A New Process for Antineoplastic Agent Clofarabine

Abstract

Clofarabine is a promising DNA polymerase inhibitor currently in clinical trials for a variety of liquid and solid tumor indications. The efforts for development of a new manufacturing process for clofarabine are presented. This new process allows for the reliable and efficient production of drug substance in high anomeric excess and high overall purity, without using chromatography. The high anomeric selectivity is achieved by reacting 2-chloroadenine with 1-bromo-2-deoxy-2-fluoro-3,5-di-O-benzoyl-α-d-ribofuranose (4) and potassium ter t-butoxide in a mixture of three solvents. Following crystallization, anomeric ratios exceeding 50 (β/α) are achieved. Deprotection and additional crystallization afford a clofarabine drug substance containing less than 0.1% of the α-anomer.

Fluorine in medicinal chemistry: A review of anti-cancer agents

“…More recently novel o-alkyglycerophospholipid derivatives of fludarabine (Fludara 1 ) 18 have also been developed [31]. Clinical trials for clofarabine 19 and tezacitabine 20 against a variety of liquid and solid tumour indications are ongoing [29,32].…”

First Synthesis of 2′‐Deoxyfluoropuromycin Analogues: Experimental Insight into the Mechanism of the Staudinger Reaction

“…[28] We are curious about a PSEUROT + J H,F analysis of our compounds, as well as that for arabinofuranose-configured 2'-deoxyfluoronucleoside derivatives such as Clofarabine. [32] Furthermore, 19 F resonances are far better sensors of diastereoisomeric forms than any other nucleus even though the fluorine atom might be at quite a distance from the symmetry breaking element, the phosphorous atom in compounds 13 and 14 a in our case. Last but not least,…”

“…Apparently, South-puckered 3'-deoxyfluororibofuranose derivatives produce 3 JA C H T U N G T R E N N U N G (F3'a,C5') values between 9.1 and 11.6 Hz, [23] while some 2'-deoxyfluoroarabino nucleosides show 3 JA C H T U N G T R E N N U N G (F2'b,C4') = 6 and 10 Hz, and one reveals a close spacial proximity through a long-range 4 JA C H T U N G T R E N N U N G (F2'b,C8b) = 7 Hz. [32] The only other substantial 3 JA C H T U N G T R E N N U N G (F3'a,C5') value that we could observe was 9.8 Hz in 10 b, the www.chemeurj.org…”

“…The corresponding hydrogen atoms exchanged rapidly against [ [22][23][24][25][26][27][28][29][30][31][32] Since the chromatographic separation of the acyltriazenes from the corresponding amides was too difficult on a column or impossible, we resorted to chemical means ( Table 2). The mixture 14 a + 14 b was first heated in refluxing 1,4-dioxane which caused the decomposition of all products (entry 1).…”

Fluorinated Nucleosides as an Important Class of Anticancer and Antiviral Agents

“…This convergent approach is used particularly in the synthesis of 2'-β-fluoro nucleosides. First the fully-protected sugar (26) is brominated to form the 1-α-glycosyl bromide (27), formation of which leads preferentially to the formation of β-nucleoside (28) as reported in the synthesis of the antineoplastic agent clofarabine (6) ( Figure 9) [19]. Schinazi et al [22].…”