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