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Henschke J.P.,ScinoPharm Taiwan Ltd | Zhang X.,ScinoPharm Changshu Pharmaceutical Ltd | Huang X.,ScinoPharm Changshu Pharmaceutical Ltd | Mei L.,ScinoPharm Changshu Pharmaceutical Ltd | And 7 more authors.
Organic Process Research and Development | Year: 2013

A practical and scalable process for the manufacture of cladribine (1) is described. Vorbrüggen glycosylation of doubly silylated 2-chloroadenine 2 with protected 1-O-acetyl-2-deoxy-α,β-d-ribofuranose 3 under reversible conditions in the presence of 20 mol % triflic acid in a solvent that selectively precipitated the desired β-anomer β-4a whilst leaving the unwanted α-anomer α-4a in solution to isomerise allowed good overall stereoselectivity with exclusive regioselectivity. An aging step allowed anomerisation of α-4a to β-4a, 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-4a 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-4a followed by recrystallisation provided drug-grade cladribine (1). 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 (5). 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. © 2013 American Chemical Society.

Henschke J.P.,ScinoPharm Taiwan Ltd. | Liu Y.,ScinoPharm Changshu Pharmaceutical Ltd. | Huang X.,ScinoPharm Changshu Pharmaceutical Ltd. | Chen Y.,ScinoPharm Taiwan Ltd. | And 12 more authors.
Organic Process Research and Development | Year: 2012

A process is described for the synthesis of kilogram quantities of homochiral 4-silyloxycyclopentenone (R)-1, a key intermediate useful for the synthesis of a plurality of prostaglandin analogue drugs. Cyclopentenone (R)-1 was synthesized in 14 isolated steps from furfural. Key steps in the synthesis include a Wittig reaction, Piancatelli rearrangement, and an enzymatic resolution featuring in situ recycling of the undesired enantiomer furnishing the desired homochiral alcohol in ≥99.5% ee. As a retort to the unsatisfactory coformation of about 8% at best of the trans-olefin in the Wittig reaction, a change to the order of several steps and the identification of a recrystallisable, amine salt derivative, 2, allowed the unwanted isomer to be controlled to as low as 0.2%. © 2012 American Chemical Society.

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