicated recrystallisation step was necessary